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Foreword Foreword The NOPHO-report survives in the most turbulent times. We have compiled Reports from the Leukemia Registry with special emphasis on therapeutic outcome and from the Solid Tumor Registry with the focus on incidence patterns and survival analyses for more than 25 years. We have now taken the decision to let the two registries unite in one server-space, but in actual fact, the NOPHO work is more diverse and de-centralised than ever. With our flexible systems, more clinicians and researchers have access to our registries than ever and it does not matter where within NOPHO you reside – the registries can easily be accessed from all countries. In recent years, we have reached even further. In literally boundless cooperation, we can incorporate such geographically diverse places as Hong-Kong, the Baltic countries, the Netherlands and Belgium into our joint efforts for the benefit of paediatric oncology patients. The Nordic region has for several reasons unique opportunities to establish reliable data and perform epidemiologic analyses, and through these efforts make a substantial contribution to expand our knowledge of childhood cancer. In the coming years, we hope for an even more extensive integration of our disease-related registries with population based mandatory registration. Even if there are many ethicolegal obstacles to such a development, the obvious usefulness of such integration will eventually make these links a part of our daily routine. This will be particularly important as we attempt to register late-effects of cancer therapy on larger scale. We want to thank all NOPHO members for considerable work with reporting data and status from all patients and for the interesting reports from the working groups. Since we have many requests for a printed version of the annual report, both a web-version and a printed version will be provided, as usual. Stockholm, Oslo and Turku, May 2011 For NOPHO

Mats Heyman1, Finn Wesenberg2, Hilde Kock Lie3, Thomas Frandsen4, Päivi Lähteenmäki5, Birgitta de Verdier1

1 Childhood Cancer Research Unit, Karolinska Hospital Stockholm, Sweden. 2 Departments of Pediatrics, University Hospital, Oslo, Norway. 3Norwegian Cancer Registry, Montebello, Oslo Norway 4Departments of Pediatrics, Rigshospitalet, Kopenhamn, Denmark 5Departments of Pediatrics, University Hospital, Turku, Finland.

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Contents

Foreword …………………………………………………………….. 1 Contents ……………………………………………………………... 2

I NOPHO Organisation …………………………………………... 3 I:1 Board...................................................................................... 3 I:2 Secretariat, Webb master………………………………. 4 I:3 Participants ……………………………………………. 5 I:4 Education Subcommittee ……………………………… 7 I:5 Young NOPHO Working Group ……………………. 8

II NOPHO - Solid and Brain Tumors Registry Group …………… 9 III NOPHO - Solid and Brain Tumors Working Goups ……………….. 30 1) Non-Hodgkin´s Lymphoma (NHL) Working Group ……… 30 2) Germ Cell Tumors Working Group…………………… 43 IV NOPHO - Leukaemia Groups……………………………………….. 45 1) All Working Group………………………………………... 45 2) ALL Registration Working Group ……………………….. 47 3) ALL 2008 PI Working Group ……………………………. 77 4) AML Working Group …………………………………….. 81

5) MDS/JMML Working Group …………………………... 90 6) Infants Leukemia Working Group ……………………… 96 7) Pharmacology Working Group ………………………… 98 8) SCT Working Group …………………………………… 102 9) ALL Relapse Working Group …………………………. 104 10) Events (ALL) Working Group ………………………… 105 11) Morphology Working Group …………………………. 108

V NOPHO - Other disease groups 1) ITP Working Group ……………………………………………. 109 2) Histiocytosis Working Group………………………………. 112 3) Late effects Working Group ………………………………. 114 4) Novel Therapies Working Group ……………………….. 117

5) Thromboembolic Working Group …………………… 119 6) NOPHO/NOBOS Working Group on Ethics ………….... 120

VI NOPHO – Publications …………………………………………… 122

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I NOPHO ORGANISATION

I:1 NOPHO BOARD Secretary- -general Thomas Frandsen (DK) elected 2010 -elected Marit Hellebostad (NO) elected 2010 Treasure Karsten Nysom (DK) elected 2007 Chairman Päivi Lähteenmäki (FI) elected 2010 Auditors of accounts Gustaf Ljungman (SE) elected 2005 Birgitte Lausen (DK) elected 2008 Stand in auditor of Svein Kolmannskog (NO) elected 2005 Accouonts Denmark Karsten Nysom elected 2007 Birgitte Klug Albertsen elected 2010 Finland Kirsi Jahnukainen elected 2007 Päivi Lähteenmäki elected 2009 Iceland Olafur G. Jonsson elected 2000 Jon Kristinssón Norway Ann Elisabeth Åsberg elected 2007 Frøydis Langmark Knut Lote, Radiology elected 1999 Ellen Ruud elected 2009 Sweden Karin Mellgren elected 2008 Göran Carlsson elected 2008 Young NOPHO Mimi Kjærsgaard (DK) elected 2007 member

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I:2 NOPHO Secretariat and Webmaster NOPHO Secretariat Birgitta de Verdier Mats Heyman Child Cancer Research Unite Astrid Lindgrens Children’s Hospital SE 171 76 Stockholm, Sverige email: birgitta.de.verdier@ki.se email: mats.heyman@ki.se tel: +46 8 517 7769/2484 Webmaster: Elisabeth Broby Simply Web Sallerup 5010, SE 241 93 Eslöv, Sverige email: elisabeth.broby@skane.se tel: +46 413 55 56 50, mobile: +46 705 18 70 34

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I:3 Participating clinics/institutions/doctors Through the years, many colleagues in NOPHO have been involved in treating and reporting of tumor childhood cancer from the Nordic countries. The main contributors are listed below: Denmark: Køpenhavn, Rikshospitalet Kjeld Schmiegelow, Karsten Nysom,

Catherine Reichnitzer, Birgitte Lausen, Harald Thomassen, Astrid Sehestad,

Anja Poulsen, Thomas Frandsen, Marianne Ifversen Odense Peder Skov Wehner

Aarhus Niels Clausen, Henrik Schroeder, Henrik Hasle, Birgitta Klug Albertsen Aalborg Sten Rosthøj, Erik Østergaard Finland: Helsinki Ulla Pihkala, Jukka Kanerva, MerviTaskinen,

Kirsi Jahnukainen, Sanna Kivivuori

Turku Päivi Lähteenmäki, Marika Grönroos

Uleåborg Merja Möttönen, Arja Harila-Saari Tampere Mikko Arola, Katriina Parto, Kim

Vettenranta

Kuopio Mikko Perkkiö, Pekka Riikonen

Iceland: Reykjavik Olafur Gisli-Jonsson, Jon Kristinsson,

HrafnTulinius, Asgeir Haraldsson, Halldora Þórarinsdóttir

Norway: Oslo, Rikshospitalet Anders Glomstein, Finn Wesenberg, Bem

Zeller, Heidi Glosli, Ellen Ruud Oslo, Ullevål Marit Hellebostad, Eva Widing Bergen Maria Gunnes, Malgor, Mikael Donner Trondheim Ann Åsberg, Svein Kolmannsskog, Randi

Nygaard Tromsø Tore Stokland, Trond Flaegstad, Niklas Stabell, Jochen Bűchner

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Sweden: Stockholm, Karolinska Stefan Söderhäll, Niklas Pal, Per Kogner, Jan-Inge Henter, Jonas Karlén, Stefan Holm, Mats Heyman, Göran Carlsson, Åke Jakobson, Staffan Eksborg, Johan Malmros, Cecilia Petersen, Tony Frisk, Trausti Oskarsson

Huddinge Jacek Winiarski, Britt Gustafsson, Åsa Gustafsson Jernberg

Lund Thomas Wiebe, Stanislaw Garwicz, Jesper Heldrup, Albert Bekassy, Lars Hjorth, Ingrid Öra, Helga Björgvinsdottir, Helena Mörse, Anders Castor, Christian Moell, Jacek Toporski, Dominik Turkiewicz, Torbjörn

Backman, Anna Börjesson, Cornelis Pronk, Anna Sällfors

Uppsala Gustav Ljungman, Anders Kreuger, Gudmar

Lönnerholm, Britt-Marie Frost, Johan Arvidsson, Susan Pfeifer, Fredrik Hedborg, Josefine Palle, Per Frisk

Göteborg Birgitta Lannering, Jonas Abrahamsson,

Gustaf Österlundh, Karin Mellgren

Umeå Per-Erik Sandström, Erik Forestier, Ulf Hjalmars, Ulrika Norén-Nyström

Linköping Mikael Behrendtz, Britt-Marie Holmqvist,

Hartmut Vogt, Irene Devenny The Leukemia Registry: Mats Heyman Childhood Cancer Research Unit Astrid Lindgrens Barnsjukhus SE-171 76 Stockholm, Sweden Tel: +46 8 5177 2484 Fax: +46 8 5177 3184 mats.heyman@ki.se The Solid Tumor Registry: Hilde Kock Lie, Finn Wesenberg Krefteregistret, Montebello N-0310 Oslo, Norway Office: Fritjofs Nansens vei 17, Oslo Tel: +47 22 45 13 00 Fax: +47 22 45 13 70 hilde.kock.lie@kreftregistret.no finn.wesenberg@rikshospitalet.no

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I:4 NOPHO Education and training committee Coordinator: Marit Hellebostad (NO) Denmark: Peder Skov Wehner Finland: Kim Vettenranta Iceland: Jón Kristinsson Norway: Marit Hellebostad Finn Wesenberg Anne Grete Bechensteen Sweden: Birgitta Lannering Estonia: Kaie Pruunsild Young NOPHO representative: Catarina Träger (SE) Mimi Kjaersgaard (DK)

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I:5 Young NOPHO Coordinator: Mimi Kjaersgaard (DK) Denmark: Mimi Kjaersgaard Nina Friesgaard Øbro Finland: Marika Grönroos Sanna Ranta Iceland: Trausti Óskarsson Norway: Adriani Kanellopoulos

Jochen Büchner Sweden: Irene Devenney

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II NOPHO – Solid and Brain Tumors Working Groups

II:1 NOPHO-Solid Tumours Registry Group Coordinator Finn Wesenberg (NO) Registry secretary Denmark Henrik Schrøder Finland Mikko Perkkio Iceland Olafur G. Jonsson Norway Finn Wesenberg Sweden Göran Gustafsson

II.1 Introduction As reported last year, files from national solid tumour centres are sent to the NOPHO registry. Also this year we have received revised data from all Nordic countries. A unified format including definitions and choice of variables has previous been established. This format not only defines required fields, but also limits them to the values described in the paper registration forms. However, still many defined parameters are missing in the received data. In addition, the format requires registering of diagnostic groups according to the new list based on Birch JM and Marsden HB: “A classification scheme for childhood cancer”. This is to avoid different interpretation of diagnosis. Each country is responsible for going through their database and adjust their data to the updated coding system. There have been some structural changes in the organisation of the Finnish paediatric solid tumor registry. At the Finnish national board meeting in February 2010, it has been decided not to continue with the paediatric registry. All new cases will be from now on only registered in in the Finnish Cancer Registry (FCR), however Finland has not reported any cases for the year 2010. Norway have not reported all cases for 2010, as one hospital has reported no cases and two others have incomplete reporting, we estimate that Norway have reported about half of the cases. We thank all the national centres and are grateful for the rapid response with the status reports.

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Cases and incidence Table 1a

NOPHO – Cases and incidence per 100 000 in the Nordic countries in the time period 1986 – 2010, main diagnostic groups of childhood cancer with subgroups, related 5 year diagnostic periods.

Leukemias

Time period 1986-90 1991-95 1996-2000 2001-05 2006-10 Diagnostic Group cases inc. cases inc. Cases inc. cases inc. cases inc. I Leukemias 01A ALL 819 3,58 869 3,97 918 4,09 926 4,12 845 3,82 01C AML 139 0,65 131 0,60 172 0,77 158 0,70 180 0,81

Total leukemias 958 4,51 1000 4,45 1090 4,86 1084 4,82 1025 4,63 Solid tumours

Time period 1986-90 1991-95 1996-2000 2001-05 2006-10 Diagnostic Group cases inc. cases inc. Cases inc. cases inc. cases inc. II Lymphomas 276 1,298 312 1,427 384 1,711 311 1,353 299 1,351

02A Hodgkin’s lymphoma 83 0,390 70 0,320 113 0,503 91 0,405 90 0,407

02B Non-Hodgkin’s lymphoma 124 0,583 158 0,723 155 0,691 135 0,600 143 0,646

02C Burkitt’s lymphoma 6 0,028 6 0,027 20 0,089 16 0,071 14 0,063

02D Miscellanous lymphoreticular neopl. 46 0,216 54 0,247 62 0,276 41 0,182 25 0,113

02E Histiocytic disorders 13 0,061 22 0,101 27 0,120 28 0,124 19 0,086

02F Unspecified lymphoma 4 0,019 2 0,009 7 0,031 0 0,000 8 0,036

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Time period 1986-90 1991-95 1996-2000 2001-05 2006-10 Diagnostic Group cases inc. cases inc. Cases inc. cases inc. cases inc. III CNS 964 4,535 1024 4,683 1071 4,772 1009 4,486 838 3,787

03A Ependymoma 88 0,414 88 0,402 95 0,423 88 0,391 57 0,258

03B Astrocytoma 354 1,665 359 1,642 375 1,671 385 1,712 308 1,392

03C Medulloblastoma. PNET 164 0,772 170 0,777 162 0,722 183 0,814 159 0,719

03D Other glioma 184 0,866 151 0,691 102 0,454 79 0,351 114 0,515

03E Misc. intracran. and intraspin. neopl. 157 0,739 245 1,120 327 1,457 252 1,120 185 0,836

03F Unspes. intracran. and intraspin. neopl 18 0,085 11 0,050 10 0,045 22 0,098 15 0,068

IV Sympathetic nervous system tumours 205 0,964 225 1,029 210 0,936 213 0,947 180 0,813

04A Neuroblastoma and ganglioneurobl. 201 0,946 220 1,006 202 0,900 204 0,907 150 0,678

04B Other 4 0,019 5 0,023 7 0,031 9 0,040 29 0,131

04C Ganglioneuroma 0 0,000 0 0,000 1 0,004 0 0,000 1 0,005

V Retinoblastoma 91 0,428 104 0,476 89 0,397 90 0,400 64 0,289

05A Retinoblastoma 91 0,428 104 0,476 89 0,397 90 0,400 64 0,289

VI Renal tumours 202 0,950 205 0,938 197 0,878 178 0,791 187 0,845

06A Wilms’ tumour 196 0,922 199 0,910 191 0,851 171 0,760 169 0,764

06B Renal carcinoma 6 0,028 4 0,018 6 0,027 3 0,013 3 0,014

06C Other and unspec. mal. renal tum. 0 0,000 2 0,009 0 0,000 4 0,018 15 0,068

VII Hepatic tumours 44 0,207 44 0,201 51 0,227 45 0,200 54 0,244

07A Hepatoblastoma 31 0,146 38 0,174 39 0,174 32 0,142 40 0,181

07B Hepatocellular carcinoma 10 0,047 6 0,027 8 0,036 11 0,049 10 0,045

07C Other and unspec. mal. hepatic tum. 3 0,014 0 0,000 3 0,013 2 0,009 4 0,018

07D Benign hepatic tumours 0 0,000 0 0,000 1 0,004 0 0,000 0 0,000

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Time period 1986-90 1991-95 1996-2000 2001-05 2006-10 Diagnostic Group cases inc. cases inc. Cases inc. cases inc. cases inc. VIII Malignant bone tumours 118 0,555 125 0,572 163 0,726 169 0,751 145 0,655

08A Osteosarcoma 60 0,282 73 0,334 76 0,339 75 0,333 64 0,289

08B Chondrosarcoma 16 0,075 8 0,037 25 0,111 30 0,133 20 0,090

08C Ewing’s sarcoma 29 0,136 28 0,128 38 0,169 43 0,191 39 0,176

08D Other and unspec. mal. bone tum. 11 0,052 11 0,050 24 0,107 21 0,093 21 0,095

08E Benign bone tumours 2 0,009 5 0,023 0 0,000 0 0,000 1 0,005

IX Soft-tissue sarcomas 211 0,993 251 1,148 209 0,931 215 0,956 202 0,913

09A Rhabdomyosarcoma 128 0,602 133 0,608 119 0,530 136 0,605 109 0,493 09B Fibrosarc. neurofibrosarc. infantile fibrosarc. and other fibrom. neopl. 42 0,198 48 0,220 39 0,174 41 0,182 38 0,172

09C Synov. sarc. and other soft-tiss. sarc. 8 0,038 21 0,096 14 0,062 8 0,036 18 0,081

09D Other specified soft-tiss. sarcoma 28 0,132 45 0,206 33 0,147 26 0,116 30 0,136

09E Unspecified soft tissue sarcoma 5 0,024 4 0,018 4 0,018 4 0,018 7 0,032

X Germ-cell. trophoblastic and other gonadal neoplasms 132 0,621 156 0,713 163 0,726 115 0,511 122 0,551

10A Non-gon. germ-cell and trophobl. neopl. 41 0,193 30 0,137 44 0,196 33 0,147 22 0,099

10B Gonadal germ-cell and trophobl. neop. 44 0,207 47 0,215 46 0,205 35 0,156 41 0,185

10C Gonadal carcinoma 40 0,188 64 0,293 51 0,227 33 0,147 22 0,099

10D Other and unspec. mal. gonadal tum. 3 0,014 5 0,023 9 0,040 5 0,022 15 0,068

10E Benign germ cell tumours 4 0,019 10 0,046 13 0,058 9 0,040 22 0,099

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Time period 1986-90 1991-95 1996-2000 2001-05 2006-10 Diagnostic Group Cases inc. Cases inc. Cases inc. Cases inc. Cases inc. XI Carcinoma and other malignant epithelial neoplasms 109 0,513 122 0,558 113 0,503 149 0,662 89 0,402

11A Adrenocortical carcinoma 6 0,028 11 0,050 5 0,022 5 0,022 4 0,018

11B Thyroid carcinoma 31 0,146 26 0,119 25 0,111 30 0,133 21 0,095

11C Nasopharyngeal carcinoma 0 0,000 4 0,018 3 0,013 10 0,044 6 0,027

11D Melanomatous neoplasms 29 0,136 26 0,119 25 0,111 31 0,138 21 0,095

11E Skin carcinomas 24 0,113 27 0,123 41 0,183 31 0,138 16 0,072

11F Other carcinomas 19 0,089 28 0,128 14 0,062 42 0,187 26 0,117

XII Other and unspecified malignant neoplasms 15 0,071 17 0,078 23 0,102 13 0,058 31 0,140

12A Other specified mal. neoplasms 7 0,033 8 0,037 12 0,053 9 0,040 11 0,050

12B Other unspec. mal. neoplasms 8 0,038 9 0,041 11 0,049 4 0,018 20 0,090

Total solid tumours 2367 11,136 2585 11,822 2673 11,909 2507 11,146 2211 9,991

Total solid tumours 12343 Incidence 11,20

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Fig. 1a

Incidences for 1986-90, 1991-95, 1996-2000, 2001-05 and 2006-10 of eleven main diagnostic groups of childhood cancer in the Nordic countries (n=12343).

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0

II Lymphomas

III CNS

IV Symp. nerv. System

V Retinoblastoma

VI Renal tumours

VII Hepatic tumours

VIII Mal. bone tumours

IX Soft-tissue sarcomas

X Germ-cell

XI Carcinoma

XII Other and unspec.2006-2010

2001-2005

1996-2000

1991-1995

1986-1990

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Table 1b

Cases of solid tumour childhood cancers (diagnostic groups II-XII) in the Nordic countries 1986-2010, all patients < 15 years of age at diagnosis.

Year of diagnosis

Cases Denmark Finland Iceland Norway Sweden Total

1986 109 86 8 88 182 473

1987 106 92 5 92 161 456

1988 104 87 2 111 174 478

1989 86 100 7 105 182 480

1990 107 96 10 82 185 480

1991 102 99 9 77 176 463

1992 113 104 5 91 203 516

1993 113 98 11 120 195 537

1994 107 98 8 131 207 551

1995 129 87 11 107 184 518

1996 131 106 8 127 204 576

1997 105 97 19 129 206 556

1998 121 86 14 112 215 548

1999 128 79 7 119 176 509

2000 108 88 7 120 161 484

2001 112 88 6 119 197 522

2002 118 95 6 123 175 517

2003 95 93 5 112 189 494

2004 116 97 6 98 181 498

2005 103 81 7 96 189 476

2006 97 87 8 81 188 461

2007 102 89 11 89 178 469

2008 129 86 10 115 166 506

2009 88 89 8 115 185 485

2010 93 0 6 49 142 290

Total 2722 2208 204 2608 4601 12343

Finland has not reported any cases for the year 2010. Norway have not reported all cases for 2010, as one hospital has reported no cases and two others have incomplete reporting, we estimate that Norway have reported about half of the cases.

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Fig. 1b

Time trends in incidence rates of solid tumour childhood cancers in the Nordic countries 1986-2010 <15 years of age at diagnosis.

CONCLUSIONS: 12343 children < 15 years of age were diagnosed with cancer during the period 1986 - 2010 in the Nordic region. Data were collected at the NOHPO solid tumour registry located at the Cancer Registry of Norway. Cancers were classified according to the Birch & Marsden classification of childhood cancers. The overall incidence rate of solid tumours computed for the whole period 1986-2010 was 11.20 per 100 000 children per year. Compared to last report, more patients have been included also for previous years.

0

5

10

15

20

25

30

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Denmark

Finland

Iceland

Norway

Sweden

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II: 2.2 Survival analyses The NOPHO solid tumour registry has recently received updates on status regarding deaths from all of the Nordic countries. Cumulative 5- and 10-year survival in 12343 children < 15 years of age diagnosed with solid tumours during the period 1986-2010 were analysed. Similar calculations were made for each diagnostic group and for the three age groups 0-4, 5-9 and 10-14 years. For neuroblastoma we also studied infants < 1 year separately. The cumulative survival estimates were computed using Kaplan-Meier methods and the crude estimates were compared with log-rank tests when the assumption of the survival curves not crossing each other was fulfilled. When this assumption was violated, the crude survival curves were not compared. All the estimates are presented with 95% confidence intervals (95%CI). Status registrations are made partly from national population registries and partly from death registries only, as conditions differ between countries. These differences may produce slight differences between alive status updates as a result of variable registration procedures between registries.

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Table 2a

NOPHO: 5-year periods 1986-2010, cumulative 5-year survival for selected diagnostic subgroups in childhood solid tumours, < 15 years of age.

Diagnostic group 5-year survival (%) Point estimate and 95%CI

1986-90 1991-95 1996-2000 2001-05 2006-2010 II Lymphomas a) Hodgkin’s lymph. 95,2

[87,7 – 98,2] 94,3

[85,5 – 96,7] 94,7

[88,6 – 97,6] 95,6

[88,7 – 98,3] -

b) NHL 77,2 [68,8 – 83,7]

78,2 [70,9 – 83,9]

83,8 [76,9 – 88,7]

85,9 [78,8 – 90,8]

-

III CNS a) Ependymoma 69,3

[58,5 – 77,8] 66,2

[55,1 – 75,1] 69,5

[59,2 – 77,7] 76,0

[65,6 – 83,7] -

b) Astrocytoma 83,4 [79,0 – 86,9]

84,6 [80,4 – 87,9]

81,3 [76,8 – 84,8]

85,3 [81,4 – 88,5]

c) Medulloblastoma 60,1 [52,2 – 67,2]

53,6 [45,8 – 60,8]

55,9 [47,9 – 63,2]

62,6 [55,1 – 69,2]

d) Other glioma 69,4 [62,2 – 75,5]

71,9 [64,0 – 78,4]

54,5 [44,3 – 63,6]

60,3 [48,5 – 70,1]

IV Symp. ner. syst. a) Neuroblastoma 49,2

[42,0 – 56,0] 60,7

[53,9 – 66,8] 65,2

[58,2 – 71,3] 71,7

[65,0 – 77,4]

VI Renal tumours a) Wilms’ tumour 86,2

[80,6 – 90,3] 92,9

[88,3 – 95,8] 88,0

[82,4 – 91,8] 87,1

[81,1 – 91,3]

VIII Bone tumours a) Osteosarcoma 63,3

[49,9 – 74,1] 65,8

[53,7 – 75,4] 69,7

[58,1 – 78,7] 71,8

[60,1- 80,6]

IX Soft tissue sarc. a) Rhabdomyosarc. 69,5

[60,8 – 76,7] 68,2

[59,5 – 75,4] 74,6

[65,7 – 81,5] 72,6

[64,2 – 79,3]

X Germ cell tumours a) Gonadal germ cell 78,1

[62,1 – 87,9] 73,9

[55,9 – 87,7] 70,5

[54,6 – 81,7] 93,9

[77,9 – 98,5]

Given the length of follow up for the last period (2006-2010) it was not possible to calculate 5-year cumulative survival for the listed diagnostic groups.

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Fig. 2a

Survival 1986-2010. All children < 15 years of age at diagnosis, diagnostic groups II - XII (n=12 343)

The overall estimates of both 5-year and 10-year survival were very similar reaching to close to 80% and not statistically different.

5-year survival: 80,0%, 95%CI [79,3 to 80.7]% 10-year survival: 77.9%, 95% CI [77,2 to 78.7]%

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Fig. 2b Survival by 5-year time periods 1986-2010 All children < 15 years of age at diagnosis, diagnostic groups II – XII. (n=12 343)

Time periode

Survival, children < 15 years of age at diagnosis, diagnostic groups II – XII related to 5 years periods

5 year 10 year % 95 % CI % 95 % CI

1986 – 1990 75,8 74,0 – 77,5 73,2 71,4 – 75,0 1991 – 1995 79,6 77,9 – 81,1 77,7 76,1 – 79,3 1996 – 2000 79,7 78,2 – 81,2 77,8 76,2 – 79,3 2001 – 2005 82,1 80,5 – 83,5 - - 2006 - 2010 - - - - The 5-year survival for the last diagnostic period and the 10 year survival for the two last periods could not be computed .

The cumulative 5-year survival was statistically significantly different between the given 5-year diagnostic time periods, p<0.001.

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Fig. 2c Survival by country 1986-2010 All children < 15 years of age at diagnose, diagnostic groups II – XII. (n=12 343)

Country

Survival, children < 15 years of age at diagnosis, diagnostic groups II – XII in the time period 1986 – 2010 related to country.

5 year 10 year % 95 % CI % 95 % CI

Denmark 76,7 75,0 – 78,3 74,7 72,9 – 76,4 Finland 81,4 79,7 – 83,0 79,3 77,5 – 81,0 Iceland 83.7 77,6 – 88,3 81,0 74,4 – 86,0 Norway 80,6 79,0 – 82,1 78,5 76,8 – 80,1 Sweden 80,8 79,6 – 82,0 78,9 77,6 – 80,1

Cumulative 5- and 10-year survival was close to 80% for all the Nordic countries.

The highest survival both for five and for ten years was achieved by Iceland followed by, Finland. However the estimates for Iceland have to be interpreted with caution due to small numbers of cases. Norway and Sweden have comparable survival for both observation periods, the figures are slightly higher for Sweden but the difference were very small and not statistically significant. The poorest survival was seen in Denmark, both 5- and 10-year survival are significantly lower than in Finland.

The cumulative 5-year survival between countries was statistically significantly different, p < 0.001.

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Fig 2d

Survival by age groups 1986-2010

All children < 15 years of age at diagnosis, diagnostic groups II - XII

(n=12 343)

Age Cases

5 and 10 years cumulative survival children < 15 years of age at diagnosis, diagnostic groups II – XII time period 1986 – 2010 related to age.

5 år 10 år % 95 % CI % 95 % CI

0 – 4.99 5450 78,3 77,1 – 79,4 76,8 75,6 – 78,0 5 – 9,99 3165 80,2 78,7 – 81,6 77,9 76,4 – 79,4

10 – 14,99 3728 82,4 81,1 – 83,6 7972 78,3 – 81,0 There was a statistically significant difference in crude survival between age groups at diagnosis, p = 0.0008.

Children in the youngest age group 0-4.99 years at diagnosis had statistically significantly worse 5-year survival than the oldest ones. This might partly be due to a slightly worse prognosis for infants (< 1 year of age). However, within all age groups there are diagnostic subgroups with different prognosis.

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Fig. 2e

Survival by sex 1986-2010

All children < 15 years of age at diagnosis, diagnostic groups II - XII

(n=12 343)

Gender Cases*

5 and 10 years cumulative survival children < 15 years of age at diagnosis, diagnostic groups II – XII time period 1986 – 2010 related to gender.

5 år 10 år % 95 % CI % 95 % CI

Girls 5727 80,5 79,4 – 81,5 78,4 77,2 – 79,5 Boys 6613 79,6 78,6 – 80,6 77,6 76,6 – 78,6 *3 children are missing gender

There was no statistically significant difference in crude survival between the genders,

p = 0,3247.

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Survival by diagnostic groups.

The figures below depict the Kaplan-Meier survival curves for the diagnostic groups II-VI and VII – XI for the time period 1986-2010.

Fig. 2f

Survival by diagnostic groups 1986-2010

Children < 15 years of age at diagnosis, diagnostic groups II – VI separately (n=8928)

Diagnostic group

5 and 10 years cumulative survival children < 15 years of age at diagnosis, time period 1986 – 2010

5 year 10 year % 95 % CI % 95 % CI

II Lymphomas 88,2 86,5 – 89,8 86,5 84,7 – 88,2 III CNS 76,7 75,5 – 77,9 74,0 72,7 – 75,3 IV Sympathetic nervous system 65,4 62,3 – 68,4 64,0 60,9 – 67,0 V Retinoblastoma 97,0 94,4 – 98,4 96,6 93,9 – 98,1 VI Renal tumors 88,3 86,0 – 90,2 87,6 85,2 – 89,6

There was a statistically significant difference in crude survival between diagnostic groups II - VI, p<.0.001.

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Fig. 2g

Survival by diagnostic groups 1986-2010

Children < 15 years of age at diagnosis, diagnostic groups VII – XI separately (n=3415)

Diagnostic group

5 and 10 years cumulative survival, children < 15 years of age at diagnosis, time period 1986 – 2010

5 year 10 year % 95 % CI % 95 % CI

VII Hepatic tumors 72,6 66,2 – 78,0 71,4 64,9 – 76,9 VIII Malignant bone tumors 72,2 68,6 – 75,5 68,0 64,1 – 71,6 IX Soft-tissue sarcomas 76,1 73,3 – 78,6 74,4 71,5 – 77,0 X Germ.cell neoplasms 90,8 88,3 – 92,8 89,6 86,9 – 91,7 XI Carcinoma 91,5 88,9 – 93,5 90,0 87,1 – 92,2

There was a statistically significant difference in crude survival between diagnostic groups VII - XI, p<.0.001.

26

Survival by specific cancerous tumors Figures 2h, i, j and k depict survival curves for selected diagnostic groups by time periods. There has been some improvement in overall survival in the recent time periods; the greatest improvement can be seen for Neuroblastoma where the 5-year survival increased significantly from 63.1% in the period 1986-90 to 82.2% for the recent period of 2001-2005 where the survival reached 82.2%. Significant improvement was also seen for Non-Hodgkin’s lymphoma where overall cumulative survival increased from 80.9% to 93.9% between the diagnostic periods 1986-90 and 2001-05. Some increase in survival in the recent time period could be noticed also for Medulloblastoma and Rhabdomyosarcoma, however the difference was not statistically significant.

Fig. 2h

Survival by 5-year time periods 1986-2010 Children < 15 years of age at diagnosis, diagnosed with Non-Hodgkin’s lymphoma (n=715)

Time periode

5 and 10 years of cumulative survival, children < 15 years of age at diagnosis, diagnostic group 02B, Non Hodgkin lymphoma, related to time periods

5 year 10 year % 95 % CI % 95 % CI

1986 – 1990 77,2 68,8 – 83,7 71,5 62,7 – 78,7 1991 – 1995 78,2 70,9 – 83,9 77,6 70,2 – 83,3 1996 – 2000 83,8 76,9 – 88,7 82,4 75,4 – 87,6 2001 – 2005 85,9 78,8 – 90,8 - - 2006 – 2010 - - - -

27

The 5-year survival for the last diagnostic period and the 10 year survival for the two last periods could not be computed .

The cumulative 5-year survival for children, < 15 year of age, diagnosed with Non Hodgkin lymphoma was not statistically significantly different between the given 5-year diagnostic time periods, p = 0.0255.

Fig. 2i Survival by 5-year time periods 1986-2010 Children < 15 years of age at diagnosis, diagnosed with Medulloblastoma (n=838)

Time periode

5 and 10 years of cumulative survival, children < 15 years of age at diagnosis, diagnostic group 03C, Medulloblastoma, related to time periods

5 year 10 year % 95 % CI % 95 % CI

1986 – 1990 60,1 52,2 – 67,2 53,4 45,4 – 60,7 1991 – 1995 53,6 45,8 – 60,8 48,2 40,5 – 55,5 1996 – 2000 55,9 47,9 – 63,2 49,1 41,1- 56,5 2001 – 2005 62,5 55,0 – 69,2 - -

2006 – 2010 - - - - The 5-year survival for the last diagnostic period and the 10 year survival for the two last periods could not be computed . The cumulative 5-year survival for children, < 15 year of age, diagnosed with Medulloblastoma was not statistically significantly different between the given 5-year diagnostic time periods, p = 0.1987.

28

Fig. 2j

Survival by 5-year time periods 1986-2010

Children < 15 years of age at diagnosis, diagnosed with Neuroblastoma – infants (<1 years of age), (n=368)

Time periode

5 and 10 years of cumulative survival, children < 1 year of age at diagnosis, diagnostic group 04A, Neuroblastoma, related to time periods

5 year 10 year % 95 % CI % 95 % CI

1986 – 1990 75,6 64,5 – 83,7 73,1 61,8 – 81,5 1991 – 1995 84,1 73,1 – 90,8 82,6 71,4 – 89,7 1996 – 2000 88,5 79,0 – 93,8 88,5 79,0 – 93,8 2001 – 2005 86,1 76,3 – 92,0 - - 2006 – 2010 - - - - The 5-year survival for the last diagnostic period and the 10 year survival for the two last periods could not be computed .

The cumulative 5-year survival for children, < 1 year of age, diagnosed with Neuroblastoma was not statistically significantly different between the given 5-year diagnostic time periods,

p = 0.0789.

29

Fig. 2k

Survival by 5-year time periods 1986-2010 Children < 15 years of age at diagnosis, diagnosed with Rhabdomyosarcoma (n=625)

Time periode

5 and 10 years cumulative survival, children < 15 years of age at diagnosis, diagnostic group 09A, Rhabdomyosarcoma, related to time periods

5 year 10 year % 95 % CI % 95 % CI

1986 – 1990 69,5 60,8 – 76,7 69,5 60,8 – 76,7 1991 – 1995 68,2 59,5 – 75,4 65,9 57,2 – 73,3 1996 – 2000 74,6 65,7 – 81,5 70,3 61,2 – 77,7 2001 – 2005 72,5 64,1 – 79,3 - - 2006 – 2010 - - - - The 5-year survival for the last diagnostic period and the 10 year survival for the two last periods could not be computed .

The cumulative 5-year survival for children, < 15 year of age, diagnosed with Rhabdomyosarcoma, was not statistically significantly different between the given 5-year diagnostic time periods, p = 0.6571.

CONCLUSIONS:

There has been some improvement in survival in recent time periods, especially for some diagnoses. However, there are no changes in the overall survival with respect to gender and there are only very limited differences in overall survival by age groups during the period 1986 to 2010.

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III NOPHO - Solid and Brain Tumors Working Groups III:1 Non-Hodgkin lymphoma – NHL

Coordinator Karin Mellgren (SE) Denmark Harald Thomassen Peder Skov Wehner Finland Päivi Läthenmäki Pasi Huttunen (2011) Iceland Olafur G. Jonsson Norway Jochen Buchner (2010) Sweden Karin Mellgren Johan Malmros Young NOPHO Maria Gunnes Reference pathologist Anna Porwit-MacDonald (SE) Ulrika Hansson (SE) Introduction The NOPHO NHL group was established in 1992. An epidemiologic analysis of 156 Nordic children diagnosed with NHL during the period 1985-1989 was published 1995. In a paper published in 2004 in J Pediatr Hematol Onc 230 Nordic children were analysed by immunophenotype, stage and risk group. It was shown that intensive chemotherapy without CNS irradiation gave 85% EFS for children with NHL without central nervous involvement. Over the last years a growing European cooperation for treatment of children with NHL has resulted in various common European protocols. NOPHO-NHL group joined the ALCL protocol in 2000 and the EURO-LB 02 in 2005. Furthermore in 2005 the NOPHO-NHL accepted to join the B-NHL BFM-04 protocol for treatment of children with B-NHL. NOPHO NHL database The NOPHO NHL-group has been working with on-line registration of patients over the last year and the web-based register has been open since the beginning of this year. All former patients have been entered into this register making reporting easier for all clinics. It has been agreed that all newly diagnosed NHL patients are to be reported to the on-line NOPHO database.

31

Survey over NHL children diagnosed 1995 - 2010. There were 708 reported cases of NHL diagnosed from 1.1.1995 to 31.12.2010 in the five Nordic countries. Thirty patients were >15 years at diagnosis and have been included in this report. Forty one patients were diagnosed with B-ALL (>25% blasts in the BM) and are reported separately. Twelve patients were excluded from analysis because of insufficient data. The remaining 655 patients with NHL, 468 boys (72%) and 187 girls (28 %), are reported here. The figure illustrates cases reported since 1995, stratified according to year of diagnosis from the five countries.

Survey of the B-ALL patients diagnosed 1995 - 20010. Forty one patients (33 M, 8 F) with B-ALL (i.e. B-cell disease with > 25% blasts in the bone marrow) diagnosed in the study period were excluded from the analysis. These children have been treated according to B-NHL - like protocols and constitute a subgroup, which show similarity with the B-NHL but will not be included here. Most of the patients have been treated according to BFM-B cell protocols. 31/41 of the B-ALL patients were in CR1 and three patients in CR2 at follow up. A total of eight events were reported and calculated EFS at follow up was 0,79 + 0,07. The B-ALL children are excluded from further analyses.

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Survey of NHL-patients diagnosed 1995-2010 Among the 655 reported patients 41 (6 %) were diagnosed with pre-B cell phenotype, 148 (23%) with T-cell, 378 (58%) with B-cell and 87 (13%) with ALCL. In one patient the diagnosis was not specified. In the group of patients with T-cell phenotype are included 13 patients with peripheral T-cell lymphoma (PTCL) and two patients with blastic NK-cell lymphoma. The six new negative events reported in 2010 Female 6 years. Dead from acute pulmonary embolism, at autopsy a Pre-B NHL, stage III was discovered. Male 13 years at diagnosis of PTLB after heart transplantation. Never in remission. Still alive with progressive disease. Male, 4 years old at diagnosis of B-NHL stage III. Relapse 3 months after end of therapy and died from disease 7 months after the relapse. Male 11 years at diagnosis of T-cell lymphoblastic lymphoma in 2009. Relapse while still on treatment and dead from disease in February 2010 Male, 9 years old at diagnosis 2008, ALCL, Stage II, Relapse 21 months after end of therapy in November 2010. Female 11 years at diagnosis in 2009 of B-NHL, stage II. Dead in remission 15 months after end of therapy. III: 1.5 Staging versus Phenotype and outcome for NHL-children diagnosed 1995-2010. The stratification of children diagnosed since 1995 has been based on immunological phenotyping of the malignant cells. The disease is classified as Lymphoblastic lymphoma (LBL), mature B cell or ALCL (large cell anaplastic lymphoma). This immunological classification creates the basis for the choice of therapy, which is further stratified according to the stage. The table shows the distribution of traditional stages versus phenotypic subgroups of NHL. The lymphoblastic lymphomas are further stratified into subgroups Pre-B and T-cells NHL. The patients are reported below (n=654)

33

1995-1999 (5 years) 2000-2004 (5 years) 2005-2010 (6 years) LBL B-cell ALCL Σ LBL B-cell ALCL Σ LBL B-cell ALCL Σ Tot Pre-B T Pre-B T Pre-B T All patients 12 54 124 31 221 15 41 108 27 191 14 53 146 29 242 654 Stage I 4 4 19 3 31 2 2 13 8 20 3 0 8 2 7 Stage II 1 4 35 5 40 3 0 35 1 36 3 5 32 5 38 Stage III 4 29 55 19 105 4 37 47 17 104 2 32 62 10 87 Stage IV 3 17 15 4 45 6 2 12 1 26 3 8 27 1 18 Stage missing 0 0 0 0 0 0 0 1 0 4 3 8 17 11 26 St IV subgroups BM+/CNS- 2 13 6 3 4 2 8 1 3 6 22 1 BM-/CNS+ 1 2 7 1 1 0 3 0 0 2 2 0 BM+/CNS+ 0 2 2 0 1 0 1 0 0 0 3 0 The distribution of immunophenotype subgroups and stages are in accordance with that expected for childhood NHL.

34

NOPHO – NHL 1995-2010 Outcome with regard to phenotypic classification

1995-2000 (5 years) 2000-2004 (5 years) 2005-2009 (5 years) LBL B-cell ALCL Σ LBL B-cell ALCL Σ LBL B-cell ALCL Σ Total Pre-B T Pre-B T Pre-B T All patients 12 54 124 31 221 15 41 108 27 191 14 53 146 29 242 655 Induction 0 3 1 0 4 0 1 2 0 3 1 0 3 0 4 11 Death RD/Progr 0 0 0 0 0 0 1 4 0 5 0 1 2 0 3 8 Disease Death in 0 2 4 0 6 0 1 7 1 9 0 2 1 1 4 19 Remission Relapse 3 7 14 5 29 3 9 9 5 26 0 3 3 6 12 67 >= CR-2 2 2 4 2 10 2 1 3 4 10 0 0 2 1 3 23 Death from 1 5 10 3 19 1 8 5 1 11 0 3 1 5 9 39 relapse Dead (n) 1 9 14 4 28 1 9 18 2 30 1 4 16 5 26 84 CCR (n) 11 45 110 27 193 14 32 90 25 161 13 49 130 24 216 570 CCR (%) 91 % 83 % 89 % 87 % 87 % 93 % 78 % 83 % 92 % 84 % 93 % 92 % 89 % 83 % 89 % 87 % p-EFS 3-years 0,92 0,80 0,89 0,84 0,80 0,71 0,78 0,81 1,0 0,89 0,86 0,71 5-years 0,75 0,80 0,89 0,84 0,80 0,71 0,78 0,81 1,0 0,89 0,83 0,71 p-Survival 3-years 0,92 0,85 0,90 0,87 0,93 0,83 0,84 0,93 1,0 0,91 0,90 0,79 5-years .0,92 0,85 0,89 0,87 0,93 0,78 0,84 0,93 1,0 0,91 0,86 0,79

35

III: 1.5 Outcome for NHL-children below four years of age. There were 87 reported cases of NHL diagnosed from 1.1.1995 to 31.12.2010 in patients below 4r years of age at time of diagnosis. It appears that the outcome of these younger children is worse than for older children. The distribution according to immunophenotype was not significantly different that what was found in older children. A total number of 16 fatal event was reported in the 87 children, 11 after relapse or progressive disease and 5 deaths in remission. The distribution of phenotype and the outcome of the patients are reported below (n=87). Phenotype group > 3 years Phenotype group < 3 years

36

Outcome with regard to phenotypic classification < 3 years All patients LBL B-cell ALCL Σ Total Pre-B T All patients 6 25 46 10 87 655 Induction 0 0 2 0 2 11 Death RD/Progr 0 0 1 0 1 8 Disease Death in 0 0 4 0 4 19 Remission Relapse 1 5 3 3 12 67 >= CR-2 1 0 0 1 2 23 Death from 0 4 3 2 9 39 relapse Dead (n) 1 9 9 4 16 84 CCR (n) 5 16 37 6 71 571 CCR (%) 83 % 64 % 80% 60 % CCR all 91 % 83 % 89 % 87 %

37

Outcome according to Age 1995-2010

<3 years: p = 0,80 + 0,04 <4-10 years: p = 0,88 + 0,02 >10 years: p = 0,86 + 0,02

OS

38

Overall and event-free survival for the three different time periods

OS EFS

1995-1999: 0,85 + 0,02 (n= 221) 2000-2004: 0,78 + 0,03 (n= 191) 2005-2010: 0,78 + 0,06 (n= 242)

1995-1999: 0,88 + 0,02 (n= 221) 2000-2004: 0,85 + 0,03 (n= 191) 2005-2010: 0,87 + 0,03 (n= 242)

39

Overall and event-free survival according to phenotype

OS

B-NHL p = 0,87 + 0,02 (n = 377) Pre-B p = 0,94 + 0,04 (n = 40) ALCL p = 0,86 + 0,04 (n = 85) T-cell p = 0,84 + 0,03 (n = 146)

EFS

B-NHL p = 0,84 + 0,02 (n = 377) Pre-B p = 0,82 + 0,07 (n = 40) ALCL p = 0,78 + 0,05 (n = 85) T-cell p = 0,79 + 0,04 (n = 146)

40

Overall survival according to Phenotype Group for the different time periods

Precursor B-cell phenotype T-cell phenotype

1995-1999: p= 0,92 + 0,08 (n= 12) 2000-2004: p= 0,93 + 0,06 (n= 15) 2005-2010: p= 1,0 (n= 13)

1995-1999: p= 0,85 + 0,05 (n= 54) 2000-2004: p= 0,78 + 0,06 (n= 41) 2005-2010: p= 0,91 + 0,04 (n= 51)

41

B-cell phenotype ALCL phenotype

1995-1999: p= 0,87 + 0,06 (n= 31) 2000-2004: p= 0,93 + 0,05 (n= 27) 2005-2010: p= 0,79 + 0,08 (n= 27)

1995-1999: p= 0,90 + 0,03 (n= 124) 2000-2004: p= 0,84 + 0,04 (n= 108) 2005-2010: p= 0,86 + 0,03 (n= 145)

42

Summary and conclusions. The results of the present inventory are in accordance with last year’s analysis. The results remain stable over time for B-NHL, pre-B NHL and ALCL. A tendency towards better results for T-cell NHL is observed in the last 5-year period as compared to the period before. Our Nordic results are well comparable with the results from other groups. Children below four years of age seem to have a worse outcome as compared to older children. A higher frequency of relapses and of death in remission can be observed in the younger children. In particular young children with B-NHL have a higher proportion of induction deaths and death in CR1 than older children. Events in patients with NHL are mainly due to progressive disease or relapse, induction deaths and deaths in CCR. These events are rare later than three years after diagnosis. The analysis of outcome according to phenotype shows the lowest EFS in patients with ALCL and the highest EFS in the very small group of patients with pre-B NHL even though this difference was not statistically significant. As expected, there is a difference in outcome between patients with a higher disease stage and patients with a lower stage. Factors with an impact on outcome were as earlier the presence of CNS disease at diagnosis with a significantly worse outcome in these patients. An international collaboration is necessary to identify patients with specific risk-factors within the very heterogeneous group of NHL.

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III:2 Germ Cell Tumor (GCT) Working Group Coordinator Cecilia Petersen (SE) Denmark Bodil Laub Petersen

Catherine Rechnitzer Henrik Schrøder

Finland Markku Heikinheimo,

Hanna Juntti

Iceland Jon Kristinson Norway Eva Widing,

Dorota Wojcik

Sweden Åke Jakobson, Cecilia Petersen

Young NOPHO Christina Høy Hansen (DK)

The NOPHO GCT group had a meeting in January 2011 in Stockholm. The minutes are published on

the NOPHO website.

The group has been reinforced by a new member. Hanna Juntti is replacing Matti Korhonen as the

second Finnish representative.

For treatment guidelines, the group still suggests treatment according to the UKCCSG GC-3 protocol,

which is considered as interim guidelines while waiting for the GC-4 protocol to be finalized.

The group has discussed the possibilities of creating a Nordic database for data collection of

GCT:s, which would be extended compared to the present NOPHO Solid Tumour registry.

The registration should include more variables and also benign teratomas due to the risk of

recurrence and malignant development. The group is currently working on a suggestion for

such extended registration. An important issue is that GCTs should be registered not only

according to the WHO classification but by the international classification which has been

agreed to be used in pediatric oncology (ref: Jillian R. Mann in Oxford Textbook of Oncology

(2nd edition, 2002, pp 2639-2655), Editors: Souhami et al, Oxford University Press (ISBN 0-19-

262 926-3)). The two classifications are not exchangeable and the specific classification for

GCT:s is needed e.g. in the GC-3 protocol. The classification is published together with staging

criteria on the NOPHO website.

44

0

20

40

60

80

100

120

140

160

1990-1997 1998-2007 2008-2010

Patolog

VSTB

No of teratomas in pathology (blue) and VSTB (red) registers (Stockholm)

The legislation in Norway makes it difficult to proceed with a common Nordic registration unless

a study is performed. The problem applies for all Nordic solid tumour registration and the working

group is awaiting information on a future, more general solution.

Concerning malignant GCTs, there is an ongoing study in selected Nordic countries, (Sweden and

Finland at the moment), run by Markku Heikinheimo, and comprising data from a 40 year period. The

report is under preparation.

The working group has previously discussed extending a Danish study under preparation by Christina

Høy Hansen into a Nordic Biological study. The group has decided to wait for the project to be

running in Denmark before presenting it to the NOPHO Scientific committee as a co-Nordic project.

Furthermore, the group has wished to do

a retrospective Nordic study concerning

the incidence of GCT (including benign

teratomas) and the possible connection

to gonadal function. In order to estimate

the completeness of childhood cancer

registries in terms of teratoma

registration, the group performed a

review on the complete incidence of

benign teratomas found in pathology

registries in the Stockholm area during

the years 1990-2010 (figure). The results showed that an extreme minority of cases are reported in the

Swedish childhood cancer registry. The group has decided that it is not feasible at present to continue

with this study since this would mean a review of all pathology databases in the Nordic countries. The

difficulties in getting accurate figures on benign teratomas emphasize the need for a reliable

prospective registration.

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IV NOPHO Leukemia Groups IV:1 ALL Working Group Coordinator: Mervi Taskinen (FI) Denmark Thomas Frandsen Birgitte Klug Albertsen Finland Päivi Lähteenmäki Mervi Taskinen Iceland Olafur Gislí Jonsson Norway Marit Hellebostad Trond Flaegstad Sweden Jonas Abrahamsson Stefan Söderhäll Representatives from Baltic countries Estonia Kaie Pruunsild Lithuania Goda Vaitkeviciene Chair of the Leukemia and Lymphoma group (Henrik Hasle; Karin Mellgren from 11/2010) MRD group (Finn Wesenberg) Pharmacology group (Arja Harila-Saari) Cytogenetic group (Erik Forestier) Flow group (Jesper Heldrup) Infant group (Birgitte Lausen) Event group (Jukka Kanerva) Relapse group (Stefan Söderhäll) ALL 2008 protocol committee (Kjeld Smiegelow) A representative from: NOPHO registry (Mats Heyman) Young NOPHO (Ines Kristensen) General secretary (Kim Vettenranta; from 5/2010 Thomas Frandsen) ALL group has met twice (October 14th 2010 in Copenhagen and April 14th 2011 in Helsinki). Both meetings have followed the NOPHO ALL-2008 Protocol Committee meeting. ALL WG has cooperated with the NOPHO ALL 2008 PI-group in the follow-up of the ALL2008 protocol.

46

The study protocol has recruited 495 patients by midApril 2011. Adult patients have corresponded of 9% of the patient accrual.

5% of the patients have indication to SCT In general the toxicity of the protocol has been acceptable. Sepsis and long myelosuppression

between the HR-blocks have complicated the HR-therapy Block C in the HR-therapy has been amended to decrease toxicity

Internationally, NOPHO ALL group has been represented in the I-BFM collaborative ALL working group and in Interfant 2006-, EsPhALL- and European ALL relapse- study groups. The amended EsPhALL (continuous imatinib to all patients) protocol is still recruiting

patients. New protocol still pending. A new European ALL-relapse protocol is in preparation. There is a consensus of the SR arm

of the study, still major disagreement of the HR arm therapy Interfant 2006 has recruited very well Nordic patients from 2008 on. MLL-PCR-collaboration

from May 2010 has been very good between Copenhagen and Frankfurt

The preparation of the next NOPHO ALL 2014 protocol has been started in spring 2011. The aim is to be able to go into more individualized therapy taking into account host –related

genetic factors and their impact on ALL therapy The work has started with literature search of interesting genes related to the metabolic

pathways of the drugs used in ALL therapy or of genes related in specific organ toxicities. The target is to evaluate whether a collection of SNPs relevant in NOrdic population could be identified to guide the ALL therapy risk grouping.

The work will continue with the most promising genes to be searched in the Nordic ALL population and compared with toxicity profiles.

47

IV:2 Leukemia – ALL Registration Working group Coordinator Mats Heyman (SE) Denmark Niels Clausen Finland Kim Vettenranta Iceland Olafur Gisli Jonsson Norway Ann Åsberg Sweden Stefan Söderhäll, Mats Heyman Data management group Stockholm: Mats Heyman Omid Mavadati Anders Larsson Scott Montgomery Data checks Copenhagen (NOPHO ALL-08) Kjeld Schmiegelow (PI, NOPHO ALL-08) Thomas Frandsen, as well as specific work on toxicity registration (see below) Louise Rold Helt Introduction As the results from the NOPHO ALL-08 trial emerges, one important question arises: Has the rather radical change in treatment strategy introduced with this protocol resulted in improved treatment results. We have tried to intensify the therapy for the high-risk group, at the same time as we have reduced it in number and down-graded patients, who have previously been treated with high-risk therapy to the intermediate risk-group. To compensate, the IR-therapy has been intensified and extended with more CNS-directed therapy. Our lowest treatment intensity group is large, but we have intensified the therapy also in this group. Taken together, this means a more intensive therapy. What has it meant to our patients and us? This is one of the questions the current survey is trying to address. Some focus will thus be on the historic comparisons with the previous protocols. As the NOPHO ALL-2008 protocols recruits more patients, the effect of the stratification is also described in better detail and the outcome for certain sub-groups will also be included as well as the usual comparisons by country and risk-group. The randomised part of the NOPHO ALL-2000 protocol is of interest. We have been waiting for these data to mature for a long time. However, only very preliminary data can be presented in the report and it should be emphasised that the data has not been scrutinised in enough detail to warrant quoting or reference to and should be viewed as preliminary findings until the data is compiled for publication. As usual, all of the NOPHO-centres and their staff are acknowledged for entering data into the database and special thanks also goes to the extended trial management group (Kjeld Schmiegelow, Thomas Frandsen and Louise Rold Helt) in Copenhagen, who contribute to quality control of entered data in the NOPHO ALL-08 protocol.

48

Abbreviations and statistical methods Induction failure (due to progressive disease or early death of other causes), resistant disease (failure to achieve CR1 on NOPHO-therapy without gross protocol violation), death in first complete remission (DCR1), relapse and second malignant neoplasm (SMN) are registered as events in the analyses. MDS, AML and other types of SMN have been grouped together under the term “SMN”. The distinction between relapsed ALL and AML may be arbitrary and in cases with proven recurrence of the original clone in the guise of an altered immunophenotype, the case has been labelled “relapse”. Resistant disease has been defined in the survey as failure to achieve CR1 on NOPHO-protocol, but achieved CR1 on alternative therapy, outside of the protocol. The definition of resistant disease is considerably more stringent in the NOPHO ALL-2008 protocol, in which a series of alternative therapy is prescribed before the patient is labelled as resistant. Induction failure/Induction death has been assigned to all cases not reaching CR1 before death, regardless of the therapy given. These patients have been defined as “Ind death” in the p-EFS-estimation and have been assigned an event-time of “0”, but they have been assigned an event-time corresponding to the time alive in the overall survival analyses. %CR1= percent of children in CR1 in relation to all children in the study group. p-EFS= Event-Free Survival, estimation of final proportion of children in CR1 compared to all children in the study group. With long follow-up time, the p-EFS will approach the percentage of children in CCR. Before the data is mature, the p-EFS value is always lower than the CCR-percentage, since the method estimates a future relapse rate within the group and compensates for this estimation. p-DFS= Disease-Free Survival, similar estimation of final outcome as p-EFS, but with the exclusion of patients that do not reach CR on NOPHO protocols. p-2EFS= an estimation of the proportion of children who will remain in a second remission after relapse. p-OS (overall survival) = an estimation of the proportion of children who will survive. In this analysis, induction death, death in remission or death following relapse constitute events. Hazard function= a spline function which calculates the risk of an adverse event for a given time interval from diagnosis. The intervals in these analyses are six or nine months. Statistical analyses were performed using the SPSS statistical software. The Kaplan-Meier method was used to generate graphs and estimate survival parameters (p-EFS, p-DFS, p-2.EFS, p-OS). Differences in prognosis between sub-groups were compared with the log rank test. The cumulative probability of deaths in CR1 and relapse were calculated according to the “one minus survival” method. This implies censoring of patients dying during induction or later in remission when analysing the probability of death in remission. Events in the analyses of event-free survival included induction-failure, resistant disease, death in CR1, relapse and SMN.

49

The NOPHO ALL-92, NOPHO ALL-2000 and NOPHO ALL-08 patients NOPHO ALL-92 Time of recruitment: 1.1.1992 - 02.10.2001 Number of patients in the NOPHO registry between these dates: 1852 Number of eligible patients: 1644 (89%) NOPHO ALL-2000 Time of recruitment: 1.1.2002 – 30.06.2008 Number of patients in the NOPHO registry between these dates: 1264 Number of eligible patients: 1091 (86%) “Between the 92 and 2000 protocols”: Diagnosis 03.10.2001- 31.12.2001 Number of patients in the NOPHO registry between these dates: 46 Number of eligible patients: 41 (89%) The NOPHO ALL-92 and NOPHO ALL-2000 registration cohorts as well as the “between the protocols” cohort have been described in detail in previous reports. Table 1. NOPHO ALL-08 Time of recruitment: 1.7.2008 – 31.12.2010 Number of patients in the NOPHO registry between these dates: 333

Reason for exclusion Total number n=625

Exclusions Remaining Mature B-cell 7 (2 plasmacytoid dendritic cell leukaemia) t(9;22) 13 Infants 33 Over age >18 years (in paediatric clinic) 3 (1 treated according to NOPHO-ALL 2000) Adult treatment clinic 55 (7 patients below 18) Predisposition / e g Mb Down 13 Diagnosis abroad and start of therapy 3 Pre-treatment (steroids/chemo) 1 Treatment according to NOPHO ALL-2000 2 Intolerance to drugs (cong conditions) 2 Previous cancer (neuroblastoma) 1 Baltic countries 58 (42 Lithuania, 16 Estonia)

Total number of exclusions 191 Evaluable NOPHO ALL-2008 patients 434 (379 1-14 years)

Pilot-patients 22 Bi-lineage/Bi-phenotypic 3 Fully eligible protocol patients 409 Fraction of included patients Out of 625 patients 434 are eligible for evaluation (69%). But out of the target group (Nordic patients with non-B cell, non Ph+ ALL 1-17 years at diagnosis) 434/463 patients (94%) were included.

50

The registry is expanding both geographically and into the adult age group. Baltic registration So far 64 patients have been registered from the Baltic countries (Lithuania, n=43; Estonia, n=21). Of these, one patient from Lithuania and two patients from Estonia were excluded because of t(9;22), one patient from Estonia was excluded because of Down-syndrome and one Estonian patient was an infant. In total some data will be presented from 58 patients. Adult registration The NOPHO ALL-08 protocol has been accepted in Denmark, Sweden and Norway and is now recruiting patients. The Finnish adult haematologists have so far chosen not to participate, but contacts have been made to exchange experiences. Adult patients can be randomised in R2 (continuous or intermittent PEG-Asp in post-consolidation therapy), but few patients have been included so far. In total 55 patients over 17 years at diagnosis have been registered. Out of these, one patient had Down’s syndrome, two patients received pre-treatment and three patients were Ph+. The remaining 49 patients have been included in some analyses. Three of the patients were treated at paediatric departments and the remaining patients in adult haematology units.

51

The survey 2011 The focus of the survey will be the emerging results from the NOPHO ALL-08 protocol and some comparisons with their historic controls. Some preliminary data from the randomised part of the NOPHO ALL-2000 study will also be presented. As in previous years, only patients diagnosed during the previous year will be included, thus for the NOPHO ALL-08 protocol, the patients diagnosed during 2011 are excluded. Table 2. Clincial characteristics at diagnosis for patients in the NOPHO ALL-08 protocol by age-group (Including NOPHO and Baltic patients as well as patients <18 years at diagnosis treated in adult departments and adolescents ≥ 18 treated in paediatric departments) Percentages are given in brackets. For the genetic analyses, the absolute number of patients with an aberration over the total number of analysed patients is given for the NOPHO ALL-08 patients. TLP = traumatic lumbar puncture at diagnosis. Parameter Age

1-5 n=308

Age 6-9 n=90

Age 10-17 n=101

Age 18-25 n=21

Age 26-45 n=26

Sex Male 166 (54) 43 (48) 68 (52) 18 (86) 19 (73)

Female 142 (46) 47 (52) 33 (48) 3 (14) 7 (27) WBC

<100 269 (87) 74 (82) 80 (79) 15 (71) 21 (81) >100 39 (13) 16 (18) 21 (21) 6 (29) 5 (19)

Immuno B-precursor 280 (91) 73 (81) 69 (68) 16 (76) 14 (54)

T-cell 28 (9) 16 (18) 29 (29) 5 (24) 11 (42) Bi-lineage 0 (0) 1 (1) 3 (3) 0 (0) 1 (4)

CNS 1 (neg) 272 (88) 83 (92) 83 (82) 18 (85) 25 (96)

2 24 (8) 4 (5) 11 (11) 1 (5) 0 (0) 3 (pos) 12 (4) 2 (2) 7 (7) 1 (5) 0 (0) Missing 0 (0) 1 (1) 0 (0) 1 (5) 1 (4)

TLP Neg/no blasts 286 (93) 83 (93) 92 (92) 19 (90) 23 (88)

with blasts 20 (6) 4 (4) 8 (8) 0 (0) 1 (4) Missing data 2 (1) 3 (3) 1 (1) 2 (10) 2 (8)

Stratific 1 Lower (Pred) 259 (84) 68 (76) 63 (62) 13 (62) 12 (46) Higher (Dexa) 49 (16) 22 (24) 38 (38) 8 (38) 14 (54)

52

In the registered patient material there is a male dominance, which is accentuated with increasing age. It is only the smaller children, who have a more balanced sex-distribution. The same is true for T-cell immunophenotype, which is increasing with age and it is really only the small children that have the “classic” T-cell/B-precursor ratio of about 1:10. Interestingly there is no clear age-association with hyperleukocytosis. The older children and adults with T-cell disease have lower WBC than the small children. but the fraction of patients with WBC>100 goes up with age in the B-precursor group. A much higher fraction of adults are treated with Dexa during induction than in paediatric departments. Table 3. Genetic aberrations and response to initial therapy for patients in the NOPHO ALL-08 protocol by age-group (same patient selection as in Table 2). RG=Risk-group Age 1-5

n=308 Age 6-9

n=90 Age 10-17

n=101 Age 18-25

n=22 Age 26-45

n=26 Genotype

HeH 117/297 (39) 24/85 (28) 17/95 (18) 4/15 (27) 4/21 (19) t(12;21) 92/306 (30) 21/89 (24) 5/101 (5) 1/20 (5) 2/26 (8) Hypodip 3/300 (1.0) 2/85 (2.4) 1/95 (1.0) 0/16 (0) 0/23 (0)

MLL 11/308 (3.6) 1/89 (1.1) 4/101 (4.0) 2/20 (10) 2/26 (8) t(1;19) 8/306 (2.6) 7/90 (7.8) 4/101 (4.0) 0/20 (0) 2/26 (8)

iamp(21) 2/297 (0.7) 4/86 (4.7) 4/98 (4.0) 0/20 (0) 0/22 (0) dic(9;20) 8/301 (2.7) 1/86 (1.1) 0/98 (0) 0/19 (0) 0/19 (0)

Other aberr detect 40/308 (13) 17/90 (19) 41/101 (41) 5/23 (9) 5/26 (17) No aberr detect 36/308 (12) 18/90 (20) 25/101 (25) 11/22 (50) 15/26 (52)

Response (MRD) d15 Pred <25% 245 (98) 62 (93) 54 (89) 11 (100) 8 (73) d15 Pred >25% 6 (2) 5 (7) 7 (11) 0 (0) 3 (27)

Missing 8* 1* 2* 3* 3* d15Dexa<25% 40 (89) 17 (81) 28 (80) 3 (60) 9 (75) d15Dexa>25% 5 (11) 4 (19) 7 (20) 2 (40) 3 (25)

Missing 3* 1* 3* 3* 3* d29 Pred <0.1% 205 (82) 48 (71) 40 (63.5) 9 (64) 4 (31) d29 Pred >0.1% 43 (17) 17 (25) 17 (27) 5 (36) 6 (46) d29 Pred >5% 3 (1) 3 (4) 6 (9.5) 0 (0) 3 (23)

Missing 2* 0 0 0 1* d29Dexa<0.1% 25 (56) 8 (38) 22 (63) 2 (29) 7 (50) d29Dexa>0.1% 15 (33) 9 (43) 10 (28) 4 (57) 5 (36) d29Dexa>5% 5 (11) 4 (19) 3 (9) 1 (14) 2 (14)

Missing 4* 1* 3* 1* 1* Post Ind RG

SR 178 (59) 32 (36) 26 (26) 6 (32) 3 (13) IR 88 (29) 38 (42) 45 (46) 8 (42) 10 (44)

HR-chemo 28 (9) 16 (18) 22 (22) 4 (21) 6 (26) HR-SCT 6 (3) 4 (4) 6 (6) 1 (5) 4 (17)

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Day 15 and day 29 assessments is given by best available marker (flow for B-precursor and PCR for T-cell; alternative method if first choice not available). *=Patients with missing data removed from percentage. Dexa-induction patients, with poor response (>25% day 15) removed from the d29 analysis. Induction failures and patients lost to follow up (n=1), early protocol violation post induction (n=1) or missing response data (n=1) excluded from RG-assessment. Figure 1. Relative Risk-group distribution by age-group. The absolute numbers are given in Table 3.

The genetic alterations have an age-dependent pattern which is well known and partly correlates with the age-peak. This is particularly true for t(12;21) group. However, there are a few outliers of high hyperdiploidy and even t(12;21) among the adults. Some of the other aberrations have no adults recorded at all. Both the fraction of patients with complete analysis and the number of patients with no detectable aberration at all is very low. Response-data indicates that older children and adults respond less well to induction therapy than small children. This is particularly true in the lower-risk group at diagnosis receiving Prednisolone, whereas the difference among the higher risk patients is less pronounced. The risk-distribution is highly age-dependent. The “peak-ages” is dominated by the SR-group, but already above 6 years of age, the IR-group is larger and for the older patients the HR-groups grow in relative importance. The group above 25 years of age have almost half the patients in the HR-groups. This is mainly due to a high fraction of T-cell disease.

0

10

20

30

40

50

60

70

80

90

100

Age 1-5 Age 6-9 Age 10-17

Age 18-25

Age 25-45

HR-SCT

HR-chemo

IR

SR

54

Figure 2. Risk-group stratification in the NOPHO ALL-2008 protocol

55

The figure illustrates the flow of patients through the stratification system. Out of 434 included patients, 426 have sufficient data for stratification at the end of induction. Six patients died during induction. Four of these had initial higher risk and Dexa-induction, two were lower-risk Pred patients. One patient was lost to follow-up due to move abroad with change of therapy and one pilot-phase patient had insufficient data registered. Four of the patients stratified at the end of induction did not achieve a final stratification result: Two patients died in CR1 in the intervening period. One patient dropped out of high-risk therapy due to toxicity and long delays and one patient had insufficient data registered day 79. Table 4. Protocol adherence day 29 Risk-group SR-therapy IR-therapy HR-therapy Other SR 216 2 0 2 IR 4 129 1 0 HR-chemo 0 1 55 0 HR-SCT-CR1 0 2 14 0 Protocol adherence after induction seems very high (414/426=97%). Most cases of protocol violation can be explained: Patients treated with alternatives to NOPHO ALL-08 have had toxicity-problems that must be expected in a few patients. Some violation is due to misinterpretation of genetic results or late incoming or even in hindsight changed MRD-results. Some are caused by teething-problems such as changed criteria for HR-therapy at the beginning of the protocol and should not be interpreted as protocol violation in any real sense. Protocol adherence with final stratification and SCT in CR1 The only possible change after the day 29 stratification is up-grading to SCT in CR1. Out of the 26 patients who have been stratified to SCT in CR1 18 have been transplanted so far. Some are awaiting SCT, but some will not be transplanted. For two patients the clinical decision has been taken to treat according to the IR-protocol due to borderline MRD at day 29 or technical ambiguities regarding the interpretation of this MRD-value. Four patients from the tentative HR-chemo group have been transplanted. Three of these had relative or absolute SCT-indications regardless: One Finnish boy in the HR-chemo-group with hypodiploidy and poor d15 response was transplanted after 4 HR-blocks in accordance with the option for SCT in CR1 for hypodiploid patients. One T-cell patient with discrepancy between flow and PCR-MRD at day 15 (<0.1% with flow and >25% with PCR) did not receive HR-blocks directly at day 15 and had high PCR-MRD day 29. One boy was transplanted due to prolonged aplasia after HR-block therapy. In conclusion, protocol adherence must be considered very high and generally with understandable reasons for protocol violations. However, we need to record and understand why some patients cannot carry out the prescribed therapy. A system for systematic registration of such outliers has been suggested and will be introduced in the coming year, so this problem can be quantified

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Outcome analysis NOPHO ALL-92 - treatment-results There have been one event in the NOPHO ALL-92 cohort since the last survey. One boy with T-cell disease, 4 years at diagnosis (HR-1), who underwent SCT in CR1 due to relatively high WBC (167), T-cell disease and positive MRD at day 29 had a supratentorial PNET-tumour diagnosed and is currently alive on therapy. The estimates for pEFS and pOS are essentially unchanged. NOPHO ALL-2000 - treatment-results – all events Table 5. The primary events of the NOPHO ALL-2000 protocol and the distribution of these events over the risk groups are shown. Standard error shown in brackets.

Event SI II Int VI EI Total All patients 383 336 204 71 97 1091

Induction failure 0 8 5 0 24 37 Resistant disease 0 0 0 0 19 19 Induction death 0 8 5 0 5 18

Remission % 100 98 98 100 75 97 Death in CCR 5 1 3 1 5 15 All Relapses 41 35 46 20 23 165

BM 17 21 35 13 14 100 BM+EM 9 3 7 4 1 24

BM+CNS 8 2 7 4 0 21 BM+testis 1 1 0 0 0 2 BM+other loc 0 0 0 0 1 1

EM 15 11 4 3 8 41 CNS 13 9 3 1 3 29 Testis 1 2 0 0 2 5 CNS+Testis 1 0 0 0 0 1 Other location 0 0 1 2 3 6

All SMN 7* 1 0 0 1* 9 All events 53 45 54 21 53 226

CCR number 330 291 150 50 44 865 CCR % 86 87 74 70 45 79

CR>/=2 (n) 36 26 25 7 8 102 5 yr pEFS 0.85 (0.02) 0.86 (0.02) 0.73 (0.03) 0.69 (0.06) 0.45 (0.05) 0.79 (0.01)

pEFS at FU 0.83 (0.02) 0.84 (0.02) 0.72 (0.03) 0.69 (0.06) 0.45 (0.05) 0.77 (0.01) All dead 17 19 29 14 35 114 All alive 366 317 175 57 62 977 alive % 96 94 86 80 64 90

5 yr pSurvival 0.96 (0.01) 0.94 (0.02) 0.85 (0.03) 0.79 (0.05) 0.62 (0.05) 0.90 (0.01) pSurvival at FU 0.94 (0.02) 0.92 (0.02) 0.84 (0.03) 0.79 (0.05) 0.60 (0.06) 0.88 (0.01)

* SI-group: One “lymphoproliferative disease” (without preceeding SCT), one EBV-lymphoma (without preceeding SCT), one Mb Hodgkin, one NHL and three cases of MDS. EI-group: one case of extramedullary myeloid disease.

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Table 6. Events in the NOPHO ALL-2000 cohort during 2010/2011 by therapy group

Event SI II Intensive VI EI Total Relapse 11 3 3 1 0 18 DCR1 0 0 0 0 0 0 SMN 1 1 0 0 0 2 Total 12 4 3 1 0 20

Comments/details: Two SMNs (one in the SI- and one in the II-group)

• SI: A boy, 6 years at diagnosis, who developed MDS less than a year after cessation of therapy. Alive with disease at the time of follow-up.

• II: A girl, 13 years at diagnosis, who developed MDS with myelofibrosis 1.5 years after cessation of therapy and died of progression to AML after SCT in CR2.

Table 7. Relapses by site and therapy-group

Rel site SI II Intensive VI EI Total BM 6 2 2 1 0 11 CNS 2 1 0 0 0 3

Testis 1 1 0 0 0 2 BM+CNS 1 0 1 0 0 2 BM+testis 1 0 0 0 0 1 CNS+testis 0 0 0 0 0 0

Other 0 0 0 0 0 0 Total 11 4 3 1 0 18

Comments all events: The rate of events has slowed down somewhat, which is in line with the maturing results and keeps the overall estimates roughly on the same level. The SI-group has taken the majority of these events, which is as expected. The initial increase in risk of relapse after cessation of therapy is wearing off with time. The profile is also adjusting to the time-frame and late BM-relapses dominate. Late extramedullary relapses also occur, mainly in the CNS, but also in the testes. Late SMN:s are mainly found in the lower risk-groups and will continue to occur in the years to come. One of the SMN:s was forgotten in last year’s reporting, but hopefully our prompt reporting in the NOPHO ALL-08 protocol will encourage timely reporting of events from the “older” protocols as well. There are a few events still occurring in the protocol preceding the NOPHO ALL-92 protocol as well.

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Table 8. NOPHO ALL-2008 - treatment-results – all events Patients 1-17 years treated at Nordic paediatric oncology clinics

Event B-precursor WBC<100

n=345

B-precursor, WBC>100/T-cell

n=89

Total

n=434 Induction failure 2 4 6

Resistant disease 0 0 0 Induction death 2 4 4 Lost to follow-up 1 0 1 CR-reached 342 85 427

Remission % 99.4 (342/344) 95.5 (85/89) 98.3 (427/434) Not assessable d29 1 0 1

SR n=220

IR n=134

HR-chemo n=56

HR-SCT n=16

n=426

Death in CR1 2 4 6 2 14 Relapses 2 4 4 1 11

SMN 0 0 0 0 0 All events 4 8 10 3 25 (31)

CCR number 216 126 46 13 401 (402) CCR % 98.2* 94.0* 82.1* 81.3* 92.6 (92.8)*

CR>/=2 (n) 2 3 2 0 7 pDFS/EFS (24mo)** 0.97 (0.02) 0.91 (0.03) 0.67 (0.10) 0.76 (0.12) 0.89 (0.02)

All dead 2 5 8 3 18 (24) All alive 218 129 48 13 408 (409) alive % 99.1* 96.3* 85.7* 81.3* 95.8 (94.5)

pOS (24mo)** 0.99 (0.01) 0.96 (0.02) 0.73 (0.10) 0.76 (0.12) 0.92 (0.02) * NB!The fraction of patients in CR1 and alive as well as the pEFS and pOS figures refers to the patients, who has reached CR1 in each risk-group (for the pEFS estimate actually corresponding to pDFS), but to the total population for the grand total, excluding the patient lost at follow-up during induction. The figures for all events and all alive are amended with the patients excluded from the risk-group stratification (in brackets). **Follow-up time for surviving patients not lost to follow-up during induction: median 441 days (range 34-1003). Events since the last survey Induction failures (n=2) both higher risk at diagnosis

• A four-year old boy with B-precursor high hyperdiploid ALL, but high WBC probably due to some delay (initial diagnosis abroad). Bacterial and fungal septicaemia, necrotic bowel and emergency laparotomy with gut-resection. CNS-infarction, gastro-intestinal bleeding, multi-organ failure and death.

• A ten-year old boy with T-cell disease and hyperleukocytosis at diagnosis. Fairly uneventful initially during induction, but on day 10 of induction sudden septic shock with quickly deteriorating general condition, capillary leak etc, which he never recovered from. Cultures from biopsies from lung and liver post mortem both showed growth of gram-positive cocci and gram-negative rods.

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Post induction events Table 9. Relapses by site and risk-group (day 29 stratification)

Event SR IR HR-chemo HR-SCT Total Relapse 1 4 2 0 7 DCR1 2 1 5 1 9 Total 3 5 7 1 16

Table 10. Relapses by site and risk-group (day 29 stratification)

Rel site SR IR HR-chemo HR-SCT Total BM 1 2 2 0 5 CNS 0 2 0 0 2 Total 1 4 2 0 7

The BM-relapse in the SR-group occurred in a patient with very severe toxicity during indction as well as post induction therapy with highly modified (reduced) therapy. Deaths in CR1 SR-group: A girl 10 years at diagnosis died after complex toxicities including both CNS, liver and in the terminal phase also cardiac function as well as extreme sensitivity to chemotherapy associated with repeated sepsis episodes during the maintenance I phase. A boy 1 year at diagnosis died of gastro-intestinal bleeding in the early maintenance I phase. IR-group: A girl 1 year at diagnosis died of pulmonary artery thrombosis associated with E.coli sepsis during the first HDM course in consolidation. HR-chemo group: A boy 8 years at diagnosis died in septic shock after the C1 block. A contributing factor was a 17 hour delay at home before seeking medical attention. When he arrived at the hospital he was in very poor condition. A 16-year old boy with extensive toxicities from previous HR-blocks died after C3 of stenotrophomonas maltophilia sepsis with associated respiratory and in due course kidney failure. A boy, 2 years at diagnosis with a final stratification to HR-SCT because of poor response. Death after SCT with so far incomplete reporting. A 15-year old girl died of brain edema associated with severe mucositis and pseudomonas sepsis after the first C-block. A boy, 8 years at diagnosis died after block B2 of respiratory failure combined with coagulation disturbances associated with candida sepsis.

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HR-SCT group: A girl 14 years at diagnosis died 9 months after SCT due to complications associated with severe GvHD. Comments all events It is obvious that the intensified therapy in the high-risk groups has resulted in significant toxicity and also in an increased rate of fatalities. This may also be the case for the lower risk-groups. The profile of events in the early phase of the protocol has changed from the previous protocols. Table 11. Events occurring within 2 years from diagnosis by protocol

NOPHO ALL-92 n=1644

NOPHO ALL-2000

n=1091

NOPHO ALL-2008

n=434

Total

n=3169 Induction death 21 (1.2) 18 (1.6) 6 (1.4) 45 (1.4) Resistant disease 9 (0.5) 19 (1.7) 0 (0) 28 (0.1)

Relapse 109 (6.6) 68 (6.2) 11 (2.5) 199 (6.3) Death in CR1 27 (1.6) 13 (1.2) 14 (3.2) 54 (1.7)

SMN 2 (0.1) 0 (0) 0 (0) 2 (0.06) Total 168 (10.2) 118 (10.8) 31 (7.1) 317 (10.0)

This is not an adequate comparison, except to some degree for the events during induction (induction death and resistant disease). All surviving patients from the previous protocols have been “at risk” for these events for 2 years, which is not the case for all the NOPHO ALL-2008 patients. But this type of compilation of events occurring during therapy illustrates the spectrum of problems in the different protocols. Also for the early events during induction the comparison is flawed: We have done away with “Resistant disease” (RD) by defining it more stringently. This is positive, but also means that more difficult to treat leukaemias remain in the EFS-analysis. One would expect this to result in more early relapses, which has not happened. Thus, the low relapse-rate is very encouraging. However, we are concerned with the high rate of death in CR1. Our hope is that this has to do with a learning-phase, which would mean that we can prevent some deaths in the latter part of the protocol. Some adjustments have also been made, particularly to the high-risk blocks. We have to remain particularly vigilant concerning the lower risk-groups, to ensure that these groups with very low expected failure rates from disease do not fare worse due to the therapy administered. The three DCR1 cases in the lower risk groups since the last survey are slightly different than the previous lower-risk cases in that they represent complex toxicity which may in part be influenced by the changed therapy, particularly PEG-Asp specifically. Relapse, death in CR1 and SMN are highly time-dependent events and better comparisons will be provided below. However, because of the re-definition of the early event RD, the EFS-comparisons will be very difficult to interpret. In these comparisons some focus will be on overall survival, which is more robust and not subject to competing risks.

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Treatment-results – Survival analyses

1. Comparisons with historic controls Figure 3. NOPHO ALL-92, NOPHO ALL-2000, NOPHO ALL-2008, Non-B cell ALL

1-<15 (92 and 2000) or 1-<17 (2008) years at diagnosis.

Overall EFS comparison (n=3169)

EFS

Cohort N Events CR1 2yr pEFS (SE) NOPHO ALL-92 1644 426 1218 0.90 (0.01) NOPHO ALL-2000 1091 226 865 0.89 (0.01) NOPHO-08 1-17 Nordic 434 31 403 0.89 (0.02) As mentioned above, the early results in terms of EFS have not changed compared to the previous cohorts. However, as mentioned already, there is an underlying shift in the type of events from under-treatment to over-treatment events. It should also be noted that some patients with worse prognosis, like Mb Down and t(9;21) have been eliminated from the NOPHO ALL-08 cohort. The difference between the NOPHO ALL-92 and the NOPHO ALL-2000 cohorts is very modest indeed and does not reach significance in a pairwise comparison.

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Figure 4. NOPHO ALL-92, NOPHO ALL-2000, NOPHO ALL-2008, Non-B cell ALL

1-<15 (92 and 2000) or 1-<17 (2008) years at diagnosis.

Overall Survival comparison (n=3169)

EFS

Cohort N Events CR1 2yr pOS (SE) NOPHO ALL-92 1644 264 1380 0.94 (0.01) NOPHO ALL-2000 1091 114 977 0.94 (0.01) NOPHO-08 1-17 Nordic 434 24 410 0.92 (0.02) The high fraction of deaths in CR1 is reflected in a small disadvantage for the NOPHO ALL-08 patients in the overall survival analysis, even though the total percentage of patients with events within two years from diagnosis has gone down. This is of course due to the prolonged survival of many of the patients with relapse. A more accurate comparison between these groups would take into account the change in definition of RD. Some such analyses are found below. These comparisons cannot be risk-group stratified, since the risk-grouping criteria have also changed. Instead up-front risk-criteria have been used to make the comparisons simple and at the same time retaining their power.

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Figure 5. NOPHO ALL-92, NOPHO ALL-2000, NOPHO ALL-2008, Non-B cell ALL

1-<15 (92 and 2000) or 1-<17 (2008) years at diagnosis. OS-comparison of patients with BCP-ALL and a) WBC <100 (n=2630) b) >100 (n=177) or c) T-cell (n=338)

FU truncated at 3 years, markers removed for clarity p-OS

p-OS

Cohort N Death Alive pOS (2yr) 92 1386 176 1210 0.96 2000 900 69 831 0.97 2008 344 10 334 0.96

Cohort N Death Alive pOS (2yr) 92 83 30 53 0.82 2000 63 13 50 0.87 2008 31 6 25 0.70

p-OS

Cum Inc of Relapse

Cohort N Death Alive pOS (2yr) 92 152 52 100 0.78 2000 127 32 95 0.80 2008 59 8 51 0.83

Cohort N Rel no Rel pRel (2yr) 92 152 43 109 0.23 2000 127 30 97 0.25 2008 59 3 56 0.08

No clear trends can be distinguished. If there is any change, it may be an improvement in the T-cell group, particularly concerning relapse, but further follow-up and more patients recruited are needed for any conclusions to be drawn.

p=NS

BCP, WBC<100

BCP, WBC>100

p=NS

T-cell

p=NS

p=0.14

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Three patients with bi-lineage label in the NOPHO ALL-08 protocol were assigned as: BCP due to typical genetic (high hyperdiploidy and t(12;21)) changes (n=2) and T-cell (T-cell+myeloid markers) n=1.

Figure 6. NOPHO ALL-92, NOPHO ALL-2000, NOPHO ALL-2008, Non-B cell ALL 1-<15 (92 and 2000) or 1-<17 (2008) years at diagnosis. Comparisons of relapse- and DCR1-rates. FU truncated at 5 years, including patients with RD in previous protocols, but excluding induction deaths (n=3124). Cumulative incidence of relapse

Cumulative incidence of DCR1

Cohort N Rel no Rel pRel (2yr) 92 1623 344 1279 0.07 2000 1073 170 903 0.07 2008 428 11 417 0.05

Cohort N Rel no Rel pDCR1 (2yr) 92 1623 35 1588 0.07 2000 1073 15 1058 0.07 2008 428 14 414 0.05

The question whether we are doing better or worse than our historic controls is difficult to answer at the moment. It is not surprising that the NOPHO ALL-92 and NOPHO ALL-2000 protocols yield similar results, since there were relatively small changes between the protocols. Some improvement may be traced, not yet statistically significant.

With the NOPHO ALL-2008 protocol we have changed treatment stratification and treatment strategy radically, which results in a clearly different outcome. The difference is, as mentioned earlier, not yet traceable in overall results, but in the spectrum of adverse events and relative importance of different treatment failures. At the moment, it seems that we have traded a gain in RD and relapse-rate for an increase in DCR1. If this is due to a learning phase and fewer of our patients will die because of the treatment in the latter part of the protocol, we may have improved the overall outcome in the end. At the moment this is not for certain and the initial increased vigilance over the emerging results of the NOPHO ALL-2008 protocol needs to remain in place. This is particularly true for the lower risk-groups, in which there should be a low tolerance for fatal toxicity.

The results remain virtually unchanged, even if the very long survival experience in the historic control groups is ignored by truncation of all follow-up at 3 years from diagnosis.

p=0.002

Relapse

DCR1

p=0.083

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2. Comparisons within the NOPHO ALL-2008 cohort

Figure 7. Comparison by risk-group.

NOPHO ALL-2008, Non-B cell ALL 1-<17 years at diagnosis. Only patients with stratification day 29 included. Induction failures (n=6), lost to follow-up during induction (n=1) and patients without stratifying MRD d29 (n=1) excluded. Final stratification used. Patients with events during consolidation (n=3) or missing final stratification MRD (n=1)

allocated to risk-group according to stratification day 29. Nordic patients included (n=426)

DFS

post induction OS

RG N Event noEvent pDFS(2yr) SR 219 3 216 0.98 IR 131 8 123 0.91 HR-chemo 50 7 43 0.81 HR-SCT 26 7 19 0.50

RG N Death Alive pOS(2yr) SR 219 2 217 0.99 IR 131 5 126 0.96 HR-chemo 50 6 44 0.83 HR-SCT 26 5 21 0.62

As expected, the risk-groups in the NOPHO ALL-2008 protocol reflect real risk-groups with different prognosis. The overall targets of the protocol are essentially met at the moment, but we need longer observation time to assess the effect on later occurring relapses and if we can reduce the DCR1-rate.

p<0.001

p<0.001

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Figure 8. Comparison by country.

NOPHO ALL-2008, Non Figure 4. NOPHO ALL-2008, Non-B cell ALL 1-<17 years at diagnosis. Nordic patients included (n=492)

EFS

OS

Country N Event noEvent pDFS(2yr) S 162 14 148 0.87 DK 90 7 83 0.91 N 71 4 67 0.91 FIN 104 6 98 0.90 ISL 7 0 7 1.0

Country N Dead Alive pDFS(2yr) S 162 11 151 0.91 DK 90 7 83 0.91 N 71 2 100 0.96 FIN 104 4 98 0.94 ISL 7 0 7 1.0

There are (as expected) no significant differences in outcome between the different Nordic countries in terms of EFS or OS. Iceland is so far the only country without any adverse events at all.

NS

NS

67

Figure 9. Comparison country by country. NOPHO ALL-2008, Non-B cell ALL 1-<17 years at diagnosis.

Comparison by Higher (SR/IR) and Lower (HR-chemo+HR-SCT) risk-groups by country. Final stratification used as above. Nordic patients (n=434)

p-DFS Sweden

p-DFS Denmark

Total n=162; Induction deaths: n=2 RG N Event CR1 pDFS (2yr) SR/IR 135 5 130 0.94 HR 25 7 18 0.62

Total n=90; Induction deaths: n=2 RG N Event CR1 pDFS (2yr) SR/IR 71 2 69 0.97 HR 16 3 13 0.74

p-DFS Norway

p-DFS Finland

Total n=71; Induction deaths: n=0 RG N Event CR1 pDFS (2yr) SR/IR 61 3 58 0.92 HR 9 1 8 0.83

Total n=104; Induction deaths: n=2 RG N Event CR1 pDFS (2yr) SR/IR 77 1 76 0.97 HR 25 3 22 0.69

Iceland has so far had 7 patients, six SR/IR and one HR. No events so far.

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Figure 9. Comparison country by country (ctd)

NOPHO ALL-2008, Non-B cell ALL 1-<17 years at diagnosis.

Comparison by Higher (SR/IR) and Lower (HR-chemo+HR-SCT) risk-groups by country. Final stratification used as above. Baltic patients (n=58)

p-DFS Lithuania

Estonia Estonia has so far had 16 patients and one induction death. Among of the 15 patients, who could be stratified day 29 (11 SR/IR-patients and 4 HR-patients) no events have occurred so far.

Induction deaths: n=1 RG N Event CR1 pDFS (2yr) SR/IR 34 4 30 0.85 HR 7 4 3 0 (43%CR1) The national results yield rather small sub-groups and the results are mostly dependent on the patient-mix SR/IR vs HR and how the HR-patients have fared. The drop in the Lithuanian HR-graph is an artifact of the method, but the HR-group in Lithuania has had a high fraction of events

p=0.051

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s Figure 10. Overall toxicity-registration by pre-defined SAE:s every 3 months. Only higher grade toxicities are recorded.

Not self-expanatory abbreviations: ICU=intensive care unit. Abdominal=serious abdominal complications leading to laparotomy, VOD=veno-occlusive disease (sinusoidal occlusion syndrome), PRES=posterior reversible encephalopathy syndrome, Other CNS=originally designed for the Depocyte randomization, but now used for otherwise not described CNS-toxicity. Some of the groups are now beginning to get so large that focus-groups for further study could be designed.

0 10 20 30 40 50 60 70 80 90 100

Allergy/AnaphylaxisICU

Pneumocystisfungal inf.

DialysisAbdominal

Liver DysThrombosis

BleedingHyperlipidemia

VODHeart FailureHypertension

Vincristine RelatedSeizures

PRESComa

PancreatitisOsteonecrosis

Other CNSAny SAE

DeathNo SAE

Total (n=555)

n=19

N=54

n=35

n=44

n=30

n=90 n=54

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Figure 11. Overall toxicity-registration by pre-defined SAE:s every 3 months and age.

Some of the toxicity is highly age-dependent. Particularly teenagers have some vulnerabilities, for instance pancreatitis and osteonecrosis. Thrombosis is more common in adults, as expected. Allergy seems to be more common in the smaller children. This registration could be the basis for directed precautions for instance directed against thrombosis or pancreatitis.

0 10 20 30 40 50 60 70 80 90 100

Allergy/Anaphylaxis

ICU

Thrombosis

Bleeding

Pancreatitis

Osteonecrosis

Fungal infection

Any SAE

Death

No SAE>18 (n=37)15-18 (n=53)11-14(n=41)1-10 (n=422)

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asas 4. Randomised part of the NOPHO ALL-2000 protocol

NB! This is a NOPHO-study, which should be fully presented at a NOPHO-meeting (likely in Uppsala 2012). These are some preliminary results, which should be seen as working-material and should not be quoted or referred to outside of NOPHO. Patients

The NOPHO ALL-2000 cohort has been defined above. In the randomised study only SI and II-patients were eligible. The study was conducted during Maintenance phase II, which is towards the end of the protocol. This means that all patients with events before the time of randomisation were also not eligible.

Enrolled: 1091 HR-stratification 372 Induction deaths 8 (all II) Other Event before time of randomisation 6 (4 SI and 2 II) Remaining Eligible 705 (379 SI and 326 II)

Table 12. Reasons for no randomisation and randomisation results per therapy-group.

Reasons for no randomisation SI n=379

II n=326

Total n=705

Clinical decision 10 15 25

Refusal 39 51 90

Lost to follow-up 2 0 2

Other 0 3 3

Unknown 42 56 98

Total not Randomised 93 (25) 115 (35) 208 (30)

Randomised 286 (75) 211 (65) 497 (70)

Almost a third of the eligible patients were not randomised. The distribution is not even, more refusals occurred in the II-group than in the SI-group. Some of the analyses below will shed some light on why this may be the case.

A large fraction of the patients do not have a recorded reason for not being randomised. Towards the end of the study, the decision to stop randomisation has in all likelihood affected the recruitment. The details of the recruitment (and the lack of recruitment) have to be further studied before publication.

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Table 13. Clinical characteristics and country of the randomised and non-randomised groups

Clinical characteristic or Country

SI n=379

p II n=326

p

Non R

n=93

Random

n=286

Non R

n=115

Random

n=211

25

Age at diagnosis 0.09 <0.001

1-5 77 212 50 154

6-9 16 74 13 23

10-14 - - 52 34

Sex 0.9 0.9

Male 51 154 59 110

Female 42 132 56 101

Country 0.3 0.8

Sweden 27 100 41 76

Denmark 18 64 21 36

Norway 24 50 27 56

Finland 24 72 26 42

Iceland - - 0 1

It is obvious from the table that the slightly better recruitment in the SR-group is largely dependent on the absence of the older children, who in the II-group were much more reluctant to take part in the randomisation. There were essentially no sex-differences at all and no major differences between the countries either.

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Figure 12. Outcome of non-randomised and randomised patients.

DFS

DFS

Random y/n N Event CR1 pDFS (5yr) Yes 286 37 249 0.87 No 93 12 81 0.85

Random y/n N Event CR1 pDFS (5yr) Yes 211 19 192 0.91 No 115 16 99 0.85

There was no statistically significant difference in outcome between patients, who were or were not randomised. However, in the II-group, the older age associated with not being randomised gave a small difference in outcome

p=0.073

SI II

NS

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Table 14. Clinical characteristics of patients with and without pulses (randomised groups)

Clinical characteristic

or Country

SI

n=286

p II

n=211

p

No Pulses

A

n=140

Pulses

B

n=146

No Pulses

A

n=103

Pulses

B

n=108

Age at diagnosis 0.7 0.4

1-5 102 110 78 76

6-9 38 36 12 11

10-14 - - 13 21

Sex 0.5 0.4

Male 72 82 57 53

Female 68 64 46 55

Country 0.99 0.7

Sweden 49 51 39 37

Denmark 32 32 18 18

Norway 24 26 28 28

Finland 35 37 18 24

Iceland - - 0 1

No significant differences between the randomised groups.

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Figure 13. Outcome of the randomised patients (pulses vs no pulses).

DFS

DFS

R-group N Event CR1 pDFS (5yr) A 140 20 120 0.85 B 146 17 129 0.87

R-group N Event CR1 pDFS (5yr) A 103 11 92 0.87 B 108 8 100 0.89

Nor were there any significant differences between the arms in the randomised study. Several more elaborate analyses as well as assessment of sub-groups remain to be performed.

NS

SI II

NS

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Concluding remarks The brief summary of the randomised part of the NOPHO ALL-2000 trial is included in the report for orientation, since the membership of NOPHO has awaited the results for a few years. The results may still change with longer follow-up and are not yet ready for publication and should therefore be treated with caution and not be quoted. The feedback to the centres on the progress of the protocol has always been an important part of the NOPHO communication and the report has played an important role in this process. Initial problems with getting used to a new protocol are overcome with time, but the overview of the results is important information for clinicians and nurses to feel motivated to continue improving the use of the protocol. It is also of importance to understand if we are moving forward or not. To this end we also include comparisons with historic controls Some important lessons can also be learned from the compilations of results, even during the lifetime of a protocol. This has meant important amendments to the NOPHO ALL-2008 protocol because of toxicity. There have been some changes in the protocol itself, but now we also start to see different outcomes emerging. The shift among the adverse events of the patients may have effects on the perception of treatment among the patients as well as among the staff. One hallmark of the NOPHO tradition is a very transparent attitude towards these results and the results should also be discussed. It is important that this discussion has facts as a base, rather than only the feelings associated with particular problems in the unit. The basis of the analyses describing these facts is always the reporting from the centres to the ALL-registry. All you, who have contributed to the registration, should, as always be gratefully acknowledged for your hard work and important efforts. The protocol adherence as well as the timely reporting of patients has been remarkably good, not least thanks to the tireless efforts of the protocol management team in Copenhagen, but also some automatic reminders that are mailed out by the registration system. The toxicity registration system is gathering large amounts of data, which in the future will be very valuable in the evaluation of the adverse effects of therapy and will hopefully help us in the design of our future therapy. All these integrated efforts will hopefully yield a fruitful discussion of the results when we meet in Turku.

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IV:3 NOPHO ALL-2008 PI Working Group Working group: E-mail addresses Jonas Abrahamsson (PI Sweden) jonas.abrahamsson@vgregion.se Birgitte K Albertsen (PI asparaginase study) biralber@rm.dk Henrik Birgens (PI adults DK) hebi@dadlnet.dk Elisabeth Björklund (MRD coordinator flow) elisabet.bjorklund@karolinska.se Thomas Frandsen (monitor of toxicity tregistration) t-frandsen@dadlnet.dk Laimonas Griskevicinius (PI adults Lithuania) laimonas.griskevicius@santa.lt Arja Harila-Saari (PI Depocyte study) arja.harila-saari@oulu.fi Helene Hallböök (PI adults Sweden) helene.hallbook@medsci.uu.se Mats Heyman (ALL registry) mats.heyman@ki.se Olafur Gisli Jonsson (PI Iceland) olafurgi@landspitali.is Jukka Kanerva (event group chair) jukka.kanerva@hus.fi Hans Ole Madsen (MRD coordinator PCR) hom@rh.dk Karin Mellgren (LLC chair) karin.mellgren@vgregion.se Katrin Palk (PI adults Estonia) katrin.palk@regionaalhaigla.ee Kaie Pruunsild (PI Estonia) kaie.pruunsild@lastehaigla.ee Kjeld Schmiegelow (Protocol chair) kschmiegelow@rh.dk Mervi Taskinen (NOPHO ALL committee) mervi.taskinen@hus.fi Petter Quist-Paulsen (PI adults Norway) petter.quist-paulsen@ntnu.no Goda Vaitkeviciene (PI Lithuania) goda.vaitkeviciene@vuvl.lt Kim Vettenranta (PI Finland) kim.vettenranta@pshp.fi Ann Åsberg (PI Norway) ann.asberg@ntnu.no For details see NOPHO Annual Report ALL2008-section. Meetings: The ALL-2008 study committee has met twice (Oct. 14th 2010, and April 13th 2011) (minutes at www.nopho.org ). In addition, meetings have been held with the adult PIs and adult hematology centre representatives (April 12th 2011). Finally, the ALL2008 group have been present at meetings with the MRD-group, the Event group, the Pharmacology group, and the ALL committee. Adults: The adult hematologists in Lithuania and Estonia have joined the protocol that now includes DK, S, N, LT and EE. They are including patients and performing registration identical to the pediatricians. The recruitment have some what lower than projected since Oslo and some smaller centres in Sweden are not entering patients. With the inclusion of LT and EE we expect to reach the target of 200+ patients >18 years included in the ALL2008 protocol. Randomisations: The protocol was opened July 1st 2008. The three randomised studies opened for children January 1st 2009, but with some delays in entering of patients depending on the approval process in the involved countries. Recruitment was somewhat below the projected last year. This is catching up

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and approximately 80% of all eligible patients are randomised. The ASP-randomisation for adults opened January 1st 2010, so far only 2 patients have been randomised. The adult PIs will by mid-may decide if the adult Randomisation is to be closed.. Baltic countries: The protocol has been approved as standard therapy in Estonia and Lithuania, and registration of patients from these countries is ongoing. Baltic patients are not study patients and they are analysed separately. The EFS have been somewhat below the Nordic results in Lithuania. The frequency of T-ALL is significantly higher in Lithuania than in the other Nordic countries. In Estonia the cytogenetic classification has been somewhat flawed, and for this reason no patients have been allocated to the SR-arm. Risk grouping: The risk group stratification has been very close to what was projected. Even with identical therapy and risk grouping criteria, older patients are heavily skewed towards the higher risk groups. This is currently being analysed with the aim of publication of these data (see figure 1). Relapse: The clinical outcome has overall been satisfactory, especially for the previous “high-risk” patients (e.g. T-ALL). For the lower risk patients it is still too early to determine, whether the EFS is superior to our previous protocols. The cumulative projected relapse rates at 2.8 years for the 495 Nordic patients diagnosed before February 1st 2011 (all age groups included) are 0.9%, 6%, 7.5%, and 29.2% for the SR, IR, HR and HR-SCT groups, respectively. Toxic deaths: Although the simplified MRD-based risk stratification and the major changes in the ALL2008 protocol compared to our previous treatment strategies have seem to have reduced the relapse rates not least for the HR patients, the protocol has been burdened by toxic death. By mid-April 2 of 372 patients (0.5%) on prednisolone induction have had induction failure versus 4 of 110 patients (3.6%, p=0.01) on dexamethasone. In total, 16 patients have died in remission: 1% in SR, 2.6% in IR, and 10.9% on the HR blocks (patients were censored at the time of SCT). 7 of 8 patients who died on the HR-blocks were males and all but one (30 years) were in the age rage 8.5-18.5 years, giving these patients a cumulative risk of toxic death of 31% compared to 3.4% for the other HR patients. This association between risk of death in remission with age is being further explored. In total 9 Nordic and Baltic patients have died after block therapy; none after block A, 5 after block B, 4 after block C. Ammendments to the protocol: A few amendments have been made to the protocol. These are listed on page 2 of the current protocol version at www.nopho.org . Due to the risk of toxic death and unacceptable long delays for normalisation of myelopoiesis after block C, we changed the structure of block C in June 2010. Prior to that 4 patients have died after block C. Since then no patients have died after block C. Amendments to block B are being discussed (to be decided at the LLC and Board meetings in Turku). Publications: Much of the work done as part of the preparation for the protocol has been published, submitted for publication, or is in the writing phase. These include: Schmiegelow K, Forestier E, Kristinsson J, Söderhäll S, Vettenranta K, Weinshilboum R, Wesenberg F. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia - results from the NOPHO ALL-92 study. Leukemia 2009; 23: 557-64. Schmiegelow K, Al-Modhawi I, Andersen MK, Berendtz M, Forestier E, Hasle H, Heyman M, Kristinsson J, Nersting J, Nygaard R, Svendsen AL, Vettenranta K, Weinshilboum R. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia - results from the NOPHO ALL-92 study. Blood 2009; 113: 1077-84. Bjorklund E, Matinlauri I, Tierens A, Axelsson S, Forestier E, Jacobsson S, et al. Quality control of flow cytometry data analysis for evaluation of minimal residual disease in bone marrow from acute leukemia patients during treatment. J Pediatr Hematol Oncol 2009; 31:406-1.

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Schmiegelow K, Heyman M, Kristinsson J, Mogensen UB, Rosthøj S, Vettenranta K, Wesenberg F, Saarinen-Pihkala U. Oral methotrexate/6-mercaptopurine may be superior to a multi-drug LSA2L2 maintenance therapy for higher risk childhood acute lymphoblastic leukemia. J Ped Hematol Oncol 2009; 31:385-92. Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Söderhäll S, Taskinen M; Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010; 24:345-54. Schmiegelow K, Heyman M, Gustafsson G, Lausen B, Wesenberg F, Kristinsson J, Vettenranta K, Schroeder H, Forestier E, Rosthoej S. The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia 2010; 24: 715-20. Brüggemann M, Schrauder A; Raff T, Pfeifer H, Dworzak M, Ottmann OG, Asnafi V, Baruchel A, Bassan R; Benoit Y, Biondi A, Cavé H, Dombret H, Fielding AK, Foa R, Gökbuget N, Goldstone AH, Goulden N, Henze G, Hoelzer D, Janka-Schaub G, Macintyre EA, Pieters R, Rambaldi A, Ribera JM, Schmiegelow K, Spinelli O, Stary J, von Stackelberg A, Kneba M, Schrappe M, van Dongen JJM, also on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG). Standardized MRDquantification in European ALL trials – proceedings of the second international symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia 2010; 24:521-35. Vaitkevciene G, Forestier E, Hellebostad M, Heyman M, Jonsson OG, Lähteenmäki PM, Rosthoej S, Söderhäll S, Schmiegelow K. On behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO). Should white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia be included in risk stratification in contemporary treatment protocols? Results from the NOPHO ALL-92 and ALL-2000 studies. Eur J Haematol 2011; 86:38-46. Lund B, Åsberg A, Heyman M, Kanerva J, Harila-Saari A, Hasle H, Söderhäll S, Jonsson OG, Lydersen S, Schmiegelow K. On behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO). Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Ped Blood Cancer 2011; 56: 551-9. Relling MV , Gardner EE , Sandborn WJ , Schmiegelow K , Pui CH , Yee SW , Stein CM , Carrillo M , Evans WE , Klein TE . Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011, 89:387-91. Pending: CNS disease at diagnosis and at relapse; in preparation (First author Mervi Taskinen). Planned publications from the ALL2008 protocol: A descriptive paper on our new All2008 toxicity registration system; in preparation (First author Thomas Frandsen). MRD results by block therapy, 90 patients (1st author: Hanne Marquart, MRD group). Comparing response and risk grouping for children, adolescents and adults (1st author: Nina Toft, adult hematologist).

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IV:4 AML Working Group

Coordinator Jonas Abrahamsson (SE) jonas.abrahamsson@vgregion.se National coordinators Denmark Birgitte Lausen birgitte.lausen@rh.regionh.dk Finland Kirsi Jahnukainen kirsi.jahnukainen@kbh.ki.se Iceland Ólafur Gísli Jónsson olafurgi@landspitali.is Norway Bem Zeller bem.zeller@rikshospitalet.no Sweden Josefine Palle josefine.palle@akademiska.se Honk Kong Shau-Yin HA syha@hkucc.hku.hk Estonia Kadri Saks kadri.saks@lastehaigla.ee Latvia Zhanna Kovalova zhanna.k@inbox.lv Lithuania Ramune Pasauliene ramune.pasauliene@vuvl.lt The Netherlands Eveline de Bont e.s.j.m.de.bont@bkk.umcg.nl Belgium Barbara De Moerloose barbara.demoerloose@UGent.be Data manager Henrik Hasle hasle@dadlnet.dk Cytogenetics Erik Forestier erik.forestier@pediatri.umu.se Immunophenotype Jesper Heldrup jesper.heldrup@skane.se Young NOPHO Denmark Lotte Abildgaard labildgaard@dadlnet.dk Finland Minna Koskenvuo minna.koskenvu@hus.fi Sweden Anna Sällfors-Holmqvist anna.sallfors-holmqvist@med.lu.se

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Organisation The group has held two meetings during 2010. After eight years of committed work as chairman for the AML group, Henrik Hasle will continue in the group as manager of the AML database. Jonas Abrahamsson has from 2011 been elected to act as coordinator of the group. At the November meeting it was decided, as an investment for the future, to increase the number of Young NOPHO participants so that each Nordic country is allowed one representative. Introduction NOPHO has treated children with AML on four common protocols since 1984: NOPHO-AML84, -88-. -93 and -2004. All protocols have been based on induction therapy with anthracycline, cytarabine and 6-thioguanin with etoposide added from 1988 followed by consolidation based on high-dose cytarabine. Since 1993 a response guided induction strategy has been used, allowing hematological recovery for children in remission after the first course prior to giving the second course. From NOPHO-AML84 to NOPHO-AML93, outcome improved significantly and the NOPHO-AML93 had a 5 year EFS of 50%. Overall survival was 66% which up until recently was the highest reported in childhood AML. Table 1. Results from recent published large collaborative trials in childhood AML.

Study Pts (n)

Early death %

5-yr EFS %

5-yr OS %

EORTC-CLG 58,9211 177 2 48 62 BFM982 473 3 49 62 CCG28913 750 4 34 45 LAME914 247 4 48 62 NOPHO935 223 2 50 66 POG88216 511 4 32 42 MRC127 455 4 56 66 AML99 (Japan) 8 240 2 61 75 AML02 (St Jude) 9 216 - 63* 71*

* EFS and OS at three years. 1. Entz-Werle N Leukemia 2009 2. Creutzig U Ann Hematol 2004 3. Smith FD Leukemia 2005 4. Perel Y Leukemia 2005 5. Lie SO Leukemia 2005 6. Ravindranath Y Leukemia 2005 7. Gibson BES Leukemia 2005 8. Tsukimoto J Clin Oncol 2009 9. Rubnitz Lancet Oncol 2010.

However, as shown below, the current NOPHO-AML2004 protocol does not seem to give a significant improvement of outcome. Therefore, the process of preparing a new protocol, has been prioritized during 2010.

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During 2010 the main work in the group has focused on

1) Supervising and analyzing results of the NOPHO-AML2004 protocol 2) Improving therapy for subgroups with poor outcome in AML2004 3) Preparations for starting a new AML trial in 2012/2013 4) Compiling and publishing data from the NOPHO AML protocols 5) Participation in international collaborative research projects

NOPHO-AML2004. The protocol opened in January 2004. The protocol, flow charts and amendments can be accessed at www.nopho.org. Patient accrual Between 2004-2010 230 protocol patients have been registered from the Nordic countries and Hong Kong and are included in the NOPHO report and I-BFM report. Fifteen patients have been registered from Estonia and three from Latvia. In 2010 both the Netherlands and Belgium started using a modified version of NOPHO-AML2004 (Identical treatment except for omission of the third course HAM) and have registered five and nine patients respectively. Toxicity Early death occurred in six (2.6%) patients, five of whom died of bleeding during the AIET course. The bleeding events mostly happened in the first years of the protocol. A further six patients have died in CR1 mainly from infections. One toxic death occurred during 2010. As expected a very high rate of febrile neutropenia is observed ranging from 98% after AIET to 69% after HA3. The registration of late effect data is still far from complete but neither acute nor late cardiac toxicity has been reported. The overall conclusion is that, although the treatment is intensive and causes significant morbidity, toxicity is tolerable and the number of toxic deaths acceptable. Outcome At three years EFS is 51% compared to 52% in NOPHO-AML93 and overall survival is 71% compared to 67%.

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Figure 1. Event-free survival (left figure) and overall survival (right figure) in NOPHO-AML2004 (green) and NOPHO-AML93 (blue). Differences are not significant. We have investigated probable reasons for the lack of improved outcome in AML2004. 5.7% of patients had resistant disease (4,7% in AML93), as defined by no CR after two induction courses. After receiving FLAG most patients entered remission giving an overall CR rate of 97% which is very high. However, patients who entered remission after two induction courses but had between 5-14.9% blasts (intermediate response) after the first course and thus were standard risk patients had an extremely high relapse rate. In contrast, high-risk patients, who were treated with SCT, and either had ≥15% blasts after AIET or were not in remission after AM, had a good outcome. Our interpretation is that SCT can overcome the negative effect of a poor early response whereas the AM course is too weak to compensate for even an intermediate response to AIET.

Figure 2. EFS in patients with poor, intermediate and good response to AIET. Intermediate responders have significantly lower EFS. From Abrahamsson et al J Clin Oncol 2011.

AML2004

AML93

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Subgroup analysis also showed that the protocol performed very poorly in patients with t(8;21) which in other protocols is associated with a favorable prognosis. The reason for this is unclear considering that they responded well to induction therapy in NOPHO-AML2004 and that most other groups also employ high-dose cytarabine for consolidation. It may well be that the AM course with a very low dose of cytarabine is insufficient for patients with t(8;21). Although many patients with t(8;21) and relapse can be salvaged, OS at slightly above 60% remains lower than in other studies. These worrying results for patients with intermediate response and t(8;21) prompted us to make an amendment to the protocol, effective from January 2011, in which AM is replaced by a FLADx (Fludarabine, Cytarabine, Daunoxome) for these two groups of patients. The amendment can be found on http://www.nopho.org.

Figure 3. EFS (left figure) and OS (right figure) in patients with t(8;21) (blue line) vs all others (green line). Of the 38 patients with t(8;21) 17 had relapse, two death in CR1 and one an SMN.

Stem cell transplant in CR1 In NOPHO-AML2004 high-risk patients are recommended SCT with any matched donor. Initially MLL aberration other than t(9;11) was a high risk criterion but interim analysis showed that compliance to the SCT recommendation in these patients was poor and consolidation with chemotherapy resulted in a satisfactory outcome. Thus, an amendment in 2009 removed MLL aberrations as a high-risk criterion. At present 24 of 227 (10.6%) evaluable patients have received SCT in CR1. This is a low rate compared to most other childhood AML protocols. Of the 25 poor responders 20 have received SCT. FLT3 ITD mutation Given the poor prognostic effect of FLT3 internal tandem duplications observed in most trials we have during 2010 updated data and re-evaluated the prognostic impact of FLT33 in NOPHO AML protocols. Although the numbers are small, patients with FLT3 ITD without NPM1 mutations, do poorly and there

t(8;21)

All others

All others

t(8;21)

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seems to be no improvement in AML2004. We have therefore made another amendment defining Flt3 ITD mutation without concomitant NPM1 mutation as a high-risk criterion with the recommendation for SCT in CR1. Gemtuzumab randomization The accrual goal of 120 randomized patients was reached during 2010. After evaluation of the AML group and the DSMC we concluded that further recruitment was unlikely to change the results and the study was closed. As of the beginning of this year the number of events were equal in the treatment arms and there seems to be no benefit of adding Gemtuzumab as post-consolidation therapy. We are planning to prepare a paper in autumn 2011 when data are more mature. NOPHO-AML2012 During the year we have thoroughly reviewed results from other treatment studies and the NOPHO AML data to prepare for the new protocol. At present the Japanese AML99 study (Tsukimoto et al J Clin Oncol 2009) has the best published results but results from the AML02 trial from St Jude (Rubnitz et al Lancet Oncol 2010) are also good. Although much of the therapy is similar to NOPHO protocols it is striking that both have a longer first induction course and they have higher CR rates after the first course. Also, the St Jude study shows that early response, as measured by MRD with flow cytometry, has a high prognostic discriminatory power. Currently the Nordic AML flow group is working hard to analyze the MRD data from NOPHO-AML2004 but their work is hampered by the fact that MRD measurements have been performed in a non-standardized way in different laboratories. We are therefore aiming for a protocol with an induction leading to higher quality remission and will evaluate this using highly standardized flow MRD for which the Nordic flow group currently is developing guidelines. Since remission quality is of such paramount importance we will compare different induction courses in a randomized setting using MRD after the first two consolidation courses as endpoints. Consolidation therapy will probably be similar to AML2004. We are currently discussing a draft concept within the group and aim for finalizing a cooperative protocol including NOPHO, Hong Kong, the Netherlands and Belgium in 2012. Intergroup studies Myeloid leukemia of Down syndrome The International DS study ML-DS 2006 reduced the dose in each course and the total number of courses from 6 to 4. The protocol is found at www.nopho.org An add-on study on MRD using WT1 analyses is centralized in Aarhus. The protocol and practical information about how to send samples are found at www.nopho.org ML-DS has been diagnosed in 27 patients from 2005 to 2010 in the Nordic countries. Most have been treated according to ML-DS 2006. One patient died during induction, one patient later developed ALL, the remaining 25 patients remain in CR1.

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AML-M3 APL The NOPHO-AML group recommended in 2009 joining the international AML-M3 APL trial. The protocol is considered best available therapy and a registration only study. PCR MRD monitoring is mandatory and should be centralized to Aarhus for all Nordic patients. Data entry will be done centrally. For protocol and PCR MRD invoice please see www.nopho.org Two Nordic patients have been treated on the protocol; both remain in CR1. International relapsed AML study A new relapse protocol has been finalized and has, as a first step to approval by the national authorities, been submitted to one national authority coordinating the voluntary harmonisation procedure. Following approval, applications will have to be made in each country. The new relapse protocol will investigate, in a randomised setting, if addition of Gemtuzumab to FLADaunoxome will improve early response. While awaiting the new relapse protocol a recommendation for relapse strategy can be found at www.nopho.org Publications from the NOPHO AML WG since 2010.

• Molgaard-Hansen L, Möttönen M, Glosli H, Jónmundsson GK, Abrahamsson J, Hasle H. Early and treatment-related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984-2003. Br J Haematol 2010;151:147-159.

• Abrahamsson J, Forestier E, Heldrup J, Jahnukainen K, Jónsson OG, Lausen B, Palle J, Zeller B, Hasle H. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol 2011;29:310-315.

• Molgaard-Hansen L, Glosli H, Jahnukainen K, Jarfelt M, Jónmundsson GK, Malmros-Svennilson J, Nysom K, Hasle H. Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: A NOPHO-AML study. Pediatr Blood Cancer 2010. Epub Dec 22.

• Molgaard-Hansen L, Möttönen M, Glosli H, Jónmundsson GK, Abrahamsson J, Hasle H. Treatment-related deaths in second complete remission in childhood acute myeloid leukaemia. Br J Haematol 2011;152:623-630.

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IV:5 MYELODYSPLASTIC SYNDROME (MDS) AND JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) Working Group

NOPHO coordinator

Henrik Hasle, Aarhus hasle@dadlnet.dk National coordinators Dominik Turkiewicz , Lund dominik.turkiewicz@skane.se Jochen Büchner, Tromsø jochen.buechner@unn.no Kirsi Jahnukainen, Helsinki kirsi.jahnukainen@ki.se In collaboration with the NOPHO AML group Nordic member of the morphology board Gitte Kerndrup, Vejle gitte.kerndrup@slb.regionsyddanmark.dk

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The NOPHO web includes a checklist for diagnosing, registration, and treatment of MDS and JMML. The checklist is linked to all relevant protocols, invoices and registration forms.

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Therapy

AML-like intensive therapy in JMML and MDS is associated with a lower remission rate, a higher risk of cytopenia related death, and a higher relapse rate than in AML. Hematopoietic stem cell transplantation (HSCT) is the only therapy with a realistic potential of cure. Conditioning with Busulfan, Cyclophosphamide, and Melphalan has shown favorable event-free survival in both MDS and JMML (Locatelli et al. Blood 2005; 105:410-419).

The main problem following HSCT in MDS is toxicity, whereas the major problem following HSCT in JMML is relapse. Intensive chemotherapy before HSCT is not recommended. Early SCT is the treatment of choice for all patients with JMML and MDS, excluding the JMML-like picture in an infant with Noonan syndrome, JMML with CBL mutation, or the stable RC without adverse cytogenetics. Patients with hypoplastic RC may be candidates for immunosuppressive therapy. EWOG-MDS 2006 The protocol, EWOG-MDS 2006 includes guidelines on diagnostics and treatment but is only a registration study.

A supplemental research protocol studies TCR in refractory cytopenia and gives guidelines on immunosuppressive therapy of hypoplastic RC.

A separate SCT protocols for RC using non-myeloablative conditioning in hypoplastic RC is available as well as guidelines for SCT in RAEB and JMML. Formal SCT protocols for advanced MDS, and JMML are under preparation.

The final protocols and forms are available at www.nopho.org and www.ewog-mds.org.

Morphology review

Gitte Kerndrup has reviewed smears and biopsy material from more than 500 patients with a suspicion of MDS or JMML since 1995. Samples from 30-40 patients are each year sent for review to Gitte Kerndrup. MDS or JMML is

confirmed in a 10-15 patients each year.

When you suspect MDS or JMML

When MDS or JMML is suspected in a child from the Nordic countries blood and bone marrow smears and preferentially biopsy material should be sent to Gitte Kerndrup, Laboratory Center, Dept Clinical Genetics, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark, Phone: 45 7940 6953 or +45 7940 6871, Fax: +45 7940 6953,

E-mail: gitte.kerndrup@slb.regionsyddanmark.dk

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For patients with suspected JMML it is also recommended to send heparinized blood and preferentially bone marrow for molecular testing to Charlotte Niemeyer, University Children’s Hospital, Mathildenstr. 1, D-79106 Freiburg, Germany.

Phone: +49-761-270-4506, Fax: +49-761-270-4518,

E-mail: charlotte.niemeyer@uniklinik-freiburg.de or ewog-mds@uniklinik-freiburg.de

The cells will be examined for mutations in N-RAS, K-RAS, and PTPN11. In selected cases in vitro culture will be performed.

When a diagnosis of MDS or JMML has been confirmed, the completed registration forms should be sent to Henrik Hasle, Department of Pediatrics, Skejby Hospital, 8200 Aarhus N, Denmark, Phone: +45 8949 6716, Fax: +45 8949 6023, e-mail: hasle@dadlnet.dk Invoice forms and registration forms are available from Henrik Hasle and at www.nopho.org For questions or problems please contact your National MDS coordinator or Henrik Hasle. Phone: +45 8949 6716, fax: +45 8949 6023, e-mail: hasle@dadlnet.dk Recent EWOG-MDS based publications

Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 2009; 114: 1859-1863.

Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, Flotho C. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia (JMML) and neurofibromatosis type 1. Haematologica 2010; 95: 320-323.

Flotho C, Batz C, Hasle H, Bergstrasser E, van den Heuvel-Eibrink MM, Zecca M, Niemeyer CM, Zenker M. Mutational analysis of SHOC2, a novel gene for Noonan-like syndrome, in JMML. Blood 2010; 115: 913.

Batz C, Hasle H, Bergstrasser E, van den Heuvel-Eibrink MM, Zecca M, Niemeyer CM, Flotho C. Does SPRED1 contribute to leukemogenesis in juvenile myelomonocytic leukemia (JMML)? Blood 2010; 115: 2557-2558.

Bresolin S, Zecca M, Flotho C, Trentin L, Zangrando A, Sainati L, Stary J, de Moerloose B, Hasle H, Niemeyer CM, te Kronnie G, Locatelli F, Basso G: Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. Journal of Clinical Oncology 2010; 28:1919-1927

Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S,

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Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics 2010; 42: 794-800.

Göhring G, Michalova K, Beverloo HB, Betts D, Harbott J, Haas OA, Kerndrup G, Sainati L, Bergstraesser E, Hasle H, Stary J, Trebo M, van den Heuvel-Eibrink MM, Zecca M, van Wering ER, Fischer A, Noellke P, Strahm B, Locatelli F, Niemeyer CM, Schlegelberger B. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 2010; 116: 3766-9.

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IV:6 Infant Leukemia Working Group Coordinator: Birgitte Lausen (DK) Denmark: Birgitte Lausen Finland: Kirsi Jahnukainen Iceland: Halldóra Kristín Þórarinsdóttir Norway: Bem Zeller Sweden: Stefan Söderhäll Erik Forestier (cytogenetics) Mats Heyman (data center) Jesper Heldrup (immunophenotyping) The main activity of the NOPHO Infant Leukemia group is to take care of the international Interfant studies. The group had two meetings during 2010. No meeting was held in the international Interfant group during 2010. During the last years the working group has implemented the protocol amendments from 2009 (protocol version 13) concerning new guidelines for MRD and SCT including a checklist for infant ALL presented on the NOPHO website.

Interfant-99 protocol was closed by the end of 2005. All 38 NOPHO infants with ALL in the Nordic countries participated in the study. Annual reports from the study centre are placed on the NOPHO website. The first report on the study was published in The Lancet 2007 (Pieters et al., see below). NOPHO has actively contributed to the MTX pharmacokinetic study in infants, and this study was published in May 2009. (Lönnerholm et al., see below). A study of 30 cases of congenital leukaemia from Interfant-99 showing a two-year survival of 20% and that toxicity is not different from that seen in older infants, justifies the administering of a full treatment regime to all patients with congenital ALL (van der Linden et al., see below). A study of stem cell transplantation in patients on the Interfant-99 protocol was published in June 2010 (Mann et al., see below) Interfant-06, the current protocol, opened in 2006. The chair of the study continues to be Rob Pieters, Rotterdam. The annual report from the international study group from 2010 is not ready yet, but will be placed on the NOPHO website later.

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Status of Interfant-06 and Infant ALL in NOPHO: The protocol is approved in Finland in 2006 and in Denmark from 2011, whereas the legalisation process is still going on in Sweden and Norway. For that reason only Danish and Finnish patients can be randomised to standard Interfant therapy or experimental AML-like therapy. A total of 50 patients are treated according to the Interfant-06 protocol, the main part not randomised and thus following the standard arm (December 31st 2010). An increasing number of infants with ALL have been diagnosed in the last years; 4 in 2006, 7 in 2007, 13 in 2008, 10 in 2009 and 15 in 2010. Almost all patients treated according to Interfant-06 in Denmark, Finland and Sweden are now registered in the Monza-database, irrespective of protocol status. Survival: EFS is 0.41 for 48 patients treated according to Interfant-06 in the Nordic countries – and OS is 0.62 (December 31st 2010). Ongoing studies: The study of pharmacokinetics of asparaginase and antibody formation in Interfant-06 is recruiting patients in Denmark and Finland after approval by the national data registration authorities. Publications on Infant ALL-studies, where NOPHO is involved:

• Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, Hovi L, LeBlanc T, Szczepanski T, Ferster A, Janka G, Rubnitz J, Silverman L, Stary J, Campbell M, Li CK, Mann G, Suppiah R, Biondi A, Vora A, Valsecchi MG. Lancet 2007; 370: 240-250. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.

• Lönnerholm G, Valsecchi MG, De Lorenzo P, Schrappe M, Hovi L, Campbell M, Mann G,

Janka-Schaub G, Li CK, Stary J, Hann I, Pieters R; Interfant-99 study group. Pediatr Blood Cancer. 2009 May; 52(5): 596-601. Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia.

• Van der Linden M, Valsecchi MG, De Lorenzo P, Möricke A, Janka G, Leblanc TM, Felice M,

Biondi A, Campbell M, Hann I, Rubnitz JE, Stary J, Szczepanski T, Vora A, Ferster A, Hovi L, Silverman LB and Pieters R. Blood 2009; 114: 3764-3768. Outcome of congenital acute lymphoblastic leukaemia treated on the Interfant-99 protocol.

• Mann G, Attarbaschi A, Peters C, Schrappe M, Lorenzo P De, Hann I, Rossi G De, Felice M, Lausen

B, LeBlanc T, Szczepanski T, Ferster A, Janka-Schaub G, Rubnitz J, Silverman L B, Stary J, Campbell M, Li C K, Suppiah R, Biondi A, Vora A, Valsecchi MG and Pieters R on behalf of the Interfant-99 Study Group. Blood 2010; 116 (15): 2644-2650

Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia - Results from the Interfant-99 Study.

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IV:7 Pharmacology Working Group

Working group members: E-mail addresses

Norway

Anna Grete Bechensteen a.g.bechensteen@medisin.uio.no

Ellen Nordal ellen.berit.nordal@unn.no

Sweden

Staffan Eksborg staffan.eksborg@karolinska.se

Jesper Heldrup jesper.heldrup@skane.se

Gudmar Lönnerholm (in vitro studies)

Finland

Arja Harila-Saari (chair) arja.harila-saari@oulu.fi

Jukka Kanerva jukka.kanerva@fimnet.fi

Iceland

Olafur Gisli Jonsson olafurgi@landspitali.is

Denmark

Birgitte Klug-Albertsen biralber@rm.dk

Kjeld Schmiegelow kjeld.schmiegelow@rh.hosp.dk

Henrik Schröder henrschr@rm.dk

Young NOPHO representative

Ines Ackerl-Kristensen ines@dadlnet.dk

Adriani Kennelopoulos adriani@getmail.no

Previous maintenance group representatives

Jon Kristinsson jonkr@landspitali.is

Birgitte Lausen lausen@dadlnet.dk

Stefan Söderhäll stefan.soderhall@karolinska.se

Finn Wesenberg finn.wesenberg@rikshospitalet.no

Kim Vettenranta kim.vettenranta@tays.fi

The NOPHO Pharmacology group has met twice within the last year (minutes at www.nopho.org) (September 24nd 2010 in Stockholm and February 4th 2011 in Helsinki). During the past year the group has continued working on the ongoing pharmacological studies, many of which are related to NOPHO ALL2008 protocol, and actively participated on the preparative work for the ALL2014 protocol by establishing ad hoc subgroups for the main drugs used in the treatment of ALL.

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Group composition

Emma Honkaniemi started in the group in September 2010, but stepped down in February 2011. Swedish group is asked elect a new country representative for the group.

Ongoing studies

Clinical significance of variations in drug disposition – Impact on efficacy and toxicity in malignant hematological cancers (chair Kjeld Schmiegelow)

The study will include several sub studies, which explore pharmacogenetic, -kinetic, and –dynamic data in children and adults with leukaemia and lymphoma. Data on pharmacogenetics and -kinetics will be linked to the clinical data of the patients to obtain a comprehensive insight into the interaction between pharmacological data and clinical outcome. The main study plan has been approved in the Nordic countries, and first sub studies are ongoing.

• DNA-6TGN analyses and maintenance and related sub studies Better monitoring methods of maintenance therapy are needed. In NOPHO ALL2008 samples are collected throughout maintenance treatment for monitoring 6MP/MTX metabolites. Levels of Ery-6TGN, Ery-MeMP, E-MTXpg, DNA-6TGN will be analysed in relation to the TPMT (geno- and phenotype), pharmacogenetic profiling, toxicity and outcome.

TPMT and outcome (chair Kjeld Schmiegelow)

The influence of TPMT status on outcome will be studied in NOPHO ALL2000 patients. TPMT genotype and phenotype data collection is under finalization.

In vitro sensitivity studies (Chair Gudmar Lönnerholm)

In vitro drug resistance studies have continued in Uppsala. New samples are requested only from ALL and AML patients with a relapse, Down syndrome or patients with WBC > 100 at diagnosis. Ongoing studies include Down syndrome patient’s resistance to glucocorticosteroids, in- vitro resistance in pre-B vs. T-cells, changes in in-vitro resistance in relapsed patients, correlation of in-vitro sensitivity with MRD in different leukemia subgroups, and correlation with SNP study to analyze the difference between the leukemic and constitutional cells. Recent publication: Lönnerholm G, Thörn I, Sundström C, Frost BM, Flaegstad T, Heyman M, Jonsson OG, Harila-Saari A, Madsen HO, Porwit A, Schmiegelow K, Söderhäll S, Wesenberg F, Vettenranta K, Larsson R, Forestier E. In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia. Leuk Res. 2011 Apr;35(4):472-8.

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Asparaginase studies (Chair Birgitte Klug-Albertsen)

• Studies in ALL2008 protocol

Randomised study comparing efficacy of continuous vs. intermittent administration of PEG-Asparaginase is ongoing in the NOPHO ALL2008 protocol. Presence of allergic reactions, IgE- and IgG class antibodies, enzyme activity, levels of amino acids and the frequency of other side effects than allergy will be studied in a subset of patients. Danish patients have been recruited since 2009 and patients from Gothenburg, Helsinki and Trondheim are starting to be recruited. Asparagine depletion in the CSF after injection of PEG-Asparaginase will be studied in Danish patients. Detailed study on frequency of thrombosis and influence of asparaginase on hemostasis in the two PEG-asparaginase treatment arms is ongoing in Århus.

• Infant asparaginase study Asparaginase pharmacokinetics will be studied in Nordic infants treated with Interfant-2006 protocol. Samples of 8 first patients have been collected from Denmark and Finland, where the study has been approved. Samples are wished from all new Interfant-2006 patients. Instructions for sampling can be found at NOPHO web.

High dose methotrexate (HDM) • Pharmacokinetic data on HDM courses in ALL2000 (Chair Jesper Heldrup)

Pharmacokinetic data on HDM courses in NOPHO ALL2000 protocol has been collected in the NOPHO HDM database. Influence of HDM pharmacokinetics on outcome will be analysed, as well as correlation between pharmacokinetics and patient characteristics.

• Carboxypeptidase G2 study (Chair Jesper Heldrup) Carboxypeptidase (Glucarpidase), which rapidly hydrolyses MTX to non-toxic metabolites can be used in patients with clearly delayed MTX elimination in order to avoid excessive doses of folinic acid and toxicity. The drug has been used in 16 ALL2008 patients. Instructions for the use are placed in the NOPHO web. If the treatment is given according to ALL2008 criteria and the treatment report is filled, the drug may be reimbursed by pharmaceutical company representing Glucarpidase (Swedish Orphan).

Questionnaire for treating clinics at the end of ALL2008 treatment Data about some patient characteristics (e.g. weight, length and pubertal status), treatment (e.g. modifications) and some side effects (allergy, fractures and neuropathy) are collected by a survey at the end of ALL2008 treatment. The data will be combined with the data in the NOPHO leukemia registry and used in analysing several issues such as the effect of treatment on growth and BMI, and the influence of BMI on outcome and side effects. Pilot version of the survey is at use.

Ad hoc groups for NOPHO-ALL 2014 NOPHO Pharmacology working group coordinates the work on identifying toxicities, potential studies and involved genes related to the pharmaceutical agents used in the treatment of ALL, which include

• Corticosteroids • Vincristine

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• Maintenance therapy • Anthracyclines • Asparaginase • Methotrexate • New drugs • Cytarabine • Cyclophosphamide

Future work of the group During the coming year a lot of effort will be put in the ad hoc group work in order to create new pharmacological study projects on the mentioned pharmaceuticals in ALL patients, and continuing and finalizing the ongoing pharmacological studies. Next meeting of the group Next meeting will be held in Copenhagen on Wednesday the 21th of September 2011 at 10.00 – 16.00.

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IV:8 SCT Working Group Coordinator: Carsten Heilmann (DK) from 1st of March 2011 (before Ulla Pihkala (FIN)). Denmark: Carsten Heilmann carsten.heilmann@dadlnet.dk Marianne Ifversen Ifversen@dadlnet.dk Finland: Ulla Pihkala ula.pihkala@hus.fi Päivi Lähteenmäki paivi.maria.lahteenmaki@tyks.fi Norway: Anders Glomstein anders.glomstein@rikshospitalet.no Finn Wesenberg finn.wesenberg@rikshospitalet.no Sweden: Jacek Winiarski jacek.winiarski@ki.se Karin Mellgren karin.mellgren@vgregion.se Jacek Toporski jacek.toporski@med.lu.se Johan Arvidson johan.arvidson@kbh.uu.se Young NOPHO Sweden: Kees-Jan Pronk kees-jan.pronk@med.lu.se

Michael Sundin mikael.sundin@ki.se SCT working group membership The principles for membership of the SCT group have been discussed again this year. The rules are as before that each transplant centre has one member. If a country has only one SCT centre, this centre may have two members. The coordinator is an additional member. Furthermore, young NOPHO appoints two members for the SCT group. It has been discussed if the SCT group should have further members e.g. a representative from LLC. This issue will be discussed further in coming meetings. As before the meetings are open and observers from the Baltic countries are encouraged. Nordic allo SCT registry The SCT group has agreed to establish a SCT registry based on the EBMT Med-A forms. Since all centers are registering to EBMT at least with Med-A this new NOPHO registry should course no major problems for the SCT centers. The data will be collected by Mats Heyman directly from the EBMT registry. The collecting of data from the EBMT registry must be accepted by each centre, which has not yet been accomplished. The rules for the NOPHO SCT registry has been agreed upon both by the SCT group and the NOPHO board however, unfortunately these rules have not been written into the minutes of a NOPHO board meeting. The registry will be discussed again at the coming NOPHO board meeting and when the rules appear in the minutes it seems all centers can accept to participate.

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The rules for the scientific work based on the coming SCT registry is, that projects as usual must be accepted by the NOPHO scientific committee and the NOPHO board, but also by the NOPHO SCT group and by the principal investigator from each participating SCT centre. Ongoing studies The ALL SCT study is progressing according to plans. Preliminary results from the study will be presented at the NOPHO meeting 2011. The AML SCT study also progress according to plans all though data from the individual SCT centers are still lacking. Preliminary results from the AML study will be presented at the annual meeting 2011. Coming SCT meetings The SCT group will probably meet this autumn primarily in order to discuss the role of SCT in the upcoming NOPHO ALL 2014 protocol. Furthermore we are going to discuss the possible benefits of harmonizing SCT procedures within the Nordic countries. It seems possible that Nordic patients within major diagnostic groups such as ALL, AML, MDS and SAA could benefit from up-to-date harmonized transplant regiments.

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IV:9 ALL Relapse Working Group

Stefan Söderhäll Johan Arvidson Birgitte Lausen Thomas Frandsen Päivi Lähteenmäki Ulla Pihkala Jon Kristinsson Marit Hellebostad Ann Åsberg/Dojota Wojcik Mats Heyman Kim Vettenranta

Coordinator Registration Affilated to the SCT group

Sweden Sweden Denmark Denmark Finland Finland Iceland Norway Norway (Change during 2010) Sweden Finland

The group has since latest NOPHO meeting had two meetings, in September 2010 and January 2011. The

main issues have been related to the IntReALL 2010 protocol. There has been a full consensus to

recommend the national boards that NOPHO should join the planned standard risk relapse protocol which

is based on a randomization between the UKALL R3 mitoxantrone arm and the BFM REZ 2002 protocol

ida II arm. These arms have in the UKALL and BFM studies proven to give the best outcome and without

significant differences between these arms. The SR protocol also includes a second randomisation

between the standard consolidation with or without epratuzumab in each arm . Patients with mrd levels

above the respective cut off levels after inductions are stratified to SCT which I scheduled to after about 4

months of total therapy. The SR groups represents the BFM S1 and S2 group

It has also been a full consensus to recommend that NOPHO should not join the high risk protocol. The

reasons for this are limited evidence of efficacy, absence of randomisation and that the experimental drug

should not be provided by the company although there is no label for this indication. Instead a HR

protocol with the same induction as the SR group has been proposed by the group. In this proposal only

the strictly defined non-responders post induction should be subject o the experimental therapy either as

given in the proposed protocol HR arm or to other early phase studies. At present a alternative with

traditional induction +/- bortezomib is discussed in parallel

The cooperative European relapse group has applied for a EU FP7 grant to perform the IntReALL 2010

study. The NOPHO countries has nation-wise joined this application. During Eastern we were reached by

a positive response and the process to organise this will thus continue immediately.

The earlier analysis of the relapses in the NOPHO ALL 92 and 2000 protocols has been updated and

completed now when the data has matured. Some interesting differences for subgroups of the SI and II

therapy groups have been observed and will be presented at the NOPHO meeting.

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IV:10 NOPHO Events Group (EVG) Members Coordinator Jukka Kanerva (FI) jukka.kanerva@hus.fi jukka.kanerva@fimnet.fi Denmark Kjeld Schmiegelow kschmiegelow@rh.dk Henrik Hasle hasle@dadlnet.dk Finland Arja Harila-Saari arja.harila-saari@oulu.fi arja.harila-saari@ppshp.fi Jukka Kanerva jukka.kanerva@hus.fi jukka.kanerva@fimnet.fi Norway Ann Åsberg ann.asberg@ntnu.no Finn Wesenberg finn.wesenberg@rikshospitalet.no Sweden Stefan Söderhäll stefan.soderhall@karolinska.se Ulrika Norén-Nyström ulrika.norennystrom@pediatri.umu.se Lithuania Goda Vaitkeviciene goda.vaitkeviciene@vuvl.lt Associate member/NOPHO Registry Mats Heyman mats.heyman@ki.se Young NOPHO Bendik Lund, Norway bendik.lund@stolav.no Mette Møller Handrup, Denmark mette.handrup@gmail.com NOPHO projects Birgitte Klug Albertsen (Asparaginase) biralber@rm.dk Thomas Frandsen (SAE reporting 2010) thomas.leth.frandsen@rh.regionh.dk Mette Levinsen (PCP study) mette.frandsen.levinsen@rh.regionh.dk

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Since last annual report the NOPHO Events group has met twice. The main focus of our work has been the adverse effect monitoring of NOPHO-ALL 2008 protocol, especially toxic deaths and fungal infections. The group functions as a reference group regarding registration of patients in the current and future NOPHO protocols. The main issues discussed during the last year: SAEs in NOPHO-ALL 2008 The monitoring has continued to work well with almost 100% coverage. Pancreatitis, vincristine related toxicity and thrombosis have been so common that detailed exploration of these SAEs is warranted and has been started by focus groups. Two new SAEs were added in the registration in August 2010: fungal infections and Pneumocystis infections. Toxic deaths continue to be a major problem especially in the HR arm. At the ALL2008 and ALL meetings in Helsinki it was decided to add the ALL2008 toxic deaths to the SNP-profiling of deaths in the ALL92 and ALL2000 protocols. Toxic deaths Two of 372 patients (0.5%) on prednisolone induction have had induction failure versus 4 of 110 patients (3.6%, p=0.01) on dexamethasone. In total, 16 patients have died in remission: 1% in SR, 2.6% in IR, and 10.9% on the HR blocks (patients were censored at the time of SCT). 7 of 8 patients who died on the HR-blocks were males and all but one (30 years) were in the age rage 8.5-18.5 years, giving these patients a cumulative risk of toxic death of 31% compared to 3.4% for the other HR patients. This association between risk of death in remission with age is being further explored. In total 9 Nordic and Baltic patients have died after block therapy; none after block A, 5 after block B, 4 after block C. Possible amendments to block B are being analyzed. Fungal infections Before the prospective registration of fungal infections started, the HR arm was analyzed and 9 fungal infections among 76 HR patients (3 deaths) were identified. The group will in collaboration with the Supportive care group write guidelines for antifungal prophylaxis and treatment. We will use international guidelines, recommendations in other pediatric ALL protocols and the detailed analysis of fungal infections in the ALL 2008 protocol as the basis of our guidelines. PCP prophylaxis There has been only one (1) death from PCP in NOPHO ALL patients since 1992. In the analysis of the ALL 1992 protocol, the prophylaxis prevented infections effectively: 10/232 infections without prophylaxis, 0/147 infections with prophylaxis. Two patients had PCP during the late maintenance phase. Prophylaxis had no effect on EFS, although it leads to lower doses of 6-MP and MTX during maintenance.

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Ad hoc groups for NOPHO-ALL 2014 The ALL, Pharmacology and Events groups coordinate the group work for defining relevant toxicities and probably involved genes to be explored. The groups in the field of the Events group include

• Infections: immunosuppression, toxicity, mucositis (GI-tox), antibiotic/antifungal prophylaxis and treatment, use of growth factors and IFN

• Encephalopathy • Pancreatitis (to be explored by a questionnaire from January 2012) • Nephrotoxicity • Hepatotoxicity • Infertility and growth • Thromboses: prothrombotic states, CV catheters, asparaginase and other drugs (a survey is

ongoing) Retrospective immunogenetic SNP study (Bendik Lund) The study of patients with infection related deaths on ALL 92 and 2000 is running, and toxic deaths in ALL 2008 will be included. The SNPs identified will be incorporated in the ALL 2014 work. Future work of the group The function as a reference group for problematic patients will continue. Monitoring and analyzing of life threatening adverse events and AE:s not directly associated with chemotherapy (e.g. infections) are tasks for the EVG. Annual evaluation of SAE:s will be performed to find out which SAE:s should be studied in detail. Fungal infections and TRM continue to be the major focus issues. Publications

• Lund B, Åsberg A, Heyman M, Kanerva J, Harila-Saari A, Hasle H, Söderhäll S, Jonsson OG, Lydersen S, Schmiegelow K. On behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO). Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Ped Blood Cancer 2011; 56: 551-9.

• Interactions between PCP-prophylaxis and MTX/6MP maintenance therapy; in preparation (First author Mette Levinsen).

Next meeting Sept 22, 2011 Copenhagen Airport Hilton at 10-16.

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IV:11 Morphology working group

Coordinator Jon Helgestad (DK) jon.helgestad@rn.dk Denmark Jon Helgestad Bodil Laub Petersen Finland Jukka Kanerva Iceland Olafur Gisli Jonsson Norway Sweden Erik Forestier As the NOPHO-ALL 2008 protocol is a therapy response stratification protocol, we are glad that the conclusions of our previous work (1,2) have been taken into account in the protocol (sections 12.1.9, 12.2, 13.3.1). Highlights of bone marrow (BM) sampling for response evaluation: 1). Bone marrow sample for response evaluation is performed by an experienced or trained physician in bone marrow sampling, who knows that both the aspirated volume and the order of aspiration is of outmost importance for the highest quality of BM sample for evaluation. 2). The order of sampling is crucial: a) aspirate to BM film for morphology 0.3 ml. b) aspirate to flow cytometry 2 ml. c) aspirate to cytogenetics/molecular cytogenetics, and PCR for clonal immune gene rearrangement. If more material is needed for response evaluation, a new puncture in the bone is recommended for aspiration of maximum 2.5 ml. for every single sample to response evaluation. Aspirates of more than 2 ml. contain mostly peripheral blood and will not contribute to therapy response evaluation (3). 3). Morphology alone is insufficient and should be supplemented with flow cytometry, PCR or FISH as needed. 1. Petersen BL, Kanerva j, Helgestad J. Morphologic response evaluatopn in ALL. Lecture, NOPHO 25th Annual Meeting, Reykjavik 2007

2.Manuscript in preparation 3.Helgestad J, Rosthøj S, Johansen P, Varming K and Østergaard E. Bone marrow aspiration technique may have an impact on therapy stratification in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2011, febr. Epub ahead of print

The group has not been gathered during the last year.

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V NOPHO – Other Disease Groups

V:1 ITP Working Group

Coordinator Steen Rosthøj (DK) steen.rosthoej@rn.dk Denmark Steen Rosthøj Birgitte Lausen birgitte.lausen@rh.regionh.dk Finland Jukka Rajantie jukka.rajantie@hus.fi Riitta Kekomäki Iceland Olafur G. Jonsson olafurgi@landspitali.is Norway Bem Zeller bem.zeller@rikshospitalet.no Finn Wesenberg finn.wesenberg@rikshospitalet.no Sweden Iris Treutiger iris.hedlund-reutiger@sodersjukhuset.se Ulf Tedgård ulf.tedgard@med.lu.se Göran Elinder goran.elinder@ki.se Jan-Inge Henter Jan-Inge.Henter@ki.se Young NOPHO Mimi Kjærsgaard (DK) mimikjaersgaard@dadlnet.dk Nadine Gretenkort (SE) nadine.gretenkort@skane.se

In 2007, an International Working Group of recognized experts met at a conference and agreed upon a

standardization of terminology, definitions and outcome criteria for immune thrombocytopenic purpura.

The new terminology, including concepts for use in clinical trials, was published in 2009 [1]. The

recommendations include the following:

• The acronym ITP is preserved, meaning now immune thrombocytopenia. A platelet count less than

100 x 109/L is established as a threshold for diagnosis. ITP may be primary (idiopathic) or secondary

(due to an underlying disease).

• Based on the duration of thrombocytopenia from the time of diagnosis ITP is classified as newly

diagnosed (0-3 months), persistent (3-12 months), or chronic (more than 12 months).

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• Severe thrombocytopenia is defined as occurrence of clinically relevant bleeding sufficient to

mandate treatment or to require additional therapeutic intervention.

• The major goal for treatment is to provide a safe platelet count >30 x 109/L preventing major

bleeding.

• Response to treatment is assessed as Complete Remission (CR, platelet count >100 x 109/L and no

bleeding), Response (R, platelet count 30-100 x 109/L and at least doubling of the baseline count),

and No Response (NR, failure to double baseline count or to rise above 30 x 109/L).

The wide acceptance of these recommendations means that the results of the NOPHO study of childhood

ITP, reported using old terminology, in some sense are outdated and that they cannot be used as

comparison for future studies. The Working Group finds this to be unfortunate, and also notes that some

of the recommendations are not supported by Nordic experience. An upcoming publication on the

duration and morbidity of chronic ITP makes this evident [2].

• The new definition of chronic ITP lasting >12 months was based on a report from ICIS showing that

a large fraction - 25% - of children with ITP lasting 6 months recovered in the next 6 months. In the

Nordic cohort only 15% recovered in this period, and the recovery rate in the next two 6-month

periods was similar. Thus, looking at Nordic data the new definition does not seem warranted.

• The definition of persistent ITP lasting more than three months, on the other hand, happens to be in

good agreement with the clinical score derived to predict ITP with duration less than three months,

with very low morbidity [3].

• Severe thrombocytopenia is defined as bleeding eliciting treatment. Since the treatment threshold is

highly variable at different centers [4] this definition is neither sharp nor objective and possibly may

be useless.

• In the Nordic follow-up study we distinguished between severe (<20 x 109/L), moderate (20-50 x

109/L) and mild thrombocytopenia (50-150 x 109/L). The results confirm that this distinction is

clinically appropriate: the were no serious grade 4 or 5 hemorrhages while thrombocytopenia was

moderate, and no spontaneous bleeding episodes while it was mild. We suggest that counts >20 x

109/L may be considered safe, noting also that ICH in children is exceedingly rare with such counts

(only one case has been reported). And we think that a rise above 50 x 109/L still constitutes a partial

reponse, i.e. clinical remission without laboratory remission.

• Accordingly, response to treatment could appropriately be defined as a rise in count above 20 x 109/L.

Whether the baseline count is doubled or not seems clinically irrelevant since clinical problems are

determined by the absolute count.

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These points of disagreement will need to be discussed further in meetings between the different

international pediatric ITP study groups.

1. Rodeghiero et al: Standardization of terminology, definitions and outcome criteria in immune

thrombocytopenic purpura of adults and children. Blood 2009;113:2386-93.

2. Rosthøj et al. Duration and morbidity of chronic immune thrombocytopenic purpura in children:

ITP: Five-year follow-up of a Nordic cohort. (Submitted).

3. Edslev et al. A clinical score predicting a brief and uneventful course of newly diagnosed

idiopathic thrombocytopenic purpura in children. Br J Haematol 2007;138:513-16.

4. Treutiger et al: Initial management of children with newly diagnosed idiopathic

thrombocytopenic purpura in the Nordic countries. Acta Pædiatr 2006;95:726-31.

New publications 2010

None

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V:2 Histiocytosis Working Group

Coordinator

Jan-Inge Henter (SE)

Denmark

Karsten Nysom

Finland

Satu Lehtinen Mervi Taskinen

Iceland

Jon Kristinsson

Norway

Marit Hellebostad Finn Wesenberg

Sweden

Åke Jakobson Jan-Inge Henter

LANGERHANS CELL HISTIOCYTOSIS (LCH): LCH-III: In April 2001 the Histiocyte Society opened LCH-III, co-ordinated in Vienna by Prof Helmut Gadner, with a Nordic subcenter co-ordinated in Stockholm by Prof Jan-Inge Henter. NOTE: As of January 30, 2008, LCH-III was closed for new randomizations. LCH-IV will be opened in 2011. It will be based on the same drugs as LCH-III, and distributed to all national coordinators once available. Until LCH-IV is opened, it is recommended that: 1) Group 1: RISK patients are treated according to the risk protocol, Arm A (the standard arm without

methotrexate) and registered. 2) Group 2: LOW RISK patients receive treatment arm LR12, with 12 months treatment duration, and are

registered. 3) Group 3: Multifocal bone / special site patients are registered and treated as scheduled. 4) All patients registered prior to January 30, 2008, continue as per the LCH-III protocol with follow-ups

and treatment. SUMMARY OF LCH-III Eligibility: All newly diagnosed patients who meet the following criteria are eligible • Definitive diagnosis of LCH • Age under 18 years • No prior treatment for LCH

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Risk patients: Involvement of the hematopoietic system, the liver, the lungs or the spleen: • The treatment is prolonged to 12 months. • A second initial treatment (wk 7 – 12) is provided if intermediate response at 6 weeks. • A randomized study upfront, with one arm in the risk protocol including methotrexate, whereas the

other arm is without methotrexate. Note that the randomization is currently closed.

Low risk patients: • PDN and VBL, the treatment duration is randomized between 6 and 12 months. Randomization is

performed soon after the first 6 weeks of therapy. Note that the randomization is currently closed. Multifocal Bone Disease: • PRD and VBL for 6 months. Special sites: Single bone lesions with involvement of the facial bones or anterior or middle cranial fossa (temporal, sphenoidal, ethmoidal, cygomatic bone, orbital bones) with intracranial tumor extension, OR soft tissue masses that may lead to spinal cord compression • PRD and VBL for 6 months. LCH-Salvage-2005: This is a highly toxic regimen based on 2CdA and ARA-C. Because of the severe toxicity, all patients for whom salvage therapy is considered are suggested to be discussed with the Nordic LCH-study coordinator (Jan-Inge Henter). LCH-HSCT-2006: This regimen is based on a reduced intensity regimen (RIC), with Campath, Fludarabine and Melphalan. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH): HLH-94: The Histiocyte Society protocol HLH-94 was based on the combination of chemotherapy and immunotherapy (VP-16, steroids and cyclosporin A), followed by HSCT. This protocol has been succeeded by the HLH-2004 protocol. HLH-2004: In January 2004 a new treatment protocol was opened (HLH-2004). There are only minor differences in comparison to the HLH-94 protocol. The study chairman is Professor Jan-Inge Henter in Stockholm. It is suggested to contact the Study Chairman (e-mail: jan-inge.henter@ki.se) prior to start of HLH-therapy for discussion of pre-treatment sampling that may be of diagnostic value.

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V:3 NOPHO late effects working group

Denmark: Catherine Rechnitzer rechnitzer@rh.dk rechnitzer@mail.dk Niels Clausen nc@dadlnet.dk Finland Mervi Taskinen mervi.taskinen@hus.fi Arja Harila-Saari arja.harila-saari@hus.fi Kirsi Jahnukainen kirsi.jahnukainen@ki.se Iceland Haldora Thorarinsdottir halldkth@landspitali.is Norway Inga Maria Johannsdottir i.m.johannsdottir@medisin.uio.no Sweden Johan Arvidson johan.arvidson@kbh.uu.se Cecilia Petersen cecilia.petersen@karolinska.se NOPHO solid Frøydis Langmark fl@kreftregisteret.no tumour registry NOPHO Mats Heyman mats.heyman@ki.se leukaemia registry Young NOPHO Adriani Kanellopoulos adriani.kanellopoulos@medisin.uio.no

Persons on the mailing list Randi Nygaard randi.nygaard@medisin.ntnu.no Lars Hjorth lars.hjorth@skane.se Astrid Sehested astrid.sehested@rh.regionh.dk Birgitta Lannering birgitta.lannering@vgregion.se Hanne Hamre hannehamre@yahoo.no Heidi Glosli heidi.glosli@rikshospitalet.no Henrik Hasle hasle@dadlnet.dk Johan Malmros johan.malmros@ki.se Lene-Moelgaard Hansen lene_moelgaard@hotmail.com Liv Hege Aksnes liv.hege.aksnes@radiumhospitalet.no Marianne Jarfelt marianne.jarfelt@vgregion.se Susanne Vinkel Koch koch@cancer.dk

Halldóra Kristín halldkth@landspitali.is Birgitte Klug Albertsen biralber@rm.dk Einar Stensvold einar.stensvold@ahus.no Eva Widing eva.widing@ulleval.no Karsten Nysom nysom@dadlnet.dk

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Meetings Group has had two meetings during the last year. One was in connection with the 3rd meeting of the Nordic Network for Gonadal Preservation after Cancer treatment of Children and Young Adults, Copenhagen 11 Nov 2010 and one organized in Astrid Lindgren Children’s hospital February 2010. Minutes can be found on NOPHO webb.

Specific activities 1) Late effect follow-up in the NOPHO ALL 2008 protocol:

The group has discussed and finalized the follow-up guidelines for ALL 2008 protocol based on the Swedish SALUB follow-up recommendations. The final recommendations have been sent to Leukemia Lymphoma committee to be approved in the Turku meeting for further implementation to the protocol. Two questionnaires that are part of quality control of ALL 2008 protocol have been presented to the late effect working group by Arja Harila-Saari.

2) Registration of parameters from end of therapy document into the Nordic databases: Status information

a) Status in Sweden (Cecilia)

Data is presently collected to national Swedish childhood cancer database which is located beside but separately from NOPHO database. It is possible to register changes continuously. Actually received cumulative doses are included. It is possible to mark late effect follow up registrations at certain time points (e.g. yearly check-ups, 18 yr registration) and print out a paper document later. The patients will receive a print-out document which follows SALUB end of therapy document and contains SALUB follow up recommendations. The document to GP is available too.

b) Status in Denmark (Niels) Most of the data are available in CPH, some in Århus (on both status and treatment). The basis for electronic end of therapy document is in national cancer database. There is possibility to make additions at later follow-up-visits, e.g. patients at risk, findings, later changes and new status. Danish end of therapy document is planned.

c) Status in Norway (Adriani asked Bem Zeller): Centralized data collection contains only basic data for NOPHO / + BMT registry. No common national childhood cancer register. No written hand-outs.

d) Status in Finland (Kirsi): Centralized data collection contains only basic data for NOPHO / + BMT registry. No common national childhood cancer register. Hand written end of therapy documents are given to patients at transition to adult medicine. Many of the units use Finnish translation of SALUB document. This data exist as hard copies in patient histories and is not centralized.

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3) Ongoing late effect studies in Nordic countries

ALiCCS = Adult Life after Childhood Cancer in Scandinavia

The study has received 5 years funding from 2010. Investigators: Jørgen Olsen, Henrik Hasle, Lene Mølgaard, Jeanette Winther and Nordic Partners. In contrast to the Childhood Cancer Survivor Study (CCSS), registration is not based on self-reported late effects but on excellent National quality registries on side effects. Summary of ALiCCS data Nordic cohort, cancer dg < 20 yrs of age, diagnosis 1943-2008 (n=55.000)

- Morbidity-specific incidence and cause-specific mortality compared to general population sample (n=275.000)

- Registry linkages – population registry, medical birth registry, prescription registry, cause of death registry (and others)

- Nested case-control study: treatment-regimens – late outcome More information can be found at www.cancer.dk/aliccs.

Study plans of all ongoing Nordic late effect studies can be find on NOPHO Webb.

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V:4 Novel Therapies working group Coordinator Sanna-Maria Kivivuori (FI) sanna.kivivuori@iki.fi

Denmark

Birgitte Klug Albertsen Kjeld Schmiegelow

Finland

Sanna-Maria Kivivuori Ulla Pihkala Olli Lohi

Iceland

coming up

Norway

Anne Grete Bechensteen Trond Flægstad

Sweden

Stefan Holm Per Kogner Jacek Toporski

Young NOPHO member Susanna Ranta (FI) The main interests of the Novel therapies working group are experimental therapies and antiangiogenic/metronomic treatments. The Nopho-wide protocol from NoT working group is Angiocomb, Antiangiogenic therapy for pediatric patients with diffuse brain stem and thalamic tumors. ITCC issues have been considered to be a task for the NoT group too. NoT working group is an open forum for all the themes concerning novel therapies in the field. The NoT 2010 meeting was in Tromsoe on the 27th of May 2010. The themes in the Agenda were 1. how to make it easier to attend new protocols concerning their paper work and bureaucracy (different facilities and research nurse capacity in different countries). 2. Angiocomb update was presented by SMK. 27 patients recruited at that moment. Pilot study has been published. 3. Also new protocol suggestion about recurrent medulloblastoma therapy from Vienna was presented by SMK. It consists of thalidomide, celecoxib, cycling etoposide and cyclophosphamide, fenofibrate, and intraventricular therapy with alternating etoposide and liposomal cytarabine every 4 weeks. It was decided to wait until the protocol is ready. ITCC (Innovative therapies for children with cancer) issues have been discussed among our group. The purpose of ITCC is to develop novel therapies for pediatric malignancies through clinical and translational research connecting new drugs, biology and the unmet needs of children with cancer. It works closely with EMEA. A special focus has been set on ALL, neuroblastoma, medulloblastoma, and sarcomas. More info in www.itcc-consortium.org. Olli Lohi from Tampere, Finland joined our group as a new member and Finnish representative.

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Next NoT meeting will be in Turku on the 20th of May 2011. Publications Kivivuori SM, Riikonen P, Valanne L, Lönnqvist T, Saarinen-Pihkala UM. Antiangiogenic Combination Therapy after Local Radiotherapy with Topotecan Radiosensitizer: Improved Quality of Life for Children with Inoperable Brainstem Gliomas. Acta Paediatr 100:134-138, 2011.

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V:5 Thromboembolic Working Group Coordinator Jon Helgestad (DK) jon.helgestad@rn.dk Denmark Jon Helgestad Ruta Tuckuviene ruta.tuckuviene@rn.dk Finland Anne Mäkipernaa anne.makipeernaa@hus.fi Vacant Iceland Olafur G. Jonsson Norway Ellen Ruud ellen.ruud@rikshospitalet.no Ann Aasberg ann.aasberg@stolav.no Sweden Vacant Young NOPHO Vacant NOPHO thrombosis and haemostasis working group We kindly ask all of you to register all new symptomatic thromboembolic events in children with ALL in the NOPHO toxicity register every 3rd. month. We prospectively register different parameters in children with ALL and symptomatic thromboembolic events. You are welcome to watch the abstract or the poster from our group, in the yearbook or during the annual meeting on patients with symptomatic thromboembolic events registered up to now. Our goal is to detect risk factors or risk persons for either prophylaxis or adaptation of the ALL therapy. Recommendation for diagnosis and therapy of children with a thromboembolic event is placed on the home page. The group has met trice the last year, two times by a phone conference.

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V:6 NOPHO/NOBOS Working Group on Ethics

Coordinators Anders Castor, chair, national coordinator (SE) Britt-Marie Frost (SE)

Lisa Törnudd, secretary (SE) Denmark Birgitte Lausen

Astrid Sehestad Pernille Wendtland Edslev Finland Satu Lehtinen Kirsti Sirkia, national coordinator Iceland Solveig Hafsteinsdottir Norway Heidi Glosli Sweden Anders Castor

Britt-Marie Frost

NOBOS members Denmark Gitte Petersen Mette Norman Hansen, national coordinator Finland Oili Papinaho Iceland Sigrún Þóroddsdóttir Norway Anne B Thorvildsen, national coordinator Hilde Frøland Hauge Sweden Pernilla Pergert Angelica Höök

Background All relations between individuals involve ethical judgements, and is therefore of concern for all of us. Ethical considerations can be quite difficult in relations that are not equal, such as in health care (and in pediatrics in particular), and even more difficult and complex when the stakes are high in terms of risks and benefits, such as in life-and-death decisions. Medical ethics has gained momentum in terms of popular interest and research activities, and is reflected by an increasing demand of more ethical deliberations in the daily work. How this is to be achieved is still

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not clear, but developments are taking place in different institutions, and networking activities are increasing. As representatives of pediatric healthcare in general, and pediatric oncology in particular, we perceive a great need for developing ethical theories, methods and knowledge with a focus on children, who presents particular ethical challenges.

The working group The working group was established at the biannual joint NOPHO and NOBOS meeting in Linköping 2008, after official approval from both boards, and represents the first working group in the history of both societies that encompasses both doctors and nurses.

Intention To be a competence group that sets the ethical questions within pediatric oncology on the agenda, by developing and spreading knowledge and methods. Focus of the working group 2010-2011 The working group on ethics has two one-day meetings in the spring, and one 2-night retreat in the autumn/early winter, for in depth discussions on a particular subject. At the retreat in November 2010, law specialist from all the Nordic countries were invited to join a workshop for two full days. At the meeting were discussed the national laws in regard to pediatric health care in general, and in pediatric oncology in particular. The workshop focused on two main themes: 1) End of life issues, and 2) who can make decisions for children in matters of health care? The discussion highlighted small, but interesting, differences in the national laws between the Nordic countries, and also grey areas were the laws are not very clear, and leave room for the health care team to use their sound judgments – and ethics. The working group is now working on (at least) two papers as a result of this workshop. For 2011, the working group is working on 4 focus themes:

1. Treatment limitations/futile treatment 2. Moral conflicts between doctors and nurses 3. Truth-telling to children 4. Children as SCT donors

We are also in the process of planning a session for the 2012 Annual NOPHO/NOBOS meeting in Uppsala.

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VI NOPHO Publications

Publications based on cooperative projects within NOPHO. 1983 1) Moe PJ, Combined Nordic Meeting of Pediatric Hematology and Oncology. Am J

Hematol Oncol 1983; 4:438. 1986 2) Moe PJ, Hertz H, Ludvigsson J, Siimes M, Jonmundsson G. Feilmedisinering hos barn –

profylakse og terapi. Nordisk Medicin 1986; 101:8-9. 1987 3) Gustafsson G, Garwicz S, Hertz H, Jonmundsson G, Johanesson G, Moe PJ, Salmi T,

Seip M, Siimes MA, Yssing M and Åhström L for NOPHO. A Population-based study of childhood acute lymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordic countries. Acta Paediatr Scand 1987; 76: 781-788.

1989 4) Gustafsson G, Berglund G, Garwicz S, Hertz H, Jonmundsson G, Moe PJ, Salmi TT,

Seip M, Siimes MA, Yssing M for NOPHO. A population-based study of children with stanard risk acute lymphoblastic leukemia in the five Nordic countries. Acta Paediatr Scand 1989; 78: 104-109.

5) Nygaard R, Moe PJ. Outcome after cessation of therapy in childhood leukemia. A population-based Nordic study of 986 patients. I and II. Acta Paediatr Scand 1989, Suppl. 354:1-24.

6) Nygaard R, Moe PJ, Brincker H, Clausen N, Nyman R, Perkkiö M, Eilertsen ME, Johansen OJ, Väre M, Brinch L, Siimes MA. Late relapses after treatment for acute lymphoblastic leukemia in childhood. A population-based study from the Nordic countries. Med Ped Oncol 1989;17:45-47.

7) Schmiegelow K, Siimes MA, Agertoft L, Berglund L, Storm-Mathiesen I, Andreassen M, Salmi TT, Nygaard R, Wiebe T, Kreuger A, Hayder S. Radio-lodobenzylguanidine scientigraphy of neuroblastoma: Conflicting results, when compared with standard investigations. Med Ped Oncol 1989;17:126-130.

1990 8) Clausen N, Garwicz S, Glomsten A, Jonmundsson G, Kruus S, Yssing M.

Medulloblastoma in Nordic children, I. Incidence and mortality. Acta Pædiatr Scand1990, suppl.371:5-11.

9) Jacobsen BB, Garwicz S, Glomstein A, Jonmundsson G, Kruus S, Yssing M. Medulloblastoma in Nordic children. III. Long term growth and endocrine sequelae. Acta Pædiatr Scand 1990;271:20-27.

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10) Lie S, Berglund G, Gustafsson G, Jonmundsson G, Siimes M, Yssing M for NOPHO. High dose ARA-C as a single agent consolidation therapy in childhood AML. In: Haematology and Blood Transfusion. Acute Leukemia II. pp 215-221. Springer Verlag, 1990. 11) Yssing M, Garwicz S, Glomstein A, Jonmundsson G, Kruus S. Medulloblastoma in Nordic children. II. Neurologic and social prognosis in long term survivors. Acta Pædiatr Scand 1990, suppl.371:12-19.

1991 12) Kreuger A, Garwitz S, Hertz H, Jonmundsson G, Lanning M, Lie SO, Moe PJ, Salmi

TT, Schroeder H, Siimes MA, Wesenberg F, Yssing M, Åhström L and Gustafsson G for NOPHO. CNS disease in childhood acute lymphoblastic leukemia. Prognostic factors and treatment results. Pediatr Hem Oncol 1991; 8:291-299.

13) Lie SO on behalf of the Nordic Society for Pediatric Hematology and Oncology (NOPHO). Progress in treatment of childhood leukemias. Eur J Cancer 1991; suppl.2:11.

14) Nygaard R. Long-term survival in childhood leukemia. Relapses and late effects after completed therapy. Thesis, University of Trondheim, Tapir, 1991.

15) Nygaard R, Clausen N, Siimes MA, Marky I, Skjeldestad FE, Kristinsson JR, Vuoristo A, Wegelius R, Moe PJ. Reproduction following treatment for childhood leukemia: A population-based prospective cohort study of fertility and offspring. Med Ped Oncol 1991;19:459-466.

16) Nygaard R, Garwicz S, Haldorsen T, Hertz H, Jonmundsson GK, Lanning M, Moe PJ. Second malignant neoplasms in patients treated for childhood leukemia. A population-based cohort study from the Nordic countries. Acta Pædiatr Scand 1991;80:1220-1228.

1992 17) Lanning M, Garwitz S, Hertz H, Jonmundsson G, Kreuger A, Lie SO, Moe PJ, Salmi

TT, Schröder H, Siimes M, Wesenberg F, Yssing M, Åhström L and Gustafsson G for NOPHO. Superior treatment results in girls with high risk acute lymphoblastic leukemia compared to boys. Acta Paediatr Scand 1992; 81:66-68.

18) Lie Sverre and Gustafsson Göran on behalf of the Nordic Society for Pediatric Hematology and Oncology (NOPHO). Progress in the treatment of childhood leukemias. Review article Annals of Medicin 1992; 24:319-323.

1993 19) Siimes MA, Lie SO, Andersen O, Marky I, Rautonen J, Hertz H. Prophylactic cranial

irradiation increases the risk of testicular damage in adult males surviving ALL in childhood. Med Ped Oncol 1993;21:117-121.

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20) Olsen JH, Garwicz S, Hertz H, Jonmundsson G, Langmark F, Lanning M, Lie SO, Moe PJ, Möller T, Sankila R and Tullinius H. Second malignant neoplasma after cancer in childhood or adolescence. Br Med J 1993; 307: 1030-1036.

1994 21) Moell C, Marky I, Hovi L, Kristinsson J, Rix M, Moe PJ and Garwicz S. Cerebral

irradiation causes blunted pubertal growth in girls treated for acute leukemia. Med Pediatr Oncol 1994;22:375-379.

1995 22) Schröder H, Garwicz S, Gustafsson G, Kristinsson J, Siiemes MA and Wesenberg F on

behalf of NOPHO. Outcome after relapse in children with acute lymphoblastic leukemia. Med Ped Onc 1995; 25:372-378. 23) Schmiegelow K, Schröder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, and Wranne L for NOPHO. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. Journal Clin Oncol 1995; 13:345-351.

24) Marky I, Jonsson O, Kreuger A, Gustafsson G, Perkkio M, Schmiegelow K, Storm-Mathiesen I and Langmark F. Childhood Non Hodgkin´s Lymphoma (NHL) in the five Nordic countries. A five year population based study. Am Journal Pediatr Hem/Onc.; 17(2): 163-166, 1995.

1996 25) Saarinen U, Mellander L, Nyström K, Ringden O, Schroeder H, Glomstein A and

Gustafsson G for NOPHO. Allogeneic bone marrow transplantation in first remission for children with very high risk acute lymphoblastic leukemia: A retrospective case-control study in the Nordic countries. Bone Marrow Transplantation; 17 (3):357-363 1996.

26) Lie S, Jonmundsson G, Mellander L, Siimes MA, Yssing M and Gustafsson G on behalf of NOPHO. A population based study of 272 children with acute myeloid leukemia treated on two consecutive protocols with different intensity: Best outcome in girls, infants and in children with Down´s syndrom. Br Journal of Hematology 1996; 94:82-88

27) Clausen N, Kreuger A, Salmi T, Storm-Mathisen I, Johannesson G. Severe aplastic anaemia in the Nordic countries: a population based study of incidence, presentation, course, and outcome. Arch Dis Child 1996;74; 319-22

28) Sankila R, Garwicz S, Olsen JH, Dollner H, Hertz H, Kreuger A, Langmark F, Lanning M, Moller T and Tulinius H. Risk of subsequent malignant neoplasms among 1641 Hodgkin´s disease patients diagnosed in childhood and adolsescence. A population based cohort study in the five Nordic countries. JCO, 1996;14(5):1442-46.

1997 29) Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse

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risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Ped Hematol Oncol, 1997;19(2):102-9.

30) Lie SO, Jonmundsson GK, Mellander L, Siimes MA, Yssing M, Gustafsson G.

Chemotherapy of acute myelocytic leukemia in children. Ann N Y Acad Sci. 1997;824:84-90. Review.

1998 31) Gustafsson G, Lie SO. Acute leukemias. In: Cancer in children, clinical

management, 4th edn. (ed PA Voute, C Kalifa, A Barrett). Oxford University Press, London, 1998, 99-118.

32) Sankila R, Olsen JH, Anderson H, Garwicz S, Glattre E, Hertz H, Langmark F,

Lanning M, Möller T and Tulinius H. Risk of cancer among offsprings of childhood-cancer survivors. New Engl J Med, 1998;338:1339.

33) Gustafsson G, Kreuger A, Clausen N, Garwicz S, Kristinsson J, Lie SO, Moe PJ, Perkkiö M, Yssing M and Saarinen-Pihkala U. Intensified treatment of acute childhood lymphoblastic leukemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Acta Paediatr, 1998;87:1151-61. 34) Jahnukainen K, Salmi TT, Kristinsson J, Müller J, Madsen B, Gustafsson G. The clinical indications for identical pathogenesis of isolated and non-isolated testicular relapse in acute lymphoblastic leukemia. Acta Paediatr,1998,87:638-643

1999 35) Schroeder H, Gustafsson G, Saarinen-Pihkala U, Glomstein A, Jonmundsson G,

Nysom K, Ringden O and Mellander L. Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries. Bone Marrow Transplant, 1999,Mar;23(6):555-560

2000 36) Garwicz S, Anderson H, Olsen JH, Döllner H, Hertz H, Jonmundsson G, Langmark F,

Lanning M, Möller T, Sankila R, Tulinius H: Second malignant neoplasms after cancer in childhood and adolescence: A population-based case-control study in the 5 nordic countries. Int J Cancer 88: 672-678, 2000.

37) Möller TR, Garwicz S, Barlow L, Falck Winther J, Glattre E, Olafsdottir G, Olsen JH, Perfekt R, Ritvanen A, Sankila R, Tulinius H: Decreasing late mortality among 5-year survivors of cancer in childhood and adolescence: A population-based study in the Nordic countries. J Clin Oncol (in press).

38) Forestier E, Johansson B, Borgstrom G, Kerndrup G, Johansson J, Heim S. Cytogenetic findings in a population-based series of 787 childhood acute lymphoblastic leukemias from the Nordic countries. The NOPHO Leukemia Cytogenetic Study Group. Eur J Haematol. 2000 Mar;64(3):194-200.

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49) Rosthøj S, Hedlund-Treutiger I, Rajantie J, Zeller B, Jonsson OG, Elinder G,

Wesenberg F, Henter JI, on behalf of the NOPHO ITP Working group and five national study groups. Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: A prospective Nordic study of an unselected cohort. J Pediatr 2003;143:302-7.

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51) Frost BM, Nygren P, Gustafsson G, Forestier E, Jonsson OG, Kanerva J, Nygaard R,

Schmiegelow K, Larsson R, Lönnerholm G. On behalf of NOPHO. Increased in vitro cellular drug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia. Br J Haematol 2003 Aug; 122(3):376-85.

52) Hjalgrim LL, Rostgaard K, Schmiegelow K, Soderhall S, Kolmannskog S,

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Kristinsson J, Lanning M, Schroeder H, Mellander L on behalf of NOPHO. Outcome of children with high-risk acute lymphoblastic leukemia (HR-ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation. Ped Blood Cancer 2004; 1: 16-26.

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B, Hasle H. Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: data from 56 children treated on NOPHO-AML protocols and a review of the literature. Annals of Hematology 85:275-280. 2006.

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77) Svahn-Tapper G, Garwicz S, Anderson H, Shamsaldin A, De Vathaire F, Olsen JH, Døllner H, Hertz H, Jonmundsson G, Langmark F, Lanning M, Sankila R, Möller T; Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: A population-based case-control study in the five Nordic countries. Acta Oncol. 45: 438-448, 2006.

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2007 80) Möller TR, Garwicz S, for the Nordic Childhood Cancer Cohort Study Group: Mortality experiences among 15+ year survivors of childhood and adolescence cancers (Letter to the Editor) Pediat Blood Cancer 48: 363, 2007.

81) Hawkins MM, Mertens AC, Möller TR, Garwicz S; Suicide among survivors of childhood cancer (Letter to the Editor). J Clin Oncol 25: 731-2, 2007.

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87) Forestier E, Andersen MK, Autio K, Blennow E, Borgström G, Golovleva I, Heim S, Heinonen K, Hovland R, Johannsson JH, Kerndrup G, Nordgren A, Rosenquist R, Swolin B, Johansson B; Nordic Society of Pediatric Hematology and Oncology (NOPHO); Swedish Cytogenetic Leukemia Study Group (SCLSG); NOPHO Leukemia Cytogenetic Study Group (NLCSG). Cytogenetic patterns in ETV6/RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia: A Nordic series of 245 cases and review of the literature. Genes Chromosomes Cancer. 2007 May;46(5):440-50.

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2010 102) Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Söderhäll S, Taskinen M; Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010; 24:345-54.

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104) Molgaard-Hansen L, Möttönen M, Glosli H, Jónmundsson GK, Abrahamsson J, Hasle H. Early and treatment-related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984-2003. Br J Haematol 2010;151:147-159. 105) Molgaard-Hansen L, Glosli H, Jahnukainen K, Jarfelt M, Jónmundsson GK, Malmros-Svennilson J, Nysom K, Hasle H. Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: A NOPHO-AML study. Pediatr Blood Cancer 2010. Epub Dec 22. 106) Mann G, Attarbaschi A, Peters C, Schrappe M, Lorenzo P De, Hann I, Rossi G De, Felice M, Lausen B, LeBlanc T, Szczepanski T, Ferster A, Janka-Schaub G, Rubnitz J, Silverman L B, Stary J, Campbell M, Li C K, Suppiah R, Biondi A, Vora A, Valsecchi MG and Pieters R on behalf of the Interfant-99 Study Group. Blood 2010; 116 (15): 2644-2650