CC OO NN TT EE NN SS REVIEWS

G. Mihailov and V. Vurbanova. Transplant programs in multiple myeloma – effectiveness of choice .................................................................................................................................................3

G. Mihailov and K. Ignatova. Current guidelines, diagnosis and continuous treatment of thrombocytopenic patients with chronic ITP ................................................................................. 14

ORIGINAL ARTICLES S. Goranov and V. Goranova-Marinova. The pathogenetic interrelations between bone and

renal damages in patients with multiple myeloma are of a “vicious circle” type.......................... 23 V. Goranova-Marinova, P. Georgiev, K. Sotirova, E. Spasov, I. Hristova, M. Dimitrova,

K. Sapunarova, V. Gryklanov, V. Babacheva and St. Goranov. Comparative analisys of the staging systems of durie & salmon and international staging system (ISS) in patients with multiple myeloma...................................................................................................... 33

V. Goranova-Marinova, A. Nedeva, P. Georgiev, I. Hristova, I. Nikolov, R. Stanchev, J. Rajnov and St. Goranov. Therapeutic response in patients with macrofocal form of multuple myeloma, treated with bortezomib-containing regimens ............................................................... 38

A Nedeva, V. Goranova-Marinova, P. Georgiev, I. Hristova, J. Raynov, St. Goranov, I. Gigov and I. Nikolov. Reversal of the renal failure after therapy with bortezomib in patients with multiple myeloma ........................................................................................................................... 43

A. Nedeva, J. Raynov, I. Nikolov, D. Yonova-Kindekova, R. Stanchev, L. Mitev, D. Popova, . Boneva, R. Vladimirova, I. Damiyanov, R. Petrova, I. Gigov and . Kancheva. Fludarabine + Cyclophosphamide+Rituximab (FCR) vs Fludarabine + Cyclophosphamide (FC) in the treatment of chronic lymphocytic leukemia: the experience of single centre............................... 48

P. Ganeva, G. Arnaudov, J. Jechev, M. Minchef, I. Tonev, M. Guenova, G. Balatzenko, L. Garcheva, S. Angelova, N. Stoyanov, S. Ivanova, V. Hrischev, B. Spassov, V. Var-banova, K. Ignatova, T. Jankova, K. Mishovska, S. Toshkov and G. Mihaylov. Is there a curative potential of autologous stem cell transplantation for multiple myeloma patients. the role of induction therapy ........................................................................................... 54

V. Uzunova, R. Stanchev, I. Gigov and L. Mitev. Molecular-biological study of JAK2 mutations emerged in patients with chronic myeloproliferative disorders .................................... 60

S Angelova, G. Balatzenko, V. Hrischev, M. Romanova and St. Toshkov. Evaluation of the cytogenetic and molecular response in patients with chronic myeloid leukemia treated with imatinib mesylate at the national specialized hospital for active treatment of hematological diseases – Sofia ....................................................................................................... 65

S Angelova, G. Balatzenko, M. Romanova, B. Spasov, N. Petkova, I. Hristov, E. Hadjiev, N. Tzvetkov and St. Toshkov. Seven cases with t(9;11)(p22;q23)/MLLT3-MLL, a re-current abnormality in acute myeloid leukemia: diagnostic characteristics and treatment response........................................................................................................................................... 71

L Mitev, M. Velizarova, T. Boneva, I. Gigov, Yu. Raynov and E. Hadzhiev. Cytogenetic abnormalities of ATM, p16 and p53 in chronic and accelerated phases of chronic myeloid leukemia............................................................................................................................ 76

A. Stancheva, L. Spasov and T. Lisichkov. Optimized algorithm for hemostasis monitoring with rotation thrombelastometry in liver transplants ..................................................................... 79

J. Grudeva-Popova, N. Boyadjiev, Z. Taralov and I. Nenova. Comparative analysis of red blood cell parameters in highly-trained football players of different age groups......................... 84

CASE REPORDS G. Mihailov and S. Simeonov. Case of a patient with triple metachronic malignancies –

hodgkin’s lymphoma, testicular teratocarcinoma and acute myeloid leukemia ........................... 90 T. Boneva, A. Nedeva, D. Ionova, I. Nikolov, J. Raynov, R. Stanchev, N. Radinov, D. Popova,

R. Vladimirova and L. Mitev. A case of multiple myeloma with t(11;14)(q13;q32)..................... 94

:

EMBASE/Excerpta Medica – -

. 1-2/2011

. . .

Klin. transfuz. hematol.

ISSN 0861-7880 616.15 + 615.38

: . :

. . : .

: 1431 , . " . . " 1 952-05-16; 851-82-65;

-mall: nmi@medun.acad.bg

. . ., XLV I, 2011, 1-2 3

–

. . –

TRANSPLANT PROGRAMS IN MULTIPLE MYELOMA – EFFECTIVENESS OF CHOICE

G. Mihailov and V. Vurbanova – Sofia

. ( ) - , (ASCT) ,

. 5000 (4345 – ASCT; 354 lo-SCT; 250 – RIC-allo) 2009 . -

65- - (OS – overall survival). -

ASCT, (allo-

SCT). (TRM),

. - , , -

- - (complete remission CR), (partial complete remission pCR)

(very good partial remission VGPR) . (Thalidomide (Thalidomide), Bortezomib (Velcade) Lenalidomide

(Revlimid) - , ASCT. - - - ASCT. - /

ASCT .

: , , -

Summary. Nowadays multiple myeloma (MM) is the disease most frequently indicated for autologous stem cell transplantation (ASCT) therapy both in Europe and the USA. The total number of transplanted MM patients reaches about five thousand within EBMT annually, (4345 – ASCT; 354 lo-SCT; 250 – RIC-allo during 2009 year). The introduction of ASCT in the treatment strategy of patients below 65 years old significantly improves overall survival (OS). Although there is an obvious benefit from the autologous transplantation program (ASCT), the only opportunity for durable remission remains the allogeneic stem cell transplantation (allo-SCT). The high percentage of transplantant-related mortality (TRM) associated with allo-SCT is the most important restiction for routine usage of allo-SCT in multiple myeloma patients treatment protocols. According to these data it is reasonable to conclude that the aim of the therapeutic designation in myeloma patients in the begininig of the XX century is the earliest achievement of a clinical plato of patients with complete remission (CR), partial remission (PR) and very good partial remission (VGPR) and its maintainance as long as possible. The clinical usage of novel agents such as Thalidomide (Thalidomid), Bortezomib (Velcade) or lenalidomide (Revlimid) in the last decade alters the therapeutic approach in

. . . ... 4

young patients eligible for ASCT. The introduction of contemporary induction protocols with reduced toxicity is a part of the strategy for posttransplantation period improvement and is used to increase the therapeutic susceptibility and response. Additionally, their role in the consolidation/maintainance treatment has been actively investigated in trying to improveme the post-ASCT period and extension of the clinical plato.

Key words: multiple myeloma, therapeutic strategy, autologous hematopoietic stem cell transplantation

1. ( ) - , -

-

-.

– - 1%

2% , . -

4,5-6,0/100 000/

63-70 [39]. 20 180 2010 .,

2007 . 189 . 0.4%

( 2007 . ),

5- , 25% 1975 . 34% 2003

. - , -

-

. -

- OS EFS

(events free survival) [4, 17], -

IMiD .

A - 15

- a

CR VGPR.

- : 1) , -

- ? 2)

? 3) -

(mono- vs. tandem, auto- compared to allo-)?

4) ? -

( . 1):

1. “ ” 2. Bortezomib- 3. IMiD- .

. 1. ,

. . ., XLV I, 2011, 1-2 5

-

- ( . 1).

, - -

.

, - – ISS ,

, , ,

( . 1).

1.

ISS [23] 2, 3 1

60 < 60

[5]

1q + t(4;14) 17p- (< 45) 13q- t(14;16)

t(11;14)

< PR VGPR

, -

XXI [1, 10, 22].

40-60%, . -

- + -

[35]. -

CR -

, - CR, - DFS (disease free survival) OS.

The Intergroupe Francophone du Myelome (IFM)

(HDT), ASCT, „ ” -

(VMCP, BVAP) MM (CR 22%, VGPR 16% vs. CR 5%, VGPR 9%;

5- EFS 28% vs. 10%; OS 52% vs. 12%, TRM) [29].

( . 2).

2. EFS OS vs. ( )

n EFS OS

Attal et al. 1 200 7-year: 16% vs 8% (P < .01) 7-year: 43% vs 27% (P < .03)

Child et al. 2 401 Median: 32 mo vs 20 mo (P < .01) Median: 54 mo vs 42 mo (P < .01)

Palumbo et al. 3 194 3-year: 37% vs 16% (P < .001) 3-year: 77% vs 62% (P < .01)

Fermand et al. 4 190 Median: 25 mo vs 19 mo (NS) Median: 47 mo vs 48 mo (NS)

Blade et al. 5 216 Median: 42 mo vs 33 mo (NS) Median: 66 mo vs 61 mo (NS)

Barlogie et al. 6 516 7-year: 16% vs 17% (NS) 7-year: 37% vs 42% (NS)

NS – p > 0.05 1Attal M. et al. N Engl J Med. 1996; 335:1844-1845; 2Child J. A. et al. N Engl J Med. 2003; 348:1875-1883; 3Palumbo A. et al. Blood 2004; 104:3052-3057; 4Fermand J. P. et al. J Clin Oncol. 2005; 23(36):9227-9233; 5Blade´ J. et al. Blood. 2005; 106(12):3755-3759; 6Barlogie B. et al. J Clin Oncol. 2006; 24(6):929-936.

. . . ... 6

(< 65 ; : PS 1-2, , ,

, – -) - (HDT), A . -

-,

, 70- .

2. „ ” -

- [12, 13]. CR - “ ” - ASCT

6-30% 52% ASC ( . 3, . 1).

3. CR ASCT “ ” “ ”

-ASCT -ASCT

Dex/VAD1 5% 35%

Cyclophosphamide/Dex2 7% 32%

VBMCP/VBAD3 10% 35%

Thal/Dex3, 4 6% 23-34%

Vel/Dex1, 5, 6 12% 33%

PAD-17 24% 43%

VTD8, 3 21-30% 43-52% 1Harousseau J. L. et al. Blood. 2009; 114:149 (Abstract 353). 2Mellqvist U. H. et al. Cancer.2008; 112(1):129-135; 3Rosinol L. et al. Blood. 2009; 114:59; 4Cavo M. et al. Blood. 2009; 114:59; 5Harousseau J. L. et al. Haematologica. 2006; 91(11):1498-1505; 6Rosinol L. et al. J Clin Oncol. 2007; 25(28): 4452-4458; 7Popal R. et al. BJH 2008; 141: 512-516; 8Barlogie et al. Br J Haematol. 2007; 138(2):176-185.

-

, , - ASCT, - -

(> VGPR, > PR, CR) - Bortezomib- . -

(Borte-zomib) 90-

,

, [24, 25].

nuclear factor-kappa B

(NF B) , . , Bortezomib -

(ORR – overall response – 67%; 21% CR/nCR 31% VGPR) [24] -

,

– ISS III, .

- Bortezomib -

- - , -

, - PFS (Vel/Dex vs.

VAD: 36.0 . vs. 29.7 . ( = .064) 3- - (81.4% vs. 77.4%,

32.2 ). - 2- (20.5% vs. 10.5%) 3/4 (9.2% vs.

2.5%)

Bortezomib Dexamethasone [24].

Thalidomide [19, 26] Lenalidomide [9]

, , .

, - , - .

Thalidomide - (alpha-phthalimido-glutarimide)

, , - .

in vitro -,

, tumor

necrosis factor-alpha (TNF- ), -10 -12, -

, - -

, .

, Thalidomide- , -

4 ( . 1). Thalidomide ASCT -

(68% vs. 49%; p = .001) (62% vs. 33% 4 ;

= .001) VGPR, TTP (61% vs. 41% 4 ; = .001) PFS (51% v 31% 4 ; = .001). -

, - Thalidomide – - OS ( = .07)

, -

. -

.

. . ., XLV I, 2011, 1-2 7

4. Thalidomide-Dexamethasone vs. Dexamethasone-

Rajkumar 1 Cavo 2 Cavo 3 Macro 4 Lokhorst 5 Morgan 6

TD vs. D TD vs. VAD TD vs. VAD TD vs. VAD TD vs. VAD TCD vs. CVAD

4 4 4 .

(Thal 2- ASCT)

4 3 NA

, n 201 200 270 204 402 251 ASCT, % CR

> VGPR > PR

4 vs. 0

63 vs.41

10 vs. 8 19 vs 14 76 vs. 52

25 vs 7

35 vs. 17

4 vs. 2

33 vs. 15 72 vs. 54

20 vs. 12 38 vs. 26 96 vs. 83

1- ASCT, % CR

> VGPR > PR

44 vs. 42

16 vs. 11 49 vs. 32 79 vs. 76

58 vs. 41 67 vs. 43 99 vs. 96

2- ASCT VGPR

68 vs. 49

DVT 17 vs. 3 15 vs. 2 23 vs. 7.5 8 vs. 4 NA

NA – , DVT – 1Rajkumar SV et al. J Clin Oncol, 2006; 24:431-436; 2Cavo M et al. JCO, 2009; Oct 20:5001-5007; 3Cavo M et al. Blood. 2005; 108(1):35-39; 4Macro M et al. Blood. 006; 108(11):22a. Abstract; 5Lokhorst HM et al. Haematologica. 2008; 93:124-127; 6Morgan GJ et al. Blood. 2007; 110. Abstract #1051

-

Thalidomide

, - ,

Thalidomide, - (IMiD). Celgene Corporation -

Thalidomide, Lenalidomide - - - -

, - [33]. Thalidomide

-

. Lenalidomide

- . III (ECOG-

E4A03) Rajkumar et al. [32] / Lenamidolide: Len +

(Dex 480 mg – LD) (Dex 160 mg – Ld) Dexamethasone.

- LD -

( PR: 81% vs. 70%, p = 0.007, CR + VGPR: 50% vs. 40%, p = 0.04), -

/ - - Ld -

OS (LD vs Ld: PR 81% vs. 70%, p = 0.009; CR + VGPR 50% vs. 40%, p = 0.04)

- LD (LD vs Ld: – 12% vs. 20%, p = 0.02; -

– DVT – 26% vs. 12%, p = 0.0003; 26% vs. 9%, p = 0.04; ( 4

) 5% vs. 1%, p = 0.03) [32]. -

- -

. , , - -

. Palumbo et al. [30] -

Thalidomide/Dexamethasone (TD) Bortezomib-Thalidomide-Dexamethasone (VTD),

ASCT .

VGPR , -

-

Bortezomib: CR 48% VTD v.s. 34% TD (P = 0.003), PFS e

82% – VTD, v.s. 73% – TD (P = 0.009). -

(VTD) -, -

. . . ... 8

[30]. - -

,

CR ASCT - .

Bortezomib- t(4;14) / del 17p

. - Vel/Dex /

- -

„ ” „ ” ( . 5, . 6, . 1).

5. VGPR ASCT

(Pts)

VD v VAD 223 219 1

VTD v TD 226 234 2

VTD v TD 56 63 3

PAD v VAD 150 150 4

Del 13 47 vs. 15 73 vs. 25 64 vs. 48

t(4;14) 40 vs. 17 81 vs. 25 36 vs. 18 52 vs. 29

Del 17p 41 vs. 0 73 vs. 6 37 vs. 0 53 vs. 0

: t(4;14) Del 17p PFS VD

1Harousseau JL et al. Blood. 2009; 114:149; 2Rosinol L. et al. ASH 2008 (abs. 654); 3Cavo M et al. ASH 2008 (abs. 158); 4Sonneveld P. et al. ASH 2008 ( bs 653).

6. CR (t(4;14) / del

17p) Bortezomib- vs.

CR (%) p-value

TD vs. VTD (GIMEMA) 1 < 10 vs. ~ 35 0.001

VBMCP/VBAD + Bortezomib vs. TD vs. VTD (PETHEMA) 2

25 vs. 0 vs. 42 0.003

VAD vs. VD (IFM 2005-01) 3 3 vs. 18 0.07

Bortezomib- CR

(t(4;14) / del 17p) 1Cavo M. et al. ASH 2008 (abs. 158); 2Rosinol L. et al. ASH 2008 (abs. 654); 3Harousseau JL et al. Blood. 2009; 114:149.

- Bortezomib- -

-

( . 2).

Thalidomide • Barlogie, B et al. Blood 2008;112:3115-3121• Attal et al. Blood 2006;108:3289-3294• Morgan, G. J., et al. Blood 2008; 112(11): 656-.• Zamagani et al. ASH Blood 2009;114(22):349-

Bortezomib• Jagannath S, et al. Leukemia 2007; 21:151-157• Sagaster V, et al. Leukemia 2007; 21:164-168• Mateos MV, et al. Haematologica 2008; 93:560-565.• San Miguel JF et al. NEJM 2008,359:906-917• Harousseau IMW meeting 2009• Barlogie B, et al. Leukemia 2008; 22, 1633–1636• Cavo M, ASH 2009; abs 1868

Lenalidomide• Reece D et al. Blood 2009;114(3):522-5.• Kapoor P et al. Blood 2009;114(3):518-21.

ЗаПротив

. 2. -

Single vs. Double ASCT

ASCT - CR -

. -

( 100% CR 5

) .

-

CR, VGPR, DFS, EFS OS - ASCT. -

- ASCT

ASCT,

double-ASCT [2, 6] double ASCT

.

ASCT CR OS, -

EFS ( . 7, . 3).

. . ., XLV I, 2011, 1-2 9

7. CR, EFS OS single vs. double ASCT ( )

ASCT n CR (%)* EFS ( .)

OS ( .)

Attal et al. (IFM94) Single

Double

199

200

42 †

50 †

25

30

48

58

Fermand et al. (MAG95) Single 94 42 ‡ NS NS

Double 99 37 ‡

Sonneveld et al. (HOVON 24) Single 148 13 20 55

Double 155 28 22 50

Cavoet al. (Bologna 96) Single

Double

115

113

33*

47*

23

35

59

73

*ITT ; † CR + VGPR; P = NS; ‡CR + MRD; P = NS

P = NS

P = NS

P = 0.002

P = 0.008

P = 0.03

P = 0.02

P = 0.01

P = NS

P = NSP = 0.001

ASCT

(n = 128)

(n = 84)

0

ASCT

(n = 46)

(n = 81)

0

25

50

75

100

220 44 66 88

Attal M, et al. N Engl J Med. 2003

22 44 660

25

50

75

100

p < 0.001

. 3. , ASCT OS

ASCT - -

- ,

. - - -

ASCT. Attal et al. [2] , -

, : -

ASCT. TRM. „Bologna 96”

Cavo et al. [16] , ASCT 3,7 TRM,

- 4% (single vs. double ASCT: 6.1% vs. 3.7% TRM). Attal et al. [2] -

, Melphalan (200 mg/m2) - - - - Melphalan

TBI (total body irradiation, -) [29].

- double ASCT

Melphalan TBI.

ASCT -,

-

. . . ... 10

. - : ASCT

CR/nCR VGPR ,

ASCT [2]. -

ASCT. Auto-SCT vs. allo-SCT

ASCT -

„ ” - , -

, , .

/ -

, -

. graft versus leukemia ,

graft versus myeloma , - - allo-SCT

-SCT - - [36]. PCR G.

Martinelli et al. [28] allo-SCT

-SCT. - -

, - 7 [18]. -

-

PFS (35 vs. 110 ) [28]. - OS -SCT

vs. -ASCT (18 34 ) -

-SCT, , - -SCT

[11]. , -

TRM ( -SCT vs. -ACT ; 41 vs. 13%). allo-SCT -

, ,

- TRM (46% 1983-1993 30% 1994-1998) [20]. EBMT

, , -

, OS EFS allo- ,

ASCT [11]. -

- (RIC) allo-SCT. -

ASCT RIC allo-SCT ( . 8). IFM99-03/99-04 [21] -

OS (35 vs. 41 ) EFS (25 vs. 30 )

RIC all -SCT ASCT. - EFS (35 vs. 31.7

) RIC allo-SCT tandem ASCT, - OS

tandem ASCT ( , 47.2 vs. 35 ; P = 0.07). , B. Bruno et al. [14] -

CR (alloRIC vs double-auto-SCT: 46 vs. 16%); OS (alloRIC vs double-auto-SCT: 84 vs. 62%) PFS (alloRIC vs double-auto-SCT 75 vs. 41%). -

-

TRM 10-11% (acute graft versus host disease (GVHD) 32%) [14, 21], allo-SCT

“salvage” - -

. 8. TRM auto- vs. allo-SCT ( )

SCT n CR, % PFS OS TRM % Tandem-ASCT 219 51 (CR + VGPR) 30 . (EFS) 741 5 Garban 1

ASCT followed by allo-SCT 65 62 (CR + VGPR) 25 . (EFS) 35 11 Tandem-ASCT 82 26 2 58 . NA Bruno 2

ASCT followed by allo-SCT 60 55 10 NA NA ASCT 166 NA 28% (4 .) 41% (4 .) 13 Alyea 3 ;

T-cell-depleted allo-SCT Allo-SCT 66 NA 18% (4 .) 39% (4 .) 24 ASCT 189 40 22 . 34 . 13 Bjorkstrand 4 EBMTR

Allo-SCT 189 48 12 . 18 . 41 ASCT 70 34 18% (4 .) 50% (4 .) 6 Arora 5

Allo-SCT 17 64 32% (4 .) 64% (4 .) 31 ASCT 86 25 (CR + VGPR) 15% (10 .) 31% (10 .) 14 Kuruvilla 6

Allo-SCT 72 38 (CR + VGPR) 31% (10 .) 40% (10 .) 22 1Garban F et al. Blood. 2006 May 1; 107(9):3474-80; 2Bruno B et al. N Engl J Med. 2007; 356:1110-1120; 3Alyea E et al. Bone Marrow Transplant. 2003; 32:1145–1151; 4Björkstrand BB et al. Blood. 1996; 88(12):4711-8; 5Arora M et al. Bone Marrow Transplant. 2005; 35:1133–1140; 6Kuruvilla J et al. Biology of blood and marrow transplantation. 2007; 13:925-931.

. . ., XLV I, 2011, 1-2 11

-. „ ” -

/ Thalidomide -

OS - [3, 34].

IFM 99-02 , - Thalidomide, - , - EFS OS

[3]. ,

, ASCT VGPR. ,

Thalidomide - -

. Thalidomide -

– „Total Therapy II”, - EFS [8], CR

OS [7] „Total Therapy I”, -

- Interferon [38]. CR

(56%, 2 ) e „Total Therapy III”, -

VTD (Velcade/Thalidomide/Dexamethasone) VRD (Velcade/Renalidomide/Dexamethasone) -

TD (Thalidomide/Dexamethasone) [38]. Palumbo et al. [31] -

PAD–MEL100–LP-L ( PAD tandem ASCT

Melphalan 100 mg/m2, Lenalido-mide/Prednisone Lenalidomide 10 mg/ -

) CR 72% .

Ladetto et al. [27], , -

, SCT,

VTD ASCT. , , -

-

„ ” (Thalidomide, Bortezomib Lenalidomide)

, -/ . -

- , -, - ,

„ -” - -

.

, -

, , . . -

. -

-

- , -

. - Van de Velde et al. [37], , - -

PFS (progression free survival) -

CR / VGPR,

, - „ ” -

. - -

“supportive care”.

- ,

- / -

, -

( . 4).

100

90

80

70

60

50

40

30

20

10

0

?CR, nCR,VGPR

%

Time

“ ”

. 4. –

. . . ... 12

1. -

D – Dexamethasone VAD – Vincristine/Adriamycin/Dexamethasone Thal/Dex, TD – Thalidomide/Dexamethasone Vel/Dex – Bortezomib/Dexamethasone VTD – Bortezomib/Thalidomide/Dexamethasone TCD – Thalidomide/Cyclophosphamide/Dexamethasone DCEP – Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin CVAD – Cyclophosphamide/Vincristin/Adriamycin/Dexamethasone PAD – Bortezomib, DoxoRubicin Dexamethasone VBMCP/VBAD – Vincristine, BCNU, Cyclophosphamide, Melphalan, Prednisone/Vincristine, BCNU, Adriamycin, Dexamethasone

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6. B a r l o g i e . B., S. Jagannath, D. H. Vesole et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. – Blood, 89, 1997, 3, 789-793.

7. B a r l o g i e , B., M. Pineda-Roman, F. van Rhee et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. – Blood, 112, 2008,

8, 3115-3121. 8. B a r l o g i e , B., G. Tricot, E. Anaissie et al. Thalidomide

and hematopoietic-cell transplantation for multiple myeloma. – N. Engl. J. Med., 354, 2006, 10, 1021-1030.

9. B a r t l e t t , J. B., K. Dredge et A. G. Dalgleish. The evolution of Thalidomide and its IMiD derivatives as anticancer agents. – Nat. Rev. Cancer, 4, 2004, 314-322,

10. B e r g s a g e l , D. E. Is aggressive chemotherapy more effective in treatment of plasma cell myeloma? – Eur. J. Cancer Clin. Oncol., 25, 1989, 159-161.

11. B j ö r k s t r a n d , B. B., P. Ljungman, H. Svensson et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. – Blood, 88, 1996,

12, 4711-4718. 12. B l a d é , J., T. Cibeira et L. Rosiñol. Novel drugs for the

treatment of multiple myeloma. – Haematologica, 95, 2010, 4, 702-704.

13. B l a d e , J., L. Rosinol, M. Cibeira et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. – Blood, 115, 2010, 3655-3663.

14. B r u n o , B., M. Rotta, F. Patriarca et al. A comparison of allografting with autografting for newly diagnosed myeloma. – N. Engl. J. Med., 356, 2007, 1110-1120.

15. C a v o , M., F. Raimando, E. Zamagni et al. Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma JCO, 2009, 5001-5007.

16. C a v o , M., P. Tosi, E. Zamagni et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. – J. Clin. Oncol., 25, 2007, 2434-2441.

17. C h i l d , J. A. et al. High-dose cheamotherapy with heamatopoetic stem-cell rescue for multiple myeloma. – N. Engl. J. Med., 348, 2003, 1875-1883.

18. C o r r a d i n i , P. et al. Molecular remission after myeoloablative allogenic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. – Blood, 102, 2003, 95, 1927-1929.

19. D ' A m a t o , M., S. Loughnan, E. Flynn et J. Folkman. Thalidomide is an inhibitor of angiogenesis. – Proc. Natl. Acad. Sci. US, 91, 1994, 4082-4085.

20. G a h r t o n , G., H. Svensson, M. Cavo et al. European Group for Blood and Marrow Transplantation. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983-93 and 1994-8 at European Group for Blood and Marrow Transplantation centres. – Br. J. Haematol., 113, 2001, 1, 209-216.

21. G a r b a n , F., M. Attal, M. Michallet et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. – Bood, 107, 2006, 9, 3474-3480.

22. G r e g o r y , W. M., M. A. Richards et J. S. Malpas. Combination chemotherapy versus melphalan and prednisone in the treatment of multiple myeloma: an overview of publish trials. – J. Clin. Oncol., 10, 1992, 334-342.

23. G r e i p p , R. R., J. S. San Migel, B. G. Durie et al. International staging system for muliple myeloma. – J. Clin. Oncol., 23, 2005, 3412-3420.

24. H a r o u s s e a u , J. L. et al. High complete and very good partial response rates with Bortezomib- dexamethasone as induction prior to ASCT in newly diagnosed patients with high-risk myeloma: results of the IFM 2005-01 phase 3 trial. – Blood, 114, 2009, 149 (Abstract 353).

25. H a r o u s s e a u , J. L., M. Attal, X. Leleu et al. Bortezomib plus dexamethasone as induction treatment prior to auto-logous stem cell transplantation in patients with newly diagnosed multiple myeloma. – Haematologica, 91, 2006,

11, 1498-1505. 26. H a s l e t t , P. A., L. G. Corral, M. Albert et G. Kaplan.

Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. – J. Exp. Med., 187, 1998, 1885-1892.

27. L a d e t t o , M, G. Pagliano, S. Ferrero et al. Major tumour shrinking and persistent molecular remissions after con-solidation with Bortezomib, Thalidomide, and dexame-thasone in patients with autografted myeloma. – J. Clin. Oncol., 28, 2010, 12, 2077-2084.

28. M a r t i n e l l i , G., C. Terragna, E. Zamagni et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma. – J. Clin. Oncol., 11, 2000, 2273-2281.

29. M o r e a u , P., T. Facon, M. Attal et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Inter-

. . ., XLV I, 2011, 1-2 13

groupe Francophone du Myelome 9502 randomized trial. – Blood, 99, 2002, 731-735.

30. P a l u m b o , A. Is Thalidomide combination a new option for myeloma? – Nat. Rev. of Clin. Oncol., 7, 2010, 425-426.

31. P a l u m b o , A., P. Falco, F. Gay et al. Bortezomibdoxorubicin-dexamethasone as induction prior to reduced intensity autologous transplantation followed by lenalidomide as consolidation/maintenance in elderly untreated myeloma patients. – Blood, 112, 2008, 11, 65a. Abstract 159.

32. R a j k u m a r , S. V. et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. – Lancet Oncol., 11, 2010, 29-37.

33. R a o , K. V. "Lenalidomide in the treatment of multiple myeloma". – AJHP, 64, 17, 1799-1807.

34. S p e n c e r , A. et al. Consolidation therapy with low-dose Thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem cell transplantation procedure. – J. Clin. Oncol., 27, 2009, 11, 1788-1793.

35. S p o r n , J, R. et O. R. McIntyre. Chemotherapy of previously untreated multiple myeloma patients: an analysis

of recent treatment results. – Emin. Oncol., 13, 1986, 318-325.

36. T r i c o t , G. et al.Graft-versus-myeloma effect: proof of principle. – Bood, 87, 1996, 3, 1196-1198.

37. V a n d e V e l d e , H. J. K., X. Lui, G. Chen et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. – Heamatologica, 92, 2007, 10, 1399-1406.

38. Z a n g a r i , M., F. van Rhee, E. Anaissie et al. Eightyear median survival in multiple myeloma after total therapy 2: roles of Thalidomide and consolidation chemotherapy in the context of total therapy 1. – Br. J. Haematol., 141, 2008,

4, 433-444. 39. http://www.multiplemyeloma.org/about_myeloma/2.03.asp.

:

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+ 359879104905 -mail: geombg@yahoo.com

. . ., XLV I, 2011, 1-2 14

,

. . , –

CURRENT GUIDELINES, DIAGNOSIS AND CONTINUOUS TREATMENT OF THROMBOCYTOPENIC PATIENTS WITH CHRONIC ITP

G. Mihailov and K. Ignatova Clinic of Hematology, – Sofia

. ( ) , .

- 100 109/L. - 1 4 100 000 .

2009 . Romiplostim,

. - Romiplostim.

: , , , , Romiplostim

Summary. Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder that is characterized by isolated thrombocytopenia without an apparent cause. It is defined by a peripheral platelet count of less than 100 x 109/L. In Europe the incidence of newly diagnosed patients with ITP varies from 1 to 4 in 100,000 people. This text presents the contemporary approaches to the diagnosis and treatment of this disease according to the international consensus for ITP of 2009, with an emphasis on the treatment with the TPO receptor agonist romiplostim. It further elaborates on the assessment of the effects of its use as a long-term therapy. In conclusion, it dwells upon the efficiency and safety in conducting of a long-term treatment with Romiplostim.

Key words: ITP, diagnosis, differential diagnosis, treatment, Romiplostim

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. . ., XLV I, 2011, 1-2 18

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. . ., XLV I, 2011, 1-2 20

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. . ., XLV I, 2011, 1-2 22

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1. P r o v a n , D. et al. International consensus report on the

investigation and management of primary immune throm-bocytopenia. – Blood, 115, 2010, 168-186.

2. J a m e s , B. et al. Safety and efficacy of long-term treatment with Romiplostim in thrombocytopenic patients with chronic ITP. – Blood, 113, 2009, 2161-2171.

3. D o u g l a s , B. et al. The ITP syndrome: pathogenic and clinical diversity. – Blood, 113, 2009, 6511-6521.

4. C i n e s , D. B. et V. S. Blanchette. Immune thrombocy-topenic purpura. – N. Engl. J. Med., 346, 2002, 995-1008.

5. K u t e r , D. J. et al. Efficacy of Romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. – Lancet., 371, 2008, 395-403.

6. R o d e g h i e r o , F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. – Blood, 113, 2009, 2386-2393.

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+ 359879104905 -mail: geombg@yahoo.com

. . ., XLV I, 2011, 1-2 23

CIRCULUS

VITIOSUS . . -

, , „ . ” –

THE PATHOGENETIC INTERRELATIONS BETWEEN BONE AND RENAL DAMAGES IN PATIENTS WITH MULTIPLE MYELOMA ARE OF A “VICIOUS CIRCLE” TYPE

S. Goranov and V. Goranova-Marinova Clinic of Hematology, Medical University – Plovdiv, UMHAT “Sv. George” – Plovdiv

. : ( ) - ( ) ( ). -

- . :

, . : 425 (223 203 )

61,1 9,3 . , - Durie & Salmon . ( < 1,3 ml/s) , . ( , ) -

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, , , , . -

OPG/RANKL, IL-6 TNF-beta Elisa . , ,

. MS Kaplan-Maier log rank test. - SPSSv18 (for Windows). : 196 (46,1%) -

, - ( r 353,0 mol/l) – 62,7%, - 91 (46,4%) . 353 (83,1%)

- “ 2” ( / ) – 210 (49,1%). 94,4% , 52,4% -

. , , - Cr ( < 0,001) ( < 0,02).

-score - (-2,32 ± 0,40), – (-1,89 ± 0,41). 5- - („odds ratio”). 26,1% -

, 41,1% 4,5 mmol/24 h. 3,1% 26,8% – 26,0 mmol/24 h. BJ

, Ccr, Cca (0,061 ± 0,003 ml/s) / cr (0,108 ± 0,013) - ( ), TR (89,23 ± 1,59%) TR (60,16 ± 5,34%) – ( < 0,05) . OPG 2 - . -

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, : 1.

. . - . ... 24

. ) v. fferens, - , )

cast nephropathy , ) - + . 2. . )

+ BJ , ( Fanconi,

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IL-6, TNF- , OPG, RANKL. ,

.

: , , , ,

Summary. Background: The combination between myeloma bone disease (MBD) and myeloma nephropathy (MNP) is distinctive and well known in the clinical evolution of myeloma multiplex. It is not verified yet if the bone and renal damages are two independent syndromes or there is an inter-relation between them. Aim. To analyze the inter-relation between bone and renal damages in multiple myeloma in clinical, pathogenetic and prognostic aspects. Patients and Methods: We studied 425 newly diagnosed patients with MM (223 men and 223 women), mean age 61.1 ± 9.3. They were diagnosed at the University Clinic of Hematology and the clinical stages were determined according to the Durie&Salmon staging system. The patients were treated by conventional chemotherapy. RF (creatinin clearance < 1.3 ml/s) was assessed by the incidence, grade and outcome after induction therapy. MBD (X-ray, CT scan) was graded acc to the Merlini scale. BMD (T-score and Z-score) was measured by the DEXA in the “anterior-posterior” plane at the L2-L4 level. The urine levels of Ca, P, creatinine, and their clearances respectively were measured at the same time. In the group of patients with RF and MBD, and in the group of healthy controls, OPG/RANKL, IL-6 and TNF-b were investigated at the same time by the ELISA. Statistics were performed by using variatiative alternative, correlative analyses and methods for comparing the means. The method of Kaplan-Maier with log rank test was used for MS evaluation (SPSSv18). Results: In a group of 196 patients (46.1%), RF grade I ( 353.0 μmol/l) was found most frequently (62.7%) and was totally reversible in 91 (46.4%) after the induction therapy. MBD was found in 353 (83.1%), as in 210 (49.1%), mostly of grade II (multiple osteolytic lesions and/or pathologic fractures). In 94.4% of the patients with RF, MBD was found and 52.4% of the patients with MBD had also RF. There was a significant correlation between the deterioration of the bone status and the incidence, stage and mean levels of Cr (p < 0.001) and the irreversibility of RF (p < 0.02). In the patients with RF, the average level of T-score was most frequently within the osteoporotic range (-2.32 ± 0.40), and in the patients without RF – within the osteopenic range (-1.89 ± 0.41). Patients with RF had 5 times higher risk of MBD (“odds ratio”). In 26.1% of the patients, hypercalciuria was found, while in 41.1% of the patients, hyperphosphatemia > 4.5 mmol/24 h was found. In 3.1% of the patients, hyperphosphatemia was found, while in 26.8% of the patients, hyperphosphaturia > 26.0 mmol/24 h was found. Despite the limitation of Ccr, in patients with BJ proteinuria and RF, Cca (0.061 ± 0.003 ml/sec) and ratio Cca/Ccr (0.108 ± 0.013) were higher, while the tubular reabsorbtion of TRCa (89.23 ± 1.59%) and TRP (60.16 ± 5.34%) were reduced (p < 0.05) because of the proximal tubular disfunction. In patients with manifested and destructive MBD with CRF, the levels of OPG were twice lower. The mean levels of IL-6 and TNF-b were higher in the advanced RF compared with RF – I stage and in the groups with advanced and destructive MBD + manifested RF. MS for the entire group was 35 months, for the patients without RF and without MBD – 46 months, while for the combination MBD + RF - 21 months. Conclusions: The association between MBD and RF is of a “circulus vitiosus” type and modulates their clinical manifestation, outcome and prognostic significance in a qualitative pattern. 1. The effect of MBD on renal function. a) Hypercalciemia causes spasm of v. afferens, reduction of the glomerulal filtration rate RF b) intensifies the co-precipitation of the light chains with an increase of the cast nephropathy RF c) blocks adenilatcyclase in the tubular epithelial cells resistance to ADH poliuria + hypostenuria. 2. The effect of the renal disfunction on MBD. a) The combination between hypercalciuria + BJ proteinuria causes different tubaular disfunctions – the proximal disfunctions are characterized by hypercalciuria and hyperphosphaturia (Fanconi syndrome, lightchain osteopenia/malacia) and intensifies the demineralisation processes in MBD. b) Probably the processes of renal osteodysthrophy in advanced RF have its significance too. 3. The mutual effect of osteolytic and renotropic cytokines IL-6, TNF- , OPG and RANKL. Different pathogenetic mechanisms of renal and bone damages are controlled by similar cytokine systems, that increase and enforce the clinical manifestations of the two syndromes.

Key words: myeloma bone disease, renal failure, hypercalciemia, calciuria, phosphaturia

. . ., XLV I, 2011, 1-2 25

-

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(DEXA) “ - ” - L2 – L4.

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.

OPG/RANKL, IL-6 TNF-beta Elisa -. SPSS v18 (for

Windows). - (MS) Kaplan-

Maier log rank test.

353

(83,1%), 196 (46,1%) . (94,4%)

( < 0,001). - – (52,4%)

( . 1).

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223 (52,5) 202 (47,5)

51 (12,0) 133 (31,3) 241 (56,7)

102 (24,0) 234 (55,1)

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„0” . „1” . /

„2” . /

„3” . /

15 ( 7,7)

123 (62,7) 45 (22,9) 11 ( 5,6) 2 (1,1)

91 (46,4) 55 (28,1) 50 (25,5)

72 (16,9) 102 (24,0)

212 (49,9)

39 (9,2)

1) „0” „3” .

( 2 = 0,0001); 2) „0” „1” . -

( < 0,02); 3) Cr -

( . 2). 2. . 86 (41,9% 58,1% ) , e

> – 2,5 T- Z-score ( ) - –

- ( . 4). -

-score - (-2,6), -

- Z-score ( . 5 6).

3. – . - -

, / Cr ( . 3).

-, /

- .

2. Merlini *

– erlini

„0” X ± Sx

„1” X ± Sx

„2” X ± Sx

„3” X ± Sx

107,90 ± 45,97 187,10 ± 98,71 228,71 ± 124,45 231,70 ± 111,77 S

*(one-way ANOVA )

46

42

12

22,2

38,9 38,9

05

101520253035404550

1 2 3

1. <-1,0 2. 1,0 -2,5 3. < -2,5

. 4.

. . ., XLVI , 2011, 1-2 27

3041N =

T-sc

ore

2

0

-2

-4

-6

-8

. 5. -score

3041N =

Z-sc

ore

2

1

0

-1

-2

-3

-4

-5

. 6. Z-score

3. , – -

r p r p r P

MK Pearson 0.254 0,000 0,209 0,000 0,220 0,0001

( ) , - 5- -

– 4 - -

( . 4).

4. dds ratio

/ 95% CI

4,63/2,81 – 12,632

4,573/2,36 – 8,99

4. - -

(BJ) . 231

, Cr. 58 (25,1%) , 7 (3,0%)

– , 96 (41,1%) – -, 38 (16,4%) – . -

- -

, - (p < 0,05).

( . 5 . 7): / -

- . –

(38,7%) (54,6%) - , -

.

- ( 2 < 0,0001): 26 (68,4%) 12 (36,8%)

( . 8). (BJ) - , BJ(-) -

/ -, BJ(+) – ( . 6).

32 (84,2%) BJ 6 (15,8%) BJ (-). -

Ca P.

81,3

15,7

68,7

31,3

61,7

38,3

45,454,6

0

10

20

30

40

50

60

70

80

90

Ca < 2,65 mmol/lCa > 2,65 mmol/l

Ca ur > 4,5 mmol/24

. 7. ,

63,2

21,6

36,8

68,4

0

10

20

30

40

50

60

70

P ur < 26,0 mmol/l P ur > 26,0 mmol/l

. 8.

BJ(+) - ( . 7).

/ cr -, TR – - .

cr „ -”

, TR .

Ca ur < 4,5 mmol/24

. . - . ... 28

, Cp - BJ(+) ,

TR – - . 5. OPG/RANKL .

, , - OPG/RANKL. -

OPG - , OPG Cr ( . 8).

- - OPG. - OPG 2

- ( < 0,05). -

OPG. (p = 0,029) -

(68,7%) OPG 6,0 pmol/l - (25,0%) 3,0 pmol/l ( . 9).

5.

-uria < 4,5

mmol/24 h %

-uria > 4,5 mmol/24 h

%

P-uria < 26,0 mmol/24 h

%

P-uria > 26.0 mmol/24 h

%

Cr < 160 μmol/l 92 (68,7)* 42 (31,3)* 122 (91,0)* 12 (9,0) 134

Cr > 160 μmol/l 44 (45,4) 53 (54,6) 71 (73,2)* 26 (26,8) 97

136 (58,9) 95 (41,1) 193 (80,1)* 38 (16,4)* 231

6.

-uria < 4,5

mmol/24 h %

-uria > 4,5 mmol/24 h

%

P-uria < 26,0 mmol/24 h

%

P-uria > 26.0 mmol/24 h

%

BJ (-) 76 (79,2)* 20 (20,8)* 90 (93,7)* 6 (6,3)* 96

BJ ( ) 41 (46,1) 48 (53,9) 68 (76,4) 21 (23,6) 89

BJ ( ) 19 (41,3) 27 (58,7) 35 (76,1) 11 (23,9) 46

BJ (+) 60 (44,4) 75 (55,6)* 103 (76,3)* 32 (23,7)* 135

136 (58,9) 95 (41,1) 193 (83,5) 38 (17,5) 231

7. *

/ cr TR Cp Cp/Ccr TRp

(n 24) 0,056 ± 0,007* 0,034 ± 0,004* 96,57 ± 1,67 0,209 ± 0,037 0,131 ± 0,022 86,75 ± 2,14*

(n 25) 0,061 ± 0,003* 0,108 ± 0,013* 89,23 ± 1,59 0,224 ± 0,018 0,398 ± 0,051 60,16 ± 5,34*

BJ(-) (n 19) 0,054 ± 0,004* 0,058 ± 0,035* 94,15 ± 4,02* 0,202 ± 0,024* 0,218 ± 0,126* 78,05 ± 12,79*

BJ(+) (n 30) 0,061 ± 0,005* 0,080 ± 0,037* 91,99 ± 3,85* 0,228 ± 0,021* 0,298 ± 0,140* 70,10 ± 14,07*

8. OPG RANKL

N OPG pmol/l

± Sx

RANKL pmol/l X ± Sx

P RANKL/OPG

X ± Sx

30 3,77 ± 0,33 < 0,001 0,203 ± 0,031 0,053 ± 0,003

< 160 mmol/l > 160 mmol/l

39 27

4,51 ± 0,30 6,60 ± 1,00

0,053 0,392 ± 0,047 0,552 ± 0,088

0,054 0,089 ± 0,013 0,150 ± 0,025

< 0,05

I II +

18 9

6,73 ± 1,37 6,21 ± 2,49

NS 0,550 ± 0,129 0,577 ± 0,106

NS 0,135 ± 0,035 0,179 ± 0,057

NS

MK “0 + 1” . “2 + 3” .

9 18

9,97 ± 2,42 4,92 ± 0,62

< 0.05 0,356 ± 0,058 0,528 ± 0,092

NS 0,051 ± 0,010 0,176 ± 0,048

0,019

. . ., XLVI , 2011, 1-2 29

75,0%

25,0%

65,8%

34,2% 31,3%

68,7%

%

OPG < 3,0 3,0-6,0 > 6,0 pmol/l

. 9. OPG

RANKL

RANKL/OPG ( . 8).

RANKL/OPG - “2 + 3” (p = 0,019).

6. IL-6 TNF- - . IL-6 TNF-

. -

6 pg/ml IL-6 5 pg/ml IL-6r TNF- -

, (cut off) ( . 10 11).

10

90

74,3

25,7 30

70 69,2

30,8

0102030405060708090

-6 > 6 pg/ml -6 < 6 pg/ml -6r > 5 ng/ml -6r < 5 ng/ml

44,6

55,6

65

35

0

10

20

30

40

50

60

70

TNF-b > 5 pg/ml TNF-b < 5 pg/ml

. 10. IL-6/IL-6r . 11. TNF-

IL-6 TNF- - - -

. +

( . 9).

9. IL-6 TNF-

IL-6 pg/ml X Sx

TNF- pg/ml ± Sx

MK “0 + 1”

“2 + 3”

20

29

2,311 9,778

4,260 4,379

4,021 2,311*

8,490 4,879*

I II +

13 6

2,021 0,649* 5,368 4,061*

5,011 ± 1,559* 9,325 ± 5,095*

MK “0 + 1”

“2 + 3” -

12

7

2,220 7,231

4,549 4,355

4,990 ± 2,077

8,743 ± 5,216

7. – . -

, - – 21 . -

MS + .

10. –

N MS 95% CI

Log Rank test

, 61 46 43-49

, 11 21 13-29

< 0.0001

, 164 32 32-40

, 185 20 18-24

< 0.0001

. . - . ... 30

: 94,4% - ,

(52,4%) ; - 38,7%

54,6% ; „0” „3” –

, Cr, ( 2 = 0,0001);

; -score

- , – .

Scarfe [1] Smith [2]. .

-

. -

. - J

- ,

( . 12). -

/ – vv. afferens, -

Cr [3, 4]. -

THp -

(cast nephropathy). (cast) -

– „ ” - „ ” -

. BJ -

[5, 6]. -

- –

- [7].

„ ” - [5], Crawford [8]

Knudsen [9]. -/

Cr .

30% – 51,6% -

Cr, 41,9% – . - -

. -

, - - / [10, 11].

. -

( ).

,

- .

- . - , - . -

TR TR ,

. --

. . “ ” - BJ

. Fanconi, -

.

, , , , -

, , -, , -

[12, 13, 14]. -, -

, - .

. 3

. OPG/RANKL -

, - . – IL-6/IL6r, – -

,

. TNF- , . . “ ”, -

: - -

. . (AL -

LCDD) [15].

. . ., XLVI , 2011, 1-2 31

. 12.

-

OPG 2 - , -

OPG - , -

.

- , OPG.

,

RANKL. - - IL-6 TNF-

+

– - , ,

, [16, 17, 18]. -

.

,

, , - ,

-, .

, - -

.

1.

v. fferens

BJp + T p cast nephropathy

+

2. Fanconi + - + -

3. IL-6, TNF- , OPG, RANKL

BJp

. . - . ... 32

1. S c a r f f e , J. H., D. B. Smith et A. Jackson Special clinical

problems in patients with multiple myeloma. – Haemat. Oncol., 6, 1988, 119-123.

2. S m i t h , D. B., J. H. Scarffe et B. Edelston. The prognostic significance of X-ray changes at presentation and reassessment in patients with multiple myeloma. – Haemat. Oncol., 6, 1988, 1-6.

3. A , ., C. A. . - . – : . e - . . . , . ., -

, 1984, 163-254. 4. , . -

, . – : . . . . . ., ,

1983, 200-207. 5. A b e , M. Hypercalcemia in myeloma. – Nippon Rinsho., 65,

2007, 12, 2245-2249. 6. H e y b u r n , P. J., J. A. Child et M. Peacock. Relative

importance of renal failure and increased bone resorption in the hypercalcaemia of myelomatosis. – J. Clin. Pathol., 34, 1981, 1, 54-57.

7. , . - . – : . . .,

. ., 1989, 134-140. 8. C r a w f o r d , S. M. Hypercalcaemia, renal failure and

relapse in multiple myeloma. – Cancer, 55, 1995, 898-901. 9. K n u d s e n , L. M., M. Hjorth et E. Hippe. Renal failure in

multiple myeloma- reversibility and impact on the prognosis. Nordic Myeloma Group – Eur. J. Haematol., 65, 2000, 3, 175-181.

10. B o c k , H. A. Pathogenesis of acute renal failure: new aspects. – Contr. Nephrol., 124, 2008, 43-55.

11. S o u s a , A., A. M. Correia et M. M. Prata. Acute renal insufficiency as presentation form of multiple myeloma. – Acta Med. Port., 4, 1991, 215-219.

12. N a r v a e z , J. et al. Aquired hypophosphatemic osteoma-lacia associated with multiple myeloma. – Jiont Bone Spine, 72, 2005, 5, 424-426.

13. R o b e r t s o n , A., R. Mansberg et V. Mansberg. Tumor-induced osteomalacia: a case of diagnostic dilemma. – Clin. Nucl. Med., 32, 2007, 8, 631-634.

14. L e e r t , P. et al. Influence of Bence Jones proteins hypervis-cosity, hypercalcemia, hyperuricemia and dehydratation on development of renal changes in plasma cell dyscrasias. – Przegl. Lek., 42, 1995, 384-386.

15. W a r z o c h a , K. et al. Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. – Eur. Cytokine. Netw., 6, 1995, 2, 83-96.

16. G o r a n o v a -M a r i n o v a , V. et al. Serum levels of OPG, RANKL and RANKL/OPG ratio in newly-diagnosed patients with multiple myeloma. Clinical correlations. – Haematologica, 92, 7, 1000-1001.

17. S h a a r a w y , M. et al. Circulating levels of osteoprotegerin and receptor activator of NF-kappaB ligand in patients with chronic renal failure. – Clin. Chem. Lab. Med., 45, 2007,

11, 1498-1503. 18. O z k a y a , O. et al. Osteoprotegerin and RANKL serum

levels and their relationship with serum ghrelin in children with chronic renal failure and on dialysis. – Nephron. Clin. Pract., 105, 2007, 4, 153-158.

:

. ” . ”

„ ” 15

4002 032 602 298

. . ., XLVI , 2011, 1-2 33

DURIE & SALMON (ISS)

. - , . , . , . , . , . ,

. , . , . . , ” . ”, –

COMPARATIVE ANALISYS OF THE STAGING SYSTEMS OF DURIE & SALMON AND INTERNATIONAL STAGING SYSTEM (ISS)

IN PATIENTS WITH MULTIPLE MYELOMA V. Goranova-Marinova, P. Georgiev, K. Sotirova, E. Spasov, I. Hristova, M. Dimitrova,

K. Sapunarova, V. Gryklanov, V. Babacheva and St. Goranov Clinic of Hematology, University Hopsital “Sv. Georgi”, Medical University – Plovdiv

. : Durie et Salmon (DS) (ISS) , -

, (MS). :

328 , DS ISS. / = 1.00/1.01, 60.9 ± 9.8 . DS-I 34 (10.4%) , DS-II – 88 (26.8%), DS-III – 206 (62.8%). ISS-I 46 (14.0%), ISS II – 120 (36.6%), ISS III – 162 (49.4%). 122 (37,2) , – 272 (82.6%). MS 36 . -

: - III – ISS-III 118 (57.3%) DS-III 74 (71.2%) DS-III . -

ISS , DS (p < 0.001, R = +0.453). - 2 ISS ( p < 0.001; R = +0.772) -

DS ISS-I ISS-II. MS DS-I 57 ., DS-II – 43 ., DS-

III – 27 .; ISS-I – 40 ., ISS-II – 38 ., ISS-III – 30 . : - . ISS -

, . MS ISS-I ISS-II. ISS - , B2M, - .

: , Durie et Salmon, ,

Summary. The aim of the study was to analyze the correlation between the staging systems of Durie and Salmon (DS) and the International Staging System (ISS) in patients with multiple myeloma (MM) in a prognostic aspect and to compare the major parameters of the disease and their significance for the separate clinical stages and the median of survival (MS). Patients and methods: 328 patients with MM had their clinical stage defined simultaneously acc to DS and ISS. M/F = 1.00/1.01, mean age 60.9 ± 9.8y. In DS-I were 34 (10.4%), DS-II – 88 (26.8%), DS-III – 206 (62.8%). In ISS-I were 46 (14.0%), ISS-II – 120 (36.6%) and in ISS-III – 162 (49.4%). Renal failure was found in 122 (37.2), bone lesions in 272 (82.6%). MS was 36 months. Results: The highest concordance was found in III clinical stage: in ISS-III were 118 (57.3%) of the DS-III and 74 (71.2%) of the DS-III . No statistically significant correlation was found between ISS and myeloma bone disease, while the correlation of bone lesions with DS was highly significant (p < 0.001, R = +0.453). The strongest correlation was found between 2 and ISS (p < 0.001; R = +0.772). The grade of plasma cell infiltration in bone marrow increases significantly in every separate clinical stage acc to DS and does not show a significant difference

. - , . , . ... ... 34

between ISS-I and ISS-II. MS in DS-I was 57 mo, DS-II – 43 mo, DS-III – 27 mo; in ISS-I 40 mo, ISS- II – 38 mo, ISS-III 30 mo. The changing of the levels of the basic parameters of the disease is typical in the corresponding clinical stages. ISS does not assess the adverse prognostic effect of the bone lesions and the degree of the plasma cell infiltration. This is how we explain the insignificant difference between MS in ISS-I and ISS- II. ISS is a powerful tool regarding the renal function because of the dual value of 2M - a parameter of the tumour burden and the involvement of the kidneys in the pathological process.

Key words: multiple myeloma, staging systems of Durie and Salmon, International Staging System, prognosis

Durie et Salmon (DS)

1975 . 72 ( ). -

e -

[1]. -

Durie et Salmon -

- .

, -

, - -

, . , -

- - .

2005 . (ISS), -

10 750 17 [2].

,

, (MS).

533 .

. -

-,

. 533 - , 328

DS ISS. / = 1.00/1.01,

60.9 ± 9.8 . - . 1.

DS ISS 2.

( ) Merlini : 0 – -

; 1 – / ; 2 –

/ ; 3 – - -

. ,

independent samples T-test one-way ANOVA.

(MS) - Kaplan-Maier log-rank test

(SPSSv18).

1.

N (%)

IgA IgG IgD BJ

76 (23.2%) 172 (52.4%) 1 (0.04%) 52 (15.9%) 12 (3.7%) 16 (4.9%)

122 (37.2%)

272 (82.6%)

( > 2.67 mmol/l) 103 (31.4%)

< 85 g/l 134 (40.9%)

LDH > 480 U/l 121 (36.9%)

CRP > 6 mg/l 134 (40.9%)

2M > 3.0 mg/l 170 (51.8%)

< 30 g/l 86 (26.2%)

36 .

10,4%14.0%26,8%

36,6%

62,8%

49,4%

0

20

40

60

80

I II III

DSISS

. 1. DS ISS

. . ., XLVI , 2011, 1-2 35

.

P < 0.001, R = +0.276. - -

III : ISS-III 118 (57.3%) DS-III 74 (71.2%) DS-III . : , 8 (4.9%) , DS-I,

ISS III 2 > 5.5 mg/L. 15/206 ISS-I a DS-III -

: 9 – , 5 – -

, 4 – , 2 – .

- -

.

ISS 2 .

2 ISS (p < 0.001, R = +0.772), a -

DS (p < 0.001, R = +0.238). ISS-I 2 > 3.5 mg/l

10 (5.9%) DS-I; DS-III 2 < 3.5 mg/l 78 (50.6%),

ISS-III 10 (6.5%), P < 0.05. 2 - -

ISS. DS - DS-I vs DS-III ( . 2).

.

P < 0.001, R = -0.220 ISS P < 0.001, R= -0.312

DS, .

DS, ISS-I

vs ISS-III ( . 2). -

Durie & Salmon

. DS-I - ISS-I -

: 30 (53.6%) vs 8 (14.3%), p < 0.05;

. 3 Merlini DS-I 32 (20.0%) ISS-I.

ISS , DS

(p < 0.001, R = +0.453). . ISS I

14 (10.4%) , DS-I -

. - ( . 3)

< 80 g/l: ISS: I/II/III = 14 (10.4%)/46 (38.3%)/74 (55.2%) (NS) DS I/II/III = 0/18 (13.4%)/116 (86.6%), (p < 0.001, R = -0.423).

. - Ca

- ( . 3). a

- III : DS 77 (74.8%) vs ISS 65 (63.8%), NS.

2. 2-

2- mg/L Sx ± SEM p g/L

Sx ± SEM p

ISS-I 2.508 ± 0.154 37.11 ± 1.32

ISS-II 3.186 ± 0.115 36.03 ± 0.89

ISS-III 10.229 ± 0.786

I vs III, p < 0.001 II vs III, p < 0.001

33.67 ± 0.89

I vs III, p = 0.03

D & S-I 4.64 ± 1.09 40.00 ± 1.83

D & S-II 5.27 ± 0.76 37.02 ± 0.61

D & S-III 7.81 ± 0.69

I vs II, NS I vs III, p = 0.027

II vs III, NS 33.08 ± 0.76

I vs III, p < 0.001 II vs III, p < 0.001

3. , Ca LDH

Hb g/L Sx ± SEM p Ca mmol/L

Sx ± SEM p LDH U/L Sx ± SEM p

ISS-I 102.74 ± 4.46 2.41 ± 0.08 403.4 ± 27.53

ISS-II 92.32 ± 2.58 2.46 ± 0.33 427.6 ± 24.23

ISS-III 90.91 ± 1.76

NS

2.74 ± 0.06

IvsIII, p = 0.019

IvsII, p = 0.02 535.3 ± 35.16

I vs III, p = 0.044

D & S-I 117.29 ± 6.07 2.46 ± 0.07 370.0 ± 34.06 I vs II, p < 0.01

D & S-II 94.68 ± 2.82 2.48 ± 0.04 390.7 ± 24.96 I vs III, p < 0.01

D & S-III 87.72 ± 2.09

I vs II, p = 0.024 I vs III, p < 0.001 II vs III, p < 0.001 2.68 ± 0.06

IIvsIII, p = 0.04

541.7 ± 32.81 II vs III, p < 0.01

. - , . , . ... ... 36

- -

DS: 24.2% vs 30.0% vs 61.6% (p < 0.05)

I II ISS: 47.2% vs 46.2% vs 61.2%.

: ISS p < 0.001, R = +0.412, DS p < 0.005, R = +0.337. -

- : ISS-II/ISS-III – 38 (31.1%)/84 (68.9%);

DS-II/DS-III – 24 (19,6%)/98 (80.9%) - .

- LDH ISS;

DS LDH - (p < 0.001, R = +0.253). -

- - LDH e III ,

( . 3).

.

Durie et Salmon MS I 57 . II – 43 ., III – 39 ., IIIB – 20

. (p < 0.05). ISS MS I 40 ., II – 38 ., III – 30 .,

I II ( . 3 . 4). -

. MS DS-IIIB ISS-III + : 20 .

. 2. -

ISS

. 3. -

Durie & Salmon

-

.

- , , -, , 2 , , CRP -

-

DS ISS. 2- - - -

: ,

, IL-6, CRP - .

- - 2 , . ., - , - -

2 [3]. -

. 2 , , –

.

.

2 ISS - - . - Greipp et al.

ISS, - - ISS-III DS-IIIB [2].

ISS-III DS-IIIB MS 20. ,

ISS-III DS-IIIB.

ISS . ,

, , - - ,

, [4, 5],

. , , -

ISS [6].

ISS

-

. -

ISS-II ISS-III, , a -

. . ., XLVI , 2011, 1-2 37

DS IMF, ISS [7]. P. N. Hari et al. 729 ,

, ISS-I ISS-II,

DS 36% [8].

MS ISS-I ISS-II. e,

ISS-I - - -

DS-I. Durie & Salmon

- [1]. -

ISS - . – -

ISS.

. -

ISS DS. , -

, - - DS -

- ISS. - „ ” „ ” [9, 10]. -

DS -

, , – -

-

- .

ISS

. Durie & Salmon -, . - FISH

[11, 12]. -

- [13, 14]. „ -

” „ ” [5]. - -

, - -

.

1. D u r i e , B. G. et S. E. Salmon. A clinical staging system for

multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. – Cancer, 36, 1975, 3, 842-854.

2. G r e i p p , P. R. et al. International staging system for multiple myeloma. – J. Clin. Oncol., 23, 2005, 15, 3412-3420.

3. M i h o u , D., E. Katodritou et K. Zervas. Multiple myeloma staging based on the combination of beta-2-microglobulin and albumin: the role of albumin in the model. – Hematology, 12, 2007, 6, 527-531.

4. C o n t é , L. G. et al. Prognostic value of the new interna-tional staging system in multiple myeloma. Comparison with Durie-Salmon staging system. – Rev. Med. Chil., 136, 2008,

1, 7-12. 5. A v e t - L o i s e a u , H. Ultra high-risk myeloma. –

Hematology Am. Soc. Hematol. Educ. Program 2010, 2010, 489-493.

6. D i m o p o u l o s , M. A. et al. The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients' renal function. – Ann. Oncol., 2011, Jun 7 e-pub ahead of print.

7. D e n g , S. H. et al. Analysis of the international staging system of multiple myeloma and its comparison with the DS and IFM staging system in 122 Chinese patients. –Zhonghua Xue Ye Xue Za Zhi, 29, 2008, 4, 217-221.

8. H a r i , P. N. et al. Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. – Leukemia, 23, 2009, 8, 1528-1534.

9. D i m o p o u l o s , M. A. et al. Macrofocal multiple myeloma in young patients: a distinct entity with favorable prognosis. – Lek. Lymphoma, 47, 2006, 8, 1553-1556.

10. B l a d e , J. et al. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. – J. Clin. Oncolol., 29, 2011, 29, 28, 3805-3812.

11. M u n s h i , N. C. et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. – Blood, 117, 2011, 18, 4696-4700.

12. B o y d , K. D. et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. – Leukemia, 2011, Aug 12. E-pub ahead of print.

13. C o r s o , A. et al. Response-adjusted ISS (RaISS) is a simple and reliable prognostic scoring system for predicting progression-free survival in transplanted patients with multiple myeloma. – Am. J. Hematol., 2011, Oct 14 E-pub ahead of print.

14. G a s t i n n e , T. et al. Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I. – Eur. J. Haematol., 79, 2007, 4, 297-304.

:

- - ,

” . ”

. „ ” 15 4002

032 602 298 e-mail: vesselina_goranova@yahoo.com

. . ., XLVI , 2011, 1-2 38

, BORTEZOMIB-

. - 1, . 2, . 1, . 1, . 2, . 2, . 2 . 1

1 , ” . ”, – , 2 , –

THERAPEUTIC RESPONSE IN PATIENTS WITH MACROFOCAL FORM OF MULTUPLE MYELOMA, TREATED WITH BORTEZOMIB-CONTAINING REGIMENS

V. Goranova-Marinova1, A. Nedeva2, P. Georgiev1, I. Hristova1, I. Nikolov2, R. Stanchev2, J. Rajnov2 and St. Goranov1

1Clinic of Hematology, University Hospital “Sv. Georgi” – Plovdiv 2Clinic of Hematology and Oncology, Military Medical Academy – Sofia

. : - ( ) , , . .

. : , , - , Bortezomib (Velcade)- .

: 111 , 58,2 ± 8.8 ., : /1.05:1. a- ISS Velcade- . 12 (10.8%) -

- . ,

. SPSSv18.0, Kaplan-Maier log rank test. : o ISS (P = 0.002, R = -0.323), -

(P < 0.001, R = +0.441). > 65 ., , , < 30 g/l,

2 (16.7%). - LDH > 480 U/l: 6 (50%) vs 11 (11.1%), P = 0.036; R = +0.409. – II + III (P < 0.001;

R = +0.658). VelDex 2 3 . 10 (83,3%) -

. 2 (16.7%) , 3 (25%) . -

, Ca, LDH 2M. , - MS. : -

MRI PET, . . - .

, : Borthezomib , -

.

: ; ; Bortezomib- ;

Summary. There is a small but well recognized in the clinical practice group of patients with multiple myeloma ( ), characterized by multiple bone lesions and a small tumour burden – the so called “macrofocal form” of MM. To analyze the incidence, clinical manifestation, therapeutic response and prognosis of the patients with macrofocal form of MM, treated with Bortezomib – containing regimens. 111 patients were studied, mean age

. - , . , . ... ... 39

58.2 ± 8.8 y, :F/1.05:1. Clinical stages were defined according to the ISS and the patients were treated with Bortezomib-containing regimens. In 12 (10.8%) of the patients, a macro-focal form of MM was proved. Therapeutic response was compared to the response in the classical form and a comparison of major parameters of the disease activity and bone metabolism was done. Statistics were performed by using the SPSSv18.0, the assessment of survival was done by the Kaplan-Maier method with a log rank test. The patients with macrofocal form of MM were predominantly in an early clinical stage acc to the ISS (P = 0.002, R = -0.323), significantly more frequent were the non- secretory and light – chain variants (P < 0.001, R= +0.441). There were no patients > 65y, severely anemic, with renal impairment, hypoalbuminemia < 30 g/l. Hypercalciemia was found in only 2 (16.7%) patients. The share of patients with macrofocal form with elevated LDH was significantly higher 6 (50%) vs 11 (11.1%), P = 0.036, R = +0.409. All the patients had generalized bone lesions, grade II + III acc to Merlini (P < 0.001; R = + 0.658). Patients with macrofocal form received therapy with VelDex as 2 and 3 line treatment. In 10 (83.3%) of the patients, therapeutic response was achieved with complete stationing of the bone lesions and alleviation of bone pain. In 2 (16.7%) of the patients, there were X-ray data of significant reduction in the size of the bone lesions; 3 (25%) underwent ASCT. After therapy, a significant increase of the AP level and decreases in Ca, LDH and 2M were found. By the time of analysis all the patients were in remission, no median of survival was formed. MRI and PET are very helpful in the diagnostics and monitoring of the macrofocal form of MM. They distinguish between the plasma cell infiltration of the bone marrow and osteolytic foci in the structure of the bone. Although this was a small group of patients, data confirm the findings from similar studies: the application of Bortezomib results in suppressing not only the activity of the disease, but bone resorbtion as well.

Key words: multuple myeloma; macrofocal form; bortezomib-containing regimens; therapeutic response

( ) ,

- , -

, . ( ) -

, , . . . -

. ,

- -

:

„ ” – , .

, -

, , Bortezomib (Velcade)-

.

111 ,

58,2 ± 8.8 . : /1.05:1. a ISS Velcade-

. 12 (10.8%) -

- , -

, . - -

- ,

. -

SPSSv18.0, Kaplan-Maier log rank test.

- o

ISS (P = 0.002, R = -0.323),

(P < 0.001, R = +0.441) ( . 1, 2).

- -

, > 65 ., -

, , - < 30 g/l, 2

(16.7%). -

LDH > 480 U/l: 6 (50%) vs 11 (11.1%), P = 0.036 R = +0.409. e Merlini – „ ” -

– II + III (P < 0.001; R = +0.658). -

- , -

( . 2). -

. . ., XLVI , 2011, 1-2 40

66,7%

22,2%

33,3%

42,4%

0

35,4%

0

10

20

30

40

50

60

70

ISS-I ISS-II ISS-III

.

. 1. (ISS)

16,7%

29,2%

0

64,6%

33,3%

6,2%

50.0%

00

10

20

30

40

50

60

70

IgA IgG BJ non-secr

.

. 2.

T 1.

< 65 . 12 (100%) 77 (77,8%) 0,154

12 (100%) 75 (75.8%)

0 24 (24.2%) 0,126

Hb > 80 g/l 12 (100%) 83 (83,8%)

Hb < 80 g/l 0 16 (16,2%) 0,363

Ca < 3,00 mmol/l 10 (83,3%) 86 (87,5%)

Ca > 3,00 mmol/l 2 (16,7%) 13 (12,5%) 0,584

LDH < 480 U/l 6 (50%) 88 (88.9%)

LDH > 480 U/l 6 (50%) 11 (11.1%) 0,036; R +0.409

beta2M < 3.00 mg/l 10 (83,3%) 44 (44,4%)

beta2M > 3.00 mg/l 2 (16,7%) 55 (55,6%) 0,083

Albumin > 30 g/l 12 (100%) 29 (29,3%)

Albumin < 30 g/l 0 70 (70,7%) 0,149

Merlini 0 0 26 (27,1)

Merlini I 0 58 (60.4%)

Merlini II + III 12 (100%) 12 (33.3%) < 0.001, R +0.658

2.

± S a ± S P

12.3 ± 2.7 63.12 ± 8.33 < 0.001

Hb 126.8 ± 79.2 100.46 ± 2.80 < 0.001

66.83 ± 5.52 157.42 ± 27.44 0.002

LDH 482.67 ± 43.29 318.83 ± 18.39 0.03

41.83 ± 1.59 35.46 ± 1.15 0.012

2 2.67 ± 0.34 6.92 ± 1.13 0.001

2.45 ± 0.06 4.08 ± 1.76 NS

180.6 ± 26.77 156.4 ± 10.43 NS

– 12.3 ± 2.7% , -, , , 2 , .

LDH 482.67 ± 43.29 vs 318.83 ± 18.39 ( = 0.03).

15 (13.0%) Velcade -, 42 (37.8%) VelDex, 42 (37,8%)

CyBorDex 12 (10.8%) PAD . - -

VelDex 2 3 .

VelDex 20.3 ., 7.3 ± 2.6 . 10 (83,3%) -

-

. 2 (16.7%) -

, 3 (25%) .

. - , . , . ... ... 41

, Ca, LDH 2M

( 3). , MS.

3. Velcade, -

± S

4- ± S P

180.67 ± 26.77 207.07 ± 24.45 0.026

2.45 ± 0.06 2.31 ± 0.04 0.002

LDH 482.67 ± 43.29 410.33 ± 34.29 0.05

2 2.67 ± 0.34 1.67 ± 0.12 0.003

-

[1], - /mm2

- GUS [2]. -

- .

, „ ”,

- . - -

„ ”, TNF- , TNF- , IL-1 , IL-6, IL-10, IL-11 -

hepatocyte growth factor (HGF), - – 2, 7, 9 (MMP), macro-

phage inflamatory protein (MIP-1 , MIP-1 ) [3].

OPG/RANKL Dickkopf protein-1 (DKK-1) -

[4-7].

- , -

. .

, -

, . Velcade - , o

,

[8].

.

. . AL- ,

- , -

- .

Velcade- [9]. -

, , -

. - , ,

/

. -

, , 2 .

- -

, - Durie & Salmon, - .

Smith et al., -, -

- 21 . 42

. [10]. ISS II -

. 2006 .

Dimopoulous et al. - 10/56 20 . , -

55% MS. -

- , 8 . [11]. - ,

. -

. -

- Velcade-

, , ,

. Zangari et al. 25% -

, CR + PR - ( )

[12]. Heider et al.

- [13].

. . ., XLVI , 2011, 1-2 42

, , a o

Velcade - NF-kB. ,

- RANKL, . . NF-kB .

MRI PET, - . . - . -

, - -

: Bortezomib - -

, .

1. V a l e n t i n - O p r a n , A. et al. Quantatitave histology of myeloma – induced bone changes. – Br. J. Hematol., 52, 1982, 601-610.

2. B a t a i l l e , R. et al. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. – J. Clin. Invest., 88, 1991, 62-66.

3. S e z e r , O. Myeloma bone disease: Recent advances in biology, diagnosis, and treatment. – Oncologist, 14, 2009, 276-283.

4. H e i d e r , U. et al. Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. – Biochem. Biophys. Res. Commun., 338, 2005, 687-693.

5. S e z e r , O. et al. RANK ligand and osteoprotegerin in myeloma bone disease. – Blood, 101, 2003, 2094-2098.

6. G i u l i a n i , N., V. Rizzoli et G. D. Roodman. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. – Blood, 108, 2006, 3992-3996.

7. T i a n , E. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. – N. Engl. J. Med., 349, 2003, 2483-2494.

8. T h e r p o s , E., O. Sezer et P. Croucher. Myeloma bone disease and proteasome inhibition therapies. – Blood, 110, 2007, 4, 1098-1104.

9. T e r p o s , E. et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. – Br. J. Haematol., 135, 2006, 5, 688-689.

10. D i m o p o u l o s , M. A. et al. Macrofocal multiple myeloma in young patients: a distinct entity with favorable prognosis. – Leuk. Lymphoma, 47, 2006, 8, 1553-1556.

11. S m i t h , D. B. et al. Non-secretory multiple myeloma: a report of 13 cases with a review of the literature. – Hematol. Oncol., 4, 1986, 4, 307-313.

12. Z a n g a r i , M. et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. – Br. J. Haematol., 131, 2005, 71-73.

13. H e i d e r , U. et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. – Eur. J. Haematol., 77, 2006, 3, 233-238.

: - - ,

” . ”

– . „ ” 15

4002 032 602 298

e-mail: vesselina_goranova@yahoo.com

. . ., XLVI , 2011, 1-2 43

T BORTEZOMIB

. 1, . - 2, . 2, . 2, . 1, . 2, . 1 . 1

1 , – 2 , ” . ”, –

REVERSAL OF THE RENAL FAILURE AFTER THERAPY WITH BORTEZOMIB IN PATIENTS WITH MULTIPLE MYELOMA

A. Nedeva1, V. Goranova-Marinova2, P. Georgiev2, I. Hristova2, J. Raynov1, St. Goranov2, I. Gigov1 and I. Nikolov1

1Clinic of Hematology, Military Medical Academy – Sofia 2Clinic of Hematology, University Hospital “Sv. Georgi”, Medical University – Plovdiv

. : - ( ) Bortezomib (Velcade®)-

( ). : 2006-2011 . a 111 , Bortezomib- , „ . ” – ,

– . 33 (29.7%) , 57.8 ± 9.1 . : /1.1:1. ISS- – 43 (38.7%) IgG 62 (55.9%). -

7/33 . , - (MS) „ ” „ ” .

( r). : , , LDH. -

ISS ( < 0.001, R = +0.659). - ( < 0.001, R = 0.292), 2 > 3,5 mg/l ( <

0.001, R = +0.614), < 35 g/l ( = 0.014, R = -0.312) ( = 0.033, R = +0.413). , LDH 2 mg/l - , Hb – (p < 0,05). (CR + VGPR + PR) - 84 (76.4%) 18 (75.0%) (NS).

Cr 15 (45.5%) , > 50% - 12 (36.4%). 14 .,

11 . 28 . (NS). MS 28 . 58 . ( < 0.005), MS a 51 . : Bortezomib

(Velcade®) - . (CR + VGPR) e -

80% . - , , .

: , , Bortezomib

Summary. Aim: To study the therapeutic response and the reversal of renal failure (RF) after therapy with Bortezomib (Velcade®) based regimens in patients with multiple myeloma. Patients and methods: For the period 2006-2011, 111 patients with , treated with Bortezomib – containing regimens were studied in two University Clinics of Hematology at the University Hospital “Sv. Georgi”, Plovdiv and Military Medical Academy, Sofia. In 33 (29.7%) RF was found. Mean age 57.8 ± 9.1y M:F/ 1.1:1. Patients in ISS- , 43 (38.7%), and these with IgG

. , . - , . ... … 44

variant, 62 (55.9%), were the predominat. 7/33 were on chroniodyalisis. The therapeutic response, its duration and the median of survival (MS) were compared between the groups with and without RF. Statistical analyses were performed by the using the SPSS v18.0. Results: No significant differences between the two groups were found in sex and age distribution, levels of and LDH. Patients with RF were predominantly in ISS- (p < 0.001, R = +0.659). In the group with RF, light-chain variants were significantly more frequent (p < 0.001, R = 0.292), the proportion of patients with level of 2 > 3.5 mg/l was significantly higher (p < 0.001, R = +0.614), so as patients with hypoalbuminemia < 35 g/l (p = 0.014, R = -0.312) and advanced bone lesions (p = 0.033, R = +0.413). Therapeutic response was achieved (CR + VGPR + PR) in 84 (76.4%) of the whole cohort and in 18 (75.0%) of the patients with RF (NS). Reversal to normal levels of serum creatinine after therapy was registered in 15 (45.5%), reduction with > 50% was found in 12 (36.4%) of the patients. Independence from hemodyalisis was achieved in 3/7 patients. ASCT was performed in 14 (17.9%) of the group without RF and in 6 (18.2%) of the group with RF (NS). Time to progression for the whole group was 14 mo, for the RF group 11 mo, and 28 mo for the patients without RF (NS). MS in the RF group was 28 mo vs MS 58 mo for the patients without RF ( < 0.005) and MS for the whole group was 51 mo. Conclusion: The application of Bortezomib-based regimens in patients with MM results in similar outcomes in patents at a standard risk and patients with RF. The high rate of therapeutic response (CR + VGPR) is combined with improved renal function in about 80%. Thus the first proteasome inhibitor is the only medicine by now which is applied without dose reduction and is therapy of choice in patients with MM and mild to moderate RF.

Key words: multiple myeloma, renal failure, Bortezomib

( ) - -.

( ) ,

,

.

- . Bor-

tezomib

, -

. , - , Bor-

tezomib- .

-

Bortezomib (Velcade®)-

.

2006-2011 . a 111 , Bortezomib-

- – ” . ” – ,

– . 33 (29.7%) , 57.8 ± 9.1 .

: /1.1:1. ISS- – 43 (38.7%), IgG 62 (55.9%) ( . 1).

1. (n = 111)

(%) (%)

59 (53,2)

52 (46,8) IgA 26 (23.4)

IgG 62 (55.9)

BJ 15 (13.5)

(ISS)

26 (23,5)

42 (37,8)

43 (38,7) 8 (7.2)

15 (13.0%) Velcade®

, 42 (37.8%) (Vel-Dex), 42 (37,8%) -

(CyBorDex) 12 (10.8%) – PAD

. 7/33 . , -

(MS) „ ” „ ”

. -

( r). EBMT . -

, ”independent

samples T-test” -,

- – Kaplan-Maier log rank test. -

Cox- - < 0.05

(SPSSv18.0 for Windows).

. . ., XLVI , 2011, 1-2 45

-

- , , , LDH -

( . 2).

2. (n = 111)

(%)

(%)

p, R

– –

47 (60.1) 31 (39.9)

12 (36.4) 21 (63.6)

NS

< 65 . > 65 .

59 (75.6) 19 (24.4)

31 (93.9) 2 (6.1)

NS

:

26 (33.3) 40 (51.3) 12 (15.4)

0 3 (9.1)

30 (90.9) P < 0.001,

R = + 0.665

Hb > 85 g/l Hb < 80 g/L

71 (90.2) 7 (9.8)

25 (75.8) 8 (24.2)

NS

> 35 g/l < 35 g/l

64 (82,1) 14 (17,9)

17 (51.5) 16 (48.5)

P = 0.014, R = -0.312

2M < 3,5 mg/l 2M > 3,5 mg/l

55 (70.5) 23 (29.5)

12 (6.1) 31 (93.9)

P < 0.001, R = +0.614

LDH < 480 U/l LDH > 480 U/L

69 (88.5) 9 (11.5)

23 (75.8) 8 (24.2)

NS

Ca < 3.00 mmol/l Ca > 3.00 mmol/l

72 (92,3) 6 (7.7)

22 (69,7) 11 (33,3)

P = 0.04, R = + 0.0243

0 26 (33,3) 6(18,2)

1 44 (56.4) 12 (36,4)

MK 2 + 3 8 (10,3) 15 (45,4)

P = 0.033, R = +0.413

ISS

( < 0.001, R = +0.659). - - - ( < 0.001, R = 0.292), -

2 > 3,5 mg/l ( < 0.001, R = +0.614), < 35 g/l ( =

0.014, R = -0.312) - ( = 0.033, R = +0.413).

, LDH 2 mg/l - –

, Hb – (p < 0,05). , - / -

- ( . 3). 1.

Velcade®, -, 1.3 mg/m2 21-

- CyBorDex D. -

Velcade®

- 15 (45.5%) / 9 (11.5%), = 0.015.

20,3 ± 8,1 . 16.1 ± 5.8 . .

4 r – 185 ±

59,5 333,53 μmol/l ( < 0,01), Hb – 97,33 ± 5,0 g/l 120 ± 56, – 32,8 ± 2,37 g/l 38,2 ± 2,4, 2 – 8,25 ± 2,56 / 13,64 ± 2,77 mg/l.

, Velcade®- ,

– > 0.05 ( . 1).

3.

(N Sx ± SEM)

(N Sx ± SEM)

– . 59.5 ± 0.96 53.7 ± 1.63 0.03

Hb (g/l) 101,26 ± 10,88 82,21 ± 15,21 0.017

A – g/l 37.65 ± 1.14 31.92 ± 2.19 0.016

B2M – mg/l 3.61 ± 0.39 14.68 ± 2.49 < 0.001

LDH – UI 421,56 ± 24,46 621,32 ± 33,39 0.023

– mmol/l 2,42 ± 0,12 2,71 ± 0,18 0.02

– g/24 h 0.357 ± 0.162 2.500 ± 0.446 0.03

9.0%

18.2%12.8%

3.0%

9,0%

21.2%

38.5%

33.3%

9,0%6.1%

21.8%

18,2%

0

5

10

15

20

25

30

35

40

.SD MR PR VGPR CR

*CR ; PR – ; VGPR –

. 1.

(CR + VGPR + PR) 84 (76.4%) 18

(75.0%) (NS). Cr 15

(45.5%) , > 50% 12 (36.4%). -

3/7 .

14 (17.9%) 6 (18.2%) (NS).

2. -

- - -

. , . - , . ... … 46

, -

Velcade®- ( . 4).

4. - Velcade®- -

(%)

(%)

17 (21.8%) 4 (12.1%) NS

24 (30.8%) 10 (30.0%) NS

36 (40.6.%) 15 (45.5%) NS

25 (32.1%) 10 (30.3%) NS

13 (16.7%) 6 (18.1%) NS

4 (5.11%) 1 (3.03%) NS

- - : -

Velcade® 1.0 mg/m2 e 8 (24.2%) 0.7 mg/m2.

1.0 mg/m2 19 (24.4%) 7 (8.9%) 0.7 mg/m2. 3. ,

Velcade®

14 ., 11 . 28 . (NS). -

MS 28 . 58 . ( < 0.005). -

MS 51 . ( . 2 3).

,

- ( . 5).

-

20-45%, –

29,7% . - , - , -

. -

MS - 18-22 . - , - ,

[1].

40-50% 1-3 .

-.

- (PR) , e [1-2]. -

Velcade® - , -

, . APEX,

CREST/SUMMIT VISTA , Velcade® , > 75% -

, 50%

[3-5].

5. – Cox- e

SE Exp B

-0.372 0.451 0.690 0.41 (NS)

ISS -0.180 0.102 0.836 0.07 (NS)

1.117 0.304 3.054 < 0.001

. 2. MS . 3.

. . ., XLVI , 2011, 1-2 47

: 27 (81.9%) -

, 15 (45.5%) a -

[6-8]. –

- ( . 3). -

Velcade® .

- , 84 (76.4%) 18 (75.0%) . -

, , -

, 2 . Velcade®

, - -

. MS MM , Velcade®, 28 . MS 20 ., -

- [9].

e Velcade® -

-

. -

( . 4)

.

Velcade® . -

-,

- - -

. Velcade® - -

3 .

Bortezomib (Velcade®) - .

(CR + VGPR) e

80% . -

, , –

400 μmol/l [10-11].

Velcade - ,

. . AL- . - -

.

,

[12-13].

1. A l e x a n i a n , R. A., B. Barlogie et D. Dixon. Renal Failure in

Multiple myeloma. – Arch. Intern. Med., 150, 1990, 1693-1695. 2. B l a d e , J. et al. Renal Failure in Multiple myeloma:

presenting features and predictors of outcomein 94 patients from a single institution. – Arch. Intern. Med., 158, 1998, 1889-1893.

3. S a n - M i g u e l , J. F. et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. – Leukemia, 22, 2008, 842-849.

4. J a g a n n a t h , S. et al. SUMMIT/CREST Investigators: Bortezomib in recurrent and/or refractory multiple myeloma: initial clinical experience in patients with impaired renal function. – Cancer, 103, 2005, 1195-1200.

5. D i m o p o u l o s , M. A. et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. – J. Clin. Oncol., 27, 2009, 6086-6093.

6. M o r a b i t o , F. et al. Safety and efficacy of bortezomib-based regimens for multiple myeloma patients with renal impairment: a retrospective study of Italian Myeloma Network GIMEMA. – Eur. J. Haematol., 84, 2010, 223-228.

7. R o u s s o u , M. et al. Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents. – Leuk. Res., 34, 2010, 1395-1397.

8. L u d w i g , H. et al. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. – J. Clin. Oncol., 28, 2010, 4635-4641.

9. , . - : , -

, , -. , . 24, , 2008 .

10. C h a n a n - K h a n , A. A. et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. – Blood, 109, 2007, 2604-2606.

11. K n a u f , W. U. et al Bortezomib in relapsed multiple myeloma: results of a non-interventional study by office-based haematologists. – Onkologie, 32, 2009, 175-180.

12. D i m o p o u l o s , M. A. et al. Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors. – Clin. Lymphoma Myeloma, 9, 2009, 302-306.

13. S i n i s c a l c h i , A. et al. Bortezomib-based therapy as induction regimen of an autograft program in front-line treat-ment of multiple myeloma with endstage renal disease. – Ann. Hematol., 89, 2010, 821-822.

: -

. „ . ” 3 1606

02 9225662

. . ., XLVI , 2011, 1-2 48

FLUDARABINE + CYCLOPHOSPHAMIDE + RITUXIMAB (FCR) FLUDARABINE + CYCLOPHOSPHAMIDE (FC)

: . 1, . 1, . 1, . 1, . 1, . 2, . 3, . 2,

. 3, . 1, . 1, . 1 . 1 1 , 2 , 3

– o

FLUDARABINE + CYCLOPHOSPHAMIDE+RITUXIMAB (FCR) vs FLUDARABINE + CYCLOPHOSPHAMIDE (FC) IN THE TREATMENT

OF CHRONIC LYMPHOCYTIC LEUKEMIA: THE EXPERIENCE OF SINGLE CENTRE A. Nedeva1, J. Raynov1, I. Nikolov1, D. Yonova-Kindekova1, R. Stanchev1, L. Mitev2, D. Popova3,

. Boneva2, R. Vladimirova3, I. Damiyanov1, R. Petrova1, I. Gigov1 and . Kancheva1 1Clinic of Hematology, 2Cytogenetic Laboratory, 3Laboratory of Immunology, Military Medical Academy – Sofia

. : FCR FC ( ). : 28 , 21

(75.0%) 7 (25.0%) 59.6 (42-74) . .

( ) BD FACSort, CellQuest, v-10 ( ZAP-70 CD38) FISH . IWCLL 2008 . (PFS) -

(CTCAEv3; ). SPSS, v-9. : 2004-2011 . -

132 , 56 (42.4%) - (14 – FCR, 39 – FC, 3 – F). FCR , 7 (50.0%) / -

. FC 14 . - (ORR) 92,9% . (CR) 42,9% FCR - 7,1% FC (p < 0,05). PFS 18.9 . FCR 17.4 . FC (p > 0,05).

(35.7% FCR 28.6% FC) (14.3% FCR ), – 1-4 . (57.1% – FCR, 35.7% – FC) 1-4 . (50.0% ). : -

, - FCR FC.

.

: , , ,

Summary. Aim: a comparative analysis of the efficacy and toxicity of FCR and FC regimens in patients with chronic lymphocytic leukemia (CLL). Material and methods: 28 patients were assessed, 21 (75.0%) of them male and 7 (25.0%) female at the average age of 59.6 (42-74) years. Diagnosing and staging were performed according to standard algorithms. Three-color flow cytometry with BD FACSort analyser, CellQuest, v-10 program (for ZAP-70 and CD38) and FISH-analysis were used for the prognostic stratification. Response assessment was performed, using the IWCLL 2008 criteria. Progression-free survival (PFS) was assessed, as well as the safety of the two regimens (CTCAEv3; Grading scale for hematologic toxicity in CLL studies. The program SPSS v-9 was used for the processing of results. Results: Over the period 2004-2011, 132 CLL-patients were analyzed, 56 (42.4%) of which were treated with Fludarabine-based therapy (14 – FCR, 39 – FC, 3 – F). 7 (50.0%) of the

. , . , . ... Fludarabine + Cyclophosphamide + Rituximab (FCR) … 49

patients, treated with FCR, were newly-diagnosed and/or untreated. The comparative FC-group consisted of 14 patients with similar clinical characteristics. The overall response rate (ORR) in both groups was 92.9%. Complete remission (CR) was achieved in 42.9% of the FCR group vs 7.1% of the FC-group (p < 0.05). The PFS at the point of the analysis was 18.9 months in the FCR group vs 17.4 months in the FC group (p > 0.05). The non-hematologic toxicity included infectious complications (35.7% – FCR vs 28.6 % – FC) and infusion reactions (14.3% only in the FCR group), and the hematologic toxicity - thrombocytopenia grades 1-4 (57.1% – FCR vs 35.7% – FC) and neutropenia grades 1-4 (50.0% in both groups). Conclusion: Regardless of the small number of the analyzed patients, the preliminary results confirmed the higher efficacy of FCR, compared to FC. The survival data were inconclusive, because of the short follow-up period in some of the cases.

Key words: chronic lymphocytic leukemia, chemoimmunotherapy, efficacy, toxicity

( )

- 25%

[1]. - 72 ., -

, 75 . - 4.2 [1, 5, 16]. -

10 ., - 3 . -

.

; ( 2- );

, FISH: 17p-, 11q-, +12, 13q-; IgVH -

: ZAP-70 CD38 [11, 12]. -

. 90- - -

, - ( )

, -

, [3]. ( -CD20 FC – FCR )

/ , .

- -

FCR FC, - .

2004-2011 . - – ,

132 , 56 (42.4%) - -

. 14 (10.6%) - (FCR), 39 (29.5%) – FC, 3 (2.3%) –

. - . 1.

1. (n = 132)

(%)

132 (100%)

- 56 (42,4%)

FCR 14 (10,6%)

FC 39 (29,5%)

F- 3 (2,3%)

28 (100%)

FCR 14 (50%)

FC 14 (50%)

28,

59.6 (42-74) ., - : 21 (75.0%) 7 (25.0%) .

- 14 , FC,

.

Rai Binet . - FCR Rai :

( . .) 0 – 1 (7.1%), . . II – 7 (50.0%), . . III – 2 (14.3%), . . IV – 4 (28.6%), FC – . . 0 – 1 (7.1%), . . I – 1 (7.1%), . . II – 6 (42.9%), . . III – 3 (21.4%), . . IV – 3 (21.4%).

Binet (FCR FC): . . – 4 (28.6%), . . – 4 (28.6%), . . – 6 (42.9%).

-

. 2. FCR -

59.6 (43-69) ., FC – 59.8 (42-74) . :

12 (85.7%), – 9 (64.3%).

. . ., XLVI , 2011, 1-2 50

, / .

2. FCR FC (n = 28)

( . .)

FCR -

FC -

Rai:

0* 1 (7,1%) 1 (7,1%) 2

* – 1 (7,1%) 1

* 7 (50,0%) 6 (42.9%) 13

2 (14,3) 3 (21.4%) 5

V 4 (28,6) 3 (21.4%) 7

Binet:

4 (28.6%) 4 (28.6%) 8

4 (28.6%) 4 (28.6%) 8

6 (42.9%) 6 (42.9%) 12

*

(ZAP-70 CD38)

( - ) BD

FACSort, CellQuest, v-10. FISH - .

IWCLL 2008 [9]. -

(PFS). -

(Hallek at al., 2008) [9], a -

CTCAEv3 [2].

FC - (25 mg/m2 .) -

(250 mg/m2 .) 1- 3 , FCR -

375 mg/m2 0 500 mg/m2 1 . -

28 4 (2-6) FCR 3.6 (2-6) FC .

-.

SPSS, v-9.

FCR - (ORR) 13 (92,9%) - (CR) – 6 (42,9%) .

FC e ORR 92,9%, CR 1 (7.1%) – . 3.

3. FCR FC (n = 28)

FC (n = 14) (%)

FCR (n = 14) (%)

CR 1 (7.1%) 6 (42.9%) p = 0.03

PR/nPR 12 (85.7%) 7 (50.0%)

ORR 13 (92.9%) 13 (92.9%) p = 1.0

SD 0 1 (7.1%)

PD 1 (7.1%) 0

-

CR FCR, FC (p = 0.03).

PFS 18.9 (3-39) . FCR 17.4 (5-44) .

FC , 7 (50.0%) .

(p = 0,7) – . 1.

. 1. , - FC FCR

OS - -

, 11 (78.6%) - .

, - FCR -

- : del(11q),

del(17p) 12. - , del(11q)

del(17p), (PR). - (

del(17p) del(11q) – . 4 . 2. -

- .

(35.7% FCR 28.6% FC)

(14.3% – FCR) – . 5.

. , . , . ... Fludarabine + Cyclophosphamide + Rituximab (FCR) … 51

4. FCR (n = 14)

FISH Zap-70 ( 20%)

CD38 ( 30%)

2-( 4)

PFS ( .)

1. 17 - (-) . – PR 14

2. 11q- (+) . (+) . CR 24*

3. 13q- – – PR 4

4. 11q- (+) . (+) . PR 19

5. 13q- – (+) . SD 3

6. 13q- (-) . (+) . CR 25*

7. – – (+) . PR 39*

8. 17p- (-) . (+) . PR 15*

9. +12 (+) . (+) . PR 11

10. 11q- – (+) . CR 36

11. +12 (-) . (-) . CR 14*

12. 17p- – (+) . CR 31*

13. 11q- (-) . (+) . PR 24

14. 17p- – (+) . CR 6*

*PFS

. 2. in situ , p53 (17p13) (2R/1G). -

–

5. , FC FCR

(%)

FC FCR

Grade 1 0 0

Grade 2 2 (14.3%) 0

Grade 3 2 (14.3%) 4 (28.6%)

Grade 4 0 0

Grade 5 0 1 (7.1%)

4 (28.6%) 5 (35.7%)

FC FCR

Grade 1 0 1 (7.1%)

Grade 2 0 1 (7.1%)

Grade 3 0 0

Grade 4 0 0

0 2 (14.3%)

, - FCR

. -, , -

, ( ) 1 2 .

(1-4 .) 57,1% FCR

35.7% FC (1-4 .), - 50.0% -

( . 6).

6. , - FC FCR

(%)

FC FCR

Grade 1 3 (21.4%) 1 (7.1%)

Grade 2 1 (7.1%) 2 (14.3%)

Grade 3 3 (21.4%) 1 (7.1%)

Grade 4 0 3 (21.4%)

7 (50.0%) 7 (50.0%)

FC FCR

Grade 1 0 0

Grade 2 5 (35.7%) 4 (28.6%)

Grade 3 0 3 (21.4%)

Grade 4 0 1 (7.1%)

5 (35.7%) 8 (57.1%)

-

FCR : 4 . - (21.4%) 3 . – (7.1%) .

, FC, - -

. . ., XLVI , 2011, 1-2 52

3 . (21,4%) . - -

, - : 3-4 . -

(28.6%) , FC 2 . .

FCR -

-/ ,

. III .

REACH , , , III -

, - R-FC FC -

CD20 [14]. T. Robak et al.

, (ORR) - R-FC FC (70% 58%, p = 0.0034), -

(CR) (24% 13%, p = 0.0007). (PFS) 10 R-FC ,

.

FC - ,

.

(GCLLSG) , - 3 , CLL8, -

FCR FC

[8]. ORR - FCR (90%) FC (80%; p < 0.0001). -

CR FCR 44% 22% FC (p < 0.0001). 65%

( PFS 51.8 ) 45% -

( PFS 32.8 -; p < 0.0001).

FCR 87%, FC – 83% (0.67 [0.48–0.92]; p = 0.01). FCR -

CTC 3 4 - (47% FC 62% FCR). FCR

- -/ ,

. , FCR -

-

. , - [8].

- CLL8 , del(17p)

- . Del(17p) -

p53 -- [4, 10,

17]. ,

del(11q), CR e 3 - FCR [8]. , - [15], ,

- del(11q). -

, -, 12

del(13q) [8]. , -

-

. , ,

, , -

. -

-.

FCR , - 4 - - .

- - -

.

: del(17p) del(11q), -

. del(17p) -

,

. : FCR FC,

(HDMP) -, ± - . CR

PR - , .

-: , -

. , . , . ... Fludarabine + Cyclophosphamide + Rituximab (FCR) … 53

, ± , HDMP ± . [6, 7, 13].

del(11q), 70- ,

FCR . / -

a , FCR - , -

± . FCR -

, 70 [6, 7, 13].

-

: FCR 70 . / [6, 7, 13].

-, -

- FCR FC.

- FCR. - e

.

1. A l t e k r u s e , SF. et al. SEER Cancer Statistics Review,

1975–2007. National Cancer Institute, Bethesda, MD 2010. 2. C a n c e r Therapy Evaluation Program, Common

Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS, March 31, 2003 (http://ctep.cancer.gov).

3. C a t o v s k y , D. et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. – Lancet, 370, 2007, (9583), 230-239.

4. D o e h n e r , H. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. – N. Engl. J. Med., 343, 2000, 1910-1916.

5. E i c h o r s t , B., V.Goede et M.Hallek. Treatment of elderly patients with chronic lymphocytic leukemia. – Leuk. Lymphoma, 50, 2009, 2, 171-178.

6. E i c h o r s t , B. et al. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. – Ann. Oncol., 22, 2011, 6, 50-54.

7. G r i b b e n , J. G. et S. O'Brien. Update on therapy of chronic lymphocytic leukemia. – J. Clin. Oncol., 29, 2011, 5, 544-550.

8. H a l l e k , M. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. – Lancet, 376, 2010, 1164-1174.

9. H a l l e k , M. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. – Blood, 111, 2008, 5446-5456.

10. K a y , N. E., S. O’Brien, A. Pettitt et S. Stilgenbauer. The role of prognostic factors in assessing ‘high-risk’ subgroups of patients with chronic lymphocytic leukemia. – Leukemia, 21, 2007, 1885-1891.

11. M o n t s e r r a t , E. et C. Moreno. Genetic lesions in chronic lymphocytic leukemia: clinical implications. – Curr. Opin. Oncol., 21, 2009, 609-614.

12. M o r e n o , C. et E. Montserrat. New prognostic markers in chronic lymphocytic leukemia. – Blood, 22, 2008, 4, 211-219.

13. N C C N Clinical Practice Guidelines in Oncology, Version 4.2011.

14. R o b a k , T. et al. Rituximab, fludarabine, and cyclophosphamide (R-FC) prolongs progression free survival in relapsed or refractory chronic lymphocytic leukemia (CLL) compared with FC alone: final results from the international randomized phase III REACH Trial [abstract]. – Blood, 112, 2008, lba-1.

15. T s i m b e r i d o u , AM. et al. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. – Cancer, 115, 2009, 2, 373-380.

16. Y a n c i k , R. Cancer burden in the aged: an epidemiologic and demographic overview. – Cancer, 80, 1997, 1273-1283.

17. Z e n z , T. et al. TP53 mutations and outcome after fludarabine and Cyclophosphamide (FC) or FC plus Rituximab (FCR) in the CLL8 Trial of the GCLLSG. – Blood (ASH Annual Meeting Abstracts), 114, 2009, 1267.

:

-

. „ . ” 3

1606 922 5662

. . ., XLVI , 2011, 1-2 54

!

. 1, . 1, . 1, . 1, . 1, . 2, . 2,

. 3, . 2, . 2, . 2, . 1, . 1, . 1, . 1, . 1, . 1, . 2 . 1

1 ,

– 2 - ,

– 3 , „ . ” –

IS THERE A CURATIVE POTENTIAL OF AUTOLOGOUS STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA PATIENTS.

THE ROLE OF INDUCTION THERAPY P. Ganeva1, G. Arnaudov1, J. Jechev1, M. Minchef1, I. Tonev1, M. Guenova2, G. Balatzenko2,

L. Gercheva3, S. Angelova2, N. Stoyanov2, S. Ivanova2, V. Hrischev1, B. Spassov1, V. Varbanova1, K. Ignatova1, T. Jankova1, K. Mishovska1, S. Toshkov2 and G. Mihaylov1

1Hematology Clinic, National Specialized Hospital for Active Treatment of Hematological Diseases – Sofia 2Consultative Diagnostic Block, National Specialized Hospital for Active Treatment of Hematological Diseases – Sofia

3Hematology Clinic, University Hospital “Sveta Marina” – Varna

. ( ) - ( ) < 65 ., - ( R),

(OS) (DFS). - ( ) VAD .

, , (Vel/Dex) (n = 37) VAD (n = 29).

( ) (Vel/Dex 3.75 106/kg ; VAD 3.23 106/kg ), ( 2.7 106/kg 2.5 106/kg ).

- (Vel/Dex + 11.1 VAD + 11.2) ( + 12.5 +

12.0). OR 2- (92% vs 92.8%), - OS - Vel/Dex VAD [ 3.4 21.6%; 98.4%

76.5% (p < 0.001)], DFS 73% 59.3%. 5 , 2- -

, . -

- .

: , , , -

. , . , . ... … 55

Summary. Autologous stem cell transplantation (ASCT) is a standard in the treatment of patients with multiple myeloma (MM) aged < 65 years, achieving better overal response (OR), overal survival (OS) and disease-free survival (DFS). In recent years induction therapy (IT) i.e. VAD is being replaced by new targetted agents (Velcade) with high anti-myeloma activity. We performed a retrospective analysis of patients with MM who received bortezomib-containing regimens (n = 37) or VAD (n = 29) to analyze the role of IT on long term results. No changes were found in yield of stem cells (SC) (Vel/Dex 3.75 106/kgbw; VAD 3.23 106/kgbw), as in the number of infused SC (2.7 106/kgbw vs 2.5 106/kgbw). There were no differences in the time of hematological recovery; neutrophils engraftment was as follows (after Vel/Dex on day + 11.1 vs after VAD on day + 11.2) and for plateletes (on day + 12.5 vs day + 12.0). OR before ASCT in the 2 groups was similar (92% vs 92.8%), but the achievment of CR and OS was better in Vel/Dex group/VAD [respectively 3.4 vs 21.6%; 98.4% vs 76.5% (p < 0.001)], while in the case of DFS, a difference was found 73% vs 59.3%. For the entire period of observation after ASCT we recorded only 5 deaths, two with early death (TRM) and 3 because of the diseases progression. Based on these results it is possible to recommend to change the IT with Bortezomid in the new induction regimens, because of the better theraputic response and no toxicity on stem cells.

Key words: autologous stem cell transplantation, mobilzation, engraftment, multiple myeloma

( ) -

( : 4.5-6.0/100 000/ .). ( 63-70 .), 2% -

< 40 ., , .

( )

( ) - MM 65 .,

75 . - . -,

- [3].

,

(VAD) . . , -

.

– [complete remission (CR)] -

[very good partial response (VGPR)] , -

- [4]. .

(IFM phase II study) [10-12], - -

IFM 2005/01 /VAD -

. (66 -) -

,

- - ( )

2009 .- 2011 .

66

, -

. ( - -

, , -

/ , , - ), Durie Salmon ISS [12].

-

. 29 - VAD/VAD- , 37 – -

(Velcade) (Vel/Dex). 14 Vel/Dex

- , 23 – Velcade

/ -

.

58.6 . ( 39-67 .), 41 (62%)

25 (38%). 15 (22.7%)

( . 1).

. . ., XLVI , 2011, 1-2 56

1. ,

(n = 66) %

( ) 58.6 . (39-67)

: / 25/41 38/62

IgG – 24 36.6

IgG l – 11 16.6

IgA k,l – 15 22.4

BJ k +BJ k urine – 9 13.1

Non secretory – 7 10.3

IgM – 0

-

IgD – 0

a n = 15 22.7%

ISS 3 n = 26 39.3%

-

[granulocyte–colony stimulating factor (G-CSF)] 10 g/kg/ 55 ,

+ G-CSF 6 , 5 + (

. . „ ") ( . 2).

2.

Vel/Dex (n = 37) VAD (n =29)

( ) 52.7 (42-63) 53.6 (41-67)

: / 23/14 18/11

:

G-CSF 33 22

HD Endoxan + G-CSF 0 6

G-CSG + Mozobil 4 1

55 (83.35%) -

200 mg/m2, 11 (16.65%) -

140 mg/m2 ( - ).

,

, -

o Blade . [13],

(VGPR) - - [International Uniform Response Criteria (IURC)]

[12] European Group for Blood and Bone Marrow Transplant (EBMT).

Kaplan–Meier

- [Disease-free survival (DFS)] -

[Overall survival (OS)].

. -

, / . (follow-up)

15.1 ( : 3-30 .). 30.09.2011 .

,

: 1. , -

(CD34+)

3.54 106/kg (1.62-8.92 106/kg ),

, 3.75 106/kg

Vel/Dex 3.23 106/kg – VAD.

2.9 x 106/kg (1.4-6.9 106/kg ). : 2.7 106/kg

Vel/Dex 2.5 106 /kg VAD .

2. ( -)

( -

Melphalan 200 mg/m2). - ( )

, - . - + 11.2

VAD + 11.1 – Vel/Dex , – + 12 VAD

– + 12.5 Vel/Dex -, .

3. –

30.09.2011 . ,

. 3, [overall response (OR)]

92/92.8%.

: 3.4/21.6%

. , . , . ... … 57

3. /

VAD vs Vel/Dex

(30.09.2011) VAD

vs Vel/Dex

CR 1/(3.4%) 8/(21.6% ) 8/(28.6%) 15/41.6%)

VGPR 15/(51.7%) 16/(43.2%) 9/(32.1%) 9/(25%)

PR 11/(37.9%) 11/(29.7%) 4/(14.2%) 4/(11.1%)

PROGR 2/(6.8%) 2/(5.4% ) 7/(25% ) 7/(19.4%)

OR 27/( 92%) 34/(92.8%) 4.

. 1, 2, 3 4, OS , - Velcade (98.4%),

- VAD (76.5%), (p < 0.001).

- (DFS) 73% Velcade

59.3% VAD (p < 0.709).

5. - (TRM) -

2 (3%) - [Treatment related morta-

lity (TRM)], .

- (Enterococcus

faecalis) ( +15), - – -

( +19).

(30.09.2011 .) - / 61 (92.4%)/5

(7.6%), 3- , -

.

( OS )(n=66)

85,6%

VAD

Vel/Dex

p= 0,175

OS :Vel/Dex vs VAD

98,4%

76,5%

. 1.

(n = 66) . 2.

: Vel/Dex VAD

63,1%

, (DFS) (n= 66)

DFS- VAD vs Vel/Dex

Vel/Dex

VAD

p=0.709

59.3%

73%

. 3.

(DFS) (n=66) . 4. -

: Vel/Dex VAD

. . ., XLVI , 2011, 1-2 58

-

, -

. - ,

. -

. -

, , ,

[9, 10]. - , -

,

(CR + VGPR), e [5, 6, 7, 8, 9].

, -

, -

. - . . „ -

” , , - , ,

[16, 17]. , -

- -. -

( + 11-12) -

. - TRM (3%), ,

TRM 3 20% [18].

, ,

,

(92/92.8% 96%) [9, 10]. -

, , Vel/Dex, “ ”, . . - -

(23, 2/3)

Velcade . -

. -

-

. - , -

- ,

, , - - .

(CR VGPR)

- - - [11,

18]. IMF90 -, , -

OS [9, 10, 14, 15]. , OS

, Velcade, e - - VAD

– 98.4% 76.5% (p < 0.001). -

Velcade DFS, (73% - 59.3% VAD ; p < 0.709).

, - -

CR/VGPR, ,

. - -

, - .

, - ,

.

.

: - CVP/01-0119 –

DO-02-35/09 03/51 12.12.2011 – „ - ” -

, .

1. C h i l d , J. A. et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. – N. Engl. J. Med., 348, 2003,1875-1883.

2. A t t a l , M. et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. – N. Engl. J. Med., 335, 1996, 91-97.

3. B a r l o g i e , B. et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. – Blood, 93, 1999, 55-65.

4. K u m a r , S. K. et al. Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT. – Bone Marrow Transplant., 41, 2008, 1013-1019.

. , . , . ... … 59

5. H i d e s h i m a , T. et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. – Blood, 101, 2003, 1530-1534.

6. R i c h a r d s o n , P. G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. – N. Engl. J. Med., 348, 2003, 2609-2617.

7. R i c h a r d s o n , P. G. et al. Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. – N. Engl. J. Med., 352, 2005, 2487-2498.

8. J a g a n n a t h , S. et al. Bortezo-mib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. – Br. J. Haematol., 129, 2005, 776-783.

9. H a r o u s s e a u , J. L. et al. Bor-tezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. – Haematologica, 91, 2006, 1498-1505.

10. H a r o u s s e a u , J. L. et al. VEL-CADE / dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 Trial. – Blood, 110, 2007, (abstr. 450).

11. D u r i e , B. G. et al. International Myeloma Working Group. International uniform response criteria for multiple myeloma. – Leukemia, 20, 2006, 1467-73.

12. B l a d é , J. et l. Crite-ria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplan-tation. Myeloma Subcommittee of the EBMT. European

Group for Blood and Marrow Transplant. – Br. J. Haematol., 102, 1998, 1115-1123.

13. A l e x a n i a n , R., B. Barlogie et S. Tucker. VAD-based regimens as primary treatment for multiple myeloma. – Am. J. Hematol., 33, 1990, 86-89.

14. L e n h o f f , S. et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study: Nordic Myeloma Study Group. – Blood, 95, 2000, 7-11.

15. S i n g h a l , S. et all. Respon-se to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma. – Bone Marrow Transplant., 30, 2002, 673-679.

16. J a n t u n e n , E. et al. Addition of plerixafor to a chemotherapy plus G-CSF mobilization in hard-to-mobilize patients. – Bone Marrow Transplant., 46, 2011, 2, 308-309

17. B e n s i n g e r , W., J. F. DiPersio et J. M. McCarty. Improving stem cell mobilization strategies: future directions. – Bone Marrow Transplant., 45, 2009, 181-195.

18. B u c k n e r , C. D. Treatment of Multiple Myeloma: An Update from the EBMT 2004 March 28-31, 2004 Barcelona, Spain.

: -

. „ ” 6 1756

(02) 9701 237

. . ., XLVI , 2011, 1-2 60

JAK2

. 1, . 2, . 2 . 1 1 , –

2 – –

MOLECULAR-BIOLOGICAL STUDY OF JAK2 MUTATIONS EMERGED IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE DISORDERS

V. Uzunova1, R. Stanchev2, I. Gigov2 and L. Mitev1 1Department of Clinical Laboratoty and Immunology, Military Medical Academy – Sofia

2Clinic of Hematology, Military Medical Academy – Sofia

. JAK2 .

( ) 12 617, - .

Jak2 e - ( ), ( ) ( ).

- . 42- , 22-

, 13 – , 3- 4- / ( / ).

( CR) e - - . JAK2 -

29 (69%), 18 , 8 , 2 1 / . - , 28% -

(20%). , JAK2 - ,

.

: , , , , JAK2

Summary. Protein product of the JAK2 gene is a cofactor of the erythropoietin receptor and is involved in regulation of erythrocyte proliferation. JAK2 gene mutated in nearly all nonleukemic myeloproliferative chronic disorders (HMPD) in exon 12 at position 617, leading to the induction of erythropoietin-independent cell signaling. Therefore, mutation of JAK2 is one of the most important laboratory markers for the diagnosis of polycythemia (PV), idiopathic myelofibrosis (IMF) and essential thrombocyithemia (ET). The aim of this study was to determine the frequency of the mutation in different HMPD and quantity of mutant cells in individual patients. We examined 42 patients: 22 with polycythaemia vera, 13 with essential thrombocythemia, 3 with idiopathic myelofibrosis and 4 with myelodysplastic/myeloproliferative syndromes (MDS/MPS). Mutation study was performed by applying a real time polymerase chain reaction. JAK2 mutation was detected in 29 cases (69%), 18 with PV, 8 with ET, 2 with IMF and 1 with MDS/MPD. Quantitative analysis showed that the average frequency of mutant cells in PV was 28% and was higher than in ET (20%). The study confirms that JAK2 mutation is a major indicator for laboratory diagnosis of HMPD and that the test is essential to distinguish PV, ET and IMF from different reactive conditions.

Key words: myeloproliferative chronic disorders, polycythemia, idiopathic myelofibrosis, essential thrombo-cyithemia, JAK2 mutation

. , . , . ... JAK2… 61

-

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,

- . JAK2 65 97%

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- ,

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[3]. - PCR

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.

PCR 44

, [1]: 25 , 14

5 . iPrepTM.

. -

- ( - )

MutaScreen (Ipsogen). - R -

Applied Biosystem. JAK2

. -

6 : 2-5%, 5-12.5%, 12.5-31%, 31-50%, 50-78% 78-100% . 13

- in situ

- 9. JAK2 - ,

JAK2 - -

.

. 1 2.

44 30 JAK2

(70%). 18 (72%) , 9 (64%) – 3 (60%) – ( . 1) PCR

, JAK2 - 3% 89%

( 26.8%): 3% 89% ( 28%), 8% 40% ( 20%)

8.8% 89% ( 35,5%)( . 2 ). e

, - 5-12.5%,

12.5-31% . ,

( 50-78% 78-100%), -

. - - 31 50% ( . 2 ). -

, - JAK2 -

, JAK2 , - JAK2 -

. - JAK2

- JAK2 , -

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. -

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- [2].

- -

. , -

. -

PCR JAK2 . -

. . .

- JAK2 [2].

. . ., XLVI , 2011, 1-2 62

JAK2 ,

- – [2].

. - ( .

3 ). ,

( . 2). ,

,

. , - -

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.

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)

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. ) in situ 9, 9

1.

/ JAK2

JAK2-

JAK2

1 . . . + 89%

2 . . . /48 + 89% 46,XY[11]/47XY,+9[1]

3 . . . /63 + 64% 46,XY[11]

4 . . . /70 + 40% 46, [11]

5 . . . /57 + 40%

6 . . . /61 + 21%

7 . . . /75 + 21%

8 . . . /56 + 8%

9 . . . /27 + 8%

10 . . . /64 + 8% 45,XY,-5[3]/46,XY[8]

11 . . . /68 + 8%

12 . . . /69 + 8% 46,XY,[11]/46,XY,del(1)(q32)[1]

13 . . . /53 + 3,5%

14 . . . /58 + 3,5%

15 . . . + 3%

16 . . . /75 + +

17 . . . /60 + +

18 . . /57 + +

JAK2

19 . . . /59 – –

20 . . . /41 – –

21 . . . /28 – –

22 . . . /30 – –

23 . . . /46 – – 46,XY[11]

24 . . . /48 – –

25 T. . . /79 – – 46,XX[11]

: (–) ; (+) ; (%)

. . ., XLVI , 2011, 1-2 64

2.

JAK2

26 . . . + 40%

27 . . . /29 + 27% 46, [11]

28 . . . + 21%

29 . . . /74 + 21% 45,XY,9+der(9)t(1;9)(q21;q22)[11]

30 . . . /33 + 8%

31 . . . /68 + 8% 46, [11]

32 . . . /56 + +

33 . . . /48 + + 46,XY[11]

34 . . . /47 + +

JAK2

35 . . . /61 – –

36 . . . /29 – –

37 . . . /75 – –

38 . . . /68 – –

39 . . . /32 – – 46,XY[5]

40 . . . + 89%

41 . . - /35 + 8,8% 46,XY[11]

42 . . . /73 – –

43 . . . /35 – – 46,XY[11]

44 . . . /73 – –

: (–) ; (+) ; (%)

1. S w e r d l o w , S. H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC. Lyon, 2008

2. S t e e n s m a , D. P. JAK2V617F in Myeloid Disorders: Molekilar Diagnostic Techniques Their Clinical Utility. – J. Mol. Diagnostics, 8, 2006, 397-411.

3. P a s s a m o n t i , F. et E. Rumi. Clinical relevance of JAK2 (V617F) mutant allele burden. – Haematologica, 94, 2009, 7-10.

4. O l s e n , R. I. et al. Detectionof JAK2V617F mutation inmyeloproliferative disorders by melting curve analysis using the lightcycler system. – Arch. Pathol. Lab. Med., 130, 2006, 997-1003.

: .

. „ . . ” 3 1606

. . ., XLVI , 2011, 1-2 65

IMATINIB MESYLATE

– . 1, . 1, . 2, . 1 . 1 1 –

2 , , –

EVALUATION OF THE CYTOGENETIC AND MOLECULAR RESPONSE IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA TREATED WITH

IMATINIB MESYLATE AT THE NATIONAL SPECIALIZED HOSPITAL FOR ACTIVE TREATMENT OF HEMATOLOGICAL DISEASES – SOFIA

S. Angelova1, G. Balatzenko1, V. Hrischev2, M. Romanova1 and St. Toshkov1 1Laboratory of Cytogenetics and Molecular Biology,

National Specializad Hospital for Active Treatment of Hematological Diseases – Sofia 2Department of Chemotherapy, Hemotherapy and Inherited Blood Diseases,

National Specializad Hospital for Active Treatment of Hematological Diseases – Sofia

. ( ) ( ) Imatinib Mesylate (IM) ( )

. , IM - European Leukemia Net. 50 , - 12 RT-

PCR. 60% (30/50) , 24 . : 25.0% (4/16) 3- , 44% (11/25) –

6- , 40% (12/30) – 12- 58% (15/26) – 18- . : 0/8 3- , 15.8% (6/38) 6- , 34.2% (13/38) – 12- 48.9% (22/45) 18- ,

2- 12- 7 18- . 2 . -

IM. - , - ,

.

: , , , BCR-ABL, -

Summary. Achievement of complete cytogenetic response (CCgR) and major molecular response (MMR) is a basic criterion for the effectiveness of Imatinib Mesylate (IM) in chronic myeloid leukemia (CML) and is crucial for the prognosis of the disease. In this study we present the results of therapeutic response achievement in patients with CML, treated with IM at a standard dose and monitored according to the criteria of the European Leukemia Net. 50 patients were followed up for 12 months by conventional cytogenetic analysis and quantitative RT-PCR. CCgR was achieved overall in 30 from 50 (60%) patients and 24 of them were with MMR. The following dynamics in achievement of CCgR was observed: 25.0% (4/16) patients – at the 3rd month, 44% (11/25) – at the 6th months, 40% (12/30) – at the 12th - month and 58% (15/26) 18th month. MMR was found in 0/8 at the 3rd month, in 15.8% (6/38) – at 6th month, in 34.2% (13/38) – at 12th month and in 48.9% (22/45)

. , . , . ... ... 66

18th month, including a complete molecular response in 2 at the 12th month and 7 at 18th month. The loss of the already achieved CCgR was observed in 2 cases. The obtained data show a very good correlation in achieving CCgR and MMR in patients treated with IM. Usage of both methods allows validation of results, at the same time it provides more information that is relevant to effectiveness of treatment of the patients.

Key words: chronic myeloid leukemia, imatinib, Philadelphia chromosome, BCR-ABL, response to treatment

Imatinib Mesylate (IM) -

(tyrosine kinase inhibitor – TKI),

( ) - .

-

Bcr-Abl,

. BCR-ABL,

t(9;22)(q34;q11), -

22- , - (Ph) [12].

- (Busulfan, Hydroxyurea, Interferon-

) IM - , ,

400 mg , -

- , 60% –

, 41% [8].

,

- , TKI [6].

-

. , -

IM -

, , -

. , - Ph- , Ph-

, e -

, .

, IM

European Leukemia Net [2].

50 Ph+

, Imatinib (35 ) (15 -

, - 12 - ).

- - 12 2005 . 2012 .

– .

, . -

- 20 - GTG -

300-400 . - [5].

in situ 2- Ph- -

dual fusion in situ (D-FISH)

LSI BCR/ABL Dual Color Dual Fusion (Vysis® , Abbot Molecular Inc., USA)

BCR/ABL . D-FISH -

,

, – 200° . - 100

. -

“Olympus”. -

, ( )

Trizol (Invitrogen) NucleoSpin RNA (MACHEREY-NAGEL).

1 μg - BCR-ABL

. . ., XLVI , 2011, 1-2 67

- (PCR) -

BCR-ABL -Actin - Van

Dongen ., 1999 . - -

K562.

BCR-ABL Real-Time PCR, Taqman , FusionQuant Kit BCR-ABL Mbcr, FusionQuant Kit ABL (Ipsogen), p Taqman PCR Master Mix Real-Time Thermocycler Corbett RotorGene,

. BCR-ABL ABL -

.

-

(BCR-ABL/ABL). ( )

ELN - : ( )

Ph+ ; ( ) – 1%-35% Ph+ ;

( ) – 35%-65% Ph+ ; ( ) – 66%-95% Ph+ ; -

– > 95% Ph+ M ( ) ,

ELN, : 1) - ( ) – BCR-ABL -

/ RT-PCR - > 104; 2) ( ) – -

BCR-ABL ABL 0,1%, -

, - [2].

50 , Imatinib, - -

- 12 . , ,

- : t(9;22)(q34;q11)

48 (96%) , 9 22 -

– .

: 46,XY,t(3;9;22)(p25;q34;q11) 46,XX,t(3;12)(q25;p13),t(9;17;22)(q34;q21; q11).

D-FISH - , BCR ABL .

Imatinib 4-

t(9;22)(q34;q11) : – Y, del(3)(p13),

t(9;21)(q22;q22), t(3;4)(p13;q25). , 210

BCR-ABL (b3a2 / b2a2) 3

.

30 (60%), - 2- -

. -

: 3- – 25,0% (4/16) , 6- -

– 44% (11/25) , 12- – 40% (12/30) , 18- –

58% (15/26) ( .1).

0%

20%

40%

60%

80%

100%

3 . 6 . 12 . 18 .

. 1. -

Imatinib -. 50

, - 50

-

BCR-ABL , 24 (80%)

- (

BCR-ABL/ABL < 0.1%), 10 - (33,3%), -

PCR 14 (46,7%) – . 6 (20%)

, - BCR-ABL/ABL, 0,58%

0,18% ( 0,40%). -

- -

- : 3-

. , . , . ... ... 68

8 , 6-

15.8%, 12- – 34.2%, 18- – 48.9%.

2- (5.3%) 12- 7 (15.6%) 18- ( . 2).

0

8

6

32

13

25

22

23

0%

20%

40%

60%

80%

100%

3 6 12 18

.

. 2

Imatinib

- 2- (6,7%

), - .

( ), .

20 (40%)

. 2- -

, 2-

. 9 (45%)

t(9;22)(q34;q11). 3-

3- , - – - , 24-

. BCR-ABL .

8

1 , 12- - .

– 52,2 . 51,8 ., - .

2 -: 1) , 12

Imatinib; 2)

, 18 (

) :

Imatinib (89,5%, 17

19 ), - - –

45,5%, 5 11 . - Imatinib

65%, 13 20 ( . 3).

1 2

3

II

17

6

13

25 7

0

2

4

6

8

10

12

14

16

18

. 3. ,

Imatinib : 1) , 12 -

; 2) , 18- + ; 3)

60% . , -

(63%) [9]. - ,

IM – 87% [10]. , -

- ,

(62% 53% , ), , -

. 25% 3-

58% 18- -. ,

, - -

I . -

H. M. Kantarjian . (2008) 50% 3- 80% –

. . ., XLVI , 2011, 1-2 69

6- Imatinib . -

, , - , -

– , I ,

. 5-10%

, t(9;22)(q34;q11) [1].

I -

. 40-50%

Ph- - BCR ABL ,

[13]. - , -

Ph-

I [4]. -

, Ph- Imatinib , -

t(9;22)(q34;q11) [15]. - Ph- -

, BCR ABL

. , - ,

, - .

. -

6- 15.8%,

34.3% 48.9% 12- 18- . -

, -

I , , -

[7]: 25-48% 61-

67% 12- [7; 10] 37% 60-65% 18- [7].

, 80% . - -

, -

[3]. -

, ELN ( . 1) , -

8% - -

Ph- , . - 44%

3- ., 8% 6- .; 13% 12- .; 58% 18- 6.7%

18- . 40%

6- .; 47% 12- .; 44% 18- . 8% 18- .

, -

, - -

[2]. , -

-

, - .

,

30 60% . ,

, . –

. – 10% - -

- . ,

RT-PCR FISH , Ph-

, – 2 -

. , -

( ) ,

.

. , . , . ... ... 70

1. IM ELNet

% ( )

% ( )

% ( )

% ( )

– – – -

Ph+ – 8% (4 50)

3 . - –

56% (9 16) – 25% (4 16)

– 44% (7 16) – 0% (0) –

6 . - – 64% (16 25)

– 44% (11 25) M – 8% (2 25) – 40% (10 25) –

12 . – 40% (12 30) – 13% (4 30) – 47% (14 30)

- – 66% (25 38)

18 . – 42 (15 36) – 56% (14 25)

- – 58% (21 36)

- – 44% (11 25) –

18 . – 58% (15 26)

– 42% (15 36)

– 6,7% (1 15) 8% (2 26)

Ph–

0% (0)

– ; – ; – ; – ; – ; Ph+ – t(9;22)(q34;q11); Ph– –

t(9;22)(q34;q11);

: - No.CVP/01-0119 –

DO-02-35/09 – „ ” - , -

.

1. A l b a n o , F. et al. Non random distribution of genomic features in breakpoint regions involved in chronic myeloid leukemia cases with variant t(9;22) or additional chromosomal rearrangements. – Mol. Cancer., 9, 2010, 120.

2. B a c c a r a n i , M. et al. Leukemianet Management recommendations. – Best Pract. Res. Clin. Haematol., 22, 2009, 3, 331-341

3. C o r t e s , J. et al, The clinical significance of achieving different levels of cytogenetic response in patients with chronic phase chronic myeloid leukemia after failure to front-line therapy: is complete cytogenetic response the only desirable endpoint? Clin Lymphoma Myeloma – Leuk., 11, 2011, 5, 421-426.

4. H s i a o , H. H. et al. Additional chromosome abnormalities in chronic myeloid leukemia. – Kaohsiung J. Med. Sci., 27, 2011, 2, 49-54.

5. I n t e r n a t i o n a l System for Human Cytogenetic Nomenclature (2009). L. G. Shaffer, M. L. Slovak, L. J. Campbell (eds), S. Karger, Basel, 2009.

6. J a b b o u r , E. et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. – Blood, 118, 2011, 17, 4541-4546.

7. J i a n g , H. et al. Seven-year response to imatinib as initial treatment versus re-treatment in Chinese patients with chronic myelogenous leukemia in the chronic phase. – Ann. Hematol., 90, 2011, 1, 41-46

8. K a n t a r j i a n , H. et al,. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. – N. Engl. J. Med., 346, 2002, 9, 645-652.

9. K a n t a r j i a n , H. M. et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. – Blood, 104, 2004, 7, 1979-1988.

10. K a n t a r j i a n , H. M. et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. – Blood, 108, 2006, 6, 1835-1840.

11. K a n t a r j i a n , H. et al. Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. – Blood, 111, 2008, 4, 1774-1780.

12. S h t i v e l m a n , E. et al. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. – Nature, 315, 1985, 6020, 550-554.

13. S i n c l a i r , P. B. et al. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. – Blood, 95, 2000, 3, 738-743.

14. v a n D o n g e n , J. J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. – Leukemia, 13, 1999, 12, 1901-1928

15. Z a c c a r i a , A. et al. Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications. – Cancer Genet Cytogenet., 199, 2010, 2, 76-80.

:

w . „ ” 6 1756

02/9701133 e-mail: sv_angelru@abv.bg

. . ., XLVI , 2011, 1-2 71

t(9;11)(p22;q23)/MLLT3-MLL:

. 1, . 1, . 1, . 1, . 2, . 3,

. 2, . 3 . 1 1 –

2 „ ” – 3 „ - . ” –

SEVEN CASES WITH t(9;11)(p22;q23)/MLLT3-MLL, A RECURRENT ABNORMALITY IN ACUTE MYELOID LEUKEMIA: DIAGNOSTIC CHARACTERISTICS

AND TREATMENT RESPONSE S. Angelova1, G. Balatzenko1, M. Romanova1, B. Spasov1, N. Petkova2, I. Hristov3,

E. Hadjiev2, N. Tzvetkov3 and St. Toshkov1 1National Specialized Hospital for Active Treatment of Hematological Diseases – Sofia

2Clinic of Hematology, University Hospital “Alexandrovska” – Sofia 3Clinic of Hematology, University Hospital “G. Stranski” – Pleven

. ( ) t(9;11)(p22;q23)/MLLT3-MLL 2% .

, t(9;11)(p22;q23)/MLLT3-MLL.

. MLLT3-MLL - RT-PCR . -

MLL (11q23) in situ (FISH) - . 7 /

t(9;11)(p22;q23) MLLT3-MLL. 5 t(9;11)(p22;q23) . – dup(3)(q21q26) e

EVI1, 3q26. (RT-PCR) MLLT3-MLL 5 6 . - . t(9;11)(p22;q23), RT-PCR MLLT3-MLL FISH , MLL . -

, t(9;11)(p22;q23)/MLLT3-MLL.

: , t(9;11)(p22;q23), MLLT3-MLL

Summary. The recurrent for acute myeloid leukemia (AML) t(9;11) (p22;q23)/MLLT3-MLL occurs in appro-ximately 2% of the adult patients with this disease and is associated with intermediate prognosis. The purpose of this study was to summarize our experience in the diagnosis, treatment and monitoring of patients with AML and t (9;11)(p22; q23)/MLLT3-MLL. Chromosomal abnormalities were analyzed by using a conventional cytogenetic method. The presence of MLLT3-MLL gene fusion was proved by RT-PCR analysis, following a standard methodology that uses specific primers. Rearrangements in the MLL gene (11q23) were studied by fluorescence in situ hybridization (FISH) with a specific DNA probe. We present 7 cytogenetic and/or molecular genetically proven cases with AML and t (9;11)(p22;q23)/MLLT3-MLL. In 5 of the cases the t (9;11)(p22;q23) was the only aberration in the karyotype. In one case it is associated with dup(3)(q21q26) without expression of the EVI1 gene, located in the region 3q26. MLLT3-MLL gene fusion was proved in 5 of 6 examined cases. In one of them

. , . , . ... ... 72

the cytogenetic study was not done. In case of a cytogenetically proven t (9;11)(p22; q23), but RT-PCR negative for MLLT3-MLL fusion, FISH analysis was made. It revealed rearrangement of the MLL gene. The clinical and diagnostic specificity, and response to therapy in our patients with t (9;11)(p22;q23)/MLLT3-MLL are discussed.

Key words: acute myeloid leukemia, t(9;11)(p22;q23), MLLT3-MLL gene fusion

– mixed lineage leukemia (MLL) e

11q23 – - ( ). -

85 , 66 -

MLL [7]. - t(9;11)(p22;q23), -

(2008), - –

t(9;11)(p22;q23)/MLLT3-MLL [12]. t(9;11)(p22;q23)

MLLT3(AF9)/MLL,

, . -

- ,

[2].

1-2% -

[3, 6, 10]. - MLL

(11q23var), t(9;11)(p22;q23) -

. (9;11)(p22;q23) -

, - ( ), -

[5].

, t(9;11)(p22;q23). -

, -, 7

t(9;11)(p22;q23).

t(9;11)(p22;q23)

, – , – ,

„ ” – .

.

, .

- 20 GTG-

, - (48- ) . - International

System for Human Cytogenetic Nomenclature (2009) [8].

in situ (FISH) - -

MLL -

(Vysis® , Abbot Molecular Inc., USA). MLLT3(AF9)/MLL -

[Reverse

Transcription Polymerase Chain Reaction (RT-PCR)]. 1 g

LV

, MLLT3(AF9)/MLL Anguita . (1999), –

Pallisgaard . (1998). -

,

-actin .

5 6

t(9;11)(p22;q23) MLLT3/MLL RT-

PCR. 6- MLLT3/MLL

MLL -

FISH . PCR , -

Pallisgaard . (1998),

, MLLT3/MLL - . -

3 ( . 1), - -

, t(9;11)(p22;q23).

1.

t(9;

11)(

p22;

q23)

/MLL

T3-M

LL

FA

B

R

T-PC

R

MLL

T3-M

LL

FLT3

-ITD

M

LL-P

TD

EVI1

.

1

16

M4

47,X

Y ,+

8,t(9

;11)

(p22

;q23

) [27

] +

>

120

2

26

M5b

46

,XX,

t(9;1

1)(p

22;q

23) [

20]

>

60

3

41

M2

+

– –

– .

>

10

4

32

M1

46,X

X,t(9

;11)

(p22

;q23

) [20

] +

– –

– .

>

21

5

33

M5

46,X

Y,du

p(3)

(q21

q26)

,t(9;

11)(p

22;q

23)

[20]

+

– –

–

1

6

53

M5b

46

,XY,

t(9;1

1)(p

22;q

23) [

25]

+*

– –

–

10

7

31

M4

46,X

X,t(9

;11)

(p22

;q23

) [16

]/46,

XX [4

] +

+ –

–

> 6

FISH

–

in s

itu

; Rea

r MLL

–

M

LL

; –

,

–

;

*

MLL

T3-M

LL

. , . , . ... ... 74

6- ( 1 5) t(9;11)(p22;q23)

: 8- 3- ( . 1). dup(3)(q21q26)

RT-PCR EVI1 ,

3q26. -

WT1 .

FLT3 (FLT3-ITD).

MLL, EVI1.

. 1. 5:

46,XY,dup(3)(q21q26),t(9;11)(p22;q23)

- . -

5 7

75-99% - .

- ( 53 )

. -

4- .

( 1) - . ( 6) -

-

,

10- .

5 WT1 7 FLT3-

ITD -.

t(9;11)(p22;q23) MLLT3-MLL -

2% (7 356) , ,

10 .

, -

[6]. , -

PCR

. , -

. t(9;11)(p22;q23)

: (+8) (dup(3)(q21q26)).

t(9;11)(p22;q23) 8 -

, . -

8 t(9;11)(p22;q23)

[4]. dup(3)(q21q26) - - -

. ,

dup(3)(q21q26) [3, 6]. -

3q21q26, EVI-1 , -

[9], , ,

, GATA2 . , -

WT1 - .

PCR - . ,

,

MLLT3-MLL . FISH

, -

-

. -

. . ., XLVI , 2011, 1-2 75

FISH - MLL -

t(9;11)(p22;q23), MLLT3-MLL

. EVI1, MLL-

PTD t(9;11)(p22;q23), -

. FLT3-ITD WT1

, -. -

. FLT3-ITD

- .

FLT3- ITD - t(9;11)(p22;q23): 3 48 (6%)

, Chandra . (2010), FLT3- ITD.

O [4].

, -

, 4- 6 (66,7%) t(9;11)(p22;q23),

, -, -

. - MRC (Medical

Research Centre, London), 80% t(9;11)(p22;q23) -

, 39% – 10- O , - 44% – 10

[6]. CALGB (Cancer and Leukemia Group B, USA) -

, , MRC, O - : 29% 5-

[10]. , - ,

, :

, -

, FLT3- ITD. ,

t(9;11)(p22;q23)/ MLLT3/MLL -

, -

MLLT3-MLL , , -

, .

: No.CVP/01-

0119 - DO-02-35/09 – „ ” , -

.

1. A n g u i t a , E. et al. Cleavage of the ALL1 gene in acute lymphoid leukemia before treatment disappears in relapse. – Haematologica, 84, 1999; 695-698.

2. A y t o n , P. M. Et Cleary M. L. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. – Genes Dev., 17, 2003, 2298-2307.

3. B y r d , J. C. et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). – Blood, 100, 2002, 13, 4325-4336.

4. C h a n d r a , P. et al. Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases. – Am. J. Clin. Pathol., 133, 2010, 5, 686-693.

5. G r i m w a d e , D. et R. K. Hills Independent prognostic factors for AML outcome. Hematology. – Am. Soc. Hematol. Educ. Program., 385, 2009, 395.

6. G r i m w a d e . D. et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. – Blood, 116, 2010, 3, 354-365.

7. H u r e t , J. L. MLL. Atlas Genet Cytogenet Oncol Haematol. 2005, update 2010. URL: http://AtlasGeneticsOncolo-gy.org/Genes/MLL.html.

8. I n t e r n a t i o n a l System for Human Cytogenetic Nomen-clature (2009). L. G. Shaffer, M. L. Slovak, L. J. Campbell (eds), S. Karger, Basel, 2009.

9. L a h o r t i g a , I. et al. Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements. – Genes Chromo-somes Cancer, 40, 2004, 3, 179-189.

10. M r o z e k , K. et al. Clinical significance of cytogenetics in acute myeloid leukemia. – Semin. Oncol., 24, 1997, 1, 17-31.

11. P a l l i s g a a r d , N. et al. Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia. – Blood, 92, 1998, 2, 574-588.

12. W o r l d Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Volume 2, Ed. by Swerdlow S. H., et al. Lyon, IARC Press, 2008, 172.

:

w . „ ” 6 1756,

02/9701133 e-mail: sv_angelru@abv.bg

. . ., XLVI , 2011, 1-2 76

, 16 53

. 1, . 2, . 1, . 3, . 3 . 4 1 , –

2 , – 3 , –

4 , „ ” –

CYTOGENETIC ABNORMALITIES OF ATM, P16 AND P53 IN CHRONIC AND ACCELERATED PHASES OF CHRONIC MYELOID LEUKEMIA

L. Mitev1, M. Velizarova2, T. Boneva1, I. Gigov, Yu. Raynov3 and E. Hadzhiev4 1Department of Clinical Laboratory and Immunology, Military Medical Academy – Sofia

2Department of Clinical Laboratory and Immunology, Medical University – Sofia 3Clinic of Hematology and Oncology, Military Medical Academy – Sofia

4Clinic of Hematology, UMHAT "Alexandrovska" – Sofia

. in situ (FISH) 5

. , - BCR-ABL - , 16 53. 4

: 4 , 2 16 53. t(9:22,21)

16. ( 2 9%). ,

, 16 53 - .

: , , , 16, 53

Summary. A cytogenetic study with G-banding techniques and fluorescent in situ hybridization was performed in 5 patients with chronic and accelerated phase of chronic myeloid leukemia. Examinations with dual-color, dual fusion assay for detection of t(9;22) and DNA specific probes for detection of tumor suppressor genes ATM, p16 and p53 were carried out. Chromosome alterations of tumor suppressor genes were found in 4 cases: 4 with deletions of ATM, 2 with deletions of p16 and one with deletion of p53. In one patient with t(9;22;21) biallelic deletions of ATM and p16 was observed. In all patients the chromosome abnormalities were presented in minor clones (2-9%). In conclusion, our results suggest that genetic alterations of ATM, p16 and p53 may occur as early as in the chronic or accelerated phase of chronic myeloid leukemia and possibly are related with the clonal evolution of the disease.

Key words: chronic myeloid leukemia, chromosome aberration, ATM, p16, p53

( )

-

Bcr-Abl.

, ,

( ) .

, - .

( ) - -

, . - ,

BCR-ABL , ,

, -

. , . , . ... , 16 53... 77

[1]. -

, 53, Rb1 P16 [2, 3, 4]. -

. ,

( )

( ) .

in sity

- ATM, p53 p16

.

5- :

22 75 . - ,

. - . -

24-

. G-

. - - 33 .

-, FISH . -

-, -. 16 -

9 21, 53 17 13 11q22. - -

FISH

. - 100 FISH .

. 1.

4- - , 16

53. - 16 . 4 , - ( . 1). 16

– -

- ( . 2). 53 - . -

- ( 2% 9%)

- - . . . -

-, 16. -

- – t(21;22)(q12;q11) ( . 3).

, FISH ,

(2R/3G/1F), , -

9, 22 21 q34, q11 q12.

, -

, 16 53 , -

. ,

1.

/FISHt(9;22)fusion

FISHATM

FISHp16/9q21

FISHp53/SE17

1 . . /22 46,XY[40] 24%

(4%)

2 . . /38 A 46,XY,t(9;22)(q34q11)[33]

100%

(4%) (2%)

3 . . /59 46,XX[33] 2%

4 . . /75 46,XX,t(9;22)(q34q11)[33]

100%

(4%) (6%)

5 . . /28 46,XY,t(21;22)(q22q11) [20]

100%

(9%)(4%)

(5%)(3%)

. . ., XLVI , 2011, 1-2 78

A. . . 1 (

. 16 . 16

. 2 ( )

. 3. G- . . ., t (21;22)

. - -

. .

. ,

-

, - ( ) . ,

,

, .

- -

- , 16 53

[1].

1.

BCR-ABL -

-

ATM, p16 53.

2. , 16 53 -

.

: 58/2011,

– .

1. M e l o , J. V. et D. J. Barnes. Chronic myeloid leukemia as a

model of disease evolution in human cancer. – Nature Revies Cancer, 7, 2007, 441-453.

2. O t e r o , E. et al. Chromosome 17 abnormalities and mutation of the TP53 gene: Correlation between cytogenetics, flow cytometry and molecular analysis in three cases of chronic myeloid leukemia. – Genetics and Molecular Biology, 28, 2005, 1, 40-43.

3. K r u g , U. et al. Tumor suppressor genes in normal and malignant hemopoiesis. – Oncogene, 21, 2002, 3475-3495.

4. S h u t , A. S. et al. Chronic myelogenous leukemia: mechanisms underlyning disease progression. – Lekemia, 16, 2002, 8, 1402-1411.

: .

. „ . . ” 3 1606

. .

. 16 . 16

. . ., XLVI , 2011, 1-2 79

. 1, . 1 . 2 1 „ ” –

2 „ ” –

OPTIMIZED ALGORITHM FOR HEMOSTASIS MONITORING WITH ROTATION THROMBELASTOMETRY IN LIVER TRANSPLANTS

A. Stancheva1, L. Spasov1 and T. Lisichkov2 1University Hospitale “Lozenets” – Sofia

2SHAT “Yoan Pavel” – Sofia

. - , ,

- . (ROTEM®, Petapharm GmbH) -

. -

30 , - , (2004-2010) -

.

: , ,

Summary. Urgent clinical-laboratory monitoring is necessary during liver transplantation, concerning diagnostics of arising coagulopathies, differential-diagnostic discussion of the results, suggestion for adequate medicamen-tous and substitutive therapy and trailing the effect of the applied therapy. The rotation thrombelastometry me-thod (ROTEM®, Petapharm GmbH) enables the performance of an extended haemostatic monitoring of the coagulation and fibrinolytic activity and the therapeutic correction and control. Perioperative haemostatic moni-toring was performed to 30 patients undergoing orthotopic liver transplantation and an algorithm for diagnostics and correspondent therapy was optimized, conformable to the International Guidelines (2004-2010) of the Expert Group on Rotation Thrombelastometry .

Key words: rotation thrombelastometry, liver transplantation, hemostasis monitoring

-

-, -

- ,

- [9].

- ROTEM® -

- -

- -

[1]. , -

. - -

, -, -

[2]. - -

. , . . . ... 80

,

- [6].

Rotem®

-- [8].

- Rotem® -

- , -

, - Rotem® -

- [5].

MCF 15 EXTEM_A15, INTEM_A15

FIBTEM_A15 , [7].

- -

-

.

30 - , “ -

”, – 2005-2010 ., 13 (42%) 17 (58%) , 21

, 5 58 . -

. :

E (R1). : – 10 min – - (R2);

– 10 min – - (R3); – 10 min – -

(R4); – 30 min –

(R5); (R6).

– (PLT) (RBC), Cell Dyn 3700 (Abbott

Diagnostics, Germany) MAPSS . -

- ROTEM® (Petapharm GmbH, Germany) -

Petapharm GmbH.

- ROTEM®

,

- :

– (TF) EXTEM; – (ellagic acid)

INTEM; – (anti IIb/IIIa) FIBTEM; – Aprotinin APTEM; – Heparinase HEPTEM – Ecarin activator ECATEM.

- , -

APTEM (ap-TEM, PENTAPHARM GmbH) HEPTEM (hep-TEM, PENTAPHARM GmbH) -

(EXTEM, INTEM, FIBTEM) -

. Lysis Index (LI) – ,

30- min, .

EXTEM/APTEM.

Rotem® - 2004-2010 .

-. -

HEPTEM, INTEM, .

: – INTEM_CT > 240 s – HEPTEM_CT / INTEM_CT < 0,75

Rotem® - 10 min -

.

Rotem® -

INTEM_MCF, EXTEM_MCF FIBTEM_MCF. -

- – 2004, Munich, -

EXTEM_MCF FIBTEM_MCF - ,

EXTEM_MCF FIBTEM_MCF .

- :

. . ., XLVI , 2011, 1-2 81

: – EXTEM_MCF < 45 mm; – FIBTEM_MCF > 7 mm.

: – EXTEM _MCF < 45 mm; – FIBTEM_MCF < 8 mm.

ROTEM , - 30 min -

. -

- -

– 2008, Münich, ROTEM® Pentapharm GmbH (4), :

. - -

: APTEM_CT << EXTEM_CT > 10%,

%10100

APTEM_A10 >>EXTEM_A10 > 10% > 10%

100 10%

. -

:

_ / _CT < 0. 75 _MCF/ _MCF > 1,25

_CT << _CT ( > 25%)

_MCF >> _MCF ( > 20%)

100 > 20%

( MCF_EXTEM < 35 mm – Steib . 1994).

-

INTEM_ML > 15% EXTEM_ML > 15%, -,

LI 30 ML 60, 30- 60- . ca R1-R6.

ROTEM® 15 min

. -

ROTEM® - -

2005-2007 ., (Internatio-nal Blood Products Transfussion Guidelines), -

: PT(INR) / APTT > 1.5 X , -

– < 50 x 109/L [1]. ca

-, - .

(cut off) ROTEM® ca -

ROC (reciever operating characteristic curves). -

ROTEM® , - -

PT(INR), APTT PLT R1:

– PT EXTEM_CFT (r = 0.834 p < 0.001); – APTT INTEM_CFT (r = 0.707 p < 0.001); – PLT INTEM_MCF (r = 0.784 p < 0.001).

-

: – PT(INR) > 1.5 ( -

EXTEM_MCF); – APTT > 1.5 . ( -

INTEM_CFT); – PLT < 50 x 109/L ( -

INTEM_MCF). R1-

R6. ROTEM - 30 min

. - -

- EXTEM_CFT 130 s ( INR

> 1,5) INTEM_CFT 134 s ( PT > 1,5 .), (65-70%)

(79-93%) . Rotem® INTEM_MCF

- (100%) (100%)

-

38 mm ( < 50 x 109 L).

-

( . 1) ,

, - , -

EXTEM_A15, INTEM_A15

FIBTEM_A15 [7] (2004-2006)

(Münich) K. Goerlinger .

. , . . . ... 82

[3], ROTEM® [2, 4].

[5, 6, 7],

(EXTEM_MCF < 38 mm

PLT < 50 x 109/L), (EXTEM_CFT > 130 s

INTEM_CFT > 134 s HEPTEM_CT INTEM_CT EXTEM_CT APTEM_CT), -

, F VIII (INTEM_CFT > 134 s HEPTEM_CFT INTEM_CFT),

- APTEM/EXTEM 15

(APTEM_A15 > EXTEM_A15 ( > 20%) APTEM_A15/EXTEM_A15 > 1,2).

-

- , -

, - -

-

. -

ROTEM , ,

, -

, .

1.

1. EXTEM_MCF 35 mm (Steib 1994)

2. APTEM_CT << EXTEM_CT ( > 25%) APTEM_CT: EXTEM_CT < 0,75

3. APTEM_A15 >> EXTEM_A15 ( > 20%) APTEM_15 : EXTEM_A15 > 1,2

Aprotinin

1. EXTEM_MCF < 45 mm FIBTEM_MCF < 8 mm

2. EXTEM_MCF < 35 mm FIBTEM_MCF < 8 mm

N. B. APTEM_MCF EXTEM_MCF

1. EXTEM_MCF < 45 mm FIBTEM_MCF > 8 mm

2. EXTEM_MCF < 35 mm FIBTEM_MCF > 8 mm

3. EXTEM_MCF < 38 mm FIBTEM_MCF > 8 mm PLT < 50 109/L

1. EXTEM_CT > 80 s INTEM_CT > 240 s HEPTEM_CT INTEM_CT EXTEM_CT APTEM_CT

2. EXTEM_CFT > 130 s INTEM_CFT > 134 s HEPTEM_CT INTEM_CT EXTEM_CT APTEM_CT

( )

INTEM_CT >240 s HEPTEM_CT/ INTEM_CT (<0,75)

1. INTEM_CT >240 s HEPTEM_CT INTEM_CT

2. INTEM_CFT > 134 s HEPTEM_CFT INTEM_CFT

3. INTEM_CT INTEM_CFT 20 . F VIII (500 IU/50ml = 10IU/ml) INTEM

F VIII

1. EXTEM_MCF < 45 mm EXTEM_ML 60 > 12% APTEM_ML 60 > 10%

2. EXTEM_ML 60 20 . F XIII (250 IU/25 ml = 10 IU/ml) EXTEM

F XIII

1. HEPTEM_CT INTEM_CT –

2. ML30 < 10% -

3. EXTEM_MCF > 30 mm (PLT > 20 x 109/L)

4. FIBTEM_MCF > 8 mm (FIB >1,5 g/l)

F VII

. . ., XLVI , 2011, 1-2 83

A10, 15,X – 10, 15, X- min APTEM – APTT – CFT (Cloth Formation Time) – CT (Clotting/ Coagulation time) – ECATEM – EXTEM – FIB – FIBTEM – / FVII – V FVIII – V FX – HEPTEM – HCT – INTEM – LI (Lysis Index.) – MCF (Maximum Cloth Firmness) – ML (Maximum Lysis) – PLT – PT(INR) – ( ) RBC – TF –

–

1. C o a k l e y , M. et al. Transfusion triggers in orthotopic liver

transplantation: a comparison of the thrombelastomethry analyzer, the thrombelastogram, and conventional coagulation tests. – J. Cardiothorac. Vasc. Anaesth., 20, 2006, 548-553.

2. C o a k l e y , M. et al. Agreement between ROTEM, TEG, and conventional coagulation test protocols, to administrate platelets, FFP, and fibrinogen. ASA 2006.

3. G a r c i a P a l e n c i a n o , C. et al. Guidelines for ROTEM® application, 2nd European ROTEM® Expert Meeting, 2006.

4. G o e r l i n g e r , K. Gerinnungsmanagement bei lebertran-tationen. – Hamostaseologie, 26, 2006, (Suppl. 1), 564-576.

5. G o e r l i n g e r , K. et al. ROTEM-based management for diagnosis and treatment of acute haemorrhage during liver transplantation. – Eur. J. Anaesth., 23, 2006, 85.

6. R o u l l e t S, Pillot J, Freyburger G, Biais M, Quinart A, Rault3 A, Revel P and Sztark F. Rotation thromboelas-

tometry detects thrombocytopenia and hypofibrinogenaemia during orthotopic liver transplantation. – Br. J. Anaesthesia, 104, 2010, 4, 422-428.

7. R u g e r y , L, et al. Diagnosis of early coagulation abnor-malities in trauma patients by rotation thrombelastography. – J. Thrombosis and Haemostasis, 2007, 5, 289-295.

8. S a m a m a , Ch. Thromboelastography: The Next Step Anesth. Analg., 92, 2001, 563-564.

9. W h i t t e n , C. W. et P. E. Greilich. Thrombelastography: past, present, future. – Anesthesiology, 92, 2000, 1223-1225.

:

.

„ ” . „ “ 1

1407

. . ., XLVI , 2011, 1-2 84

. - 1, . 2, . 3 . 1 1 , „ . ” –

2 , – 3 , –

COMPARATIVE ANALYSIS OF RED BLOOD CELL PARAMETERS IN HIGHLY-TRAINED FOOTBALL PLAYERS OF DIFFERENT AGE GROUPS

J. Grudeva-Popova1, N. Boyadjiev2, Z. Taralov3 and I. Nenova1 1Clinic of ncology and Hematology, University Hospital “Sv. Georgi” – Plovdiv

2Department of Physiology, Medical University – Plovdiv 3Department of Clinical Laboratory, Medical University – Plovdiv

. , - . “ ”,

.

. 2314 , - 2004-2010 .

3 : – (n = 1178) 9-14 .; B – - (n = 1029) 15-19 ., C – (n = 107),

20-35 . 90- -, 5 . RBC, HCT, HGB, MCV,

MCH, MCHC, WBC PLT. Jaegger 900 ( ) - T. Sjostrand PWC170. : -

, . - RBC

– 5.17 ± 0.27/1012/ l-1, (5.08 ± 0.41/1012/l-1). HGB - – 151.75 ± 7.55, -

– 149.06 ± 6.02 144.69 ± 6.39 g/l-1 ( < 0.001). - e -

. , PWC170, - - ( 20.64 ± 2.34 19.25 ±

3.26 kgm/min-1/kg-1, P < 0.001). - - . ,

RBC HGB, RBC , - PWC170.

: , , ,

Summary. Values of hematological parameters around the lower limit of normal have often been recorded in young athletes involved in intense physical activity. There have been reports on “sports anemia” resulting from intensive physical training. The aims of current study were to evaluate the hematological parameters of 2,314 football players; to compare the results for different age groups (pre-pubescent, pubescent boys and adult males) and to relate the obtained values to the individual aerobic functional capacity. Materials: A total of 2,314 highly trained football players entered the study. The sportsmen were divided into three groups according to

. - , . , . ... ... 85

their age: group A (n = 1,178) pre-pubescent (9-14 yrs) – 13.22 ± 1.05 yrs (158.6 ± 12.6 months); group B (n = 1029) pubescent (15-19 yrs) – 16.57 ± 1.04 yrs (198.9 ± 12.6 months); group C (n = 107) adults (20-35 yrs) – 24.30 ± 3.78 yrs (291.6 ± 45.3 months). All sportsmen underwent profound clinical examination prior to obtaining blood samples. Hematological parameters (RBC, HCT, HGB, MCV, MCH, MCHC, WBC and PLT) were analyzed on a Sysmex K800 (Japan) analyser. The working capacity of each football player was assessed by PWC170-test on AT-104 Spiro-Ergo equipment (Schiller, Switzerland). Results: All hematological parameters in the groups were in normal ranges and the RBC was highest in group B (5.17 ± 0.28 /1012/l vs. 5.03 ± 0.28 /1012/l for group A, and 5.08 ± 0.41 /1012/l for group C). Group A demonstrated the lowest values besides for RBC also for HGB (144.7 ± 6.4 g/l vs. 149.1 ± 6.0 g/l for group B, and 151.8 ± 7.5 g/l for group C, P < 0.001), and for HCT (0.437±0.02 vs. 0.451±0.02 for group B, and 0.451 ± 0.03 for group C, P < 0.001). Similar values were found for taller and shorter boys of the same age within Group A. Pre-pubescent football players (group A) had lower MCV (87.1 ± 2.8 fl) compared to players from group B (87.5 ± 2.9 fl) and to players from group C (88.1 ± 3.0 fl). No evidence for blood dilution resulting from long-term training has been found in groups B and C. No difference was found in the WBC and PLT counts between the age groups. Adult players (C-group) demonstrated higher PWC/kg than the pre-pubescent (20.6 ± 2.3 vs. 19.2 ± 2.3 kgm/min/kg) and pubescent boys (19.8 ± 2.7 kgm/min/kg). Linear correlations were found between age and HGB level, as well as between age and HCT in groups A (0.19 and 0.19 respectively) and B (0.24 and 0.15 respectively). In all groups investigated a linear correlation was found between RBC and PWC170/kg. Conclusions: Pre-pubescent highly trained football players have lower values of the red blood cell parameters than pubescent and adult footballers, which correlates with lower aerobic working capacity.

Key words: red blood cells (erythrocyte lineage), footballers, age, working capacity

-, ,

[1]. - “ ”

, , [9, 14, 16], [21].

- - -

. - (RBC), -

(HGB), (HCT), (MCV) -

(MHC) [3, 4, 6, 12, 23]. - –

. [5, 20]. - , -

- [1, 9, 14, 18, 19].

, - -

[1, 8, 10, 13] [2, 17].

-

- ( )

( , ),

, - .

2314 ,

, -

2004-2010 . 3 : – -

(n = 1178), 9-14 ., B – (n = 1029)

15-19 ., C – (n = 107), (20-35

.). - . 1.

90- - 5 . , -

, - , -

. -

, 07:00 09:00 , -

Expert Panel on Theory of Reference Values (EPTRV) International Federation of Clinical Chemistry (IFCC) (IFCC, 1984), 48

. Sarstedt -

, EDTA ( ). - RBC, HGB, HTC, MCH, MCHC,

WBC, PLT - Sysmex K800 ( ).

- T. Sjostrand – PWC170, -

Jaegger 900 ( ).

. . ., XLVI , 2011, 1-2 86

Statistica 10.0 (StatSoft, Inc, USA). ANOVA -

-

. - p < 0.05.

X ± SD.

13.22 ± 1.05 . (158.65 ± 12.64 ), -

– 16.57 ± 1.04 . (198.89 ± 12.57 ), – 24.30 ± 3.78 . (291.63 ± 45.32 -), < 0.001.

, -

( . 1). ,

PWC170, - - - –

( 20.64 ± 2.34 19.25 ± 3.26 kgm/min-1/kg-1, P < 0.001).

PWC170 19.76 ± 2.69 kgm/min-1/kg-1 ( . 2).

-

: WBC – 7.21 ± 1.24, 7.18 ± 1.22 7.09 ± 1.39 /109/l-1 -

, , PLT – 257.20 ± 39.43, 258.07 ± 39.02 256.64 ± 44.66 /109/l-1 ( > 0.05) ( . 2).

- RBC - – 5.17

± 0.27/1012/l-1, (5.08 ± 0.41 /1012/l-1) –

(5.03 ± 0.28 /1012/l-1). -

( /1012/l-1) - ( )

:

y = 4.384 + 0.004x; SE = 0.0995; P < 0.001

B y = 4.908 + 0.001x; SE = 0.1348; P < 0.001

C y = 5.865 – 0.003x; SE = 0.2603; P < 0.001,

y – RBC ( /1012/ l-1), x – ( -), SE – ,

RBC/ . 1. ,

.

1. (X ± SD).

m

. kg

BMI g/m2

PWC170 gm/min-1/kg-1

A (9-14 .) n = 1178 13.22 ± 1.05 158.65 ± 12.64 1.60 ± 0.11 47.17 ± 10.31 18.21 ± 2.27 19.25 ± 3.26

B (15-19 .) n = 1029 16.57 ± 1.04 198.89 ± 12.57 1.76 ± 0.07 64.93 ± 8.09 20.92 ± 1.94 19.76 ± 2.69

C ( 20-35 .) n = 107 24.30 ± 3.78 291.63 ± 45.32 1.81 ± 0.06 74.88 ± 6.56 22.88 ± 1.64 20.64 ± 2.34

PA-PB < PA-PC < PB-PC <

0.001 0.001 0.001

0.001 0.001 0.001

0.001 0.001 0.001

0.001 0.001 0.001

0.001 0.001 0.001

0.05 0.001 0.01

2. (X ± SD).

RBC ./1012/l-1

HGB g/l-1

HCT l/l-1

MCV fl

MCH pg

MCHC g/l-1

A (9-14 .) n = 1178

5.03 ± 0.28 144.69 ± 6.39 0.437 ± 0.022 87.10 ± 2.81 28.70 ± 1.36 330.13 ± 10.88

B (15-19 .) n = 1029

5.17 ± 0.27 149.06 ± 6.02 0.451 ± 0.023 87.50 ± 2.86 28.83 ± 1.40 330.40 ± 12.41

C ( 20-35 .) n = 107

5.08 ± 0.41 151.75 ± 7.55 0.451 ± 0.027 88.06 ± 2.95 29.82 ± 1.27 336.86 ± 12.70

PA-PB < PA-PC < PB-PC <

0.001 0.05 0.01

0.001 0.001 0.001

0.001 0.001 NS

0.01 0.001 0.05

0.05 0.001 0.001

NS 0.001 0.001

. - , . , . ... ... 87

A-RBC = 4,3842+0,004*x

100 110 120 130 140 150 160 170 180 190

A - ( )

3,73

3,92

4,15

4,34

4,52

4,70

4,88

5,06

5,24

5,42

5,61

5,84

6,03

RB

C -

*10

12*l-1

B-RBC = 4,9076+0,0013*x

170 180 190 200 210 220 230 240 250

- ( )

3,8

4,0

4,2

4,4

4,6

4,8

5,0

5,2

5,4

5,6

5,8

6,0

6,2

6,4

6,6

6,8

B-R

BC *

1012

*l-1

C-RBC = 5,8653-0,0027*x

220 240 260 280 300 320 340 360 380 400 420 440

- ( )

1,5

2,0

2,5

3,0

3,5

4,0

4,5

5,0

5,5

6,0

6,5

C-R

BC

*10

12*l

-1

. 1. -

( ) -

HGB - - – 151.75 ± 7.55,

– 149.06 ± 6.02 144.69 ± 6.39 g/l-1 ( < 0.001).

- , -

: y = 129.62 + 0.095x; SE = 2.31;

P < 0.001.

B y = 126.49 + 0.114x; SE = 5.86; P < 0.001.

C y = 159.21 – 0.026x; SE = 4.94; P < 0.001,

y – HGB (g/l-1), x – ( ), SE –

, -, -

(0.437 ± 0.022 l/l-1), 0.451 ± 0.023 0.451 ± 0.027 l/l-1 ,

.

- , -

- MCV – 88.06 ± 2.95 87.50 ± 2.86

fl (P < 0.05) ( . 1). - -

(MCH) , , - –

– 29.82 ± 1.27, 28.83 ± 1.40 28.70 ± 1.36 pg.

(MCHC) -

– 336.86 ± 12.70 g/l-1 ( < 0.001).

PWC170 - .

: y = 10.48 + 1.70x; SE = 4.20;

P < 0.05. B y = 14.59 + 1.00x; SE = 1.67;

P < 0.001. C y = 30.86 – 2.04x; SE = 4.43;

P < 0.001, y – PWC170 (kgm/min-1/kg-1), x – RBC

( ./1012/l-1), SE – - ( . 2).

. - .

- - -

. - RBC -

, - -

[2, 24]. HGB - ,

- [7, 11, 15, 22]. -

-

. . ., XLVI , 2011, 1-2 88

. -

, - .

. - , -

PWC170, - - – -

.

A-PWC/kg = 10,4834+1,7056*x

4,034,22

4,374,52

4,664,80

4,945,08

5,225,36

5,505,64

5,845,99

- RBC (* 10 12 * l -1)

8

10

12

14

16

18

20

22

24

26

28

30

A-P

WC

/kg

(kgm

*m

in-1

* kg

-1)

B-PWC/kg = 14,5878+0,9996*x

3,8 4,0 4,2 4,4 4,6 4,8 5,0 5,2 5,4 5,6 5,8 6,0 6,2 6,4

- RBC (* 10 12 * l -1)

8

10

12

14

16

18

20

22

24

26

28

30

32

B-P

WC

/kg

(kgm

* m

in-1

* kg

-1)

C-PWC/kg = 30,8657-2,039*x

4,0 4,2 4,4 4,6 4,8 5,0 5,2 5,4 5,6 5,8 6,0 6,2

- RBC (* 10 12 * l -1)

12

14

16

18

20

22

24

26

28

C-P

WC

/kg

(kgm

* m

in-1

* kg

-1)

. 2. - (PWC170) -

-

. - - -

– RBC, HGB, HCT, MCV, MCH MCHC. -

, RBC HGB, RBC

, PWC170.

1. B i a n c o t t i , P. et al. Hematological status in a group of

male athletes of different sports. – J. Sports. Med. Phys. Fitness., 32, 1992, 70-75.

2. B o y a d j i e v , N. et Z. Taralov. Red blood cell variables in highly trained pubescent athletes: a comparative analysis. – Br. J. Sports Med., 34, 2000, 200-204.

3. B r o d t h a g e n , U. et al. Red blood cell, 2,3-DPG, ATP and mean cell volume in highly trained athletes. Effect of long-term submaximal exercise. – Eur. J. Appl. Physiol., 53, 1985, 334-338.

4. C o r d o v a M a r t i n e z , A. et J. Escanero. Iron, transferring, and haptoglobin levels after a single bout of exercise in men. – Physiol. Behav., 51, 1992, 719-722.

5. C o r d o v a , A., F. Navas, J. Escanero. The effect of exercise and zinc supplementation on the hematological parameters in rats. – Biol. Trace Elem. Res., 39, 1993, 13-20.

6. G i m e n e z , M. et al. Leucocyte, lymphocyte and platelet response to dynamic exercise. Duration or intensity effect? – Uur. J. Appl. Physiol., 55, 1986, 465-470.

7. G o o d n o u g h t , L., E. Nemeth et T. Ganz. Detection, evaluation, and management of iron-restricted erythropoiesis. – Blood, 116, 2010, 23, 4754-4761.

8. H a n s e n , L. et K. Klausen. Development of aerobic power in pubescent male soccer players related to hematocrit, haemoglobin and maturation. A longitudinal study. – J. Sports Med. Phys. Fitness, 44, 2004, 3, 219-223.

9. H a s i b e d e r , W., W. Schobersberger et H. Mairbaurl. Red cell oxygen transport before and after short-term maximal swimming in dependence on training status. – Int. J. Sports Med., 8, 1987, 105-108.

10. K a r a k o c , Y. et al. Effects of training period on haemorheological variables in regularly trained footballers. – Br. J. Sports Med., 39, 2005, 101-107.

11. K e r e n y i , M, et E. Mullner. Muscle iron in stress erythropoiesis? – Blood, 113, 2009, 26, 6507-6058.

12. L a u b , M. et al. Spleen emptying and venous hematocrit in humans during exercise. – J. Appl. Physiol., 74, 1993, 1024-1026.

13. L o l l o , P. et al.Yo-Yo intermittent recovery performance test, body composition and biochemistry markers in young soccer players. – J. Sports Sci. Med., 2007, S10, 111-116.

14. M a g a z a n i k , A. et al. Iron deficiency caused by 7 weeks intensive physical exercise. – Eur. J. Appl. Physiol., 57, 1988, 198-202.

15. N o d a , Y. R et al. Nutrient intake and blood iron status of male collegiate soccer players. – Asia Pac. J. Clin. Nutr., 18, 2009, 3, 344-350.

16. R a d o m s k i , M., B. Sabiston et P. Isoard. Development of ‘sports anemia’ in physically fit men after daily sustained

C

. . ., XLVI , 2011, 1-2 90

– ,

. .

–

CASE OF A PATIENT WITH TRIPLE METACHRONIC MALIGNANCIES – HODGKIN’S LYMPHOMA, TESTICULAR TERATOCARCINOMA

AND ACUTE MYELOID LEUKEMIA G. Mihailov and S. Simeonov

Clinic of Hematology, National Specialized Hospital for Active Treatment of Hematological Diseases – Sofia

. - ( ) o . -

51- , : 1) , , III ( ), 1994 .; 2) , IV , 2001

. 3) , ( - ), .10.2011 ., . .

. - , . -

- - - .

: , , , , ,

Summary. Patients with successfully treated malignancies are at a higher risk for developing second (late) neoplasm than the general population. In the following report we present a case of a 51-year old man with a metachronic triple neoplasm including: (1) Hodgkin’s disease – mixed cellularity subtype, stage III, 1994; (2) teratocarcinoma of the left testis, stage IV, 2001 and (3) Acute myeloid leukemia-therapy related (t-AML), diagnosed in October 2011 and still being treated. Cytological remission is not (to be) achieved. The development of a second neoplasm among the Hodgkin’s lymphoma patients in remission is a predictable event with certain statistically determined risks. Secondary malignancies of third or higher order are very rare. The reported case is an example of multiple late complications of complex chemo- and radiotherapy with t-AML being the third malignancy.

Key words: secondary malignancy, Hodgkin’s disease, acute myeloid leukemia-therapy related, teratocarci-noma of testis, splenectomy

- . : 1) -

2) -

.

- . -

/ - . ,

. . . ... 91

20% - ( ) , -

.

15% 20- , 3 10

- , - [1].

, - - [8].

- .

: 1) ; 2) -

[2] 3) . - , . (PRDM1) -

-

[3]. , ,

. . 1932 . [4]

: 1) -; 2)

3) -

.

. . . 51 -

, , ( ).

1993 . , -

. . -

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-. 4

( ) – , 2 ABVC, MOPP, –

- ( ) 34

36 . 4 .

- 1994 .

2001 . -

.

. . - -

( ) . e -

„ -”. e V ( -

) 5 - ( , ,

). e 2001 . .

2011 . , -

, 2011 . . -

. -

- ( 34 G/l) -

(10 G/l) - ,

. - -

– 69%, 65% - - 4% .

. -

- -

: 1) ( 20%

) FSC/SSC ( -

), CD45 -: CD33(+), CD13(+), CD71(+), CD117(+), HLA-

DR(+), CD34(+), (+); 2) ( 25% -

) CD45: CD11 (+), CD13(+), CD14(+), CD33(+), CD64(+), CD4(+).

M BCR-ABL; mBCR-ABL; AML1-

ETO; CBFb-MYH11 FLT3-ITD. - -

, - ( - ), 4 -- - (FAB).

, , - - , - ,

.

. . ., XLVI , 2011, 1-2 92

( ) : 2, – -

, - – 7 cm, o- .

2011 . - 7 + 3, -

. - -

. -

- -

(54,5% )

, . 300 mg/m2

2011 . 2011 . /

. 28.12.11 . -

13% 8% .

( 42%) 2012 . -

7 + 3 -.

22- -

12% 9%.

-

– 17 -, -

10 - .

, , -

: , -

, - , -

, -

[5]. -

-

[6]. 20- -

6-7% - [7], -

-.

3% [8]. -

. - , -

, - ,

, . -

,

, - ABVD. - -

, -

[7]. , - -

, - -

- [7, 9].

- -

.

. - - [6].

- .

- - - [9, 10].

- .

, -,

.

1. B h a t i a , S. Secondary malignancies: What, When, Why,

in Whom? Presented at 2008 NCCN Clinical Practice Oncology Forum.

2. B a l a t z e n k o , G. et al. Chronic eosinophilic leukemia with FIP1L1-PDGFRA transcripts after occupational and

. . . ... 93

therapeutic exposure to radiation. – Hematol. Rep., 2011, 3, e17 47-49.

3. B e s t , T. et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. – Nat. Med., 17, 2011, 941-943.

4. W a r r e n , S. et O. Gates. Multiple primary malignant tumors. – Am. J. Cancer, 16, 1932, 1358-1414.

5. S t r a u s , D. J. Therapy and toxicities in the adult Hodgkin lymphoma patient: second malignancies. – Ther Adv. Hem., 2, 2011, 111-119.

6. M u n k e r , R. et al. Second malignancies after Hodgkin's disease: the Munich experience. – Ann. Hematol., 78, 1999, 544-554.

7. S E E R Cancer Statistics Review 1975-2008 National Cancer Institute. Section 09-Hodgkin’s lymphoma.

8. D o r e s Graca, M. et al. Second malignant neoplasms among long-term survivors of Hodgkin’s disease: a

population-based evaluation over 25 years. – J. Clin. Oncol., 20, 2002, 3484-3494.

9. J o s t i n g , A. et al. Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin’s disease: a report from the German Hodgkin’s lymphoma study group. – J. Clin. Oncol., 21, 2003, 3440-3446.

10. F e d o r i w , G. et C. H. Dunphy (ed.). Pathology of therapy-related myeloid neoplasms. Medscape Reference (online), updated 2011 Jul 15.

:

. .

. „ ” 6 1756

. . ., XLVI , 2011, 1-2 94

t(11;14)(q13;q32) . 1, . 2, . 2, . 2, . 2, . 2,

. 3, . 1 , . 1 . 1 1 , – 2 , –

3 –

A CASE OF MULTIPLE MYELOMA WITH t(11;14)(q13;q32) T. Boneva1, A. Nedeva2, D. Ionova2, I. Nikolov2, J. Raynov2, R. Stanchev1,

N. Radinov2, D. Popova1, R. Vladimirova1 and L. Mitev1 1Department of Clinical Laboratory and Immunology, MMA – Sofia

2Clinic of Hematology and Medical Oncology, MMA – Sofia 3MHAT Tokuda – Sofia

. t(11;14)(q13;q32) - . ,

- - ( ). t(11;14) -

, - . t(11;14), -

in situ . - . -

CD38 CD56 CD20 D1. -

t(11;14) D1.

: , ,

Summary. The reciprocal translocation t(11;14)(q13;q32) is a specific cytogenetic sign for mantle cell lymphoma. During the last few years, abnormalities that are associated with another B-cell neoplasmas like B-cell prolymphocytic leukemia and multiple myeloma ( ) have been established. Cases with and t (11;14) are gathered into a cytogenetic subgrup within the framework of and are characterized by lymphoplasmocytic morphology, lower levels of serum monoclonal protein (M-protein) and relatively good prognosis. We describe the first patient in our country with and t(11;14), proved by a standard cytogenetic analysis and fluorescent in situ hybridization. Lymphoplasmocytic morphology in bone marrow and high levels of serum monoclonal protein were established. Immunophenotiping showed positive expressions for CD38 and CD56 and negative ones for CD20 and cyclin D1. Based on this findings we categorize this case as a variant of t (11;14) with negative expression of cyclin D1.

Key words: multiple myeloma, cytogenetics, chromosome aberrations

(MM) -

, - -

/ , , , . -

- ,

, -. -

. . 14q [1, 3]. t(11;14)(q13;q32),

. e t(11;14) -

.

. , . , . ... t(11;14)(q13;q32) 95

- - ,

, CD20 - [2, 4].

t(11;14) -

.

. ., 61 ., -

, . 10- 11-

-,

( – 103 g/l) , (150 mm), -

(80.7 g/l) (509 mol/l).

, . -

- (37,44 g/l),

IgA/ .

60% , 100%.

-

. . -

, - , -

(36%) ( . 1). G- -

. 1.

. . a

: 46, ,t(11;14)(q13;q32) [25] ( . 3). in situ (FISH)

, , BCL1/IGH, t(11;14) ( . 4).

-,

: CD38 CD56, CD138

CD19, CD20, CD22, CD79b, CD10, CD117 D1 ( . 2).

, IgA/ - 2 ( - 1000 mg, BCNU 50 mg, VCR 2 mg, Dexa-

methason, 4 10 mg). -

28,92 g/l, -

30% . , - .

. 2.

R 1 ( ) – CD38 CD56 (A-C) R 2 ( ) – CD38 CD56 (A-C)

CD20 (2,9% RH 1,5% R5-C) D1(1,1% R6 – D)

. . ., XLVI , 2011, 1-2 96

. 3. G- . ., t(11;14)(q13;q32).

) ) . 4. in situ , BCL1/IGH

t(11;14)(q13;q32) A) , BCL1/IGH (1G/1R/2F) ) , BCL1/IGH (1G/1R/2F)

. . 14q32 ,

, 4p16, 16q23, 6p21 20q11 [1, 3]. - (34% ).

D1 , -

–

. t(11;14) - , -

CD20 , D1 , -

[2, 4]. -

. 30% t(11;14) D1

CD20 [2]. , -

t(11;14) : ci D1 CD20

[5].

, - D1 CD20.

, -

t(11;14) ,

D1- t(11;14). ,

- - ,

. -

CD20 (Rituximab),

CD20 [2].

. , . , . ... t(11;14)(q13;q32) 97

1. S w e r d l o w , S. H. t al. (Eds.):WHO Classification of

Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon 2008.

2. R o b i l l a r d , N. et al. CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. – Blood, 102, 2003, 1070-1071.

3. F o n s e c a , R. et al. Genetics and Cytogenetics of Multiple myeloma. – Cancer Res., 4, 1-64.

4. F o n s e c a , R. et al. Myeloma and the t(11;14)(q13;q32); evi-dence for a biologically defined unique subset of patients. – Blood, 99, 2002, 10, 3735-3741

5. C o o k , J. R. et al. Immunohistochemical analysis identifies 2 Cyclin D1 + subset of Plasma Cell Myeloma. – Am. J. Clin. Pathol., 125, 2006, 615-624 .

: -

w .” . . ” 3 e-mail: dr_t.boneva@abv.bg

98

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