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DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is...
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DLBCL: First line treatment
Dr Wendy OsborneNewcastle
Oxford management courseJune 2018
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DLBCL is most common NHL 30-40% of cases
10-15% have primary refractory disease
20-30% relapse
Only 20 % of patients alive at 2 years if they relapse
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
![Page 4: DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse](https://reader035.fdocuments.net/reader035/viewer/2022071507/61285b550ec75835d5693e5b/html5/thumbnails/4.jpg)
Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
![Page 5: DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse](https://reader035.fdocuments.net/reader035/viewer/2022071507/61285b550ec75835d5693e5b/html5/thumbnails/5.jpg)
Is DLBCL just one disease?Diffuse large B-cell lymphoma (DLBCL), NOS
Germinal center B-cell type*
Activated B-cell type*
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the central nervous system (CNS)
Primary cutaneous DLBCL, leg type
EBV+ DLBCL, NOS*
EBV+ mucocutaneous ulcer*
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK+ large B-cell lymphoma
Plasmablastic lymphoma
Primary effusion lymphoma
HHV8+ DLBCL, NOS*
Burkitt lymphoma
Burkitt-like lymphoma with 11q aberration*
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements*
High-grade B-cell lymphoma, NOS*
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Swerdlow et al 2016 Blood ; 127(20):2375-2390
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WHO 2016 recognises molecular heterogeneity of DLBCL
Cell of origin:
IHC is insufficient to reliably distinguish GC from non-GC(Hans algorithm based on CD10, IRF4 and BCL6 expression (1))
Distinct gene expression dependent on COO classifies into ABC, GCB, and unclassifiable (10-15%)
Inferior outcome after RCHOP in non-GC phenotype DLBCL (2)
Rearrangements of MYC and BCL2/BCL6
Dual positivity for MYC and BCL2 protein expression:“Dual-expressers” which lack identifiable translocations: (not WHO distinct entity
1)Hans et al Blood 2004, 2) Lenz et al NEJM 2008
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
![Page 8: DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse](https://reader035.fdocuments.net/reader035/viewer/2022071507/61285b550ec75835d5693e5b/html5/thumbnails/8.jpg)
Before the chemotherapy…
Staging : PET scan/CT
Prognostic score:IPI (age >60, stage III,IV, PS>1, LDH, EN sites>2) (1)
The revised IPI (2) confirms the prognostic significance of IPI in the R-CHOP eraNCCN-IPI (3), superior at discriminating low and high risk groups.
Cardiac function
Bloods: Viral screen including hepatitis B/HIV and LDH
Fertility preservation
Specialist nurse and contact details
MDT discussion
1) NEJM 329, 987-994 (2) Sehn et al 2007 Blood 109, 1857-1861, (3) Zhou et l 2014 Blood 123,837-842
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PET-CTStaging :
94% sensitivity for BM involvement, cf 24% with BMA T (1)
Extra-nodal disease and calculation of CNS IPIAssessment of bulk (>7.5cm)
Not for mid-point assessment : Interim PET(2),predictive, no benefit with escalation Mid-point CT should be performed
EOT scan:
Consider radiotherapy if PET positive
1)Berthet, L. et al. (2013) Journal of Nuclear Medicine; 2013 54: 1244–1250. 2) Duhrsen et al 2017 PETAL study 76.8093
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RCHOP: How much? How often?
Combined modality therapy for non-bulky stage IA
No difference in PFS and OS between 6 and 8 cycles RCHOP 14 : RICOVER-60 (1)
RCHOP 14 vs RCHOP 21: No difference in outcome in 2 large phase III studies (2,3)
1) Pfreundschuh et al 2008, 2) Cunningham et al Lancet . 2013;381(9880):1817-1826, 3)Delarue et al Lancet Oncol.2013;14(6):525-533
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Which antibody?
GOYA (1):
Is obinutuzumab (gycloengineered type II humanised anti-CD20) superior to rituximab
1400 patients
Randomisation of RCHOP vs OCHOP
1)Vitolo et al Blood 2016;21 (128);470
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Which antibody? GOYA study
INV-assessed PFS G-CHOP (n=706) R-CHOP (n=712)
Patients with events, n (%) 201 (28.5) 215 (30.2)3-year PFS, % 69.6 66.9HR (95% CI), stratified p value* 0.92 (0.76 1.11), p=0.3868
Time (months)
Median follow-up: 29 months
R-CHOP (n=712)
G-CHOP (n=706)
6 12 18 24 30 36 42 48 54 60
Pro
ba
bil
ity
1.0
0.8
0.6
0.4
0.2
0
0
Vitolo U, et al. J Clin Oncol 2017; Aug 10 doi: 10.1200/JCO.2017.73.3402;
3 yr PFS ABC 59%, GCB 75% unclassified 63%
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Addition of targeted agent?
Bortezomib, maintain NF-kB in inactive state
Does addition of bortezomib improve PFS? (ABC COO has chronic active B-cell receptor signalling with constitutive activation of NF-kB pathway)
ReMoDL-B, randomised addition of bortezomib to RCHOP
Central real time GEP to determine COO
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Study design
Amendment 2nd May 2014Bortezomib 1.6 mg/m2 day 1+8 sub cut
Powered to detect a 10%
improvement in 30 month PFS
(α=0.05; power 0.9). n=688 ABC and
GCB randomised. ABC 260
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Davies et al 2017;Ann Onc 35:130-131
Progression-free survival according to
molecular classification
30monthPFSGCB:74.3%:HR=0.774,p=0.079Unc: 68.2%:HR=0.884,p=0.480ABC:68.1%:HR=1(Referencecategory)
Medianfollow-upofsurvivingpatients:28.4months NodifferenceinOSeither
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Addition of targeted agent?
Ibrutinib : Not yetAwait PHOENIX study comparing RCHOP with RCHOP plus ibrutinib in non-GCB DLBCL (study completion expected June 2020)Central review of COO IHC before randomisation
Lenalidomide: Not YetR len CHOP compared with historical controls, improvement in PFS and OS in non-GCB group (1). Further evidence needed. GEP needed to identify true ABC patients which may cause selection bias
Lenalidomide maintenance: Maybe…REMARC study (2)
1) Nowakowski et al 2015; JCO 33(3): 251-257 2)Thieblemont et al JCO 2017;35(22):2473-2481
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REMARC: Lenalidomide maintenance vs placebo in responding elderly patients treated with RCHOP
Thieblemont et al JCO 2017;35(22):2473-2481
PFS benefit irrespective of COO. No OS benefit, this was not due to toxicity.
Patients aged 60-80 yrs, 2yrs of lenalidomide 25mg/day for 21 days
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
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Should we consolidate with autologous stem cell transplant?
SWOG (1) study, half of patients had RCHOP first line, PFS benefit if high or high/intermediate IPI but no OS benefit
Meta-analysis (2) shows that there is no clear value in up front auto
Cannot be recommended outside of a clinical trial
1) Stiff et al NEJM 2013;369(18):1681-1690, 2)Greb et al Cochrane Database Systemic Rev 2008: (1):CD004024
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Is DA-R-EPOCH superior to RCHOP?
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CALGB/Alliance Group ph III RCT
Only 6% with PMBCLFree Survival
Years from Study Entry
Pro
ba
bili
ty e
ve
nt
fre
e
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
R-CHOPDA-EPOCH-R
Bartlett et al ASH 2016 abstract #469, Wilson et al Blood 2016;128(22);496
No difference in 3 yr EFS (80%) or OS (85%) and increased toxicity with DA-R-EPOCH
465 pts RCHOP vs DA-R EPOCH (6% PMBCL)
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Are there subgroups which would benefit from intensification?
High IPI
Double Hit/Dual-expresser
Primary mediastinal lymphoma
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High IPI patients IPI 3-5
German DSHNHL 2002-1 3 year EFS of 69.5% with RCHOEP-14
Large RCT phase III but not randomised with RCHOP but does suggest improvement in patients with high IPI (1)
UK NCRI phase II (2) intensification with RCODOX M/IVAC
(1)Dilhurdy et al 2010, BBMT 16, 672-677 (2)McMillan et al 2013 Blood 122,4348
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High IPI: Phase 2 R-CODOX-M trial (1)
18-65 yrs stage II-IV untreated DLBCL/HGBL/BL IPI score ≥3 (1)
116 pts in the DLBCL/HGBL cohort. (2)
Median age was 50 years (range 18–65),IPI score was 3 (n=74; 64%), 4 (n=41; 35%) or 5 (n=1; 1%).11 pts (9.5%) had CNS involvement 62 (53%) had a performance status (PS) ≥2FISH available for 57 pts (7 patients were double/triple hit)
Median follow-up 53 months whole cohort: 3-year PFS 68% and OS 76 %
Good outcome in poor risk group of but further trials needed
1)McMillan et al, ICML 2015 2)Phillips et al S1548 EHA 23
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Double Hit LymphomaCharacteristic %
Median age (range) 61 (19-87)
ECOG 0-1 71%
ECOG 2-4 29%
Stage 3-4 84% (69-100)
LDH elevated 78% (50-100)
CNS disease 17% (4-44)
BM disease 53% (26-89)
IPI ≥ 4 44% (26-87)
Ki67 median 80%
Cheah et al BJH 168, 2014. Sesques and Johnson, Blood 129, 2017. Petrich et al Blood 124, 2014. Howlett et al BJH 170, 2015
Intensification not possible in many
5-10 % of DLBCL
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Dual-Expresser Lymphoma, similar but not to be confused with DHL
Swerdlow et al .Blood 2016
Defined only by protein expression
20-35% of DLBCL (do not have own WHO category)
Associated with a poorer prognosis but the data is difficult to interpret due to different cut offs and poor IHC reproducibility
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What is the prognosis of DHL?
Johnson N A et al. JCO 2012;30:3452-3459
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Improved PFS with intensification
Petrich et al Blood 2014;124(15):2354-2361
Retrospective data
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But no OS benefit
Petrich et al Blood 2014;124(15):2354-2361
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ASCT in CR1: No OS difference
N=39
Petrich et al Blood 2014;124(15):2354-2361
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Double Hit Lymphoma
Current literature is retrospective
Petrich (multicentre) : Intensive induction had high rate of PFS but no OS benefit
Oki (single centre) : DA REPOCH had an improved EFS and OS cf RCHOP
Landsberg (multicentre): Analysis of pts who achieved CR, intensive induction associated with improved relapse free survival and OS cf RCHOP
Petrich et al Blood 2014;124(15):2354-2361, Oki et al BJHaem,. 2014;166(6):891-901,Landsburg et al JCO 2017;35(20)2260-2267
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Primary mediastinal lymphoma
A subtype of DLBCL (7% of all DLBCL) : clinical, morphological biological characteristics overlap nodular sclerosing Hodgkin
Immunophenotypically distinct from DLBCL, >80% of cases expressing CD30
75% stage 1 or II (relapses usually stage IV)
50% have pleural or pericardial effusion
Frequent airway compromise and SVCO
Thrombotic complications in 28% of patients with PMBCL(1), consider LMWH
1) Roth ICML 2017
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6 x CHOP-like (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) chemotherapy +/- rituximab
Of 824 pts enrolled, 87 pts had PMBCL (1)
IFRT (30–40 Gy) was given to sites of primary bulky disease; Also given to sites of primary extra nodal disease at the physician’s discretion
Definition of bulk varied 5-10cm
73% had radiotherapy, concern about secondary breast cancer/ IHD (2)
MInT subgroup analysis
1)Rieger et al Ann Oncol 2011;22(3):664-670 2) 2)Castellino et al Blood 2011;117,6
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MInT subgroup analysis
3 Year EFS 78% PMBCL, R CHOP like chemo (73% of pts had radiotherapy)
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Prospective, 51 pts, DA-R- EPOCH x 6-8, no radiotherapy
5 yr EFS 93% OS 97%
DA EPOCH-R Therapy in PMBCL.
Dunleavy et al NEJM 2013;368(15):1408-1416
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6 weekly PET scans until negative or progression
36/51 had residual mediastinal masses
Half had Deauville 3 on first PET
Only 3 progressed
2 proceeded to radiotherapy
DA-R-EPOCH Therapy in PMBCL.
Dunleavy et al NEJM 2013;368(15):1408-1416
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EOT PET
DA-EPOCH R in 156 pts including children
75% PET negative Deauville 1-3 post chemo
14% had radiotherapy
Roth et al ICML 2017
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PMBCL EOT PET
No prospective RCT of front line therapy
Low threshold for biopsy
IELSG 37 randomisation to address role of radiotherapy consolidation
Deauville score , highest positivity for disease (1)
Deauville 4, monitor at a minimum
1)Martelli et al JCO 2014; 32(17):1769-1775
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
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Less fit patients
How should we assess? CGA (1), Charlson Comorbidity Index (2), Cumulative Illness Rating Scale(CIRS) …
R-mini CHOP (3), 2 yr PFS 47%, OS 59% in >80yrs (TRM 21%)
RCVP/ RCGVP if cardiac compromise (4)
Steroid pre-phase if PS >2 (5)
Primary GCSF prophylaxis if >65 years (6)
INCA (Inotuzumab Ozogamicin with RCVP)
1) Olivieri et al 2012, the Onc 17, 663-672 2) Kobayashi et al 2011 J Ca Res Clin Onc 137, 1079-1084, 3) Peyrade et al 2011 Lancet Onc 12, 460-468 4)Fields et al 2014 JCO 32, 282-287 5) Pfreundschuh et al 2010 Blood 116, 5103-5110 6) Repetto et al 2003 Eur Journ Canc 39, 2264-2272
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
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CNS IPI: >2000 patients analysed for CNS relapse DSHNHL and MINT studies(validated by BCCA)
Schmitz et al JCO 2016;34(26):3150-3156
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CNS IPI: Risk of CNS relapse by number of risk factors
Risk Factors
Age>60yrsElevated LDHPS>1>1 EN siteStage III or IVRenal or adrenal
Schmitz et al JCO 2016;34(26):3150-3156
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CNS prophylaxis: Newcastle guidelines
Offer prophylaxis to patients with renal, adrenal, breast , testicular disease and double hit lymphomas. (NICE guidance)
Offer prophylaxis to patients with 4 points or more on CNS IPI as below
CNS IPI Risk factors : 1 point scored for each risk factor (2 yr risk CNS disease 0.6% in low risk group, 3.4% in int med gp, 10.2 % in high risk)
LDHAge above 60Performance status >1>1 Extranodal siteStage III or IVRenal or adrenal
CNS IPI: Schmitz et al JCO 2016;34(26):3150-3156
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The debate of optimal prophylaxis
First do no harm
Must not delay primary curative therapy
Intrathecal vs intravenous methotrexate
Methotrexate 3.5g/M square at day 10 cycles 2,4 and 6 of RCHOP
Delivery during induction as events often early (1)
1)Boehme et al Ann Onc 2007 ; 18(1):149-157
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Is DLBCL just one disease?
It’s just RCHOP isn’t it ?
Should we intensify treatment upfront?
What about the less fit patient?
Who should we give CNS prophylaxis to?
Is there a role for radiotherapy in DLBCL?
![Page 47: DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse](https://reader035.fdocuments.net/reader035/viewer/2022071507/61285b550ec75835d5693e5b/html5/thumbnails/47.jpg)
Radiotherapy : Newcastle approach
Bulk disease > 7.5cm (? Only if PET positive)
PET positive disease at end of treatment
Extra-nodal sites : BulkLimited stageBone (1-3 sites)Contralateral testisCritical sites e.g. presenting with SCC
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Radiotherapy
30Gy as effective as higher doses (1)
Unfolder:Patients with bulk >7.5cm were randomised to 36Gy IFRT or no further treatment. Closed early due to benefit of radiotherapy
RICOVER-60: (pts 61-80 comparing 6 vs 8 RCHOP)
addition of 36Gy IFRT to bulk >7.5 cm and extra nodal disease resulted in EFS, PFS, and OS benefit (2)
OPTIMAL >60: Radiotherapy can be spared in elderly (aged 61 to 80) if negative PET after immunochemotherapy (3)
1) Lowry et al 2011 rad and onc 100,86-92 2) Held et al 2014 JCO 32, 1112-1118 3) Pfreundschuh et al abstract 120
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PET guided approach to bulk, Canadian data
Freeman et al ASH 2017 Abstract 823
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Freeman et al ASH 2017 Abstract 823
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Conclusions
Is DLBCL just one disease? No
It’s just RCHOP isn’t it ? At the moment ….
Should we intensify treatment upfront? High IPI/DHL/PMBCL
What about the less fit patient? Co-morbidity assessment
Who should we give CNS prophylaxis to? CNS IPI
Is there a role for radiotherapy in DLBCL? PET may inform this
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Conclusions
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Any Questions?