dlbcl: first line treatmentdr wendy osborne newcastle oxford management course june 2018 dlbcl is...
Post on 19-Apr-2021
3 Views
Preview:
TRANSCRIPT
DLBCL: First line treatment
Dr Wendy OsborneNewcastle
Oxford management courseJune 2018
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
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?
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?
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
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
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?
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
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
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
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
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%
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
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
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
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
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
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?
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
Is DA-R-EPOCH superior to RCHOP?
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)
Are there subgroups which would benefit from intensification?
High IPI
Double Hit/Dual-expresser
Primary mediastinal lymphoma
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
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
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
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
What is the prognosis of DHL?
Johnson N A et al. JCO 2012;30:3452-3459
Improved PFS with intensification
Petrich et al Blood 2014;124(15):2354-2361
Retrospective data
But no OS benefit
Petrich et al Blood 2014;124(15):2354-2361
ASCT in CR1: No OS difference
N=39
Petrich et al Blood 2014;124(15):2354-2361
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
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
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
MInT subgroup analysis
3 Year EFS 78% PMBCL, R CHOP like chemo (73% of pts had radiotherapy)
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
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
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
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
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?
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
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?
CNS IPI: >2000 patients analysed for CNS relapse DSHNHL and MINT studies(validated by BCCA)
Schmitz et al JCO 2016;34(26):3150-3156
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
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
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
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?
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
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
PET guided approach to bulk, Canadian data
Freeman et al ASH 2017 Abstract 823
Freeman et al ASH 2017 Abstract 823
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
Conclusions
Any Questions?
top related