Post-ESMO Berne 23.10.2015 Lymphoma Update Panagiotis Samaras Department of Oncology Hemato-Oncology Center University Hospital Zurich
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Vitamin D levels and rituximab? (RICOVER-60 post hoc) N=422 DLBCL, 61-80y, all IPI 6 x CHOP 14 8 x CHOP 14 6 x R-CHOP 14 + 2 x R 8 x R-CHOP 14 CHOP R-CHOP No difference WITHOUT Rituximab 3y-EFS 59% versus 79% WITH Rituximab Vitamin D- deficiency impairs ADCC Bittenbring et al, JCO 2014
Radiotherapy to bulky disease? (UNFOLDER, 18-60j, 2x2 Design) +/- Bestrahlung von Bulky Disease +/- Bestrahlung von Bulky Disease preplanned interim-analysis (n=285): 3y-EFS: 81% vs 64%; p=0.004 Stopping rule met: Non-radiotherapy arms were closed RT-advantage confirmed by retrospective analysis of RICOVER-data Held et al, JCO 2014 Kubuschok et al, in: Non-Hodgkin Lymphoma (Springer); ed. Evens and Blum 2015
Radiotherapy to bulky disease? (RICOVER-60 post hoc) N=470 DLBCL, 61-80y, all IPI 6 x R-CHOP 14 + 2 x R bulkrt 6 x R-CHOP 14 + 2 x R no bulkrt per protocol analysis radiotherapy of initial bulky disease recommended Open question: RT necessary in negative PET after chemo? ongoing OPTIMAL >60 trial! Held et al, JCO 2014
CNS-relapse risk and prophylaxis. What s new? No prospective data, only retrospective analyses Intrathekal MTX not sufficient 1-3 Risk in part compensated by Etoposide and Rituximab 2 Craniofacial involvement due to R no independend risk factor 3 High-risk factors: Elevated LDH / >1 extranodal lesion / ECOG PS>1 (2/3): 2j-Risiko 33.5% High risk-localisations: Testis, Breast, kidney, adrenal gland, BM MYC-Rearrangement +/- BCL2 (DH) Retrospective post hoc analyses show benefit of HD-Methotrexat i.v. 4-7 1 Chua et al. Leukemia Lymphoma 2002 2 Boehme et al, Blood 2009 3 Murawski et al. Blood 2014 4 Ferreri et al. BJH 2014 5 Abramson et al. Cancer 2010 6 Tilly et al. Blood 2003 7 Cheah et al. Br J Cancer 2014
Prognostic model for CNS-relapse risk (NCCN 2.2015) Renal/adrenal involvement All patients received Rituximab and CHOP-based 1st-Line CNS-relapse risk with 0-1 RF: <1%: no further measures 2-3 RF: 3-4%: diagnostics recommended (MRI, cerebrospinal fluid analysis with FACS) 4-6 RF: 10-15%: diagnostics and prophylaxis recommended kidney/adrenal involvement: 15% (DSHNHL), 33% (BCCA) El-Galaly et al, ICML 2015 Savage et al, ASH 2014 Schmitz et al. ICML 2013
Double hit Lymphoma (DHL) chromosomal breakpoint in MYC/8q24 locus combined with another recurrent breakpoint, mainly t(14;18), but also breakpoints in BCL6, Cyclin D1, BCL3 Incidence: 0-12% of DLBCL based on larger published FISH series 62% BCL2+/MYC+; 8% BCL6+/MYC+; 16% BCL2+/BCL6+/MYC+ MYC cell cycle progression differentiation altered metabolism Apoptosis telomerase activity cell adhesion proliferation genomic instability increased cell growth blocked by secondary mutations or epigenetic changes and Immortalization escape from immune surveillance Bcl2 Potent antiapoptotic function impaired DNA-Repair
Double-hit Lymphoma (DHL) cytogenetic DHL worse than IHC double expressors! Johnson et al. JCO 2012
What treatment is promising in DHL? MD Anderson Experience: DHL diagnosis by FISH; n=129 2y-EFS 25% (R-CHOP) vs 67% (DA-EPOCH-R) vs 32% (R-HyperCVAD) cumulative 3y-incidence for CNS-involvement 13% Very dismal prognosis at relapse/refractory disease (2y-OS <5%) Cheah et al. BJH 2015 Oki et al. BJH 2014
What treatment is promising in DHL? Meta-analysis, 11 studies, 394 patients R-CHOP: n=180; DI=R-CODOX-M/R-IVAC or R-HyperCVAD: n=123; DA-EPOCH-R: n=91 DA-EPOCH-R seems to be the most efficacious 1st-Line Treatment! Consider CNS-prophylaxis Howlett et al. BJH 2015
DLBCL-Subtypes differ in terms of outcome Lenz and Staudt NEJM 2010
Different prognosis ABC vs GCB Gene expression profiling from paraffin-embedded tissue, n=344, R-CHOP 1st line COO independend from IPI and MYC/BCL2-immunohistochemistry Scott et al JCO 2015
Targeted Treatment for r/rdlbcl or 1st line R-CHOP+X Nowakowski and Czuczman ASCO 2015
Clinical Trials with new Substances Ongoing Phase III Studies in ABC DLBCL: Presented by Nowakowski and Czuczman ASCO 2015 ROBUST: R-CHOP vs R2-CHOP (GEP) start Q1/2015 PHOENIX: R-CHOP vs IR-CHOP (IHC) start Q4/2013 REMoDL-B: R-CHOP vs BR-CHOP (GEP) completed! (also GCB included)
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Impact of Thiotepa and Rituximab in PCNSL (IELSG 32) MATRix Ferreri et al, ICML 2015
Impact of Thiotepa and Rituximab in PCNSL (IELSG 32) MTX/AraC R-MTX/AraC R-MTX/AraC/TT MTX/AraC R-MTX/AraC R-MTX/AraC/TT Failure-Free Survival (21 mo FU) 32% vs 54% vs 65% 2y-OS 40% vs 58% vs 66% More hematologic toxicity in Arm C MATRix: new standard induction for future trials Ferreri et al, ICML 2015
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Impact of radiotherapy? (HD.6 - NCIC) N=405 Stage IA/IIA fav./unfav./non-bulky 4-6 X ABVD Subtotal nodal RT (favorable) Subtotal nodal RT + 2 x ABVD (unfavorable) FFDP 87% vs 92%; OS 94% vs 87% Better initial disease control, but worse survival in the long-term! Meyer et al. NEJM 2012 Meyer et al. JCO 2005
Stage IA/IIA Early stage HL (RAPID UK) 3XABVD N=602 PET favorable/unfavorable neg. pos. Observation 30 Gy IFRT 1xABVD+30Gy IFRT 3y-PFS 90.8% vs. 94.6% (ITT), excellent outcome with/wo RT Omitting RT in PET- : balancing disease control and late effects Radford et al. NEJM 2015
Advanced HL (RATHL UK) Phase III randomized, N=1214; untreated chl; >18 years, stages IIB-IV / stage IIA plus adverse features (bulk, +3 sites) Escalation De-Escalation PET-negativity: Deauville Score 1-3 Johnson et al. ICML 2015
Advanced HL (RATHL UK) N=954 (84%) 3y-PFS: ABVD 85.4% vs AVD 84.4% 3y-OS: ABVD 97% vs AVD 97.5% Bleomycin may be omitted after neg. PET2 Johnson et al. ICML 2015
Advanced HL (RATHL UK) Phase III randomized, N=1214; untreated chl; >18 years, stages IIB-IV / stage IIA plus adverse features (bulk, +3 sites) Escalation De-Escalation PET-negativity: Deauville Score 1-3 Johnson et al. ICML 2015
Advanced HL (RATHL UK) Overall 3y-PFS: 83%; HD15: 5y-PFS 90% PET2+: n=174 (16%) 74% PET3-: 3y-PFS: 68%; 3y-OS 86% No difference between BEACOPP-14 and BEACOPP escalated Interim-PET for treatment stratification! Johnson et al. ICML 2015 adapt. Engert ICML2015
New regimen: BrECADD BEACOPPesk 10 200 35 1250 1.4 7x 100 14x 40 Borchmann et al. EHA 2014
Less toxic, still efficacious? BrECADD Borchmann et al. EHA 2014
Less toxic, still efficacious? BrECADD Borchmann et al. EHA 2014
Advanced HL (HD21) Study Start 2016
Nivolumab in r/r HL 23 patients with r/rhl 78% ASCT-failure; 78% Brentuximab-failure; 83% RT 87% 3 pretreatments Response Rate 87% (17% CR, 70% PR) Durable remissions up to 2 years (end of Follow-Up, 10/23 patients) Ansell et al. NEJM 2015 Armand et al. ASH 2014
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Rituximab-Maintenance after ASCT in MCL (LyMa) MCL <66y N=299 MIPI low 53%, intermed. R-BEAM 27%, high 19% 4xDHAP CR/PR Observation R every 2 mo for 3y Le Gouill et al. ICML 2015 Continued improvement in EFS; no OS difference (4y: 85% vs 93%) final results next year, possible new standard for young MCL patients
Diffuse Large B-Cell Lymphoma (DLBCL) PCNSL Hodgkin s Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Type II Ab Obinutuzumab after R in inhl (GADOLIN) N=413 6 x Benda 90 mg/m 2 + Obi 1000 mg Rit-ref inhl (80% FL), 63y, 2TL 6 x Benda 120 mg/m 2 no PD 2y Obi 1000 mg Med PFS n.r. vs 14.9 mo (p<0.0001); no difference in OS (trend, HR 0.8) Effect seen in all subgroups analyzed New option for patients with rit-ref inhl Sehn et al., ASCO 2015
Thank you for your attention!
A Randomized Evaluation of Molecular guided therapy for Diffuse Large B-cell Lymphoma with Bortezomib REMoDL-B Patient with DLBCL requiring full course chemoimmunotherapy Consents Biopsy material forwarded to HMDS for Expression Profiling -R - -CHOP 1 cycle recruitment completed Two interim analysis of GCB group receiving R-CHOP + B Randomisation, stratified for molecular phenotype Initially all cases with molecular phenotype randomised Initially all cases with molecular R-CHOP + Bortezomib 5 cycles R-CHOP 5 cycles Follow-up
Long-term impact of ASCT in FL (Geltamo Spain) retrospective analysis, 640 patients, no FU<7y, Median FU from ASCT: 12.2y; 1/3 prior R 31% CR1, 26% CR2; 5% CR3; 21% PR1; 5% active disease; 12% chemosensitive relapse Med PFS: 9.4y/OS: 21.3y; CR1: PFS 68%/OS 73%; 6 deaths after 10y FU No prognostic impact of prior rituximab or FLIPI in CR1 Plateau reached after 15y, cure possible? Ubieto et al., ASH 2014
Ongoing study in DLBCL older patients (less favorable): OPTIMAL >60
Ongoing study in DLBCL older patients (favorable): OPTIMAL >60
Ongoing study in DLBCL young patients (favorable IPI 0): FLYER