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Lymphoma: Treatment Updates

This document summarizes new therapies presented at an ASCO/ICML conference for lymphomas. For aggressive NHLs, novel targeted drugs and cell therapies were discussed. Studies showed improved outcomes for DLBCL with regimens adding drugs like lenalidomide or bortezomib to R-CHOP. Intensive therapies did not clearly improve survival for double hit lymphomas over R-CHOP. For indolent NHLs, new drugs and initial therapy strategies were reviewed. The document provided details on clinical trials and outcomes for various lymphoma subtypes and treatments.

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New Therapies for Lymphoma: An ASCO/ICML Update F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 28 August 2015
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
GCB and ABC DLBCLs: Two Different Mechanisms for Malignant Change BCL-2 translocation Apoptosis miR-17-92 mTOR amplification Activation PTEN deletion ING1 deletion MDM2 gain or Genomic amp Instability P53 mutation MYC translocation BCL-2 amplification Apoptosis NFK-B activation Apoptosis IL-6, IL-10 STAT3 IRF4 Essential 19Q gain Regulatory or amp SPIB Network Trisomy 3 FOXP1 Del ink4A-ARF Senescense Genomic Instability AID Switch Translocations MYC amp GCB ABC GCB Cell Plasmablast Plasma Cell
ADCC Activity with Rituximab Improves When Patients Are Given Vitamin D Bittenbring et al. JCO 10: 3242-3428, 2014. • Vitamin D levels tested at diagnosis of DLBCL • “Low” level: 8.4 + 3 ng/ml • Pts achieved 40.6 +13.6 ng/ml after given Vit D • ADCC activity tested before/after Vit D given
Effect of Vitamin D3 Levels on Results for Patients Receiving R-CHOP-14 Proportion ProgressionFree ProportionAlive Bittenbring et al. JCO 10: 3242-3428, 2014. ProportionAlive Proportion EventFree Results from RICOVER-60 (Training Cohort) Results from RICOVER-noRTh (Validation Cohort)
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
Novel Drugs for Aggressive NHLs? Agent Comment ABT-199 Platelets-sparing BCL-2 inhibitor BET Bromodomain Inhibitors Down regulators of MYC transcription CAR-T cells T cell killing of CD-19 positive NHLs Aurora kinase inhibitors Kinase needed for survival of MYC mTOR inhibitors mTOR pathway important in MYC drive Ixasomib (proteasome inhibitor) Inhibits MYC at n-molar concentrations PI3K inibhitors Loss of PTEN leads to PI3K activation and increased MYC SIRT4 protein Inhibits glutamine metabolism in MYC driven tumors Inhibitors of mitochondrial peptide deformylase In tumor models, cause apoptosis in MYC driven tumors by depolarizing mitochondrial membnrane
BV for Relapsed/Refractory CD30 Positive DLBCL • 118 patients with DLBCL, Med prior TXs = 2, tested for CD30 by visual IHC and computer assisted method, all had elevated soluble CD30 blood levels • Dose: 1.8 mg/kg q 3 wk with or without rituximab • CD30U = Undetected, but mRNA CD30 similar to those with CD30 + cells Smith et al. ICML-13, 2015, # 91. CD30 + CD30U Feature BV + R, # (%) BV, # (%) BV, # (%) Refractory last TX 10 (63) 40 (82) 37 (70) % CD30 Expression ND 37 2 CR 2 (15) 9 (19) 5 (10) PR 4 (31) 11 (23) 8 (16) Med PFS, Mo (Max) 2.4 (12+) 4 (24+) 1.4 (12.2+)
Lenalidomide + Rituximab for Ref/Rel DLBCL Group No. of Pt. ORR CRR Reference US 49 (various histology) 35% 12% Wiernik 2008 Italian 23 DLBCL 35% 4% Zinzani 2011 International 217 DLBCL 35% 13% Witzig 2011 Retrospective from 4 sites 40 DLBCL GCB 23 Non-GCB 17 9% 53% 4% 24% Hernandez -Illizaliturri 2011
Ibrutinib for Relapsed/Refractory DLBCL: Responses by Molecular Phenotype Wilson et al. ASH, 2012.
Phase I CUDC-907, a Dual PI3K/HDAC Inhibitor for Ref/Rel NHL and Myeloma • 51 patients enrolled, 41 evaluable for response • Dose: 3X3 escalation, with both frequency and dose given, 30-120 mg and 2 x wk, 3 x wk, 5 x wk • DLT in 3 = Diarrhea, hyperglycemia • 4/41 objective responses ( 1 CR, 3 PR, all in DLBCLs) Younes et al. ICML-13, 2015, # 80. Schedule Dose No. Pts Tumor Regression, # (%) QD 30-60 10 3 (38) BIW 60-150 12 7 (58) TIW 60-150 15 5 (38) 5 x wk 60 14 4 (50)
PD-1 is Inactivated by PD-L1 and PD- L2 on Tumor Cells • PD-1 is a protein on T-Cells that dampens the normal immune response • Tumor cells can evade normal T-cell attack • Inactivate T-cell function by activation of PD-1 via PD-L1 and PD- L2 present on lymphoma cells • T-Cells are “exhausted” • Cannot attack tumor cells • Inactivation is reversible
Phase I Nivolumab (BMS-936558) for Rel/Ref Lymphoid Malignancies Lesokhin et al. ASH 2014 # 291 Resp All B 29 FL 10 DLCL 11 All T 23 MF 13 PTCL 5 MM 27 PMBL 2 %OR 28 40 36 17 15 40 0 0 %CR 7 10 9 0 0 0 0 0 %PR 21 30 27 17 15 40 0 0 %SD 48 60 27 43 69 0 67 100 Ongoing studies in DLBCL and FL
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
Phase II Lenalidomide Plus R-CHOP for Patients with Untreated DLBCL • 64 pts: Med age 65, 53% IPI 4-5. • Doses: Lenalidomide 25 mg qd,, d 1-10, plus R-CHOP-21 X 6 Support: PegFilgrastin day 2, aspirin prophylaxis • 60 evaluable pts compared with 87 historical pts treated with R-CHOP from same center • Result: ORR-98%, CR-80%. 2 yr EFS-59%, 2 yr OS- 78%. • By Hans Criteria: • Conclude: Lenalidomide may erase the differences seen with R-CHOP by improving the results for non-GCB subtypes. R-CHOP R2-CHOP Feature GCB Non-GCB P GCB Non-GCB P 2 Yr PFS 64 28 <0.001 59 60 0.83 2 yr OS 78 46 <0.001 75 83 0.61 Nowakowski et al. JCO 32: 5s, 2014 (abst 8520).
R-CHOP Compared with R2-CHOP for GCB and Non-GCB DLBCLs: PFS and OS Results Nowakowski et al. JCO 33: 251-258, 2014. Results with R-CHOP 2 Yr PFS: G-64%; Non-G-28% 2 Yr PFS: G-59%; Non-G-60% Results with R2-CHOP P = 0.08P<0.001 2 Yr OS: G-76%; Non-G-82%2 Yr OS: G-74%; Non-G-46% P = 0.61P<0.001 GCBGCB GCB GCB Non-GCB Non-GCB Non-GCBNon-GCB
Phase I Ibrutinib with R-CHOP for Patients with B-Cell NHLs Dosing: R-CHOP standard doses, plus Ibrutinib at 280, 420, 560 mg daily ORR = 100%, CR = 69%, PR = 31% Responses at all dose levels, MTD not reached Toxicities: ANC-77%, PLT -65%, and vomiting -59% The basis of a trial of Ibrutinib-R-CHOP vs R-CHOP-placebo for pts with non-GCB subtype Younes et al, ASCO 2013 # 8502. Response DLBCL (N=8) MCL (N=5) FL (N=4) Total (N=17)* CR 2 4 1 7 PR 2 1 2 5
Other Studies in DLBCL 2015 UK R-CHOP + Bortezomib (REMoDL-B, up to 900 pt!) – 2nd similar trial in US – Based on Ph 2 BR-CHOP, 95% CR, 4 yr PFS 58% Intnl R-CHOP + Ibrutinib – Only for Non-GCB type by Hans Criteria – Based on Ph 1-2 IR-CHOP, 18 pt, 83% CR R-CHOP + Maint Everolimus vs R-CHOP, 600 pt – Completed, not reported – Based on Ph 2 ER-CHOP, 3 yr PFS 76% – Alliance PH 1-2 R-CHOP + E also final to report Furman et al. Cancer 116: 5432-5436, 2010. Younes et al. Lancet Oncol 15: 1019-1026, 2014. Micaleff et al. Blood 118: 4053-4061, 2011.
GOYA Phase III G-CHOP vs R-CHOP for Untreated CD20+ DLBCL: Study Design Rituximab + CHOP GA101 + CHOPPreviously untreated CD20+ DLBCL (N=1400) R Primary endpoint: ● PFS (investigator- assessed) ● TTNLT ● Safety ● QOL ● Resource utilization Secondary endpoints: ● OS ● Response rates ● EFS ● DFS ● DOR http://www.clinicaltrials.gov/ct2/show/NCT01287741 as of 09/01/13. GA101=1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d; rituximab 375 mg/m2 on d1 q21d cycles 1-8; CHOP=q21d 6-8 cycles
Phase II Randomized Dose BV + R-CHOP for Advanced Untreated DLBCL • 51 patients: IPI 3 in 62%, IPI 4-5 in 38%. – ECOG 2 – 28%, Stage IV – 70%. • Dose: 1.2 vs 1.8 mg/kg q 3 wk plus R-CHOP vs R-CHOP alone, reduced to 1.2 early on due to neuropathy with 1.8. • Gr 3-4 AEs: FN 27%, ANC 25%, HGB 24% – All Gr PN: 38% at 1.2 mg/kg, 77% at 1.8 mg/kg. • CR rates: ABC=GCB (69% vs 65%), but CD30 pos > CD30 neg (92% vs 69%). No PD for CD30+ with med f/u 5 mo. Bartlett et al. ASCO 2015, Abst 8506. Response 1.2 mg/kg N (%) 1.8 mg/kg N (%) Total N (%) CR 19 (66) 15 (68) 34 (67) PR 4 (14) 3 (14) 7 (14) PD 2 (7) 3 (14) 5 (10)
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
MYC Rearrangement (MYC-R) in DLBCL: DHL or DEL? • In general, R positivity infers an inferior prognosis – R-CHOP therapy is inadequate, with < 12 mo OS • High MYC protein expression without MYC-R has also been identified (alternate mechanism) – DLBCL with high MYC (>40%) and BCL-2 (50-70%) protein expression by IHC = Double Expressor DLBCL (DEL) – Also has a poor prognosis with R-CHOP • Should the approach to therapy be the same for both DHLs and DELs? – Majority of DHL = GCB DLBCL – Majority of DEL = ABC DLBCL
R-CHOP-21 or Variants for DHLs Author No. Pts Therapy % MYC-R %DHLs (BCL-2-R) Outcome Klapper 177 CHOP or CHOEP 8 NR OS worse for MYC-R Barrans 303 R-CHOP 14 11 2 yr OS 35% (MYC-R) vs 61% (MYC-N) Savage 135 R-CHOP 9 5 5 yr OS 33% (MYC-R) vs 72% (MYC-N) Cunningham 1080 R-CHOP 14 or 21 6 3 No differences in 2 yr OS for MRC-R or N MYC-R = Rearranged; MYC-N = Not rearranged
OtherTrials of Intensive Therapy for DHLs Author No. Pts Therapy (% Pts) Outcome (Mo, Median) Comments Petrich 311 R-CHOP -32 R-HCVAD-21 R-EPOCH-21 R-CODOX-14 OS=22, PFS=10.9 PFS 7.8 R-CHOP vs 26.6 Other (p=0.001) Med F/U=23 mo No OS diff among intensive TXs; OS not affected by SCT Oki 129 R-CHOP-44 R-HCVAD-26 R-EPOCH-22 2 yr EFS= 33% CR rates: 20% vs 70% vs 68% OS better with R- EPOCH vs R-CHOP (p=0.057); no benefit with SCT; 13% CNS Johnson 54 CHOP-43 R-CHOP-20 OS: R-CHOP=15 mo CHOP=5 mo BCL-2 Protein negative cases favorable Li 56 R-CHOP-39 RHCVAD-59 OS: 19 mo Neither SCT nor intensive therapy made OS better Petrich. Blood 124: 2354-2361, 2014. Oki. Br J Haematol 166: 891-901, 2014. Johnson. JCO 30: 3452-3459, 2012. Li. Adv Anat Path 20: 315-326, 2013.
Double Hit DLBCL in 100 MDACC Patients: A Retrospective Analysis • CR rates: All 59%, CHOP + R 49%, EPOCH + R 50%, HCVAD + R 60% (P=NS). • 3 Year PFS (All pt) = 32%, OS = 41%. No diff by chemo regimen Oki et al. ASH 2013 #1776 Dunleavy et al. ASH 2013 Hu et al, Blood 122: 2014 PFS by Therapy Regimen OS by Therapy Regimen Similar results for DA-EPOCH-R from NCI., and R-CHOP consortium data.
Double Hit DLBCL in 100 MDACC Patients: A Retrospective Analysis • SCT performed in 19 of 59 CRs • 3 Yr PFS: SCT 66%, None 45%. OS: SCT 67%, None 62% Oki et al. ASH 2013 #1776. PFS By SCT or None OS by SCT or None But for 15 CRs after EPOCH + R, PFS = 100% (SCT in 8)
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
Ibrutinib Monotherapy in Relapsed/ Refractory FL: Max Tumor Vol Reduction Bartlett NL, et al. ASH 2014. Abstract 800. 60 20 -20 -60 -100 TumorSize (%ChangeinSPDFromBaseline) CR PR SD PD 72% of pts had reduction in tumor volume Individual Pts
Phase 2 Idelalisib for 125 Alkylator-Rituximab Ref iNHL: Nodal Response and PFS Results -100 -75 -25 0 -50a +25 +50 Individual Patients (N=125) SPDofMeasuredLymphNodes, Best%ChangefromBaseline •90% had improvement in lymphadenopathy •57% had ≥50% decrease from baseline Gopal et al. ASH 2013 #85 . 0 (125) 3 (100) 6 (34) 9 (19) 12 (13) 15 (6) 18 (0) 0 25 50 75 100 Time from Start of Idelalisib, Months (N, Patients at Risk) %Progression-Free Median PFS = 11.4 monthsMaximum Nodal Response Historical Control: Bendamustine: DOR 10mo 53% ORR
Phase I IPI-145 (PI3K δ,γ Inhibitor) for NHLs and HL: Clinical Activity Horwitz et al. ASCO 2012.
Phase I Ublituximab, TGR-1202, and Ibrutinib for Relapsed B-Cell NHLs • Background – Ublituximab: A glycoengineered anti-CD20 MAB against a unique epitope on CD20. – TGR-1202: A highly active oral PI3K inhibitor (Burris 2014). • TX: UTX-900 mg d 1,8,15 cycles 1-2, then q 2 mo – TGR-400-1200 mg + Ibrutinib 420 (CLL) or 560 (NHL) QD • 12 pts, could have had Ibru or Idela; any # prior txs – AEs (Gr 1-2): 30% diarrhea, constipation, fatigue, no DLT – Response: OR-75%, all iNHL or MCL • Phase II study planned. Fowler et al. ASCO 2015, Abst 2801. Nastoupil et al. ICML-13 2015, # 106.
Phase IIa Anti-CD19 Antibody (MOR208) for Rel/Ref NHLS • Fc engineered humanized monoclonal antibody directed against CD19 • 89 patients, previously received rituximab, not candidates for SCT; Med prior therapies – 2. • Dose 12 mg/kg IV weekly for 2, 28 day cycles • Gr 3-4 AEs: Non-hematologic in 30 pts (34%) • Hematologic Gr 3-4 events in 8 (9%) Jurczak et al. ASCO 2015 Abst 8500. Best Resp (N, %) DLBCL (N=35) FL (N=34) MCL (N=12) iNHL (N=11) Total (N=92) CR 2 (6) 2 (6) 0 2 (18) 6 (7) PR 7 (20) 7 (21) 0 1 (9) 15 (16) SD 5 (14) 17 (50) 6 (50) 4 (36) 32 (35) Med DoR 2.6 (DLBCL), 7.7 (FL). Longest resp 62 and 67 wks. Combination trials planned.
Phase II Obinutuzumab for Relapsed or Refractory iNHL: Gauguin Study Salles et al. JCO 31: 2920-2926, 2013. Response Rates Progression Free Survival
GADOLIN Phase III Safety and Efficacy of G- Benda vs SA Benda for R-Refractory iNHL G: 1000 mg d1, d8, d15 cycle 1; d1 cycles 2-6 q28d a Bendamustine: 90 mg/m2 d2, d3 cycle 1; d1, d2 cycles 2-6 q28d; b Bendamustine: 120 mg/m2 on d1, d2 cycles 1-6 q28d Bendamustineb CR/PR/SD Maintenance G q2m × 2 years G + Bendamustinea Rituximab- refractory iNHL (N=360) R Primary endpoint: ● PFS Secondary endpoints: ● OS ● Response rates Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123.
Phase III G-Benda vs SA Benda for R- Refractory iNHL: Pathology and Prior R Type 19.6 22.3 80.4 77.7 0 20 40 60 80 100 G-B (n=194) B (n=202) R-chemotherapy combination* R-monotherapy FL, follicular lymphoma; MZL, marginal zone lymphoma including extranodal, nodal and splenic; SLL, small lymphocytic lymphoma; WM, Waldenström macroglobulinemia. Patients(%) 79.9 82.2 13.9 9.4 0 20 40 60 80 100 G-B (n=194) B (n=202) WD SLL MZL FL Rituximab-refractory type * Includes patients with relapse within 6 months of last dose of rituximab Patients(%) 6.2 7.9 0.5 Lymphoma subtype Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. WMWM
Phase III G-Benda vs SA Benda for R- Refractory iNHL: Response Rates End-of-induction response (IRF) Best overall response to 12 months (IRF) 69.2 63.0 78.7 76.7 Patients(%) Patients(%) • 19 patients still in induction (G-B, n=6; B, n=13) 11.7 18.5 9.0 9.010.1 9.5 58.0 50.8 11.2 12.2 0 20 40 60 80 100 G-B n=188* B n=189* G-B n=188* B n=189* Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. Patients still in induction therapy are excluded from analysis. Patients with end of induction response > 60 days shown as missing. Best overall response excludes patients who have not yet had response analysis.
GADOLIN Trial: Investigator-Assessed PFS Investigator-assessed PFS G-B (n=194) B (n=202) Events, n 77 (40%) 115 (57%) Median PFS, months (95% CI) 29.2 (20.2–NR) 14.0 (11.7–16.0) Stratified HR (95% CI) 0.52 (0.39–0.70) Log-rank p-value p<0.0001 1.0 0.8 0.6 0.4 0.2 0 6 12 18 24 30 36 42 48 54 Time (months) ProbabilityofPFS 0.0 194 202 157 150 108 89 77 46 51 28 27 15 7 5 2 2 1 1 No. at risk G-B B 14.0 29.2 Median follow-up: 21 months Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. GB B
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
GALLIUM Phase III CT vs R + CT Followed by G or R Maint for Untreated Advanced iNHL 68 G:1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d or cycles 2-6 q28d; CT=CHOP (6 cycles q21d), CVP (8 cycles q21d) or benda (6 cycles q28d); Rituximab 375 mg/m2 on d1 cycles 2-8 q21d a FL: Each site chooses CHOP, CVP, or benda. Non-FL: CHOP, CVP, or benda selected on a patient-by-patient basis Maintenance R q2m × 2 years Maintenance G q2m × 2 years Rituximab + CTa CR PR SD GA101 + CTa Previously untreated advanced iNHL (N=1400) R Primary endpoint: ● PFS (investigator assessed) in FL patients Secondary endpoints: ● PFS ● ITT (investigator and IRC assessed) ● Response rates ● OS ● EFS ● Safety ● DFS ● DOR ● PROs ● Resource utilization http://www.clinicaltrials.gov/ct2/show/NCT01332968 as of 09/01/13.
R2 for Untreated FL: Response by Tumor Burden and Molecular Features By GELF Criteria (N=46) High Tumor Burden (N=22, 48%) Low Tumor Burden (N=24, 52%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1 (5%) 21(95%) 100% 1(4%) 4(17%) 19 (79%) 96% By Bulk of Disease (N=46) Bulky (N=13, 28%) Non-Bulky (N=33, 72%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1(8%) 12(92%) 100% 1(3%) 4 (12%) 28 (85%) 97% Fowler et al. ASH 2012, abst 901. Molecular Response (N=44 Evaluable, Marrow and Blood) PCR Positive PCR Negative PRETREATMENT 17(41%) 26(59%) POST CYCLE 3 5(11%) 39(89%) POST CYCLE 6 2(5%) 42(95%)
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
Phase II Rituximab, Bendamustine, Cytarabine (R-BAC) for MCL > 60 Years • 57 patients, med age 71 (61-79), stage III-IV-91%, High MIPI in 45%, Blastoid in 9%. • 91% received 4, 63% received 6 cycles • Gr 3-4 ANC in 49%, PLT in 52% of cycles, FN in 6% • Results: Med F/U 18 mo; ORR-96%, CR-93%. • Projected 2 yr PFS and OS: 83% and 91%. Visco et al. ICML-13, 2015, # 59. Albertsson Linblad et al. ICML-13, 2015, # 60. Lenalidomide, Bendamustine, Rituximab (LenBenRit) for MCL > 65 • 51 patients, med age 72, stages II-IV • Doses: Len-10 mg d 1-14, Ben-90/m2 d1-2, Rituximab d1 • Med F/U 31 mo: ORR-91%, CR-78%. Med PFS-42 mo, OS-53 mo. • Infection in 21/51 patients, and 12 deaths 3 due to toxicity
R-DHAP and SCT + R Maintenance for MCL Under 66 Years: The LYMA trial • 299 patients, Med age 57. MIPI-Low in 53%, Intermeidate in 27%, High in 19%. • TX: 4 cycles of R-DHAP followed by R-BEAM and ASCT for CR/PRs; MR given q 2 mo X 3 yrs for CR/PRs after ASCT. • 257 (86%) went to ASCT; CR rates before and after ASCT were 81% and 93%. • Overall 3 Yr PFS and OS are 75% and 83%. Le Gouill et al. ICML-13, 2015, #61. 3 Yr Result MR N=119 W+W N=120 P value EFS 88 73 0.006 OS 93 86 0.72
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
AutoSCT vs AlloSCT for Newly Diagnosed PTCL Author Pt Ind Chemo AutoSCT 3 Yr PFS 3 Yr OS d’Amore 166 CHOEP14x6 BEAM 48 56 Reimer 83 CHOP21x4-6, Dexa-BEAM HdCy-TBI 36 48 Schmitz et al. ASCO 2015, Abst 8507. Schmitz et al. ICML-13, 2015, # 33. d’Amore et al. JCO 2012. Reimer et al. JCO 2009. • Background • Treatment Plan 4 CHOEP-14 N=30 DHAP N=19 SC Harvest N=24 4 CHOEP-14 N=28 DHAP N=18 AlloSCT N=13 AutoSCT N=23 5 No Donor
Auto vs AlloSCT After Induction Chemotherapy for PTCL • Pathology included any mature T-Cell NHL excluding Anaplastic CD30 Positive NHL • ECOG PS 0-3, Any Stage except Stage I and aaIPI=0 • 38% could not go to SCT due to PD with induction • 21/36 randomized patients died; 12 of NHL (7 post auto, 6 post allo), and 4 in the allo arm died of GVH or late infection • For ITT analysis: 1 yr EFS=41%, OS=69%. • Study closed due to futility. Schnitz et al. ICM:L-13, # 33. Schmitz et al. ASCO 2015, Abst 8507.
New Therapies for Lymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
New Therapies for Lymphoma: An ASCO/ICML Update F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 28 August 2015

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Lymphoma: Treatment Updates

  • 1.
    New Therapies forLymphoma: An ASCO/ICML Update F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 28 August 2015
  • 2.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 3.
    GCB and ABCDLBCLs: Two Different Mechanisms for Malignant Change BCL-2 translocation Apoptosis miR-17-92 mTOR amplification Activation PTEN deletion ING1 deletion MDM2 gain or Genomic amp Instability P53 mutation MYC translocation BCL-2 amplification Apoptosis NFK-B activation Apoptosis IL-6, IL-10 STAT3 IRF4 Essential 19Q gain Regulatory or amp SPIB Network Trisomy 3 FOXP1 Del ink4A-ARF Senescense Genomic Instability AID Switch Translocations MYC amp GCB ABC GCB Cell Plasmablast Plasma Cell
  • 4.
    ADCC Activity withRituximab Improves When Patients Are Given Vitamin D Bittenbring et al. JCO 10: 3242-3428, 2014. • Vitamin D levels tested at diagnosis of DLBCL • “Low” level: 8.4 + 3 ng/ml • Pts achieved 40.6 +13.6 ng/ml after given Vit D • ADCC activity tested before/after Vit D given
  • 5.
    Effect of VitaminD3 Levels on Results for Patients Receiving R-CHOP-14 Proportion ProgressionFree ProportionAlive Bittenbring et al. JCO 10: 3242-3428, 2014. ProportionAlive Proportion EventFree Results from RICOVER-60 (Training Cohort) Results from RICOVER-noRTh (Validation Cohort)
  • 6.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 7.
    Novel Drugs forAggressive NHLs? Agent Comment ABT-199 Platelets-sparing BCL-2 inhibitor BET Bromodomain Inhibitors Down regulators of MYC transcription CAR-T cells T cell killing of CD-19 positive NHLs Aurora kinase inhibitors Kinase needed for survival of MYC mTOR inhibitors mTOR pathway important in MYC drive Ixasomib (proteasome inhibitor) Inhibits MYC at n-molar concentrations PI3K inibhitors Loss of PTEN leads to PI3K activation and increased MYC SIRT4 protein Inhibits glutamine metabolism in MYC driven tumors Inhibitors of mitochondrial peptide deformylase In tumor models, cause apoptosis in MYC driven tumors by depolarizing mitochondrial membnrane
  • 8.
    BV for Relapsed/RefractoryCD30 Positive DLBCL • 118 patients with DLBCL, Med prior TXs = 2, tested for CD30 by visual IHC and computer assisted method, all had elevated soluble CD30 blood levels • Dose: 1.8 mg/kg q 3 wk with or without rituximab • CD30U = Undetected, but mRNA CD30 similar to those with CD30 + cells Smith et al. ICML-13, 2015, # 91. CD30 + CD30U Feature BV + R, # (%) BV, # (%) BV, # (%) Refractory last TX 10 (63) 40 (82) 37 (70) % CD30 Expression ND 37 2 CR 2 (15) 9 (19) 5 (10) PR 4 (31) 11 (23) 8 (16) Med PFS, Mo (Max) 2.4 (12+) 4 (24+) 1.4 (12.2+)
  • 9.
    Lenalidomide + Rituximab forRef/Rel DLBCL Group No. of Pt. ORR CRR Reference US 49 (various histology) 35% 12% Wiernik 2008 Italian 23 DLBCL 35% 4% Zinzani 2011 International 217 DLBCL 35% 13% Witzig 2011 Retrospective from 4 sites 40 DLBCL GCB 23 Non-GCB 17 9% 53% 4% 24% Hernandez -Illizaliturri 2011
  • 10.
    Ibrutinib for Relapsed/RefractoryDLBCL: Responses by Molecular Phenotype Wilson et al. ASH, 2012.
  • 11.
    Phase I CUDC-907,a Dual PI3K/HDAC Inhibitor for Ref/Rel NHL and Myeloma • 51 patients enrolled, 41 evaluable for response • Dose: 3X3 escalation, with both frequency and dose given, 30-120 mg and 2 x wk, 3 x wk, 5 x wk • DLT in 3 = Diarrhea, hyperglycemia • 4/41 objective responses ( 1 CR, 3 PR, all in DLBCLs) Younes et al. ICML-13, 2015, # 80. Schedule Dose No. Pts Tumor Regression, # (%) QD 30-60 10 3 (38) BIW 60-150 12 7 (58) TIW 60-150 15 5 (38) 5 x wk 60 14 4 (50)
  • 12.
    PD-1 is Inactivatedby PD-L1 and PD- L2 on Tumor Cells • PD-1 is a protein on T-Cells that dampens the normal immune response • Tumor cells can evade normal T-cell attack • Inactivate T-cell function by activation of PD-1 via PD-L1 and PD- L2 present on lymphoma cells • T-Cells are “exhausted” • Cannot attack tumor cells • Inactivation is reversible
  • 13.
    Phase I Nivolumab(BMS-936558) for Rel/Ref Lymphoid Malignancies Lesokhin et al. ASH 2014 # 291 Resp All B 29 FL 10 DLCL 11 All T 23 MF 13 PTCL 5 MM 27 PMBL 2 %OR 28 40 36 17 15 40 0 0 %CR 7 10 9 0 0 0 0 0 %PR 21 30 27 17 15 40 0 0 %SD 48 60 27 43 69 0 67 100 Ongoing studies in DLBCL and FL
  • 14.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 15.
    Phase II LenalidomidePlus R-CHOP for Patients with Untreated DLBCL • 64 pts: Med age 65, 53% IPI 4-5. • Doses: Lenalidomide 25 mg qd,, d 1-10, plus R-CHOP-21 X 6 Support: PegFilgrastin day 2, aspirin prophylaxis • 60 evaluable pts compared with 87 historical pts treated with R-CHOP from same center • Result: ORR-98%, CR-80%. 2 yr EFS-59%, 2 yr OS- 78%. • By Hans Criteria: • Conclude: Lenalidomide may erase the differences seen with R-CHOP by improving the results for non-GCB subtypes. R-CHOP R2-CHOP Feature GCB Non-GCB P GCB Non-GCB P 2 Yr PFS 64 28 <0.001 59 60 0.83 2 yr OS 78 46 <0.001 75 83 0.61 Nowakowski et al. JCO 32: 5s, 2014 (abst 8520).
  • 16.
    R-CHOP Compared withR2-CHOP for GCB and Non-GCB DLBCLs: PFS and OS Results Nowakowski et al. JCO 33: 251-258, 2014. Results with R-CHOP 2 Yr PFS: G-64%; Non-G-28% 2 Yr PFS: G-59%; Non-G-60% Results with R2-CHOP P = 0.08P<0.001 2 Yr OS: G-76%; Non-G-82%2 Yr OS: G-74%; Non-G-46% P = 0.61P<0.001 GCBGCB GCB GCB Non-GCB Non-GCB Non-GCBNon-GCB
  • 17.
    Phase I Ibrutinibwith R-CHOP for Patients with B-Cell NHLs Dosing: R-CHOP standard doses, plus Ibrutinib at 280, 420, 560 mg daily ORR = 100%, CR = 69%, PR = 31% Responses at all dose levels, MTD not reached Toxicities: ANC-77%, PLT -65%, and vomiting -59% The basis of a trial of Ibrutinib-R-CHOP vs R-CHOP-placebo for pts with non-GCB subtype Younes et al, ASCO 2013 # 8502. Response DLBCL (N=8) MCL (N=5) FL (N=4) Total (N=17)* CR 2 4 1 7 PR 2 1 2 5
  • 18.
    Other Studies inDLBCL 2015 UK R-CHOP + Bortezomib (REMoDL-B, up to 900 pt!) – 2nd similar trial in US – Based on Ph 2 BR-CHOP, 95% CR, 4 yr PFS 58% Intnl R-CHOP + Ibrutinib – Only for Non-GCB type by Hans Criteria – Based on Ph 1-2 IR-CHOP, 18 pt, 83% CR R-CHOP + Maint Everolimus vs R-CHOP, 600 pt – Completed, not reported – Based on Ph 2 ER-CHOP, 3 yr PFS 76% – Alliance PH 1-2 R-CHOP + E also final to report Furman et al. Cancer 116: 5432-5436, 2010. Younes et al. Lancet Oncol 15: 1019-1026, 2014. Micaleff et al. Blood 118: 4053-4061, 2011.
  • 19.
    GOYA Phase IIIG-CHOP vs R-CHOP for Untreated CD20+ DLBCL: Study Design Rituximab + CHOP GA101 + CHOPPreviously untreated CD20+ DLBCL (N=1400) R Primary endpoint: ● PFS (investigator- assessed) ● TTNLT ● Safety ● QOL ● Resource utilization Secondary endpoints: ● OS ● Response rates ● EFS ● DFS ● DOR http://www.clinicaltrials.gov/ct2/show/NCT01287741 as of 09/01/13. GA101=1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d; rituximab 375 mg/m2 on d1 q21d cycles 1-8; CHOP=q21d 6-8 cycles
  • 20.
    Phase II RandomizedDose BV + R-CHOP for Advanced Untreated DLBCL • 51 patients: IPI 3 in 62%, IPI 4-5 in 38%. – ECOG 2 – 28%, Stage IV – 70%. • Dose: 1.2 vs 1.8 mg/kg q 3 wk plus R-CHOP vs R-CHOP alone, reduced to 1.2 early on due to neuropathy with 1.8. • Gr 3-4 AEs: FN 27%, ANC 25%, HGB 24% – All Gr PN: 38% at 1.2 mg/kg, 77% at 1.8 mg/kg. • CR rates: ABC=GCB (69% vs 65%), but CD30 pos > CD30 neg (92% vs 69%). No PD for CD30+ with med f/u 5 mo. Bartlett et al. ASCO 2015, Abst 8506. Response 1.2 mg/kg N (%) 1.8 mg/kg N (%) Total N (%) CR 19 (66) 15 (68) 34 (67) PR 4 (14) 3 (14) 7 (14) PD 2 (7) 3 (14) 5 (10)
  • 21.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 22.
    MYC Rearrangement (MYC-R)in DLBCL: DHL or DEL? • In general, R positivity infers an inferior prognosis – R-CHOP therapy is inadequate, with < 12 mo OS • High MYC protein expression without MYC-R has also been identified (alternate mechanism) – DLBCL with high MYC (>40%) and BCL-2 (50-70%) protein expression by IHC = Double Expressor DLBCL (DEL) – Also has a poor prognosis with R-CHOP • Should the approach to therapy be the same for both DHLs and DELs? – Majority of DHL = GCB DLBCL – Majority of DEL = ABC DLBCL
  • 23.
    R-CHOP-21 or Variantsfor DHLs Author No. Pts Therapy % MYC-R %DHLs (BCL-2-R) Outcome Klapper 177 CHOP or CHOEP 8 NR OS worse for MYC-R Barrans 303 R-CHOP 14 11 2 yr OS 35% (MYC-R) vs 61% (MYC-N) Savage 135 R-CHOP 9 5 5 yr OS 33% (MYC-R) vs 72% (MYC-N) Cunningham 1080 R-CHOP 14 or 21 6 3 No differences in 2 yr OS for MRC-R or N MYC-R = Rearranged; MYC-N = Not rearranged
  • 24.
    OtherTrials of IntensiveTherapy for DHLs Author No. Pts Therapy (% Pts) Outcome (Mo, Median) Comments Petrich 311 R-CHOP -32 R-HCVAD-21 R-EPOCH-21 R-CODOX-14 OS=22, PFS=10.9 PFS 7.8 R-CHOP vs 26.6 Other (p=0.001) Med F/U=23 mo No OS diff among intensive TXs; OS not affected by SCT Oki 129 R-CHOP-44 R-HCVAD-26 R-EPOCH-22 2 yr EFS= 33% CR rates: 20% vs 70% vs 68% OS better with R- EPOCH vs R-CHOP (p=0.057); no benefit with SCT; 13% CNS Johnson 54 CHOP-43 R-CHOP-20 OS: R-CHOP=15 mo CHOP=5 mo BCL-2 Protein negative cases favorable Li 56 R-CHOP-39 RHCVAD-59 OS: 19 mo Neither SCT nor intensive therapy made OS better Petrich. Blood 124: 2354-2361, 2014. Oki. Br J Haematol 166: 891-901, 2014. Johnson. JCO 30: 3452-3459, 2012. Li. Adv Anat Path 20: 315-326, 2013.
  • 25.
    Double Hit DLBCLin 100 MDACC Patients: A Retrospective Analysis • CR rates: All 59%, CHOP + R 49%, EPOCH + R 50%, HCVAD + R 60% (P=NS). • 3 Year PFS (All pt) = 32%, OS = 41%. No diff by chemo regimen Oki et al. ASH 2013 #1776 Dunleavy et al. ASH 2013 Hu et al, Blood 122: 2014 PFS by Therapy Regimen OS by Therapy Regimen Similar results for DA-EPOCH-R from NCI., and R-CHOP consortium data.
  • 26.
    Double Hit DLBCLin 100 MDACC Patients: A Retrospective Analysis • SCT performed in 19 of 59 CRs • 3 Yr PFS: SCT 66%, None 45%. OS: SCT 67%, None 62% Oki et al. ASH 2013 #1776. PFS By SCT or None OS by SCT or None But for 15 CRs after EPOCH + R, PFS = 100% (SCT in 8)
  • 27.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 30.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 31.
    Ibrutinib Monotherapy inRelapsed/ Refractory FL: Max Tumor Vol Reduction Bartlett NL, et al. ASH 2014. Abstract 800. 60 20 -20 -60 -100 TumorSize (%ChangeinSPDFromBaseline) CR PR SD PD 72% of pts had reduction in tumor volume Individual Pts
  • 32.
    Phase 2 Idelalisibfor 125 Alkylator-Rituximab Ref iNHL: Nodal Response and PFS Results -100 -75 -25 0 -50a +25 +50 Individual Patients (N=125) SPDofMeasuredLymphNodes, Best%ChangefromBaseline •90% had improvement in lymphadenopathy •57% had ≥50% decrease from baseline Gopal et al. ASH 2013 #85 . 0 (125) 3 (100) 6 (34) 9 (19) 12 (13) 15 (6) 18 (0) 0 25 50 75 100 Time from Start of Idelalisib, Months (N, Patients at Risk) %Progression-Free Median PFS = 11.4 monthsMaximum Nodal Response Historical Control: Bendamustine: DOR 10mo 53% ORR
  • 33.
    Phase I IPI-145(PI3K δ,γ Inhibitor) for NHLs and HL: Clinical Activity Horwitz et al. ASCO 2012.
  • 34.
    Phase I Ublituximab,TGR-1202, and Ibrutinib for Relapsed B-Cell NHLs • Background – Ublituximab: A glycoengineered anti-CD20 MAB against a unique epitope on CD20. – TGR-1202: A highly active oral PI3K inhibitor (Burris 2014). • TX: UTX-900 mg d 1,8,15 cycles 1-2, then q 2 mo – TGR-400-1200 mg + Ibrutinib 420 (CLL) or 560 (NHL) QD • 12 pts, could have had Ibru or Idela; any # prior txs – AEs (Gr 1-2): 30% diarrhea, constipation, fatigue, no DLT – Response: OR-75%, all iNHL or MCL • Phase II study planned. Fowler et al. ASCO 2015, Abst 2801. Nastoupil et al. ICML-13 2015, # 106.
  • 35.
    Phase IIa Anti-CD19Antibody (MOR208) for Rel/Ref NHLS • Fc engineered humanized monoclonal antibody directed against CD19 • 89 patients, previously received rituximab, not candidates for SCT; Med prior therapies – 2. • Dose 12 mg/kg IV weekly for 2, 28 day cycles • Gr 3-4 AEs: Non-hematologic in 30 pts (34%) • Hematologic Gr 3-4 events in 8 (9%) Jurczak et al. ASCO 2015 Abst 8500. Best Resp (N, %) DLBCL (N=35) FL (N=34) MCL (N=12) iNHL (N=11) Total (N=92) CR 2 (6) 2 (6) 0 2 (18) 6 (7) PR 7 (20) 7 (21) 0 1 (9) 15 (16) SD 5 (14) 17 (50) 6 (50) 4 (36) 32 (35) Med DoR 2.6 (DLBCL), 7.7 (FL). Longest resp 62 and 67 wks. Combination trials planned.
  • 36.
    Phase II Obinutuzumabfor Relapsed or Refractory iNHL: Gauguin Study Salles et al. JCO 31: 2920-2926, 2013. Response Rates Progression Free Survival
  • 37.
    GADOLIN Phase IIISafety and Efficacy of G- Benda vs SA Benda for R-Refractory iNHL G: 1000 mg d1, d8, d15 cycle 1; d1 cycles 2-6 q28d a Bendamustine: 90 mg/m2 d2, d3 cycle 1; d1, d2 cycles 2-6 q28d; b Bendamustine: 120 mg/m2 on d1, d2 cycles 1-6 q28d Bendamustineb CR/PR/SD Maintenance G q2m × 2 years G + Bendamustinea Rituximab- refractory iNHL (N=360) R Primary endpoint: ● PFS Secondary endpoints: ● OS ● Response rates Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123.
  • 38.
    Phase III G-Bendavs SA Benda for R- Refractory iNHL: Pathology and Prior R Type 19.6 22.3 80.4 77.7 0 20 40 60 80 100 G-B (n=194) B (n=202) R-chemotherapy combination* R-monotherapy FL, follicular lymphoma; MZL, marginal zone lymphoma including extranodal, nodal and splenic; SLL, small lymphocytic lymphoma; WM, Waldenström macroglobulinemia. Patients(%) 79.9 82.2 13.9 9.4 0 20 40 60 80 100 G-B (n=194) B (n=202) WD SLL MZL FL Rituximab-refractory type * Includes patients with relapse within 6 months of last dose of rituximab Patients(%) 6.2 7.9 0.5 Lymphoma subtype Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. WMWM
  • 39.
    Phase III G-Bendavs SA Benda for R- Refractory iNHL: Response Rates End-of-induction response (IRF) Best overall response to 12 months (IRF) 69.2 63.0 78.7 76.7 Patients(%) Patients(%) • 19 patients still in induction (G-B, n=6; B, n=13) 11.7 18.5 9.0 9.010.1 9.5 58.0 50.8 11.2 12.2 0 20 40 60 80 100 G-B n=188* B n=189* G-B n=188* B n=189* Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. Patients still in induction therapy are excluded from analysis. Patients with end of induction response > 60 days shown as missing. Best overall response excludes patients who have not yet had response analysis.
  • 40.
    GADOLIN Trial: Investigator-AssessedPFS Investigator-assessed PFS G-B (n=194) B (n=202) Events, n 77 (40%) 115 (57%) Median PFS, months (95% CI) 29.2 (20.2–NR) 14.0 (11.7–16.0) Stratified HR (95% CI) 0.52 (0.39–0.70) Log-rank p-value p<0.0001 1.0 0.8 0.6 0.4 0.2 0 6 12 18 24 30 36 42 48 54 Time (months) ProbabilityofPFS 0.0 194 202 157 150 108 89 77 46 51 28 27 15 7 5 2 2 1 1 No. at risk G-B B 14.0 29.2 Median follow-up: 21 months Sehn et al. ASCO 2015 Abst 8502; Cheson et al ICML-13, 2015, #123. GB B
  • 41.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 42.
    GALLIUM Phase IIICT vs R + CT Followed by G or R Maint for Untreated Advanced iNHL 68 G:1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d or cycles 2-6 q28d; CT=CHOP (6 cycles q21d), CVP (8 cycles q21d) or benda (6 cycles q28d); Rituximab 375 mg/m2 on d1 cycles 2-8 q21d a FL: Each site chooses CHOP, CVP, or benda. Non-FL: CHOP, CVP, or benda selected on a patient-by-patient basis Maintenance R q2m × 2 years Maintenance G q2m × 2 years Rituximab + CTa CR PR SD GA101 + CTa Previously untreated advanced iNHL (N=1400) R Primary endpoint: ● PFS (investigator assessed) in FL patients Secondary endpoints: ● PFS ● ITT (investigator and IRC assessed) ● Response rates ● OS ● EFS ● Safety ● DFS ● DOR ● PROs ● Resource utilization http://www.clinicaltrials.gov/ct2/show/NCT01332968 as of 09/01/13.
  • 43.
    R2 for Untreated FL:Response by Tumor Burden and Molecular Features By GELF Criteria (N=46) High Tumor Burden (N=22, 48%) Low Tumor Burden (N=24, 52%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1 (5%) 21(95%) 100% 1(4%) 4(17%) 19 (79%) 96% By Bulk of Disease (N=46) Bulky (N=13, 28%) Non-Bulky (N=33, 72%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1(8%) 12(92%) 100% 1(3%) 4 (12%) 28 (85%) 97% Fowler et al. ASH 2012, abst 901. Molecular Response (N=44 Evaluable, Marrow and Blood) PCR Positive PCR Negative PRETREATMENT 17(41%) 26(59%) POST CYCLE 3 5(11%) 39(89%) POST CYCLE 6 2(5%) 42(95%)
  • 45.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 46.
    Phase II Rituximab,Bendamustine, Cytarabine (R-BAC) for MCL > 60 Years • 57 patients, med age 71 (61-79), stage III-IV-91%, High MIPI in 45%, Blastoid in 9%. • 91% received 4, 63% received 6 cycles • Gr 3-4 ANC in 49%, PLT in 52% of cycles, FN in 6% • Results: Med F/U 18 mo; ORR-96%, CR-93%. • Projected 2 yr PFS and OS: 83% and 91%. Visco et al. ICML-13, 2015, # 59. Albertsson Linblad et al. ICML-13, 2015, # 60. Lenalidomide, Bendamustine, Rituximab (LenBenRit) for MCL > 65 • 51 patients, med age 72, stages II-IV • Doses: Len-10 mg d 1-14, Ben-90/m2 d1-2, Rituximab d1 • Med F/U 31 mo: ORR-91%, CR-78%. Med PFS-42 mo, OS-53 mo. • Infection in 21/51 patients, and 12 deaths 3 due to toxicity
  • 47.
    R-DHAP and SCT+ R Maintenance for MCL Under 66 Years: The LYMA trial • 299 patients, Med age 57. MIPI-Low in 53%, Intermeidate in 27%, High in 19%. • TX: 4 cycles of R-DHAP followed by R-BEAM and ASCT for CR/PRs; MR given q 2 mo X 3 yrs for CR/PRs after ASCT. • 257 (86%) went to ASCT; CR rates before and after ASCT were 81% and 93%. • Overall 3 Yr PFS and OS are 75% and 83%. Le Gouill et al. ICML-13, 2015, #61. 3 Yr Result MR N=119 W+W N=120 P value EFS 88 73 0.006 OS 93 86 0.72
  • 48.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 49.
    AutoSCT vs AlloSCTfor Newly Diagnosed PTCL Author Pt Ind Chemo AutoSCT 3 Yr PFS 3 Yr OS d’Amore 166 CHOEP14x6 BEAM 48 56 Reimer 83 CHOP21x4-6, Dexa-BEAM HdCy-TBI 36 48 Schmitz et al. ASCO 2015, Abst 8507. Schmitz et al. ICML-13, 2015, # 33. d’Amore et al. JCO 2012. Reimer et al. JCO 2009. • Background • Treatment Plan 4 CHOEP-14 N=30 DHAP N=19 SC Harvest N=24 4 CHOEP-14 N=28 DHAP N=18 AlloSCT N=13 AutoSCT N=23 5 No Donor
  • 50.
    Auto vs AlloSCTAfter Induction Chemotherapy for PTCL • Pathology included any mature T-Cell NHL excluding Anaplastic CD30 Positive NHL • ECOG PS 0-3, Any Stage except Stage I and aaIPI=0 • 38% could not go to SCT due to PD with induction • 21/36 randomized patients died; 12 of NHL (7 post auto, 6 post allo), and 4 in the allo arm died of GVH or late infection • For ITT analysis: 1 yr EFS=41%, OS=69%. • Study closed due to futility. Schnitz et al. ICM:L-13, # 33. Schmitz et al. ASCO 2015, Abst 8507.
  • 51.
    New Therapies forLymphoma: An ASCO/ICML Update • Aggressive NHLs – Novel Drugs – Initial Therapy – Management of Double Hit Lymphomas • Indolent NHLs – Novel Drugs – Initial Therapy • Other NHLs – MCL – T-Cell
  • 52.
    New Therapies forLymphoma: An ASCO/ICML Update F B Hagemeister, MD Professor of Medicine Department of Lymphoma and Myeloma M D Anderson Cancer Center Bangkok 28 August 2015

Editor's Notes

  • #6 DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT, radiotherapy Ian W. Flinn, MD, PhD: There was no significant difference in event-free survival (HR: 0.55; P = .13) or OS (HR: 0.6; P = .33) between the 2 treatment strategies. The 5-year event-free survival was 88% and the 5-year OS was 92%.
  • #16 CI, confidence interval; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; ORR, overall response; PD, progressive disease; PR, partial response; SD, stable disease.
  • #44 DA-EPOCH-R, dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; OS, overall survival; PFS, progression free survival. Ian W. Flinn, MD, PhD: The PFS and OS curves illustrate excellent outcomes in patients with MYC rearrangement, although it is difficult to know the true value of this approach without a randomized trial.
  • #55 CR, complete response; FL, follicular lymphoma; PD, progressive disease; PR, partial response; SD, stable disease; SPD, sum of the products of the greatest perpendicular diameters.
  • #71 CR, complete response; CRu, unconfirmed complete response; FL, follicular lymphoma; ITT, intent to treat; PP, per protocol; PR, partial response; R, rituximab