Evolving Approaches inRelapsed / RefractoryLarge Cell LymphomaWhy do we cure less patients with relapsedand refractory DLBCL?Craig Moskowitz, MDClinical Director, Division of Hematologic OncologyAssociate Member, Lymphoma ServiceMemorial Sloan-Kettering Cancer CenterAssociate Professor of MedicineCornell University Medical CollegeNew York, New York
DisclosuresResearch Support / P.I.EmployeeConsultantMajor StockholderSpeakers’ BureauHonorariaScientific Advisory BoardSeattle Genetics, Eli Lilly, Genentech,CephalonNoneNoneNoneNoneNoneSeattle Genetics, GlaxoSmithKline,Genentech
Question• 51-year-old male with DLBCL presents for evaluation 9 monthspost R-CHOP-14 with unexplained fever and hip pain: CT ofchest, abdomen and pelvis disclosed a 12 cm intra-abdominalmass as well as multiple splenic; LDH is elevated, bone marrowis negative. FDG-PET confirms these sites as well asabnormalities in the left iliac bone. Biopsy of retroperitonealnode confirms relapsed DLBCL.What is the likelihood that this patient can be cured?1) > 50%2) 40%3) 30%4) < 20%
% Event-free SurvivalParma Trial: Event-Free Survival1008060ABMT (N = 55)4020DHAP (N = 54)00 15 30 45 60 75 90Philip, et al. N Engl J Med. 1995;333:1540-1545.Months from Inclusion
Management of Transplant-Eligible PtsWith DLBCL: Pre-Rituximab EraCHOP45 pts cured65 pts 100 pts35 ptsCR5 ptsInvestigationalor BSCRelapse20 ptsSecond-linetherapyNRCR/PR15 ptsHDT/ASCTPrimary refractoryCR/PRSecond-linetherapy18 pts15 pts curedNR17 ptsInvestigationalor BSC
ICE → HDT / ASCT forRelapsed / Refractory NHL• Pretreatment evaluation– Biopsy-proven refractory or relapsed disease– EF > 50, DLCO > 50, CrCl > 60; no active Hepatitis B or C• All patients receive ICE-based second-line chemotherapy• PBPCs are collected following cycle 3• For chemosensitive patients (PR or CR):– In selected patients (≤ 2 fields), prior to HDT, involved-fieldaccelerated fractionation radiation therapy is administered to a doseup to 36 Gy– HDT/ASCT• Patients are analyzed from initiation of ICE-based therapyMoskowitz CH, et al. J Clin Oncol. 1999;17:3776-3785.
Relapsed / Primary Refractory DLBCL• 5-year event-free-survival (EFS) is 25-30% but 40-45% for patientstransplanted• Chemosensitive disease is required for transplant eligibility in the USAand the addition of rituximab increases the number of patients in CRpre-ASCT• Kewalramani, et al. Blood. 2004;103:3684-3688.• Pre-treatment clinical prognostic factors predict outcome– Second-line age adjusted IPI• Hamlin, et al. Blood. 2003;102:1989-1996.– Relapse vs primary refractory• Kewalramani, et al. Blood. 2000;96:2399-2404.• The cell of origin as defined by IHC does not predict outcome in therelapse / refractory setting• Moskowitz, et al. Blood. 2005;06:3383-3386.
Cumulative SurvivalEFS: ICE Followed by HDT-ASCT220.127.116.11.7n = 264, 91 censored.18.104.22.168.2.10.001234567891011121314Years
Cumulative SurvivalEFS: Sequential ICE Programs(1993-2004)22.214.171.124RICE+R post-ASCT: n = 30, 23 censoredP < 0.0001.7.6.5.4.3RICE: n = 69, 29 censoredTPO: n = 22, 7 censored.2.1ICE: n = 143, 32 censored0.001234567891011121314Years
Cumulative survivalOverall Survival:Second-Line Age Adjusted IPI1.00.8LR: N = 18, 13 censored0.6LIR: N = 39, 17 censored0.40.2P < 0.00001HIR: N = 55, 12 censoredHR: N = 35, 6 censored0.00 1 2 3 4Hamlin P, et al. Blood. 2003;102:1989-1996..56 7Years891011121314
Rituximab as an Adjuvant Therapy toHDT in NHLHorwitz, et al. Blood. 2004 Feb 1;103(3):777-783.
Treatment PlanCyclophosphamide 4 gm/m 2 , G-CSF 10 g/kg/dLeukapheresisCD34 + enriched; Purged: Anti CD9, CD10, CD19, CD20BCNU (TBI) / VP/CYASCTDay 42Rituximab weekly x 4Day 180Rituximab weekly x 4Patients 5-356 and 9 months post-RituximabVaccinations: S. Pneumoniae, H. Influenzae, TetanusLymphocyte subsets / Ig
Rituximab Post-ASCT:OutcomesDLCL Freedom from ProgressionDLCL Overall SurvivalHorwitz, et al. Blood. 2004 Feb 1;103(3):777-783.
HOVON 44 Randomized Trial:Salvage Chemotherapy With or Without Rituximabn = 239Relapsed /refractoryaggressive NHLCD20+RANDOMIDHAPVIM+ RituximabDHAPVIMRESTAGER-DHAP+ PBSCcollectionCR, PRDHAP +PBSCcollectionBEAM+ ASCTZEOff studySD, PDPrimary endpoint: 2-year EFSVellenga E, et al. Blood. 2006;106. Abstract 328.
HOVON-44: Patient CharacteristicsDHAP arm R-DHAP arm(n = 106) (n = 110)Age, median (range) 52 (25-65) 53 (25-65)B-symptoms 23% 24%sAAIPIlow (0 risk factors) 24% 15%intermediate (1 risk factor) 33% 45%high (2-3 risk factors) 43% 40%DLBCL histology 87% 92%Previous chemotherapyCHOP-21 62% 67%CHOP-intensified 16% 12%CHOP-14 6% 6%Other 16% 15%+ rituximab < 5% < 5%Vellenga E, et al. Blood. 2006;106. Abstract 328.
Rituximab Improves Treatment Results of DHAP-VIM-DHAPand ASCT in Relapsed / Progressive Aggressive CD20(+)NHL: Prospective Rituximab HOVON TrialFailure-free survivalOverall survival2 yr est. DHAP R-DHAPHazardRatioP valueFFS 21% 52% 0.4 < 0.001DFS 46% 82% 0.32 0.003OS 48% 62% 0.61 0.03
What happens if R-X therapy does notwork?
CORAL Trial (GELA and others):R-ICE vs R-DHAPARM A: R-ICEC1 C2 C3CollectPSCARM 1: RituximabmaintenanceRA0 3 69RA+M1 +M3 +M5 +M7 +M9 +M11 +M12NDOMEvaluationBEAM +autograftNDOMEvaluationIS0 3 69IS+M3 +M7 +M12EDC1 C2 C3ARM B: R-DHAPCollectPSCD0EDD28ARM 2: Observation
CONSORT Diagram of Distribution of Patients Accordingto Arm Resulting From the First Random AssignmentGisselbrecht C, et al. J Clin Oncol. 2010;28:4184-4190.
Coral Study: OutcomesRICE vs RDHAP by ITT56%56%45%42%RICERDHAPOrlando ASCO May 2009 / Coral study C. Gisselbrecht.
Coral Study: EFS by Prior RituximabInduction (ITT)Failure from Diagnosis> 12 monthsFailure from Diagnosis≤ 12 monthsN = 106N = 41N = 54N = 187Orlando ASCO May 2009 / Coral study C. Gisselbrecht.Prior rituximab: noPrior rituximab: yes
Results: Cox Regression Model forEvent-Free SurvivalPrior rituximab P < 0.013-year EFS 21% vs 47%Relapse < 12 months P < 0.0013-year EFS 20% vs 45%Second-line aaIPILR-LIR vs HIR-HRP < 0.0013-year EFS 18% vs 40%
Intent to Treat Outcome Stratified bysAAIPI (MSKCC)sAAIPI riskgroupPFSat 4yrsOSat 4yrsResponse to ICEchemotherapyCR PR FAILN % % % % %Low (0) 20 70 74 60 30 10Int. (1) 40 39 49 28 58 15High (2,3) 90 16 18 12 41 38High-Risk Patients can be identified PRIOR to second-line therapy
Management of Transplant-Eligible PtsWith DLBCL: 2010R-CHOP57 pts cured77 pts 100 pts23 ptsCR5 ptsInvestigationalor BSCRitux sens.20 ptsSecond-linetherapyNRCR/PR15 ptsHDT / ASCTRitux-refractoryCR/PRSecond-linetherapy10 pts12 pts curedNR13 ptsInvestigationalor BSC
Relapsed / Primary Refractory DLBCL• 5-year event-free-survival (EFS) in the rituximab era is< 25% because:– No one is rituximab naïve– The majority of relapses occur within 12 months– The majority of patients have HIR / HR disease• Chemosensitive disease is required for transplanteligibility in the USA– In the rituximab era, should a negative pre-ASCT FDG-PET scan berequired– Patients with all 3 of the above risk factors should not get aRICE / RDHAP-based autotransplant program– What should oncologists do?
Question• 51-year-old male with DLBCL presents for evaluation 9 monthspost R-CHOP-14 with unexplained fever and hip pain: CT ofchest, abdomen, and pelvis disclosed a 12 cm intra-abdominalmass as well as multiple splenic; LDH is elevated, bone marrowis negative. FDG-PET confirms these sites as well asabnormalities in the left iliac bone. Biopsy of retroperitonealnode confirms relapsed DLBCL.What is the likelihood that this patient can be cured?1) > 50%2) 40%3) 30%4) < 20%
Can PET add prognostic information?
2 yr FFS: PET response72%38%Despiteresidual PETavidity pre-ASCT,FFS~40%10%PR = minimal residual uptakeSchot BW, et al. Blood. 2007;109:486-491.
EFS According to Pre- and Post-ASCTPET ResultsPRE-ASCTPET (-)PET (+)All patientsDespiteresidual PETavidity pre-ASCT, FFS~ 40%Post-ASCTPET (-)PET (+)1 yr EFS for aNHL:79% vs 42%1 yr EFS for aNHL:78% vs 42%Filmont, et al. Cancer. 2007;110:1361-1369.
Priority of research in curable patientswith relapsed / refractory DLBCL / HLshould be to achieve a negative FDG-PET scan after salvage therapyHow is this going to be achieved?What new agents can beincorporated?
The St. Thomas Hospital CriteriaCourtesy of S. Barringhton, Modena, 2009.
O-ICE / O-DHAP: Rationale• Ofatumumab (fully humanized IgG1 anti-CD20) activein B-cell lymphoma– In vitro killing of rituximab-resistant Raji cell lines (low CD20expression, high expression of CD55, CD59); similar ADCC torituximab– Active and well tolerated as single-agent in relapsed CLL (6%grade 3/4 infxn, 3% grade 5 interstitial pna), 50% ORR– In FL, 2 patients had grade 3 infxn, no grade 4/5 toxicities;43% ORR; 64% in rituximab-treated, and 3 of 4 rituximabrefractorypatients responded• Ofatumumab substitution in relapsed / refractory largecell lymphoma could potentially improve responserates
O-ICE / O-DHAP: Study Schema
Safety, Pharmacokinetics, and Preliminary ClinicalActivity of Inotuzumab Ozogamicin, a NovelImmunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I StudyAdvani, et al. J Clin Oncol. 2010;28(12):2085-2093.
Inotuzumab OzogamicinG544: Humanised-IgG4 Anti-CD22 (Target on B-cells)LINKERCalicheamicinCMC-544InternalizedLinkerHydrolizedCalicheamicinReleasedIntracellularlyDS DNABreaksApoptosis• Preferential delivery of a cytotoxin to tumor cells• Specificity of target: CD22• Efficient internalization of immunotoxin• Linker: Stable in plasma, acid-labile• Potent cytotoxic component: calicheamicin• Reduction of non-specific toxicity (off-target effects)
Advani, et. al. J Clin Oncol. 2010;28(12):2085-2093.CONSORT Diagram
(A) Tumor response at end of treatment for all patients in dose-escalationcohorts and for all patients with follicular lymphoma and diffuse large B-celllymphoma (DLBCL) receiving maximum-tolerated dose (MTD) treatment (leadincohort, n = 5; expanded MTD cohort, n = 43)Advani, et. al. J Clin Oncol. 2010;28(12):2085-2093.
Patients (%)Lenalidomide• Lenalidomide: oral immunomodulatory agent– Antiangiogenic, less-toxic derivative of thalidomide– Recommended by NCCN as second-line regimen for MCL • Phase II study (N = 49) in relapsed /refractory aggressive NHL – ORR: 35%, including12% CR / CRu– Responses seen inDLBCL, FL, MCL,transformed lymphomas– Primary grade 3/4 toxicity:myelosuppression• Phase I/II trial of first-line lenalidomide plus R-CHOP in DLBCL or FL 1007550PFS25Median PFS: 4 mos00 5.0 10.0 15.0Mos1. NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas. Available at: http:// www.nccn.org.2. Wiernik PH, et al. J Clin Oncol. 2008;26:4952-4957. 3. ClinicalTrials.gov. NCT00670358.
Management of Transplant-Eligible Pts2011R-CHOP57 pts cured77 pts 100 pts23 ptsCR?New agents-alloCured?Relapse20 ptsSecond-linetherapyPET(+)PET(-)?HDT / ASCTCured?Primary refractoryPET(-)?Second-linetherapyPET(+)?New agents-alloCured?
Lymphoma Service-MSKCC– John Gerecitano– Paul Hamlin– Steve Horwitz– Matt Matasar– Alison Moskowitz– Craig Moskowitz– Ariela Noy– Lia Palomba– Carol Portlock– David Straus– Joachim Yahalom– Andrew Zelenetz