Evolving Approaches in Relapsed / Refractory Large Cell Lymphoma

web.educationalconcepts.net
  • No tags were found...

Evolving Approaches in Relapsed / Refractory Large Cell Lymphoma

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-ASCT1.0.9.8.7n = 264, 91 censored.6.5.4.3.2.10.001234567891011121314Years


Cumulative SurvivalEFS: Sequential ICE Programs(1993-2004)1.0.9.8RICE+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 [1]• Phase II study (N = 49) in relapsed /refractory aggressive NHL [2]– 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 [3]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

More magazines by this user
Similar magazines