The Role and Selection of Maintenance Therapy in Follicular ...

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The Role and Selection of Maintenance Therapy in Follicular ...

WHO/REAL Grading For FollicularGrade 1LymphomaGrade 2< 5/hpfGrade 3a6-15/hpfGrade 3b> 15/hpfSheetsZelenetz. ASCO, 2006.


Rituximab as a Targeted Therapy in FL• Murine/human IgG 1 kappamAb• Binds to CD20 antigen• Half-life (at 375 mg/m 2 )~76.3 hours after 1stinfusion and 205.8 hoursafter the 4th infusion• Mechanism of action– CDC, ADCC,apoptosis, and ionizingradiation–induced celldeathMurine variableregions bindspecifically to CD20on B cellsHuman k constantregionsHuman IgG 1 Fc domainworks in synergy withhuman effectormechanismsCDC = complement-mediated cell death; ADCC = antibody-dependent cell cytotoxicity.


Complement Dependent Cytotoxicity(CDC)CDC– Induced by rituximab binding to C1q, resulting inactivation of the complement cascade and generation of.the membrane attack complexReff ME, et al. Blood.1994;83:435-445.


Mechanisms of Action: ADCCADCC– Recruitment of natural killer (NK) cells, macrophages andmonocytes by rituximab through its binding to their Fc g receptorsAnderson DR, et al. Biochem Soc Trans. 1997;25:705-708; Clynes RA, et al. Nat Med. 2000;6:443-446.


Maintenance Rituximab for IndolentB-cell lymphomas• Following chemotherapy• Following rituximab monotherapy• Following chemo-immunotherapy


Rituximab Maintenance vsRe-treatment at Time of Progression• Maintenanceimproves PFS (32 mvs 7 m)• Actuarial duration ofrituximab benefit: atmedian follow up of 41months, overall“benefit” similar to retreatmentat relapse(31 m vs 27 m)Hainsworth JD, et al. J Clin Oncol. 2005;23:1088-1095.


Rituximab Maintenance AfterInitial Therapy with CVP (E 1496)CVP every 21 daysCyclophosphamide 1 gm/m 2Vincristine 1.4 mg/m 2Prednisone 100 mg/m 2 x 5dCRPRRANDOMIZEObservationRituximabmaintenance**375 mg/m 2 weekly x 4 q 6 monthsfor 2 years or until relapseHochster H, et al. J Clin Oncol. 2009;27:1607-1614.


Maintenance Rituximab Improves PFS inIndolent and FL Patients Following CVPChemotherapy (E 1496)All Patients (n = 311) FL (n = 228)Hochster H, et al. J Clin Oncol. 2009;27:1607-1614.


There is No improvement in OS WhenMaintenance Rituximab is Compared withObservationAll Patients (n = 311) FL (n = 228)Hochster H, et al. J Clin Oncol. 2009;27:1607-1614.


Rituximab Maintenance AfterChemotherapy + R for RelapsedDiseaseRANDOMIZECHOP every21 daysmaximum six cyclesRituximab + CHOP every21 daysmaximum six cyclesCRPRRANDOMIZEObservationRituximabmaintenance**375mg/m 2 every 3 months for 2 years or until relapsevan Oers MH, et al. Blood. 2006;108:3295-3301.


Effect of Rituximab Maintenance Treatment onProgression-Free Survival (PFS)van Oers MH, et al. J Clin Oncol. 2010;28:2853-2858.


Effect of Rituximab Maintenance Treatment onPFS After Remission Induction With Either:CHOP OR R-CHOPvan Oers MH, et al. J Clin Oncol. 2010;28:2853-2858.


Effect of Rituximab Maintenance Treatment onPFS in Patients in Partial Remission (PR) orComplete Remission (CR) After RemissionInduction TreatmentPRCRvan Oers MH, et al. J Clin Oncol. 2010;28:2853-2858.


Effect of Rituximab Maintenance Treatment onOverall Survivalvan Oers MH, et al. J Clin Oncol. 2010;28:2853-2858.


Randomized Comparison of Maintenance Rituximabin Patients With Recurrent MCL and FL• Recurrent MCL or FL (n = 176 evaluable)• FCM x 4 vs R-FCM x 4 (initial randomization)• Responders randomized again to R x 4 weeks at 3 and 9months• First randomization stopped at 147 patients. Overall, 138patients had R-FCM• All further patients had R-FCM and were randomized to Rmaintenance or notForstpointner R, et al. Blood. 2006;108:4003-4008.


Response Duration for R Maintenance andObservation in All Patients(FL and MCL, RCM and R-FCM)Forstpointner R, et al. Blood. 2006;108:4003-4008.


Response Duration After R-FCM inPatients With FLForstpointner R, et al. Blood. 2006; 108:4003-4008.


SAKK 35/98 Study: LT Follow-up of FL PtsReceiving Rituximab at 2 Different SchedulesN = 202N = 151375 mg/m 2wkly x 4RANDOMIZATIONStandard(Observation)Prolonged(Consolidation)PDofftrialSD, PR, CR375 mg/m 2 every 2 mos x 4Ghielmini M, et al. ASCO 2009. Abstract 8512.


Event-Free Survival by Treatment Arm According toResponse to the Induction Treatment (Complete Response[CR]/Partial Response [PR] or Stable Disease [SD])Martinelli G, et al. J Clin Oncol. 2010;28:4480-4484.


Event-Free Survival by Treatment Arm for the Subgroup ofPreviously Untreated Patients Responding to theInduction TreatmentMartinelli G, et al. J Clin Oncol. 2010;28:4480-4484.


Overall Survival by Treatment ArmMartinelli G, et al. J Clin Oncol. 2010;28:4480-4484.


SAKK 35/03 Phase III Trial: SafetyAnalysis Study DesignN = 151Untreated,chemo-resistantor relapsed FL(N = 270)Induction375 mg/m 2wkly x 4PD,SD offstudyRANDOMIZATIONPR,CR375 mg/m 2 every 2 mos x 4375 mg/m 2 every 2 mos for a maximumof 5 yrs or until progression, relapse,or unacceptable toxicityShortmaintenanceLongmaintenance270 pts registered105 pts not randomized99 SD, PD165 pts randomized82 arm A 83 arm B6 other reasonsTaverna C, et al. ASCO 2009. Abstract 8534.


FIT: Study SchemaFirst LineChemotherapy(n = 414):CHOP/CHOP-likeCVP/COPRituximab combosChlorambucilPurine analogsCR/CruPRRandomizeControlNo furthertreatment (n = 208)Ibritumomabtiuxetan (n = 206)PFS from time of randomizatonMedian 7 months from start of treatment to study entryMorschhauser F, et al. J Clin Oncol. 2008;26:5156-5164.


FIT: Randomized Phase III Trial of 90 Y-Ibritumomab Tiuxetan Consolidation of FirstRemission in Advanced Stage FL: PFS% Remaining progression-free100806040200P < 0.0001HR 0.463Months from randomizationMedian PFS (mo)90Y-Ibritumomab 37.0Control 13.50 6 12 18 24 30 36 42 48 54 60 66Median observation period was 3.5 years.HR = hazard ratio.Hagenbeek, et al. ASH, 2007. Abstract 643...


Maintenance Rituximab or RIT: Is Therean Advantage in PFS or EFS?• Following chemo-immunotherapy for relapsed indolentdisease?– YES (Van Oers, et al Blood.2006;108:3295; J Clin Oncol.2010;28:2853-2858; Forstpointer Blood.2006;108:4003)• Following rituximab monotherapy in relapsed (n = 138) orchemotherapy naïve (n = 64) patients?– YES, for 25-45% of patients depending on initial response(SAKK trials 2004; Martinelli. J Clin Oncol. 2010;28:4480;and 5 years maintenance Taverna ASCO 2009)• Following initial chemotherapy alone?– YES (Hochster J Clin Oncol. 2009; 27:1607; Morchhauser JClin Oncol. 2008;26:5156)• Following initial chemo-immunotherapy?– PRIMA trial results (Salles)


PRIMA: Study DesignINDUCTIONMAINTENANCERegistrationHightumor burdenuntreatedfollicularlymphomaImmunochemotherapy8 x Rituximab+8 x CVP or6 x CHOP or6 x FCMCR/CRuPRRituximab maintenance375 mg/m 2every 8 weeksfor 2 years ‡Random 1:1*PD/SDoff studyObservation ‡*Stratified by response after induction, regimen of chemo, and geographic region.‡Frequency of clinical, biological, and CT-scan assessments identical in both arms.Five additional years of follow-up.Salles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.


PRIMA: Inclusion Criteria• Patients over 18 years previously untreated with histologicallyconfirmed follicular lymphoma grade 1, 2, or 3a• Patients with at least one of the following symptoms requiringinitiation of treatment:– Bulky disease at study entry (nodal or extranodal mass > 7cm)– Involvement of ≥ 3 nodal sites (each > 3 cm)– Symptomatic splenic enlargement, compressive syndrome,pleural/peritoneal effusion– B symptoms present– Elevated serum LDH (> ULN) or 2-microglobulin (> 3 mg/L)• ECOG performance status < 2• Written informed consentSalles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.ClinicalTrials.gov: NCT00140582


PRIMA: Study Endpoints• Primary endpoint:– Progression-free survival (PFS) from randomization (to rituximabmaintenance or observation)• Secondary endpoints:– Event-free survival (EFS), overall survival (OS)– Time to next anti-lymphoma treatment (TTNLT), time to nextchemotherapy (TTNCT)– Response rates at end of maintenance– Safety and toxicity– Quality of life (QoL) (FACT-G and EORTC scales)• An Independent Review Committee (IRC) also examined all response andprogression data (CT scans + clinical/biological findings)Salles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.ClinicalTrials.gov: NCT00140582


Progression-free ratePrimary Endpoint (PFS) Met at the PlannedInterim AnalysisRituximab maintenance significantly reduced the risk ofprogression by 50%1.00.80.60.40.20Patients at riskstratified HR = 0.5095% CI 0.39; 0.64P < 0.00010 6 12 18 24 30 36505513Time (months)82%66%472 443 336 230 103 18469 411 289 195 82 15Rituximab maintenanceN = 505ObservationN = 513Salles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.


Benefits of Rituximab Maintenance Seen in AllMajor Subgroups EvaluatedCategorySubgroupHazard ratioNHazardratio*95% CIsAllAll10180.490.38–0.64Age< 60≥ 606243940.450.590.33–0.620.39–0.90FLIPl IndexFLIPl ≤ 1FLIPl = 2FLIPl ≥ 32163704310.380.390.610.19–0.770.25–0.610.43–0.67InductionChemotherapyR-CHOPR-CVPR-FCM768222280.430.690.510.31–0.590.44–1.080.13–2.07Response toInductionCR/CRuPR7212900.520.450.38–0.700.29–0.720 1 2 3Favors maintenance Favors observationSalles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.* Non-stratified analysis


Event-free rateEvent-free ratePRIMA: Consistent Results AcrossSecondary EndpointsTime to nextanti-lymphoma treatmentTime to nextchemotherapy treatment1.00.8Rituximabmaintenance1.00.8Rituximabmaintenance0.60.60.4HR = 0.61P = 0.0003Observation0.4HR = 0.60P = 0.0011Observation0.20.200 6 12 18 24 30 36Time (months)00 6 12 18 24 30 36Time (months)Patients at risk505483 453 349 235 103 18505484 457 351 243 108 19513487 447 327 218 87 15513492 454 332 225 91 17Salles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.


Summary• Rituximab maintenance for 2 years significantly improved PFS forpatients with previously untreated FL who responded to induction withchemotherapy plus rituximab• Benefits of rituximab maintenance seen in all major sub-groups• Consistent improvements in secondary endpoints including EFS, TNLT,TNCT, ORR and CR rate at the end of maintenance• IRC-assessed endpoints were consistent (not shown)• Safety of maintenance was consistent with the known safety profile ofrituximab, with no new or unexpected findings• Additional follow-up will allow evaluation of a possible effect on overallsurvivalSalles GA, et al. J Clin Oncol. 2010;28(15s). Abstract 8004.Update: abstract 1788Saturday 5:30-7:30Hall A3/A4, poster board I-768


Conclusions• The benefit of rituximab maintenance in first line appears superior tothat described in relapsing patients:– After R-CHOP in the EORTC study* HR = 0.69– After R-CHOP in PRIMA HR = 0.43• R-chemotherapy followed by 2 years of rituximab maintenance– Represents a new standard of care for FL patients in need oftreatment– Constitutes a new platform to further develop more efficient(and well tolerated) strategies*van Oers MHJ, et al. J Clin Oncol. 2010;28:2853-2858.


Pooled Estimates of Overall Survival WithRituximab Maintenance Therapy for Patients WithFollicular Lymphoma Compared With Observationand Rituximab at Disease ProgressionVidal L, et al. JNCI J Natl Cancer Inst. 2009;101:248-255.Update: abstract 1798Saturday 5:30-7:30Hall A3/A4, poster board I-778


IMiDs: Pharmacodynamic Effects onImmune System• Suppresses TNF-α by accelerating mRNA degradation andinhibiting activation of NF-κB• Cellular response influenced by cell lineage and type ofreceptor• Suppress IL-12 generation• Inhibit angiogenesis• Augments T-cell (CD8) responses• Act as second co-stimulatory signal for T-cells


Untreated High Risk FollicularLymphoma: E2408 Study SchemaBIONIC: Bortezomib Induction Or New Imid ContinuationHigh RiskFollicularLymphomaFLIPI 3-5 orGELF hightumor burdenAccrual: 250 patientsStudy PI: A. EvensRANDOMIZE*INDUCTIONR-Bendamustineq 28 d cycles x 6R-Bendamustine +Bortezomibq 28 d cycles x 6R-Bendamustineq 28 d cycles x 6*1:2:2 randomizationCorrelative studies:CONTINUATIONRituximab 1 infusion q 2 mo x 2 yrRituximab 1 infusion q 2 mo x 2 yrRituximab 1 infusion q 2 mo x 2 yrLenalidomide 20 mg d1-21 x 1yrQuantitative t(14;18) PCR, PET, T-cell/NK markers, serumproteasome and TNF-a levels, host SNPs, TMAs, and QOLAvailable at: www.clinicaltrials.gov. NCT01216683.


Conclusions• Maintenance rituximab improves DFS in patients withrecurrent FL (Van Oers, Hainsworth, Forstpointer, Martinelli[SAK 35/98])• Maintenance rituximab improves DFS in patients withpreviously untreated FL (Hochster (E 1496), Martinelli (SAK35/98), Salles (PRIMA)• Maintenance rituximab is feasible for 5 years (Taverna SAK35/03)• Survival data are lacking, though recent meta analysissuggests improvement in survival but increase in infection(Vidal)


Conclusions• Long term toxicity data (>5 years) are lacking• Short term toxicity includes hypogammaglobulinemia withsinus and pulmonary infections, a higher incidence ofneutropenia• Role of rituximab in JC virus infection (PML) deserves furtherinvestigation (Carson)12/15/2010 ECG 46

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