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Is there Long-Term Benefit from Maintenance Rituximab?

Is there Long-Term Benefit from Maintenance Rituximab?. Emanuele Zucca, MD Oncology Institute of Southern Switzerland (IOSI) Swiss Group for Clinical Cancer Research (SAKK). Rationale and aim of maintenance in haematological malignancies.

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Is there Long-Term Benefit from Maintenance Rituximab?

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  1. Is there Long-Term Benefit from Maintenance Rituximab? Emanuele Zucca, MD Oncology Institute of Southern Switzerland (IOSI) Swiss Group for Clinical Cancer Research (SAKK)

  2. Rationale and aim of maintenance in haematological malignancies In patients who have responded to initial induction • Prolong quality and duration of remission • Prolong overall survival (if possible)

  3. Results of maintenance rituximab trials were not the same in different B-cell lymphoma subtypes

  4. Maintenance rituximab in DLBCL • ECOG 4494 trial: no benefit of 2-year maintenance (4xR weekly q6 mos) in elderly pts after R-CHOPHabermannTM, et al. J Clin Oncol. 2006 • Potential benefit for maintenance rituximab recently reported in a retrospective Chinese study (N = 207)Huang BT, et al. J Cancer Res Clin Oncol. 2012 • NHL13/NCT00400478 randomized study:maintenance reduced relapse rate but did not prolong EFS nor OS in DLBCL (or FL grade 3) Jaeger at al. Abstr 119, 12-ICML, Lugano 2013

  5. Event Free Survival(ITT population) AA 100% 100% 90% 90% 80% 80% 70% 70% 60% 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% 0 0 3 3 6 6 9 9 12 12 15 18 15 21 18 24 21 27 24 30 33 27 36 30 39 33 42 36 45 39 48 51 42 54 45 57 48 60 51 63 54 66 69 57 72 60 75 63 78 66 81 84 69 87 72 90 75 93 78 96 99 81 Time [months] Time [months] 2-yr maintenance rituximab or not after R-CHOP-like regimens for DLBCL Rituximab maintenance Austrian/Czech study group 27 countries, 2004-8 N=683 Observation Rituximab maintenance Observation Overall Survival(ITT population) p = NS p = NS Jaeger at al., 12-ICML, Hematol Oncol 2013. 31(suppl 1):128, abstr 119

  6. Maintenance rituximab benefit after R-CHOP but not after R-FC in MCL Among patients who had a response to R-CHOP, maintenance rituximab significantly improved survival (4-year OS rate, 87%, vs. 63% with IFN-alfa; P=0.005). Kluin-Nelemans, NEJM 2012

  7. Improvement of FL outcome

  8. What does R-maintenance mean? From GribbenJG. Blood 2007;109:4617-4626

  9. Rituximab maintenancein relapsed/resistant FL GLSG study FCM PR/CR 105 pts R-maintenance R-FCM Forstpointner et al, Blood. 2006;108:4003-8

  10. ECOG 1496 – Progression-free survival follicular NHL after CVP (n = 237) 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 Maintenance (n = 120)Median PFS: 5 yrs Probability Observation (n = 117)Median PFS: 15 months LR one-sided P = 0.0000003 HR 0.4 (0.3–0.6) Years from maintenance randomisation Hochster HS, et al. Blood 2005; 106:Abstract 349.

  11. EORTC 20981 Initial Results median follow-up from 2ndrandomization, 33 months Footer Text van Oers et al. Blood 2006;108:3295-3301

  12. Rituximab-based induction and maintenance therapy became the standard of care for FL R-chemo vs chemo induction1 R-maintenance vs observation2 HR for OS (95% CI) HR for OS (95% CI) p < 0.001 p < 0.0003 0.2 0.5 1 2 0.001 0.1 1 10 1000 Favours R-chemo Favours chemo FavoursR-maintenance Favours observation 1.Schulz H et al. J Natl Cancer Inst. 2007;99:706-142.Vidal L et al. J Natl Cancer Inst. 2009;101:248-55

  13. EORTC 20981 Long-Term Outcome median follow-up from 2nd randomization, 72 months With long-term follow-up the superior PFS with R-maintenance was confirmed in R/R FL van Oers et al. J Clin Oncol 2010; 28:2853-8

  14. EORTC 20981 Long-Term Outcome • The OS improvement did not reach statistical significance, possibly because of the unbalanced use of rituximab at progression. • R-containing salvage therapy to 59% of patients after CHOP followed by observation, vs. 26% after R-CHOP plus R-maintenance. • R-maintenance associated with a significant increase in grades 3 to 4 infections: 9.7% vs. 2.4% (P = .01). van Oers et al. J Clin Oncol 2010; 28:2853-8

  15. FIL phase III Study Design 234 patients >60 yro with advanced FL • R-FND induction phase • Rituximab 375 mg/m2 (d 1) • Fludarabine25 mg/m2 /d (d 2-4) • Mitoxantrone10 mg/m2 (d 2) • Dexamethasone 10 mg/d (d 2-4) • Monthly x4 N=101 • Arm A, Maintenance • Rituximab 375 mg/m2Q 2 months x4 • Restaging • CR/CRuPRSD N=210 • Restaging • CR/Cru • PRstratifiedby MRD ® • consolidation phase • Rituximab 375 mg/m2Weekly x4 1:1 N=101 Arm B, Observation Vitolo U et al. JCO 2013;31:3351-3359

  16. FIL study: Overall and progression-free survival in elderly patients with advanced FL Vitolo U et al. JCO 2013;31:3351-3359

  17. R- maintenance vs. observation in elderly FL patients after induction with 4 R-FND cycles and consolidation with 4x weekly R 2-year PFS 81% versus 69% HR 0.74 not statistically significant. No differences between the two arms detected for OS. Is the maintenanceeffect the sameafteranyinductionregimen in FL? P = 0.226 Vitolo U et al. JCO 2013;31:3351-3359

  18. MAINTAIN TRIAL (NCT00877214):Significance of Duration of Maintenance Therapy With Rituximab in Non-Hodgkin Lymphomas after Front-Line Therapy with R-Bendamustine • ExperimentalArm • FL: Maintenancerituximab q2 mosfor 4 yrs • WM, MZL and MCL: Maintenancerituximab q2 mos for 2 yrs Vs. • Standard Arm • FL: Maintenancerituximab q2 mos for 2 yrs • WM, MZL and MCL: Observation

  19. R- maintenance toxicity in elderly FL Vitolo et al. JCO 2013;31:3351-3359

  20. Questions on prolonged rituximab treatment in FL When? Front-line or at first relapse? How long? Is chemotherapy always needed?

  21. PRIMA study of front line maintenance 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 100 100 Rituximab maintenance Observation 80 80 60 60 40 40 20 20 0 0 3-year PFS 74.9% Rituximab maintenance Probability 57.6% Observation p < 0.0001 PFS (months) Conversion from PR to CR/CRu during maintenance/observation CR/CRu at end of treatment p = 0.0001 p = 0.0001 72% 52% 52% Patients (%) Patients (%) 30% Salles G, et al. Lancet. 2011;377:42-51.

  22. PRIMA study of front line maintenance 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 3-year PFS 74.9% Rituximab maintenance Probability 57.6% Observation p < 0.0001 But…No significant difference in OS Salles G, et al. Lancet. 2011;377:42-51.

  23. Rituximab vs. watch & wait in asymptomatic, advanced-stage, non-bulky FL: PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3-year PFS Rx4 + RM: 81% Rx4: 60% Probability W + W: 33% R vs W + W: p < 0.001 R + RM vs W + W: p < 0.001 Median follow-up = 32 months 0 5 1 2 3 4 PFS (years from randomization) Ardeshna KM, et al. Blood. 2010;116:[abstract 6]

  24. Rituximab vs. watch & wait in asymptomatic, advanced-stage, non-bulky FL: OS Ardeshna KM, et al. Blood. 2010;116:[abstract 6]

  25. Which is the optimal duration of rituximab treatment in FL?

  26. Single-agent rituximab in FL: the SAKK 35/98 study Randomization FL pre-treated and untreated in need of treatment FL (n = 151) n = 202 OBSERVATION Standard treatment Prolonged treatment 375 mg/m² weekly x 4 SD, PR, CR (n = 151) 375 mg/m² every 2 months x 4 PD off study Ghielmini M, et al. Blood. 2004; 103(12):4416-23

  27. SAKK 35/98R-maintenance after single agent rituximab 100 80 60 40 20 0 Prolonged: median 23 mos FL Event-free survival (%) Observation: median 12 mos P = 0.024 0 6 12 18 24 30 36 42 48 Months Ghielmini M, et al. Blood. 2004; 103(12):4416-23

  28. Long-term EFS by arm according to response to the induction treatment 35% of respondersstill in remission at 8 years Martinelli et al. JCO 2010 Martinelli JCO 2010

  29. SAKK 35/98: long-term follow-up 1.0 1.0 0.8 0.8 0.6 0.6 / / / 0.4 0.4 / / / / / / / / / / / / / / / / / / / / / / / / / 0.2 0.2 / ProlongedStandard ProlongedStandard 0.0 0.0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 Event-free survival in randomized follicular lymphoma patients Event-free survival in chemo-naive patients with CR/PR at 12 weeks Probability Probability p = 0.045 p = 0.0007 Years since start of treatment Years since start of treatment 27% still in remission at 8 years 45% of chemo-naïve responders in remission at 8 years Martinelli G, et al. JClinOncol. 2010;28:4480-4

  30. SAKK 35/98: Overall Survival Martinelli G, et al. JClinOncol. 2010;28:4480-4

  31. SAKK 35/98 Long-Term Results • The optimal way to give single-agent rituximab is at a prolonged schedule • When treated this way, the chance of being still in remission at 8 years is ~25% • For chemotherapy naïve patients responding to induction, the chance is ~45% at 8 years • Schedule is the only and most potent prognostic factor for response duration • Prolonged rituximab treatment appears safe and improves EFS

  32. Nordic Lymphoma Group ML16865 trialR + IFN vs. R (313 randomizedpatients) 375 mg/m² weekly x 4 375 mg/m² weekly x 4 +/- IFN E. Kimby et al. 11-ICML, Lugano 2011

  33. Rituximab maintenance for how long?SAKK 35/03 study design Randomization SAKK 35/03 trial Short maintenanceRituximab 375 mg/m² q2 months x 4 PR + CR Rituximab375 mg/m² qwk x 4 restageweek 12 SD + PDoff study Rituximab 375 mg/m² q2 monthsuntil progression (max. 5 years) Long maintenance Taverna CJ, et al. J ClinOncol. 2009;27:[abstract 8534]

  34. Rituximab maintenance for how long? SAKK 35/03 trial: short vs. prolonged maintenance Final results (“per arm” analysis) to be first presented at ASH 2013 Median OS: 8.1 years (95% CI 7.8-NA) 7-year OS: 85% (95% CI 77-90) • Median PFS: 5.5 years (95% CI 3.6-7.7) • 7-year PFS: 44.5% (95% CI 35-53) Median follow-up time: 6.4 years (95% CI 6.1-6.5) Median follow-up time: 6.4 years (95% CI 6.1-6.5) Taverna CJ, et al. ASH 2013 (submitted)

  35. Conclusions • Role of maintenance rituximabis still unclear in DLBCL (and MCL), while is better defined in FL where it improves PFS either front-line or at relapse. • OS improvement is less evident. • It is generally accepted that FL patients in need of therapy should receive rituximabwith and after R-CVP or R-CHOP relapse • However, is thistrue for allpatients? and is thistrue for anychemotherapy? • Moreover, is chemotherapyalways needed? • The long term results of SAKK 35/98 together with few available data from other studies indicate immunotherapy alone can have a role in FL • This should be specifically addressed in controlled trials

  36. Acknowledgements • Christian J. Taverna, Giovanni Martinelli,FelicitasHitz, Walter Mingrone, Thomas Pabst, Andreas Lohri, Christine Biaggi Rudolf, StéphanieRondeau, Corinne Rusterholz, SimonaBerardi and Michele Ghielmini, for the Swiss Group for Clinical Cancer Research SAKK • Eva Kimby and all the Nordic Lymphoma Group Investigators

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