Challenges in the Treatment of Follicular Lymphoma

Transcription

1 Challenges in the Treatment of Follicular Lymphoma Prof. Michele Ghielmini Clinical Director Oncology Institute of Southern Switzerland Bellinzona

2 ESMO guidelines 2014 (simplified) Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

3 Is RT alone sufficient for early stage? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

4 Initial treatment for stage I-II FL Center N Median age Treatment 10y OS Stanford observation 86% Toronto Gy 58% BNLI Gy 64% MD ACC Rxt + chemo 80% Advani, JCO 2004

5 US: Lymphocare survey Incompletely staged patients had inferior outcome PET seems not to be essential Patients on systemic therapy ± RT improved PFS compared to RT alone No difference in OS between Tx groups Friedberg JW, et al. J Clin Oncol 2012; 30:

6 Relapse after RT: NCCN centres Stage Size of bulk Stage Size of bulk Charpentier et al., Abstr. 62, ICML-12, 2013

7 Is W+W still an option in 2015? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

8 3 randomised studies of W + W vs. immediate chemotherapy W+W vs. ProMACE-MOPP 89 pts Young, 1988 Overall survival W+W vs. Prednimustine 130 pts Brice, 1997 W+W vs. Chlorambucil 309 pts Ardeshna, 2003 With permission from The Lancet, Ardeshna K M et al., The Lancet, August 2003, Vol ):

9 Potential advantages of waiting Delayed acute side-effects of treatment Delayed late side-effects Delayed infertility or menopause Median time to treatment: 3 years 20% of patients still not in need of treatment at 10 years Ardeshna et al., Lancet 2003

10 Probability Life threatening side-effects keep increasing from the time of treatment start HL: Competing Causes of Mortality Hodgkin s s Disease Second Malignancy Infection Cardiac/Pulmonary Other Years Diehl et al. Lancet Oncol 2004

11 Risk of follicular lymphoma transformation by initial therapy Link B K et al. J Clin Oncol 2013;31:

12 Does waiting increase the chance of transformation? Al Tourah et al., JCO, 2008

13 Cumulative incidence of histologic transformation according to front-line treatment of follicular lymphoma. Conconi et al, Br J Haematol. 2012; 157:188-96

14 UK study on W+W patients: Time to Initiation of New Therapy (TINT) Proportion of patients with no new treatment initiated Survival W+W R4 R4 + M Years from randomisation Years from randomisation ICML update: R + M reduces anxiety compared to W+W Ardeshna et al., Abstr. 19, ICML-11, 2011

15 Risk of Transformation Ardeshna et al, Lancet Oncol 15:424, 2014

16 Which chemotherapy should be associated to rituximab? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

17 Meta-analysis of chemo vs R-chemo: Overall survival Schulz H, et al. J Natl Cancer Inst 2007; 99:

18 «More is better»? Ardeshna et al, The Lancet 2003 Peterson et al., JCO 2003 Sebban et al, Blood, 2006 Ladetto, M. et al. Blood 2008

19 Italian randomised study (N = 504) Is R-CHOP standard? No difference in OS! R-CHOP vs R-CVP R-FM vs R-CVP R-CHOP vs R-FM Federico M, et al. J Clin Oncol 2013 Mar 25. Epub ahead of print.

20 FL: STIL vs BRIGHT study (PFS) Time (months) Rummel MJ, et al. Lancet Flinn IW et al. ASH 2012; abstract 902.

21 Bendamustine-Rituximab (B-R) vs Fludarabine-Rituximab (F-R) Protocol amended in July 2006 to allow Rituximab maintenance following regulatory approval in this setting Follicular Waldenströms Marginal zone Small lymphocytic Mantle cell R Bendamustine-Rituximab + 2 years Rituximab (n=25) Fludarabine-Rituximab + 2 years Rituximab (n=19) Rummel et al, ASH 2014

22 Progression-free and overall survival BR HR: 0.54 (95%-CI: ) p = HR: 0.64 (95%-CI: ) p = months months

23 FL Grading < 15 Cb/HPF 1 3a 3b 2 > 15 Cb/HPF All Cb/follicular LBCL/follicular 1-2 3a 3b LBCL = large B-cell lymphoma Images courtesy of Stefano A Pileri, MD

24 Overall Survival (%) Overall survival (%) Grade IS a predictive factor: Nebraska Follicular lymphoma mean counts No adriamycin p < Grade 1 Grade 2 Grade Years Follicular lymphoma mean counts Adriamycin p = 0.87 Grade 1 Grade 3 Grade Years Grade 3 FL must be treated with an anthracyclinecontaining regimen Nathwani BN, et al. Follicular lymphoma. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissue. Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). IARC Press: Lyon 2001.

25 Grade is NOT a predictive factor: Vancouver DFS DFS DFS OS OS OS 82% of FL 3B vs 36% of FL 3A received anthracyclines Shustik J, et al. Ann Oncol 2011; 22:

26 Overall survival Overall survival Grade 3A vs 3B is a predictive factor: Nordic group Overall survival Grade 3B Grade 3A Time (years) Grade Grade 3A with anthra Grade 3B no anthra Time (years) Grade 3B with anthra Grade 1 2 no anthra Grade 1 2 with anthra Grade 3A no anthra Wahlin BE, et al. Br J Haemtaol 2012; 156:

27 To be on the safe side... Theoretically: give R-CHOP only to grade 3B BUT 20 30% of FL are grade % of grade 3 are 3B 30 50% of pathologists do not agree on grade Practically: R-CHOP to all grade 3?

28 Is there any room for a chemotherapy-free treatment? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

29 Patients usually respond to upfront R RR of prolonged rituximab in first-line FL Colombat 2001 (n= 50) 73% Hainsworth 2002 (n= 60) 73% Witzig 2005 (n= 37) 72% Ghielmini 2005 (n= 202) 75% Kimby 2008 (n= 123) 78% Ardeshna 2010 (n= 192) 85%

30 The response to upfront R can be longlasting R + M 0.6 / / / 4R Prolonged Standard / / / /// p = W+W Years since start of treatment Martinelli et al, JCO 2010 Ardeshna et al, ASH 2010

31 Obinutuzumab vs rituximab with maintenance in relapsed inhl: the GAUSS study All patients relapsing after R-containing treatment ORR GA101: 44.6% RITUXIMAB: 26.7% p = 0.01 Weekly x 4 O: 1000 mg R: 375 mg/m2 Sehn, JCO, 2015

32 R 2 in first line FL MDACC n= CALGB Lenalidomide 20 mg d 1-21 x 6 20 g d 1-21 x 12 Rituximab 375 mg/m2 qd 4 wks x mg/m2 weekly x 4 + cycle 4, 6, 8, 10 Median age FLIPI 2 78% 69% RR 98% 93% CR 87% 72% 2y. PFS 89% - Ref Fowler et al. Abstr. 901, ASH 2012 Martin et al. Abstr. 63, ICML-12, 2013 Conclusion: is R 2 as active as R-chemo?

33 Proportion of patients (%) R2 in FL patients in need of treatment Week 10 Week p< p= % 80 75% % 45% % 62% 36% PR 30 35% CR/CRu % 13% 25% 36% Rituximab (N=77) Rituximab + Lenalidomide (N=77) Rituximab (N=77) Rituximab + Lenalidomide (N=77) 33 Eva Kimby - December 9, 2014 Kimby et al, ASH 2014, abstr. 799 NLG

34 Idelalisib approved for R/R inhl 126 indolent lymphomas ORR 57% Gopal AK, NEJM, 2014

35 Ibrutinib in 40 R/R FL: RR 28% Bartlett et al, ASH 2014, abstr. 800

36 Oral drugs = better quality of life? Oral drug Mechanism of action Toxicities Lenalidomide Immunomodulator Diarrhea/constipation Fatigue/ muscle cramps Thrombosis/embolism Idelalisib PI3K inhibitor Diarrhea / colitis / perforation Liver toxicity/ Pneumonitis Severe cutaneous reactions Ibrutinib BTK inhibitor Fatigue / atrial fibrillation Muskulo-skeletal pain Dyspnea /pneumonia Venetoclax Anti-BCL2 Diarrhea/ fatigue Respiratory tract infections Tumour lysis syndrome

37 Radio-Immunotherapy as Initial Therapy for Indolent NHL I-131 Tositumomab n = 76 patients, 97% RR, 76% CR 90-Y Ibritumomab n = 50 patients, 94% RR, 86% CR Kaminski MS, et al. N Engl J Med. 2005;352(5): Ibatici A, et al. Br J Haematol. 2014;164(5):

38 Should everybody receive maintenance? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

39 The PRIMA trial 3 years FU 1.0 Rituximab maintenance 1.0 Rituximab maintenance % 0.8 Observation Observation Stratified HR = % CI: p < % Time (months) p = Time (months) Patients at risk Salles G, et al. Lancet 2011; 377:42 51.

40 Meta-analysis of rituximab maintenance in indolent lymphomas : survival Vidal L, et al., JNCI, 2011 in press

41 SAKK 35/03: 1 vs 5 years maintenance EFS Long-term maintenance Median 5.3 y PFS Long-term maintenance Median 7.4 y Short-term maintenance Median 3.4 y P=0.14 Short-term maintenance Median 3.5 y P=0.04 Christian Taverna _

42 Remission duration with several schedules n PFS Witzig Ghielmini m 19m 20 Ghielmini m 98 Kimby m 36 Hainsworth m 83 Taverna m

43 Time to treatment failure: Maintenance vs Re-treatment RESORT trial Hainsworth JD, et al. J Clin Oncol Median number of rituximab doses Re-treatment: 4 Maintenance: 18 Kahl B, et al. JCO 2014.

44 Optimal duration of R-treatment The RR to rituximab in first line is 60-70% Duration of response is longer with longer treatment FL who responded to R often respond to re-treatment Optimal schedule: 4 weekly doses followed by 4 more doses?

45 When should patients be transplanted? Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT Relapse (R-mono) W + W R-monotherapy R-chemo + maintenance Radioimmunotherapy Palliative RT HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2014

46 ABMT in relapsed FL: Bart s historical comparison EFS OS Rohatiner, A. et al. J Clin Oncol; 2007

47 FL: autologous transplant in first-line GELF: n = 402 PFS OS True also for high FLIPI patients!! Sebban et al, Blood, 2006

48 FL: autologous transplant in the R-aera: 1st line setting Ladetto, M. et al. Blood 2008 Conclusion: autologous transplantation is best used at relapse

49 Can transplant cure? Autologous: no Allogeneic: yes Hosing et al., Ann Onc 2003

50 Mini-allo transplant (RIC) for relapsed FL MDACC: OS and PFS Multicenter French study 60% chronic GvHD (36% extensive) Khouri, I. F. et al. Blood % chronic GvHD (20% extensive) Vigouroux, S. et al. Haematologica 2007

51 The IOSI guidelines for advanced FL: out-of-study patients FIRST LINE Low tumor burden W + W High tumor burden Grade 1-2 Grade 3A Grade 3B R-monotherapy R-bendamustine R-chlorambucil R-CHOP x 6 +/- R-maintenance R-CHOP x 6 RELAPSE HDCT R-bendamustine Zevalin R-CVP R-CHOP Idelalisib Allo-transplant If aggressive relapse in young and fit From the 2nd relapse Relapse after HDCT in young and fit