Advances in CLL 2016

Transcription

1 Advances in CLL 2016 The Geoffrey P. Herzig Memorial Symposium, Louisville, KY Kanti R. Rai, MD Northwell-Hofstra School of Medicine Long Island Jewish Medical Center New Hyde Park, NY

2 Disclosures Member Medical Advisory Board Genentech/Roche, Celgene, Pharmacyclics, Gilead

3 Advances in CLL 2016 Advances in Prognosis Advances in Therapy Future Directions

4 Progress in Prognostication Recurrent mutations in CLL refine prognosis Screening of 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes. BIRC3 mutations (2.5%) were associated with Unmutated IGHV, del(11q) and tri 12. MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1 mutations, SF3B1 and TP53 aberrations (deletion/mutation,tp53ab) correlated with shorter TTFT (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53 ab. along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Baliakas P et al Leukemia 2014

5 Should we incorporate therapy based on the newly proposed mutation-cytogenetics based prognostic model in early stage patients? Very Low Risk Sole del13q only (10 year OS -69.3%) Low Risk - +12/normal genetics (10 year OS 57%) Intermediate Risk NOTCH1/SF3B1 mutations with del11q (10 year OS - 37%) High Risk TP53/BIRC3 mutations (10 yr OS -29%) Rossi D et al Blood Feb 2013

6 Treatment options in CLL are changing 1960s 1970s 1980s 1990s 2000s Wait and watch or Alkylating Agents Chlorambucil Cyclophosphamide 5% CR 30-50% ORR Rai K et al AJH 2016 Purine Analogs Fludarabine Pentostatin Cladribine 20-30% CR 50-80% ORR Purine Analogs + alkylators FC, PC 35% CR 75-90% ORR TKI Ibrutinib mab Obinutuzumab Bcl2 antagonist Venetoclax Chemo-immunotherapy FCR, FR, PCR,BR + Newer Biological Agents 41-70% CR 90-95% ORR

7 FCR in CLL Keating et al introduced FCR and its dramatic results in front line CLL Byrd et al (CALGB) introduced - FR. FCR - Keating et al JCO 2005;23: , Blood 2008;112: FR - Byrd et al Blood 2003;101:6-14

8 FCR vs FC Phase III Trial 6 year Follow up PFS Results The median PFS was (57 vs 33 months; p<0.001) and OS (not reached vs 86 months; p <0.001) were significantly longer in patients treated with FCR as compared to the FC arm Fischer K et al Blood 2016

9 FCR 13 year Follow up Mutated CLL can achieve long term remissions OS Results M-CLL who achieved MRD negative CR had significantly longer PFS (80% vs 37%) and OS (87% vs 56%) These results have shown that patients with M-CLL who are physically fit can achieve long term disease free survival with FCR alone Thompson et al Blood 2016

10 Concerns with Chemoimmunotherapy Myelosuppression and associated Infections Need for admission Second cancers and Richter s transformation High risk for elderly patients with comorbidities Inadequate response in patients with del17p/tp53 mutations

11 Therapeutic advances in CLL BCR signaling kinases Btk, PI3K delta have been identified as major kinases which promote CLL cell survival and proliferation and are of therapeutic relevance Bcl2 antagonists - Venetoclax Combination therapy with newer anti-cd20 mab such as Obinutuzumab

12 Changing paradigms in Treatment Clinical trials with novel tyrosine kinase inhibitors alone and in combination with Rituximab/Obinutuzumab TKI s offer a BIG hope for elderly, physically unfit patients with CLL with Rituximab/Obinutuzumab or Ibrutinib

13 BCR signaling kinase pathways in CLL Wiestner A. Blood 2012

14 BCR signaling tyrosine kinase inhibitors (TKI) Btk (Bruton tyrosine kinase) Inhibitor Ibrutinib, acalabrutinib and others PI3Kδ-p110 isoform inhibitor- Idelalisib and Duvelisib (PI3Kδγ)

15 What will probably happen in 2016 or 2016 onwards Big Question is Whether the results seen with TKI s in CLL will be similar to results seen with TKI s in CML??

16 Ibrutinib in patients with TP53/del17p N=51 patients (35 previously untreated;16 with RR- CLL Median follow-up of 24 months 32/33 patients achieved ORR (97%) all PR PFS for all patients at 24 months was 82% and OS was 80% Grade 3 or worse adverse events were Neutropenia in 12 (24%) patients, Anemia in 7 (14%) and thrombocytopenia in 5 (10%) patients Grade 3 pneumonia occurred in 3 (6%) patients, and grade 3 rash in 1 (2%) patient. Faroouqui. et al Lancet Oncol 2015

17 3 Year Follow up with Ibrutinib Median PFS was not reached for all TN or RR patients. PFS rate was 96% (95% CI, 76.5%-99.5%) at 30 months in TN and 69% (95% CI, 58%-78%) in RR patients. Median OS was not reached for all patients. The estimated 30-month OS rate was 97% (95% CI, 78%-99.5%) in TN and 79% (95% CI, 69%- 86%). Byrd J et al Blood 2015

18 Rituximab combined with Ibrutinib Combination of ibrutinib with rituximab is studied in 40 patients with high risk CLL 87% achieved PR and 8% CR. The ORR in patients with del17p or TP53 mutation was 95%. The combination was well tolerated Shorter redistribution Lymphocytosis likely due to Rituximab Burger J et al Lancet Oncology Aug 2014

19 BTK Mutations after Ibrutinib discontinuation Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations. BTK C481 mutations interfere with ibrutinib binding, and PLCG2 mutations potentially have gain-of function effects. Maddocks et al JAMA Oncology 2015

20 Obinutuzumab A type II glycoengineered humanized anti CD20 Monoclonal Ab It promotes direct apoptosis, has higher binding affinity to CD20 resulting in higher ADCC than Rituximab and mediates phagocytosis via neutrophils Phase I trial in relapsed ref CLL showed response in 8/13 patients Combination with Clb is compared with Clb alone Goede et al Leukemia Nov 2012, Byrd J et al Blood 2010, Golay J et al Blood Oct 2013

21 Obinutuzumab - Updated CLL-11 results PFS was longer with G-Clb compared with R-Clb treatment (median PFS 29.2 versus 15.4 months, hazard ratio (HR) 0.40, 95%CI ( , P<0.001). Time to next treatment was longer with G-Clb than with R-Clb (42.7 versus 32.7 months, HR 0.54, 95%CI ,P<0.001). Goede J et al Leukemia 2015 Ibrutinib with Ofatumumab Phase1b/2 study In relapsed CLL ORR of 83% with median time to response of less than 3 months. Jaglowski et al Blood 2015

22 What should be the treatment strategy for patients with del17p and/or TP53 mutations? Ibrutinib with/without anti CD20 mab? Allo-SCT

23 Updates on allo-sct in CLL Most patients who fail allo-sct are salvageable Young and physically fit patients with biopsy proven Richter s transformation Refractory patients with del17p or TP53 mutations who progress on Ibrutinib R-DHAP followed by allo-sct is a reasonable treatment to be considered for high-risk CLL patients without access or resistance to targeted therapies Recovery of full donor chimerism with ibrutinib therapy in an anecdotal case Rozovski U. et al JCO 2015, Gelder MV et al Leukemia 2016, Quinquenel A et al BJH 2016

24 Will CAR-T cells therapy lead the way in CLL? Possible as per the recent update from Porter D et al in 14 patients The ORR in heavily pretreated CLL patients was 8 of 14 (57%), with 4 CR and 4 PR The CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. None relapsed and were negative for MRD Porter D et al Sci. Transl. Med Ibrutinib therapy improved the expansion of CD19-directed CAR T-cells (CTL019), in association with decreased expression of PD1 on T-cells and CD200 on CLL cells Fraietta et al Blood 2016

25 We don t know the long term effects of Ibrutinib or its combinations with anti-cd20 mab with/without Bcl2 antagonist therapy on MRD status Future challenges for CLL Second cancers Immune dysfunction Transformations Patterns of relapse BTK mutations and resistance

26 CLL Collaborations CLL Research Consortium (CRC) International Workshop on CLL (iwcll) German CLL Study Group CLL Global Research Foundation Alliance for Clinical Trials in Oncology (CALGB)

27 THANKS