Chronic Lymphocytic Leukemia (CLL): Refresher Course for Hematologists Ekarat Rattarittamrong, MD

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1 Chronic Lymphocytic Leukemia (CLL): Refresher Course for Hematologists Ekarat Rattarittamrong, MD Division of Hematology Department of Internal Medicine Faculty of Medicine Chiang-Mai University

2 Outline Education program: Individualizing therapy in CLL The mutational landscape of CLL and its impact on prognosis and treatment Optimizing frontline therapy of CLL based on clinical and biological factors How should we sequence and combine novel therapies in CLL? Interesting abstracts

3 Outline Education program: Individualizing therapy in CLL The mutational landscape of CLL and its impact on prognosis and treatment Optimizing frontline therapy of CLL based on clinical and biological factors How should we sequence and combine novel therapies in CLL? Interesting abstracts

4 The Mutational Landscape of CLL Typical genome of CLL carries about 2000 molecular lesions Few mutations recur with frequency > 5% About 80% of CLL patients carry at least 1 of 4 common chromosomal alterations Deletion 13q14 Deletion 11q22-23 Deletion 17p13 Trisomy 12 Gaidano G, et al. Hematology Am Soc Hematol Educ Program 2017;

5 Mutated Pathways in CLL BCR NF-κB TLR NOTCH Gaidano G, et al. Hematology Am Soc Hematol Educ Program 2017;

6 Prognostic and Predictive Biomarkers Commonly Used in Clinical Practice Age CIRS Stage Beta 2-microglobulin CD49d CD38 ZAP70 IGHV mutation 17p13 deletion 11q22-23 deletion Trisomy 12 13q14 deletion TP53 mutation SF3B1 mutation NOTCH1 mutation Prognostic Predictive Gaidano G, et al. Hematology Am Soc Hematol Educ Program 2017;

7 The Contribution of Gene Mutations to Long-term Clinical Outcomes: UK LRF CLL4 Mutations associated with reduced PFS Mutation Median PFS (months) Mutated vs. WT HR Mutations associated with reduced OS P value TP53 7 vs <0.001 EGR2 13 vs Mutation Median OS (months) Mutated vs. WT HR P value TP53 31 vs <0.001 NOTCH1 51 vs SF3B1 53 vs <0.001 NRAS 50.5 vs Only MYD88 associated with superior OS (median = 121 vs. 68, HR = 0.41, P = 0.01), but not in IGHV-mutated cases Blakemore S, et al. Oral presentation ASH 2017.

8 The contribution of gene mutations to long-term clinical outcomes: Data from the randomised UK LRF CLL4 trial Blakemore S, et al. Oral presentation ASH 2017.

9 CLL-IPI Age < 65 years > 65 years Biomarker Stage Rai 0/Binet A Rai I-IV/Binet B-C Beta 2-microglobulin < 3.5 mg/l > 3.5 mg/l IGHV Mutated Unmutated TP53 No abnormalities Deletion and/or mutation Score Risk group Score 5-year survival (%) Low Intermediate High Very high International CLL-IPI Working Group. Lancet Oncol 2016;17:

10 Molecular Abnormalities and Treatment Response FCR Good outcomes: Mutated IGHV 1 Poor outcomes: BRAF and BIRC3 mutations 2 Rituximab Poor outcomes: NOTCH1 mutation 3 Ibrutinib Poor outcomes: NOTCH1 mutation, apoptosis resistance (Bax/Bcl-2 <1.5) 4 1 Chai-Adisaksopha C. Blood 2017;130: Diop F, et al. Oral presentation ASH Stilgenbauer S, et al. Blood 2014:123; Del Poeta G, et al. Oral presentation ASH 2017.

11 Mutated IGHV and Treatment Outcomes Chai-Adisaksopha C, et al. Blood 2017;130:

12 BRAF and BIRC3 Mutations Stratify a Poor Prognostic Subgroup in FCR Treated CLL Median PFS IGHV M NR Other 5.3 years TP years BRAF or BIRC3 0.3 years Diop F, et al. Oral presentation ASH 2017.

13 Mutations and Outcomes in CLL8 Study (FCR vs. FC) TP53 NOTCH1 SF3B1 Rutuximab failed to improve PFS and OS in patients with NOTCH1 mutation Stilgenbauer S, et al. Blood 2014:123;

14 Apoptosis Resistance and NOTCH1 Mutations Impair Clinical Outcome in CLL Patients Treated with Ibrutinib 24 months PFS 55% vs. 91% 24 months PFS 42% vs. 76% Lack of response/progression not with del(17)p/tp53 mutation (p=0.09) 24 months PFS 43% vs. 86% Lack of response/progression not with del(17)p/tp53 mutation (p=0.09) Del Poeta G, et al. Oral presentation ASH 2017.

15 Mutations and Treatment Decision TP53 Mutated and/or deletion Mutated IGHV Unmutated Kinase inhibitors Chemotherapy plus anti CD20 Kinase inhibitor Age CIRS Cr clearance Chemotherapy regimen e.g. BR, FCR, Chlorambucil+anti-CD20 Gaidano G, et al. Hematology Am Soc Hematol Educ Program 2017;

16 Outline Education program: Individualizing therapy in CLL The mutational landscape of CLL and its impact on prognosis and treatment Optimizing frontline therapy of CLL based on clinical and biological factors How should we sequence and combine novel therapies in CLL? Interesting abstracts

17 Clinical stage Asymptomatic Rai 0-II or Binet A-B Symptomatic Rai III-IV or Binet C Algorithm for Front-line Treatment in CLL Del(17p) and/or TP53 mutation Irrelevant Not present Fit Unfit Present Physical fitness Irrelevant Watch and wait Recommendation for frontline treatment FCR, consider BR if > 65 y Chlorambucil + Obinutuzumab Chlorambucil + Ofatumumab Ibrutinib Irrelevant Ibrutinib Consider venetoclax or idelalisib + rituximab if unsuitable for ibrutinib Irrelevant Frail Best supportive care Fischer K, et al. Hematology Am Soc Hematol Educ Program 2017;

18 Eichhorst B, et al. Lancet Oncol 2016;17: CLL10 Study: FCR vs. BR Median PFS 55.2 months 41.7 months

19 Goede V, et al. N Engl J Med 2014;370: CLL11: Chlorambucil plus Obinutuzumab in unfit CLL

20 Hillmen P, et al. Lancet 2015;385: COMPLEMENT1: Chlorambucil plus Ofatumumab in CLL PFS OS

21 Burger JA, et al. N Engl J Med 2015;373: RESONATE-2: Ibrutinib vs. Chlorambucil in CLL NR 18.9 Mo 24 months OS 98% vs. 85%, p=0.001 PFS OS

22 RESONATE-17: Ibrutinib in R/R del17p CLL Phase II study: 145 patients ORR 83% PR 63%, PR with lymphocytosis 17%, CR 2% 24-month PFS 63% 24-month OS 75% O Brien S, et al. Lancet Oncol 2016;17:

23 Venetoclax in R/R del17p CLL Phase II study: 107 patients ORR 79% PR 69%, nodular PR 3%, CR 8% 12-month PFS 72% 12-month OS 86.7% Stilgenbauer S, et al. Lancet Oncol 2016;17:

24 Optimizing Frontline Therapy of CLL based on Clinical and Biological factors Interesting abstracts TP53 mutation: ibrutinib + rituximab Non TP53 mutation: Ibrutinib + obinutuzumab with MRD adapted Mutated IGHV: ifcg Young patients: ifcr

25 Ibrutinib vs. Ibrutinib plus Rituximab in CLL RCT single center: 206 patients Relapsed CLL and treatment naïve patients with high-risk disease (del17p or TP53) Outcomes Ibrutinib (N = 102) Ibrutinib + R ( N = 104) P value PFS (primary end-point) 90.4% 91.2% CR rate 21% 28% ORR rate 98% 100% NA MRD by flow cytometry 17.1% 4.9% Median time to normal ALC 8.9 Mo 3.0 Mo < Median time to CR 21.1 Mo 11.5 Mo Burger JA, et al. Oral presentation ASH 2017.

26 Ibrutinib vs. Ibrutinib plus Rituximab in CLL Time to normal ALC PFS Single-agent ibrutinib should remain standard-of-care therapy in CLL Burger JA, et al. Oral presentation ASH 2017.

27 Ibrutinib plus Obinutuzumab Followed By MRD Driven Strategy in CLL: Phase II Icll-07 Filo Study Induction therapy with ibrutinib plus obinutuzumab for 9 months followed by Immunochemotherapy (addition of FC x 4) only in case of PR or detectable MRD Ibrutinib x 6 months if undetectable MRD ORR 100% with CR 37% after 9 months Positive BM MRD 86% AEs: IRR 69.5% Michallet AS, et al. Oral presentation ASH 2017.

28 Ibrutinib plus Obinutuzumab Followed By MRD Driven Strategy in CLL: Phase II Icll-07 Filo Study Not included TP53 mutation Michallet AS, et al. Oral presentation ASH 2017.

29 Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (ifcg) for CLL with Mutated IGHV without TP53 Aberrations Phase II trail: 32 patients Induction with ifcg 3 cycles CR with undetectable MRD: ig (C4-6) then ibrutinib (C7-12) Not reach: ig (C4-12) AEs: grade 3-4 neutropenia 68%, thrombocytopenia 48% Jain N, et al. Oral presentation ASH 2017.

30 ifcg for CLL with Mutated IGHV without TP53 Aberrations All except 3 patients continue treatment Jain N, et al. Oral presentation ASH 2017.

31 Ibrutinib Plus FCR (ifcr) in Younger CLL Phase II study: 49 patients Ibrutinib monotherapy for 7 days then combination with FCR for 6 cycles then ibrutinib maintenance at least 2 years ORR 100% with CR 63% CR with MRD negative 2 months after FCR (primary end-point) 37% Best response 57% (83% if included PR) Mutated IGHV 100% vs. unmutated IGHV 71% AEs: Grade 3-4 neutropenia 29%, thrombocytopenia 26% Davids MS, et al. Oral presentation ASH 2017.

32 New Frontline Combination Therapy with Novel Agents (NA) for CLL Interesting abstracts NA with NA Ibrutinib + venetoclax NA with anti-cd20 antibodies Venetoclax + obinutuzumab Ibrutinib + venetoclax + obinutuzumab Acalabrutinib + obinutuzumab NA with chemoimmunotherapy Bendamustine followed by ofatumumab + Ibrutinib

33 Ibrutinib plus Venetoclax in CLL: Phase II Study Rationale 1) Synergistic effect Reduction of pro-apoptotic molecules e.g. MCL1 2) Non-overlapping toxicity profiles 3) Non-overlapping mechanisms of action 4) Complementary activity in treating disease compartment IBR: LN with redistribution to peripheral blood VEN: Blood and BM Jain N, et al. Oral presentation ASH 2017.

34 Ibrutinib plus Venetoclax in CLL: Phase II Study IBR monotherapy in the first 3 months then combination with VEN (IBR indefinitely, VEN 2 years) ORR 100% Jain N, et al. Oral presentation ASH 2017.

35 Venetoclax plus Obinutuzumab in CLL: Phase Ib Study 6 cycles of VEN+OBIN then VEN monotherapy 6 cycles - ORR 100% with CR 56.3% - MRD negativity 62.5% including two 17p del patients - Common grade 3 4 AEs: neutropenia, febrile neutropenia and thrombocytopenia - No clinical TLS Flinn IW, et al. Oral presentation ASH 2017.

36 Obinutuzumab plus Ibrutinib and Venetoclax in CLL: Phase Ib/II Study OBIN+IBR+VEN started sequentially OBIN in C1, IBR in C2, and VEN in C3 - ORR 100% with CR 50% - MRD negativity 58% - Common grade 3 4 AEs: neutropenia (44%), thrombocytopenia (36%) - No clinical TLS Rogers KA, et al. Oral presentation ASH 2017.

37 Acalabrutinib Monotherapy in Relapsed/Refractory CLL: Phase 1/2 ACE-CL-001 Study Byrd JC, et al. Oral presentation ASH 2017.

38 Acalabrutinib with Obinutuzumab in CLL: Phase 1b/2 Study Median PFS: not reached Median DOR: not reached Acalabrutinib until PD + Obinutuzumab 7 cycles - 18-months DOR 86% - Continue treatment 89% - Grade 3-4 AEs: neutropenia 24%, thrombocytopenia 9% Woyach JA, et al. Oral presentation ASH 2017.

39 Bendamustine Followed By Ofatumumab and Ibrutinib in CLL: CLL2-BIO Trial Sequential triple-t therapy Tailored, targeted therapies and total eradication of MRD Bendamustine debulking, followed by ofatumumab and ibrutinib as induction and maintenance therapy Phase II study: 55 patients (32 TN, 23 RR) Cramer P, et al. Oral presentation ASH 2017.

40 Bendamustine Followed By Ofatumumab and Ibrutinib in CLL: CLL2-BIO Trial At the end of induction - ORR 93% (TN 97%, RR 87%) - 84% still MRD positive Cramer P, et al. Oral presentation ASH 2017.

41 Opportunistic Infections during Ibrutinib Treatment Cumulative incidence 4.1% Risk factors: > 3 prior treatment, DM, liver disease Rogers KA, et al. Oral presentation ASH 2017.

42 Outline Education program: Individualizing therapy in CLL The mutational landscape of CLL and its impact on prognosis and treatment Optimizing frontline therapy of CLL based on clinical and biological factors How should we sequence and combine novel therapies in CLL? Interesting abstracts

43 How to Choose Second-line Therapy in CLL? Consideration Patients characteristics Prognostic factors Re-access TP53 mutation to consider addition of kinase inhibitors (KI) Response to prior treatment Repeat chemoimmunotherapy (CIT) if long DOR after CIT Davids MS. Hematology Am Soc Hematol Educ Program 2017;

44 How Should We Sequence and Combine Novel Therapies in CLL? Frontline Current treatment options - Ibrutinib - Older regimens (HDMP, alemtuzumab) Possible future treatment options - Ibrutinib +/- CD20 mab - Venetoclax +/- CD20 mab - Ibrutinib + Venetoclax +/- CD20 mab - 2 nd generation NA combinations CLL patients with TP53 dysfunction Relapsed/refractory - Ibrutinib (if no prior ibrutinib) - Venetoclax - Idelalisib + Rituximab - Allo-SCT - Ibrutinib +/- CD20 mab - Venetoclax +/- CD20 mab - Idelalisib +/- Rituximab - Ibrutinib + Venetoclax +/- CD20 mab - 2 nd generation NA combinations - CAR-T - Allo-SCT Davids MS. Hematology Am Soc Hematol Educ Program 2017;

45 How Should We Sequence and Combine Novel Therapies in CLL? Frontline Current treatment options Young, fit - IGHV mutated: FCR - IGHV unmutated: FCR, ibrutinib Older, frail - IGHV mutated: BR, Chl + anticd20 - IGHV unmutated: Chl + anticd20, ibrutinib CLL patients with intact TP53 Relapsed/refractory - Ibrutinib - Venetoclax - Idelalisib + Rituximab - Ibrutinib + BR - Idelalisib + BR Davids MS. Hematology Am Soc Hematol Educ Program 2017;

46 How Should We Sequence and Combine Novel Therapies in CLL? Frontline Possible future treatment options Young, fit - Ibrutinib + FCR - Ibrutinib + CD20 mab - Venetoclax + CD20 mab - Ibrutinib + Venetoclax +/- CD20 mab - 2 nd generation NA combinations Older, frail - BR (IGHV mutated only) - Ibrutinib +/- CD20 mab - Venetoclax +/- CD20 mab - Ibrutinib + Venetoclax +/- CD20 mab - 2 nd generation NA combinations CLL patients with intact TP53 Relapsed/refractory - Ibrutinib +/- CD20 mab - Venetoclax +/- CD20 mab - Idelalisib +/- Rituximab - 2 nd generation NA combinations - CAR-T Davids MS. Hematology Am Soc Hematol Educ Program 2017;

47 Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in CLL Multicenter, retrospective analysis: 683 patients Mato AR, et al. Ann Oncol 2017;28:

48 Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in CLL Multicenter, retrospective analysis: 683 patients - Ibrutinib appears superior to idelalisib as first KI. - In setting of KI failure, alternate KI or venetoclax appear superior to CIT. - The use of venetoclax upon ibrutinib failure might be superior to idelalisib. Mato AR, et al. Ann Oncol 2017;28:

49 Ibrutinib+BR vs. BR in RR CLL PFS OS Chanan-Khan A, et al. Lancet Oncol 2016;17:

50 How Should We Sequence and Combine Novel Therapies in R/R CLL? Interesting abstracts Phase III Venetoclax + rituximab vs. Bendamustine + rituximab Phase II Ibrutinib + venetoclax Ibrutinib + nivolumab

51 Venetoclax Plus Rituximab vs. Bendamustine Plus Rituximab in R/R CLL Phase III study: MURANO trial R/R CLL requiring treatment, 1 3 prior lines of therapy (including 1 chemo-containing) VR 6 cycles then V for 2 years or PD BR 6 cycles Primary end-point: PFS Seymour JF, et al. Oral presentation ASH 2017.

52 Venetoclax Plus Rituximab vs. Bendamustine Plus Rituximab in R/R CLL 24-mo PFS 84.9% 36.3%, Improvement in OS with VR 2 yr OS 91.9% vs. 86.6% (HR 0.48, 95% CI ) Seymour JF, et al. Oral presentation ASH Seymour JF, et al. Oral presentation ASH 2017.

53 Venetoclax Plus Rituximab vs. Bendamustine Plus Rituximab in R/R CLL Seymour JF, et al. Oral presentation ASH Seymour JF, et al. Oral presentation ASH 2017.

54 Venetoclax Plus Rituximab vs. vs. Bendamustine Plus Rituximab in in R/R CLL Negative MRD at 9 months: VR 62% vs. BR 13% Seymour JF, et al. Oral presentation ASH Seymour JF, et al. Oral presentation ASH 2017.

55 Venetoclax Plus Rituximab vs. Bendamustine Plus Rituximab in R/R CLL Seymour JF, JF, et et al. al. Oral Oral presentation ASH ASH 2017.

56 Ibrutinib plus Venetoclax in R/R CLL: Phase II CLARITY Rationale 1) Synergistic effect Reduction of pro-apoptotic molecules e.g. MCL1 2) Non-overlapping toxicity profiles 3) Non-overlapping mechanisms of action 4) Complementary activity in treating disease compartment IBR: LN with redistribution to peripheral blood VEN: Blood and BM Hillmen P, et al. Oral presentation ASH 2017.

57 Ibrutinib plus Venetoclax in R/R CLL: Phase II CLARITY 50 patients with CLL requiring therapy Relapsed within 3 years of FCR or BR Had 17p deletion and failed > 1line of therapy Dose escalation of VEN after 8-week of IBR monotherapy 2/41 patients had biochemical TLS ORR 100% with 60% CR/Cri MRD negativity 28% at 6 months Hillmen P, et al. Oral presentation ASH 2017.

58 Ibrutinib plus Nivolumab in Relapsed NHL or CLL Median PFS CLL: NR (at median F/U 20 months) RT: 3.6 months for RT Younes A, et al. Oral presentation ASH 2017.

59 Conclusions Individualizing therapy in CLL The mutational landscape of CLL and its impact on prognosis and treatment TP53 and IGHV mutation Optimizing frontline therapy of CLL based on clinical and biological factors Stage, fitness, TP53 mutation/del17p How should we sequence and combine novel therapies in CLL? Patient, disease, response to prior therapy

60 Thank You for Your Attention