Venetoclax in Chronic Lymphocytic Leukemia

VENETOCLAX –RITUXIMAB IN RELAPSED
OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

1. VENETOCLAX –RITUXIMAB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA SPEAKER Dr. Khushboo Garg MD Resident Banaras Hindu University

2. CHRONIC LYMPHOCYTIC LEUKEMIA CLL is characterized by accumulation of mature appearing lymphocytes in blood , bone marrow ,lymph nodes and spleen. SLL is a disease of the same spectrum involving primarily lymph nodes and spleen . Both CLL and SLL antedated by Monoclonal B cell Lymphocytosis in which small number of CLL cells can be detected in the blood of asymptomatic individuals . It is primarily a disease of elderly with a median age 71 years.

3. CLINICAL FEATURES Many patients are asymptomatic and are diagnosed incidentally on routine counts. Symptoms- -Most common symptom is fatigue and vague sense of being unwell. - Enlargement of lymphnodes. - Symptoms due to infections, most common being bacterial pneumonia. -Symptoms caused by anemia and thrombocytopenia. - Weight loss, fever.

4. International Workshop on CLL (IWCLL) Diagnostic Criteria for CLL- Detection of clonal B –lymphocytes at a count of >5,000 per microlitre in peripheral blood. Pro-lymphocytes or larger atypical lymphocyte may comprise no more than 55% of total circulating lymphocytes in peripheral blood. (i.e. Predominance of small, morphologically mature lymphocytes upon cytological examination of the blood smear) . Typical immune phenotypes - co-expression of the B cell antigen CD19, CD23, and the T cell antigen CD5. Other characteristics are relatively weak expression of CD20, CD79b/CD22, FMC7, and surface immunoglobulin .

5. CLL STAGING -

6. CLL – WHEN TO TREAT Indication for treatment - NCCN Guidelines 1.2017 , Version

7. CLL –Treatment Regimens NCCN GUIDELINES 1.2017 VERSION FIRST LINE THERAPY( IN ORDER OF PREFERENCE ) Age> 65 years and younger patients with significant co-morbidities Age < 65 years without significant co-morbidities Obinutuzumab +chlorambucil (category1) Ibrutinib (category1) Ofatumumab + chlorambucil Rituximab + chlorambucil Bendamustine +/- rituximab Chemoimmunotherapy FCR (fludarabine, cyclophosphamide, rituximab) (category1) FR (fludrabine , rituximab) PCR (pentostatin, cyclophosphamide, rituximab) Bendamustine +/- rituximab Ibrutinib

8. Continued- Therapy in Relapsed/Refractory CLL (in order of preference) Age >65yrs and younger patients with significant comorbidities Age < 65yrs without significant comorbidities Ibrutinib (category1) Idelalisib +rituximab (category1) Idelalisib Venetoclax Chemoimmunotherapy - bendamustine +/- rituximab - Reduced dose FCR - Reduced dose PCR - HDMP + rituximab - Rituximab + chlorambucil Ofatumumab Obinutuzumab Lenalidomide+/- rituximab Alemtuzumab +/- rituximab Ibrutinib (category1) Idelalisib +rituximab (category1) Idelalisib Venetoclax Chemoimmunotherapy - FCR - FC + Ofatumumab - PCR - Bendamustine +/- rituximab - RCHOP Ofatumumab Obinutuzumab Lenalidomide +/- rituximab Alemtuzumab +/- rituximab NCCN Guidelines, 1.2017 Version

9. VENETOCLAX – MECHANISM OF ACTION . Venetoclax highly selective,orally available, small-molecule BCL2 family protein inhibitor act independently of TP53, leading to programmed cell death of CLL cells. CLL cells pathologically overexpressed high levels of Bcl-2(anti-apoptotic protein , a key regulator of intrinsic apoptotic pathway) pre-bound to pro-death proteins such as Bim, thus priming these cells for death such that treatment with a BH3 mimetic like venetoclax will rapidly drive them into apoptosis .

10. Studies on Venetoclax- 1. Semyour JF et al study- A Phase 1b study to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax plus rituximab in 49 patients with relapsed/ refractory CLL started in 2012. Result- Grade 3-4 adverse events occurred in 76% of patients; most common were related to bone marrow supression. Clinical TLS (tumor lysis syndrome) occurred in two patients. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study . Lancet Oncol. 2017 Feb;18(2):230-240 . 2. Stilgenbauer S et al study - A open label Phase 2 study evaluating the efficacy and safety of venetoclax in 107 patients with relapsed or refractory CLL with 17p deletion started in 2013. Result- at a median follow-up period of 12.1 mnth, ORR was 79.4 % , PFS was 72% and over all survival was 86.7% . The most common grade 3-4 adverse events were related to bone marrow suppression. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukemia with 17p deletion: a multicenter, open-label, phase 2 study. Lancet Oncol 2016;17:768–778. 3. Jones J et al study- A open-label, Phase 2 study evaluating the efficacy and safety of venetoclax in 120 patients with relapsed or refractory CLL who have failed to respond or are intolerant to ibrutinib or idelalisib started in 2014. Result- objective response rate (ORR) in patients with prior treatment with ibrutinib or idelalisib was 70% and 48% respectively. Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib [abstract]. Blood 2016;128:Abstract 637.

11. STUDY DESIGN - Interventional study ( clinical trial) - Phase 3 - Open label - Multi- centre - Randomized 389 patients were enrolled for randomization from march 31,2014 to September 23,2015 (20 months). Primary analysis was done on 8 may, 2017.

12. OBJECTIVES - 1. Efficacy objectives - The primary efficacy objective for this study is :- To evaluate the efficacy of Venetoclax plus Rituximab(VR) compared with Bendamustine plus Rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) as measured by progression-free survival (PFS) (which was defined as the time from randomization to the first occurrence of disease progression or relapse or death from any cause whichever occurred first).

13. Secondary efficacy objectives - To analyze PFS in the subset of CLL patients with 17p deletion identified by fluorescence in situ hybridization (FISH) testing performed at a central laboratory. To evaluate overall survival (OS) , defined as the time from randomization to death from any cause . To evaluate rates of overall response (OR); defined as complete response [CR], Cri [complete response with incomplete marrow recovery], and PR [partial response]), PR, and CR and CRi at 12 weeks after Day 1 of the last cycle of multi-agent therapy. To evaluate duration of response (DOR) , defined for patients with a best OR of CR, Cri, or PR as the time from first occurrence of a documented CR or PR to disease progression / relapse or death from any cause. To evaluate time to next anti-CLL treatment (TTNT), defined as the time from randomization to start of new non-protocol anti- CLL therapy or death from any cause.

14. Continued as- To evaluate the proportion of patients with minimal residual disease (MRD-to below the threshold of 1 tumor cell per 10000 white cells)-negativity at the disease response assessment time points as measured at a central laboratory by PCR or flow cytometry performed on peripheral blood and/or BM samples. 2. Safety Objectives- Incidence , nature, and severity of adverse events (AEs) and serious adverse events (SAEs). Incidence of AEs of special interest : grade >3 TLS (tumor lysis syndrome) and IRRs (infusion related reactions).

15. INCLUSION CRITERIA - 1 . Age ≥ 18 years. 2 . Patients must meet the following criteria for relapsed or refractory CLL (per the iwCLL guidelines [Hallek et al. 2008] that require therapy • Relapsed disease: a patient who previously achieved a CR or PR, but after a period of 6 months or more demonstrates evidence of progression; • Refractory disease: treatment failure or disease progression within 6 months of the last anti-leukemia therapy. 3 . Previously treated with at least one but not more than three lines of therapy (a line of therapy is defined as completing at least two cycles of treatment for a given line of therapy), including at least one prior standard chemotherapy-containing regimen according to current guidelines. 4 . Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 1. 5 . Patients previously treated with bendamustine only if their duration of response was ≥ 24 months.

16. CONTINUED- 6. Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows: - • platelet count ≥ 75, 000/mm3. • absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement of CLL; • total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening). 7 . Adequate renal and hepatic function, per laboratory reference range at screening as follows: - • Calculated creatinine clearance ≥ 50 mL/ min . • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN) of the institution's normal range; • bilirubin ≤ 1.5 × ULN. • prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution’s normal range.

17. EXCLUSION CRITERIA - Transformation of CLL to aggressive NHL (eg, Richter’s transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL. 2. Undergone an allogeneic stem cell transplant. 3. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia. History of intolerance to prior bendamustine treatment (defined as toxicity requiring permanent discontinuation of bendamustine) or other contraindication to bendamustine treatment. History of severe (ie, requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab 6. Known HIV-positivity. 7. Positive hepatitis serology (serology testing required at screening), 8. History of prior venetoclax treatment A significant history of renal, neurologic, psychiatric,endocrine,metabolic,immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient’s participation in this study or interpretation of study outcomes. 10. A female patient who is pregnant or breast-feeding.

18. INTERVENTION - 389 patients were randomly assigned, in a 1:1 ratio, to receive venetoclax plus rituximab or bendamustine plus rituximab. Randomization was stratified according to the presence or absence of chromosome 17p deletion, responsiveness to previous therapy , and geographic region. ARM – A (VR GROUP) Venetoclax was administered according to a 5-week schedule of a gradual increase in the dose (ramp-up) from 20 mg per day to 400 mg per day; prophylactic and monitoring measures were instituted to mitigate the potential for development of the tumor lysis syndrome. After completion of the dose ramp-up period for venetoclax, administration of rituximab (375 mg per square meter of body-surface area intravenously for the first dose [day 1 of cycle 1] and 500 mg per square meter intravenously thereafter [day 1 of cycles 2 through 6]) was initiated in 28-day treatment cycles, while daily administration of venetoclax was continued for 2 years (which was calculated from day 1 of cycle 1) unless disease progression or unacceptable toxic effects occurred sooner. ARM –B (BR GROUP) Bendamustine at a dose of 70 mg per square meter was administered intravenously on days 1 and 2 of each 28-day cycle for six cycles in combination with rituximab according to the aforementioned dosing schedule.

19. Randomization, Treatment and Follow-up

20. Continued-

21. PRIMARY EFFICACY OUTCOME The 2 – year rate of PFS were 84.9% in the venetoclax – rituximab group and 36.3% in the bendamustine-rituximab group (hazard ratio for progression or death,0.17; 95%CI,(0.11 to 0.25); P<0.001 by the stratified log- rank test). In the venetoclax – rituximab group ,32 events of progression or death in 194 patients and in the bendamustine – rituximab group ,114 events in 195 patients.

22. SECONDARY EFFICACY OUTCOMES-

23. OTHER SECONDARY EFFICACY OUTCOMES- SECONDARY EFFICACY OUTCOMES VENETOCLAX- RITUXIMAB GROUP BENDAMUSTINE-RITUXIMAB GROUP HAZARD RATIO and 95% CI 1. 2year rate of progression free survival(PFS) in 17 p deletion chromosome patients. Present Absent 81.5% 85.9% 27.8% 41.0% 0.13; 95%CI (0.05 to 0.29) 0.19; 95%CI (0.12 to 0.32) 2. Rate of over all survival(OS) at 2 years 91.9% 86.6% 0.48;95% CI (0.25 to 0.90) 3. Event free survival(EFS) at 2 years 84.9% 34.8% 0.17; 95%CI( 0.11 to 0.25) 4. Time to next treatment for CLL at 2 years 90.0% (not received) 52.1%( not received) 0.19;95% CI (0.12 to 0.31)

24. Prespecified Subgroup Analysis of Progression Free Survival

25. ADVERSE EVENTS -

26. DISCUSSION The primary analysis of the trial of venetoclax plus rituximab in relapsed or refractory CLL showed a significantly higher rate of progression-free survival with venetoclax plus rituximab than with a standard chemoimmunotherapy, with benefit observed in all subgroups analyzed. Prespecified secondary efficacy measures, including the complete response rate, the overall response rate, and overall survival, also showed consistent patterns of clinically meaningful benefit with venetoclax plus rituximab, with substantial rates of clearance of minimal residual disease. The high rate of clearance of minimal residual disease that were observed in the venetoclax–rituximab group exceed those previously attained with other agents and combinations of agents in trials of relapsed or refractory chronic lymphocytic leukemia , findings that suggest that greater efficacy results can be attained by replacing chemotherapy with venetoclax than by adding other targeted agents to chemoimmunotherapy.

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