Highlights in chronic lymphocytic leukemia

Congress Highlights CLL Highlights in chronic lymphocytic leukemia A. Janssens, MD, PhD 1 As new data on indolent non-hodgkin lymphoma (inhl) were not that compelling, only highlights on chronic lymphocytic leukemia (CLL) will be presented in the following summary. The recently published updated BHS guidelines for the treatment of CLL, anno 2016, incorporated obinutuzumab, ibrutinib and idelalisib. Results of multiple plase 3 trials were presented at ASH 2015 and will probably challenge the proposed guidelines in the near future. 1 (Belg J Hematol 2016;7(1):3-8) Adding idelalisib to bendamustine/ rituximab delays progression and prolongs survival in relapsed/ refractory CLL Idelalisib is a first-in-class targeted PI3k-delta inhibitor approved, in combination with rituximab, for the treatment of patients with relapsed/refractory (R/R) CLL and as first-line treatment for patients with a 17p deletion or a TP53 mutation that are unsuitable for chemo-immunotherapy (CIT). The results of a randomized, placebo-controlled phase 3 study evaluating the efficacy of idelalisib added to bendamustine-rituximab (BR), a common CIT regimen for R/R CLL, were communicated as a late breaking abstract. The independent review committee (IRC) recommended unblinding the study based on overwhelming efficacy. In total, 416 patients were randomized to BR for 6 cycles and idelalisib 150mg BID or placebo continuously. Treatment with idelalisib or placebo was administered until disease progression (PD), death, intolerable toxicity, or withdrawal of consent. Crossover was not permitted at the time of PD. The interim analysis demonstrated that progression free survival (PFS) (23 vs. 11 months (HR: 0.33, p<0.0001)) (Figure 1), the primary endpoint, and overall survival (OS) (not reached for either arm (HR: 0.55, p=0.008)), a secondary endpoint, were superior in the investigational vs. control arm. The most common grades 3 AEs with idelalisib + BR were neutropenia (60%) and febrile neutropenia (20%) and were neutropenia (46%), anemia and thrombocytopenia (both 12%) with BR + placebo. 2 Treatment with idelalisib added to BR was superior to BR in terms of PFS, OS and overall response rate (ORR) in R/R CLL with a 67% and 45% reduction in the risk of progression and death, without new safety signals seen with the combination. Idelalisib added to BR could be a new treatment option for patients with R/R CLL. 2 Ibrutinib as initial therapy for patients with CLL Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton s tyrosine kinase approved for patiens with R/R CLL and 17p deleted CLL patients (including first-line). Ibrutinib also showed high activity in treatment-naïve patients age 65 years. A randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibrutinib (420mg daily until progression) vs. chlorambucil (clb) (0.5mg/kg (up to 0.8mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles) in treatment-naïve patients (N=269) without 17p deletion, aged 65 years with CLL/SLL has been conducted. Patients with IRC-confirmed progres- 1 Department of Hematology, UZ Leuven. Please send all correspondence to: Ann Janssens, MD, PhD, Department of Hematology, UZ Leuven, Herestraat 49, 3000 Leuven, Tel: +32 (0)16 346862, E-mail: ann.janssens@uzleuven.be Conflict of interest: The author has nothing to disclose and indicated no potential conflict of interest. 3

1 Special Edition sion could be treated with ibrutinib in an extension study. At a median follow-up of 18.4 months, ibrutinib significantly prolonged PFS, the primary endpoint, vs. clb (median not reached vs. 18.9 months; HR: 0.16, p<0.0001). This was consistent within subgroups including age 70 years, 11q deletion, and unmutated IGV H. Ibrutinib also significantly prolonged OS, a secondary endpoint vs. clb (median not reached for either arm; HR: 0.16, p=0.0010). The most frequent AEs with ibrutinib included diarrhea, fatigue, cough and nausea, while the most frequent AEs with clb were nausea, fatigue, neutropenia, anemia and vomiting. AEs leading to treatment discontinuation were less frequent with ibrutinib (9% vs. 23%). Atrial fibrillation (AF) occurred in 6% with ibrutinib and 1% with clb. Hypertension was noted more frequently on ibrutinib and managed without ibrutinib dose modification or discontinuation. Major hemorrhage occurred in 4% with ibrutinib over a median follow-up of approximately 1.5 years, and in 2% with clb. At the time of study closure, 87% of patients randomized to ibrutinib continue to receive ibrutinib. 3 Treatment with single-agent ibrutinib was superior to clb in terms of PFS, OS, ORR, and hematologic improvement in treatment-naïve older CLL/SLL patients, with an 84% reduction in risk of progression and death, and an acceptable safety profile. 3 Improved quality of response by adding ibrutinib to bendamustine/rituximab in previously treated CLL/SLL patients Recent results from the HELIOS phase 3 study in R/R CLL/SLL (N=578) patients demonstrated that the addition of ibrutinib to BR leads to an 80% and 45% reduction in risk of progression and death as compared to placebo + BR. 4 ORR and rates of complete response (CR) or CR with incomplete marrow recovery (CRi) were significantly improved with ibrutinib + BR (ORR: 82.7% vs. 67.8%; CR/CRi: 10.4% vs. 2.8%). Additional analyses on the quality of response with ibrutinib combined with BR were reported. Minimal residual disease (MRD) was assessed by flow cytometry using an 8-color panel. IRC assessed as complete resolution of lymph nodes (34.6% vs. 15.2%), spleen (56.7% vs. 37.0%), overall radiology (21.1% vs. 9.0%), and bone marrow (19.7% vs. 5.9%) was more frequently achieved in the ibrutinib + BR arm in comparison with placebo + BR. MRD was assessed in 120 patients treated with ibrutinib + BR and 57 patients treated with placebo + BR and was negative in 37 and 14 patients, respectively, which corresponds with an MRD-negative response rate of 12.8% vs. 4.8% for ibrutinib + BR vs. placebo + BR (p=0.0011). The percentage of patients with an MRD level < 1% was higher with ibrutinib + BR vs. placebo + BR (32.2% vs. 11.8%). Moreover, the percentage of patients with an MRD level <0.1% was higher for ibrutinib + BR vs placebo + BR (24.6% vs. 7.6%) suggesting that the depth of response with ibrutinib + BR was superior. Kaplan-Meier plots by MRD level show that a lower MRD level was associated with a longer PFS. However, patients in the ibrutinib + BR arm had a more sustained response at every MRD level compared with patients in the placebo + BR arm. 5 Patients treated with ibrutinib + BR showed a greater depth of response, with more CRs and a higher rate of resolution of lymph nodes, spleen, and bone marrow involvement. Furthermore, the rate and depth of MRD negativity was improved, and appeared to last longer in patients treated with ibrutinib + BR as compared to patients receiving placebo + BR. 5 Impact of high-risk prognostic parameters on the outcome of ibrutinib plus bendamustine/rituximab in relapsed CLL/SLL The presented analysis reported on the efficacy of ibrutinib + BR vs. placebo + BR in patients in the HELIOS trial with relevant high-risk biomarkers. Subgroups of patients with 11q deletion, complex karyotype, unmutated IGV H and elevated ZAP70 levels, had a significantly longer PFS with the addition of ibrutinib to BR as compared with placebo + BR. As expected, each of these adverse prognostic parameters had a negative impact on PFS in the placebo + BR arm. The median PFS was shortest in patients with a complex karyotype (8.5 vs. 13.8 months in patients without complex karyotype) and in patients with unmutated IGV H (11.3 vs. 22.1 months in patients with mutated IGV H ). Interestingly, in the ibrutinib + BR arm, the adverse impact of these risk factors could not be detected (median PFS 4

Congress Highlights CLL Probability of PFS (%) 100 80 60 40 20 Median PFS (mo) HR (95% CI) p-value IDELA + BR BR + Placebo 23.1 11.1 0.33 (0.24, 0.45) <0.0001 Median follow-up time = 12 months 0 0 6 12 18 24 30 No. at risk (events) Time (months) IDELA + BR 207 (0) 154 (25) 74 (51) 27 (61) 6 (63) 1 (643) BR + Placebo 209 (0) 145 (46) 36 (111) 11 (126) 1 (131) 0 (132) HR, hazard ratio; IRC, independent review committee. Figure 1. Adding idelalisib to bendamustine-rituximab significantly improves progression-free survival. 2 not reached irrespective of the presence of risk factors). In patients with an 11q deletion, unmutated IGV H, or elevated ZAP70, there were also statistically significant benefits in OS for those receiving ibrutinib + BR vs. placebo + BR (11q deletion: HR: 0.326, p=0.025; unmutated IGV H : HR: 0.515, p=0.017; elevated ZAP70, HR 0.536, p=0.048). Addition of ibrutinib also increased PFS in patient subgroups with other cytogenetic or clinical prognostic markers (such as del13q or bulky disease) compared with placebo. 6 All subgroups of patients, irrespective of adverse risk factors, such as 11q deletion, complex karyotype, elevated ZAP70, and unmutated IGV H, benefit from the addition of ibrutinib to BR as compared to placebo + BR. The negative impact of these known risk factors is not seen in the ibrutinib + BR arm. These results suggest that ibrutinib + BR is a suitable treatment regimen for all patients with previously treated CLL/SLL, including those with high-risk prognostic markers. 6 Management of adverse events to ibrutinib + BR in patients with previously treated CLL/SLL The safety and management of AEs with ibrutinib + BR vs. placebo + BR in HELIOS were also examined. Rates of infection in the ibrutinib + BR and placebo + BR arms were similar (all-grade, 70.4%; grade 3, 26.8% vs. all-grade, 70.0%; grade 3, 22.6%, respectively). Rates of all-grade anemia were 22.3% with ibrutinib + BR and 28.9% with placebo + BR. Patients also required fewer transfusions with ibrutinib + BR. Similar proportions of patients used growth factors in both arms (54% vs. 52%, respectively). Grade 3/4 neutropenia was reported at similar rates in both arms (53.7% vs. 50.5%, respectively). Rates of thrombocytopenia were slightly higher with ibrutinib + BR (30.7%) than placebo + BR (24.0%), but rates of grade 3/4 events were similar between arms (15.0% each arm). AF was observed more frequently in patients on ibrutinib + BR than placebo + BR (7.3% vs. 2.8%). Importantly, in those with a prior history of AF or abnormal heart rhythm, 7/25 receiving ibrutinib + BR and 2/22 receiving placebo + BR developed AF/atrial flutter on 5

1 Special Edition study. The rates of any-grade bleeding were 31.0% and 14.6%, respectively, with the majority being grade 1. Many patients (41.8% ibrutinib + BR, 41.1% placebo + BR) were receiving concomitant anticoagulant/antiplatelet medication. A low rate of treatment-related lymphocytosis was observed in both arms (7.0% ibrutinib + BR, 5.9% placebo + BR). The majority of cases resolved within 2 weeks. 7 The addition of ibrutinib to BR was well tolerated and did not significantly impact the safety profile of BR. In addition, ibrutinib was associated with reduced rates of anemia and transfusional support. Consistent with its known toxicity profile, patients in the ibrutinib + BR arm had higher rates of bleeding (mostly grade 1 or 2) and AF; however, few patients discontinued therapy as a result of these AEs. Taken together, the results from HELIOS establish the significant efficacy of ibrutinib and also the overall positive risk-benefit profile of ibrutinib + BR. 7 The adjusted indirect comparisons suggest superiority of single-agent ibrutinib over BR for PFS and OS in patients with R/R CLL/SLL. This comparison also suggest that the addition of BR to ibrutinib did not improve PFS or OS compared with single-agent ibrutinib. Longer follow-up in the ibrutinib arms of these studies will be required to give an indication of whether CIT adds any benefit to ibrutinib for PFS and OS. Overall, these findings provide support for single-agent ibrutinib as an appropriate choice for all patients with R/R CLL/SLL. 8 Indirect comparison of single-agent ibrutinib vs. BR or ibrutinib + BR in patients with R/R CLL/SLL. In two large phase 3 trials of patients with R/R CLL/SLL, single-agent ibrutinib was superior to ofatumumab and ibrutinib + BR was superior to placebo + BR (HELIOS). In the absence of head-to-head evaluations of singleagent ibrutinib vs. BR or ibrutinib + BR, indirect comparisons can provide insights on the relative efficacy of both treatments. As such, an indirect comparative analysis of data from RESONATE and HELIOS was performed. In the overall CLL/SLL and CLL only population, the PFS (Figure 2) and OS were comparable for single-agent ibrutinib vs. ibrutinib + BR, and were significantly improved for single-agent ibrutinib vs. BR. Singleagent ibrutinib reduced the risk of progression/death by 87% vs. BR and the risk of death by 55% vs. BR. 8 Favorable outcomes in CLL patients with alternate kinase inhibitors following ibrutinib or idelalisib discontinuation There are limited data regarding real world practice patterns of BCRi discontinuation and response to subsequent therapies. Two centers reported an extremely poor prognosis for patients failing ibrutinib. For patients failing idelalisib, no data are available. Ten large American cancer centers collaborated to capture the experience of 178 CLL patients who discontinued ibrutinib (N=143) or idelalisib-based (N=35) regimens focusing on reasons for discontinuation and response to subsequent BCRi therapies. The most common reasons for BCRi discontinuation were toxicity (51% ibrutinib, 52% idelalisib), CLL progression (28% ibrutinib, 31% idelalisib), and Richter transformation (RT) DLBCL (8% ibrutinib, 6% idelalisib). The most common toxicities leading to ibrutinib discontinuation were AF, infection, hematologic toxicity, bleeding and pneumonitis. Pneumonitis, colitis, rash and transaminitis were the idelalisib toxicities leading to discontinuation. At the time of analysis, 74 (41%) patients following BCRi discontinuation received a first salvage regimen (CIT, ibrutinib or idelalisib-based, anti-cd20 monoclonal antibody, BCL2-inhibitor, cellular therapy, experimental BCRi, IMID or other treatment). In evaluable patients, the ORR to non-bcri therapies was 40%. ORR to idelalisib-based therapy following ibrutinib discontinuation was 50%, while the ORR to ibrutinibbased therapy following idelalisib discontinuation was 77%. Responses to alternate BCRi were similar in patients who discontinued BCRi for toxicity and progression. However, the PFS seems shorter for those patients who changed the BCRi due to progressive disease. 9 The major reason for BCRi discontinuation is toxicity. Treatment with an alternate BCRi therapy is efficacious in >50% of patients. Non-overlapping toxicity profiles permit utilization of alternate BCRi following discontinuation due to toxicity. Mechanisms of BCRi resistance may not overlap and explain responses following discontinuation due to progression. 9 6

Congress Highlights CLL Pts still alive and not progressed (%) 100 90 80 70 60 50 40 30 20 10 0 0 Addition of BR to Ibr did not impact the risk of progression or death Single-agent Ibr significantly reduced the risk of progression or death by 85% vs BR 3 6 9 12 15 18 21 24 Months since baseline Ibr Ofa Ibr + BR BR Ibr (RESONATE, n=132) Ofa (RESONATE, n=132) Ibr + BR (HELIOS, n=287) BR (HELIOS, n=289) HR (95% CI) p Value 1-20.22 (12.80-31.94) < 0.0001 1.07 (0.65-1.76) 0.7808 6.84 (4.37-10.70) < 0.0001 Figure 2. Indirect comparison of PFS with ibrutinib monotherapy and ibrutinib in combination with bendamustine en rituximab. 8 Early activity of venetoclax monotherapy in patients with CLL relapsed after, or refractory to ibrutinib or idelalisib Venetoclax (ABT-199) is a selective, potent, oral BCL-2 inhibitor with a BCR and p53 independent mechanism of action and substantial activity in patients with heavily pretreated R/R CLL, including 17p deleted CLL. Preliminary results from an ongoing phase 2, open-label study evaluating venetoclax monotherapy in CLL patients R/R to ibrutinib or idelalisib has been reported. Patients with RT were ineligible. In total, 54 patients received venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of 400 mg. The primary objectives were to assess the efficacy and safety of venetoclax. In the ibrutinib arm, 61% achieved a response at the week 8 assessment and 50% achieved a response in the idelalisb arm. No new Venetoclax monotherapy demonstrated early activity in patients R/R to BCRi. Responses seem similar in patients who have discontinued BCRi for refractory disease or intolerance. Venetoclax monotherapy exhibited a tolerable safety profile without events of clinical TLS using the weekly ramp-up protocol. 10 safety signals for venetoclax were observed. The most important AEs (all grades) were neutropenia (57%), anemia (35%), diarrhea (32%) and nausea (32%). One patient with high disease burden developed laboratory tumor lysis syndrome (TLS) in week 4. No patient experienced clinical TLS. 10 High overall response rate and acceptable toxicity with venetoclax in R/R CLL A pivotal phase 2, single-arm, multicenter study evaluated venetoclax monotherapy in patients with R/R CLL with a 17p deletion (N=107) (>7% cells by Vysis FISH probe in peripheral blood). Patients were treated daily with 400 mg venetoclax until disease progression or discontinuation for another reason after the weekly ramp-up dosing. The IRC-assessed ORR was 79.4% including deep responses (7.5% CR/CRi and 2.8% npr). 45 patients had an MRD assessment. Notably, 18 patients (17% of whole cohort, 21% of responders) had no detectable MRD in the PB. Ten of these patients were also tested in BM and 6 were found to be MRD-negative. Median time-to-first response was 0.8 months and the median time to CR/CRi was 8.2 months. Overall median DoR, PFS, and OS were not reached. The actuarial 12-month PFS and OS rates were 72.0% and 86.7%, respectively. In total, 37 patients discontinued treatment: 7

1 Special Edition 22 due to PD (9 RT), 9 due to AE, 2 withdrew consent, 1 was non-compliant; and 3 patients proceeded to an allo-sct (2 PR, 1 CR by IRC at time of transplant). Treatment-emergent AEs (all grades) were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), and fatigue (22%). Laboratory TLS was reported in 5 patients; none had clinical consequences. 11 Venetoclax monotherapy achieved a high ORR and sustained remissions with acceptable toxicity in R/R CLL patients with 17p deletion. More than 10% of all patients achieved deep responses (CR, CRi, or npr). Undetectable MRD was observed in >20% of responders. Such depth of response has not yet been reported for this population. 11 References 1. Janssens A, Van den Neste E, Offner F, Bron D. Updated BHS guidelines for the treatment of CLL, anno 2016. Belg J Hematol 2015, 6, 195-202. 2. Zelenetz A, Robak T, Coiffier B, et al. Idelalisib plus bendamustine nd rituximab (BR) is superior to BR alone in patients with relapsed/refractory CLL: results of a phase 3 randomized double-blind placebo-controlled study. Blood 2015;126(23): Abstract LBA-5. 3. Burger J, Tedeschi A, Barr P, et al. Ibrutinib as initial therapy for patients with CLL. New Eng J Med, 2015, epub ahead of print. 4. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine and rituximab for previously treated CLL or SLL (HELIOS): a randomized, double-blind, phase 3 study. Lancet oncol, 2015, epub ahead of print. 5. Cramer P, Chanan-Khan A, Fraser G, et al. Improvement of quality of response with ibrutinib plus bendamustine/rituximab vs placebo plus bendamustine/rituximab for previously treated CLL/SLL. Blood 2015;126(23): Abstract 2937. 6. Chanan-Khan A, Cramer P, Fraser G, et al. Impact of high-risk prognostic parameters and addition of ibrutinib to bendamustine/rituximab on outcomes for patients with relapsed CLL/SLL from the phase 3 double-blind HELIOS trial. Blood 2015;126(23): Abstract 1732. 7. Chanan-Khan A, Cramer P, Fraser G, et al. Insights into the management of adverse events in patients with previously treated CLL/SLL: experience from the phase 3 Helios study of ibrutinib combined with bendamustine/rituximab. Blood 2015;126(23): Abstract 2936. 8. Hillmen P, Fraser G, Jones J, et al. Comparing single-agent ibrutinib, bendamutine+rituximab (BR) and ibrutinib+br in patients with previously treated CLL/SLL. An indirect comparison of the Resonate and Helios trials. Blood 2015;126(23): Abstract 2944. 9. Mato A, Barr P, Zent C, et al. Favorable outcomes in CLL patients with alternate kinase inhibitors following ibrutinib or idelalisib discontinuation: results from a large multi-center study Blood 2015;126(23): Abstract 719. 10. Jones J, Mato A, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with CLL relapsed after or refractory to ibrutinib or idelalisib therapy. Blood 2015;126(23): Abstract 715. 11. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase 2 study. Blood 2015; 126(23): Abstract LBA-6. 8