Kaitlin Kennard

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Abstract Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; P = .7) and HR 1.2 (95% CI, 0.6-2.3; P = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; P = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; P = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.

Abstract Introduction: Preclinical data suggest that PD-1 and PD-L1/PD-L2 mediate immune evasion in CLL. However, clinical data (Ding, BLOOD 2017) demonstrate that pembrolizumab monotherapy (pembro) is ineffective in relapsed/refractory (r/r) CLL patients (pts) (ORR 0%, med PFS 2.4 months). Additional data with an anti-PD1 demonstrated a 90% failure rate in Richter's Transformation (RT) with a med 2-month OS (Rogers, BJH 2018). Combinations may represent the future of anti-PD-1 therapy in CLL/RT, especially in RT pts rel/ref to ibrutinib, where median OS is ~3.5 mos. We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (UMB), is a highly-specific PI3K-δ inhibitor with additional effects on casein kinase-1 epsilon (CK-1ε), which may have an inhibitory effect on Treg function (Deng et al, 2016). We tested the safety and activity of UMB in combination with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported combination of a PD-1 inhibitor + PI3K-δ inhibitor in this population. Methods: Ph I (3+3 design), multicenter study to assess the safety/efficacy of UMB + UTX + pembro in pts with r/r CLL and RT. Treatment for CLL pts involved three stages: Induction: UMB (800mg daily) and UTX (900mg 3 out of 4 wks) for the first two 28-day cycles. Consolidation: Pembro (dose level 1=100mg, dose level 2=200mg) was then initiated every 3 wks in combination with UMB and UTX (900mg week 2 of cycle 4 and 6) for cycles 3-6. Maintenance: Cycle > 6, UMB 800 mg daily until progressive disease (PD) or unacceptable AE. For RT pts, all study drugs are started in cycle 1 with the following schedule: UMB 800 mg daily; UTX 900 mg cycle 1 (D1, 8, 15), D1 cycles 2-4, cycle 7 and q3 cycles thereafter; and pembro D3 of cycle 1 and D2 of cycles 2-4. The primary endpoint is safety of the triple combination with efficacy as a secondary endpoint. Response assessments for CLL, based on the iwCLL 2008 criteria, were performed after cycles 2, 6 and 12. RT response assessments (Cheson 2007) were completed at the end of cycles 2, 4 and every 3 cycles until month 12. Peripheral blood and/or bone marrow biopsy, enriched for mononuclear cells, were obtained for correlative analyses at screening, month 2 and 6. Results: Fourteen pts have been treated to date: 9 with CLL (3 at 100 mg pembro / 6 at 200 mg pembro) and 5 with RT (4 at 100 mg pembro / 1 at 200 mg). Baseline demographics were as follows: male/female (9/5), med age 71 yrs (range 60-81), med prior therapies 2 (1-8), 79% were refractory to immediate prior therapy. 10 pts had prior ibrutinib of which 9 were ibrutinib refractory. 64% of pts had at least 1 high risk genetic feature (del17p, del11q, TP53 mut, NOTCH1 mut or complex karyotype). AE's (all causality) were manageable. Grade 3/4 AE's occurring in ≥ 3 pts included neutropenia (n=6, 43%), ALT/AST increase (n=3, 21%) and hypophosphatemia (n=3, 21%). One DLT occurred in a CLL pt at 200 mg dose level (ALT/AST elevation) which trigged expansion to 6 pts. No additional DLTs were reported, and no MTD was achieved. No increase in expected grade ≥ 3 PI3Kδ-associated toxicities were noted (1 pneumonitis event, no colitis events). ORR was 89% for CLL pts with ORR of 75% in BTK refractory CLL pts (3/4). Notably 2/4 BTK refractory CLL pts achieved a response to UMB + UTX (U2) induction alone prior to the addition of pembro. 4/5 RT pts were eligible for efficacy evaluation with 50% ORR (2/4, CR). The 2 RT CRs were durable and are ongoing (15+ mos and 7+ mos); both pts were ibrutinib refractory and had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. With a med follow up of 15 mos, 10/14 (71%) remain progression free (range 3 - 44 mos, Fig 1), including one CLL pt who completed consolidation and has been off therapy for 27+ mos. Sequential sampling for correlative studies demonstrated modest changes in Tregs numbers (Fig 2). Conclusion: The triplet combination of umbralisib + ublituximab + pembro was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CR's in RT pts. In contrast to pembro monotherapy, data suggest that CLL/RT pts who achieve ≥ PR with this checkpoint inhibitor-containing regimen can achieve durable responses. Correlative studies suggest that maintenance of Tregs may limit autoimmune sequelae. Enrollment is ongoing in both the CLL (BTK refractory only) and RT cohorts. Disclosures Mato: AbbVie: Consultancy, Research Funding; Portola: Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria. Svoboda:Regeneron: Research Funding; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding. Becker:GlycoMimetics: Research Funding. Brander:DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Dwivedy Nasta:Aileron: Research Funding; Pharmacyclics: Research Funding; Debiopharm: Research Funding; Incyte: Research Funding; Rafael/WF: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Kennard:AbbVie, Gilead, Verastem: Consultancy. Zelenetz:Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Purdom:TG Therapeutics: Employment, Equity Ownership. Paskalis:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy.