Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States

Abstract

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.

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post‐BCRinhibitor setting: aUKwide analysis

“…Our data provide the first evidence in the non‐trial setting of equivalent efficacy and survival in patients exposed to BTKi, PI3Ki or both classes of BCRi. Notably, and by contrast to recently published US RWD (Mato et al , 2018b), we did not find significant differences in response or survival outcomes according to TP53 status. Consistent with a pooled analysis of 3 clinical trials of venetoclax monotherapy (Wierda et al , 2017b), we demonstrate that more heavily pre‐treated patients had an inferior PFS, although significance was not retained as an independent predictive factor in a multivariable analysis.…”

“…By contrast to published non‐clinical trial BCRi data, where toxicity was the most common reason for BCRi discontinuation (followed by CLL PD (Mato et al , 2018a)), PD was the commonest reason for venetoclax discontinuation. These data are strikingly similar to results reported by Mato et al (2018b) (22/45 PD [CLL and RT] and 7/45 toxicity in the present UK series; 22/41 PD [CLL and RT] and 9/41 toxicity in the US series).…”

“…The vast majority were BCRi exposed and almost half had evidence of TP53 ‐disruption. Our dataset clearly demonstrates the efficacy of venetoclax monotherapy in routine practice for patients across a large and representative range of academic and non‐academic centres with R/R, high‐risk CLL with ORR, DOR and PFS comparable to clinical trial cohorts (Stilgenbauer et al , ; Jones et al , ; Coutre et al , ) and recently published US RWD (for example, 1‐year PFS 65% compared to 1‐year PFS 68% in US RWD)(Mato et al , 2018b). Our data provide the first evidence in the non‐trial setting of equivalent efficacy and survival in patients exposed to BTKi, PI3Ki or both classes of BCRi.…”

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia

“…Recent large retrospective, multicentre series (Mato et al, ; Eyre et al, ) have demonstrated reassuringly similar efficacy and survival to trial outcomes. A toxicity analysis [including rates of tumour lysis syndrome (TLS), dose interruptions and discontinuations] has been assessed in a recent all‐age cohort (Roeker et al, ) but the specific question of efficacy and tolerability in elderly non‐trial patients has not been specifically addressed.…”

Is venetoclax a new wonder drug in CLL?

“…Also, given the potency of venetoclax, with its ability to cause TLS, it is perhaps surprising and very reassuring that real‐world clinicians are able to replicate the response rates and clinical benefits achieved in clinical trials using an agent which many would regard as less than easy to deliver. A similar real‐world study from the USA revealed a rather disappointing ORR of 72% but follow‐up was very short at only 7 months and results may improve (Mato et al , ). Also, 29% of patients stopped the venetoclax therapy in the USA study (Mato et al , ) compared to only 8% in the study reported by Eyre et al ().…”