Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients

Mato, Anthony R.; Hill, Brian T.; Lamanna, Nicole; Barr, Paul M.; Ujjani, Chaitra S.; Brander, Danielle M.; Howlett, Christina; Skarbnik, Alan P; Cheson, Bruce D.; Zent, Clive S.; Pu, Jeffrey J.; Kiselev, Pavel; Foon, Kenneth A.; Lenhart, J.; Bachow, Spencer Henick; Winter, Allison M.; Cruz, Allan-Louie; Claxton, David F.; Goy, André; Daniel, Catherine; Isaac, Krista; Kennard, Kaitlin; Timlin, Colleen; Fanning, Molly; Gashonia, L.; Yacur, Melissa; Svoboda, Jakub; Schuster, Stephen J.; Nabhan, Chadi

doi:10.1093/annonc/mdx031

Cited by 192 publications

(206 citation statements)

References 28 publications

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“…Seven patients have received subsequent treatment, mostly chemoimmunotherapy (BR, FCR); 6 of those patients are still alive, with a median of 21 months of follow up. While retrospective analyses of real-world data have previously suggested that treatment with an alternate kinase inhibitor is more effective than chemoimmunotherapy following discontinuation of ibrutinib, 31,32 our data suggests that patients who discontinue ibrutinib can respond to chemoimmunotherapy as second-line therapy. Continued follow up of patients in the RESONATE-2 trial who have discontinued ibrutinib will provide the needed further data as relatively few patients have progressed or stopped therapy to date.…”

Section: Discussionmentioning

confidence: 61%

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2

et al. 2018

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Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs. 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346.

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Section: Discussionmentioning

confidence: 61%

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2

et al. 2018

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“…As we know from prior studies, outcomes can differ significantly in patients who discontinue a kinase inhibitor due to toxicity as compared to progression. 8 Future studies of venetoclax should consider stratifying patients by these subgroups. While we did include data from community practices, the fact that most patients were treated in academic centers could introduce a selection bias.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…In CLL, because of higher rates of toxicity with idelalisib when compared to ibrutinib, PI3K inhibition is best reserved for patients who have contraindications to the use of BTK inhibitors, are intolerant of BTK inhibitors, or have progressed on BTK inhibitors. We have relatively little data regarding the effectiveness of PI3K inhibitors specifically in such patients, but retrospective data do suggest activity particularly in the context of those who discontinue ibrutinib for adverse events [104]. In relapsed/refractory FL, idelalisib should be reserved until subjects have failed at least two prior lines of therapy.…”

Section: Expert Opinionmentioning

confidence: 99%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients

Cited by 192 publications

References 28 publications

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2

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

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

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