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

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Citation: Annals of Oncology. 28(5):1050-1056, 2017 May 01PMID: 28453705Institution: MedStar Washington Hospital CenterDepartment: Hematology/OncologyForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] | *Leukemia, Lymphocytic, Chronic, B-Cell/dt [Drug Therapy] | Adult | Aged | Aged, 80 and over | Bridged Bicyclo Compounds, Heterocyclic/ad [Administration & Dosage] | Disease-Free Survival | Drug Administration Schedule | Humans | Kaplan-Meier Estimate | Leukemia, Lymphocytic, Chronic, B-Cell/mo [Mortality] | Middle Aged | Proportional Hazards Models | Purines/ad [Administration & Dosage] | Pyrazoles/ad [Administration & Dosage] | Pyrimidines/ad [Administration & Dosage] | Quinazolinones/ad [Administration & Dosage] | Retrospective Studies | Sulfonamides/ad [Administration & Dosage] | Treatment Outcome | Young AdultYear: 2017 ISSN:

0923-7534

Name of journal: Annals of oncology : official journal of the European Society for Medical OncologyAbstract: Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).All authors: Barr PM, Brander DM, Cheson BD, Claxton DF, Cruz AL, Daniel C, Fanning M, Foon K, Gashonia L, Goy A, Henick Bachow S, Hill BT, Howlett C, Isaac K, Kennard KH, Kiselev P, Lamanna N, Lenhart J, Mato AR, Nabhan C, Pu JJ, Schuster SJ, Skarbnik AP, Svoboda J, Timlin C, Ujjani CS, Winter AM, Yacur M, Zent CSFiscal year: FY2017Digital Object Identifier:

https://dx.doi.org/10.1093/annonc/mdx031

Date added to catalog: 2017-05-08

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Title notes ( 5 )

Holdings
Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	28453705	Available		28453705

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.

Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).

Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).

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