Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

Abstract

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10 was achieved in this high-risk population.

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

“…Interestingly, reflecting pre-clinical data showing a TP53-independent induced apoptosis of CLL cells [11], venetoclax then showed a potent activity in high-risk CLL harboring a 17p deletion in a phase II study [12], leading to US Food and Drug Agency (FDA) approval in this setting in 2016. The updated results of this study [13] showed an overall response rate (ORR) of 77% and minimal residual disease (MRD) negativity of 30% with a sensitivity of 10 −4 , in a population of CLL patients with 17p deletion, mostly in the relapse setting.…”

Real‐world testing and treatment patterns in chronic lymphocytic leukemia: A SEER patterns of care analysis

“…Because of the striking improvement in clinical outcomes among patients with del17p using ibrutinib and venetoclax, we expect that CLL FISH testing will continue to increase in the future. 20, 21 …”

“…Because of the striking improvements in clinical outcomes noted among patients with del17p treated with ibrutinib and venetoclax, we expect that FISH testing for CLL will continue to increase in the future. 20,21 In contrast, IgV H mutation analysis has remained prognostic and has not been incorporated into guideline treatment algorithms since 2009. Now that FCR also has been found to demonstrate a progression-free survival of >10 years in a sizeable percentage of patients with mutated IgV H status, 22,23 there may be an increase in the use of this test in the future.…”

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

“…Venetoclax (ABT-199/GDC-0199) is a potent, selective B-cell lymphoma-2 (BCL-2) inhibitor 8 that was first indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. 9,10 Venetoclax demonstrated modest single-agent activity in patients with relapsed or refractory AML 11 and synergistic activity with HMAs and LDAC in preclinical models of AML. 12 These findings prompted evaluation of venetoclax in combination with an HMA (azacitidine or decitabine; NCT02203773) or LDAC (NCT02287233) in patients 65 years of age or older newly diagnosed with AML and not eligible for standard induction therapy.…”