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Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax
Anderson, Mary Ann Tam, Constantine Lew, Thomas E. Juneja, Surender Juneja, Manu Westerman, David Wall, Meaghan Lade, Stephen Gorelik, Alex Huang, David C. S.
Anderson, Mary Ann
Tam, Constantine
Lew, Thomas E.
Juneja, Surender
Juneja, Manu
Westerman, David
Wall, Meaghan
Lade, Stephen
Gorelik, Alex
Huang, David C. S.
Abstract
The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not (P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy.
Keywords
Clinical Trials and Observations, Free Research Articles, Lymphoid Neoplasia
Date
2017
Type
Journal article
Journal
Blood
Book
Volume
129
Issue
25
Page Range
3362-3370
Article Number
ACU Department
Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled