Journal
BLOOD
Volume 129, Issue 25, Pages 3362-3370Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-01-763003
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Funding
- AbbVie
- Genentech
- Australian National Health and Medical Research Council [1016647, 1016701, 9000220]
- Leukemia and Lymphoma Society (SCOR) [7001-13]
- Victorian Cancer Agency
- Cancer Council Victoria
- Australian Cancer Research Foundation
- Victorian State Government Operational Infrastructure Support grant
- Webster bequest
- Snowdome Foundation
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The BCL2 inhibitor venetoclax achieves responses in similar to 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.
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