Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax

• Published in: Blood 2017-06, Vol.129 (25), p.3362-3370
• Main Authors: Anderson, Mary Ann, Tam, Constantine, Lew, Thomas E., Juneja, Surender, Juneja, Manu, Westerman, David, Wall, Meaghan, Lade, Stephen, Gorelik, Alexandra, Huang, David C.S., Seymour, John F., Roberts, Andrew W.
• Format: Article
• Language: English
• Subjects: Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Disease Progression; Female; Humans; Karyotype; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Retrospective Studies; Sulfonamides - therapeutic use; Treatment Outcome; Vidarabine - analogs & derivatives; Vidarabine - therapeutic use; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-01-763003

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 (