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

Abstract

Key Points• Complex karyotype and fludarabine refractoriness are key risk factors for progression of CLL on venetoclax.• Bruton tyrosine kinase inhibitors are active in patients with CLL after prior therapy with venetoclax.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 5 .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 5 .002 and 6.6 [1.5-29.8]; P 5 .005, respectively), whereas del(17p) and/or TP53 mutation were not (P 5 .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. (Blood. 2017;129(25):3362-3370)

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States

“…reported that, in a group of heavily pretreated patients, 37% of patients progressed on venetoclax at a median follow up of 23 months, and that 8.2% of patients discontinued therapy due to other reasons with no patients discontinuing due to toxicity. 2 We also note these results differ from recent real world BCR inhibitor series where AEs were the most common reason for drug discontinuation, followed by CLL progression. 20 …”

“…Complex karyotype was not associated with inferior PFS, despite being shown to be a risk factor for progression in patients receiving venetoclax in a recent study by Anderson et al . 2 It is possible that our shorter follow up accounts for this discrepancy. Interestingly, del(11q) did not adversely affect PFS.…”

“…7–11 Furthermore, there is one study to date regarding strategies for early identification of high-risk patients, particularly those previously treated with kinase inhibitor based therapy, for progression on venetoclax and how treatment is selected after its discontinuation is selected. 2 …”

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

“…The mutation profile in patients with CLL is dynamic and complex and therefore it is of immense interest to understand the status of BTK mutations and mutational evolution patterns after discontinuation of BTKi therapy. Patients with disease progression often are treated with the Bcl‐2 inhibitor venetoclax . In the current study, we examined the mutation evolution in 3 patients with CLL with disease progression after discontinuation of BTKi therapy and treatment with venetoclax.…”

Richter transformation driven by Epstein–Barr virus reactivation during therapy‐related immunosuppression in chronic lymphocytic leukaemia

“…Whereas some in vitro studies have shown that EBV can transform CLL cells into an aggressive, clonally related DLBCL [27][28][29], others have suggested that, in CLL patients, EBV can transform normal bystander B lymphocytes into clonally unrelated DLBCL, particularly in those receiving immunosuppressive fludarabine, alkylating agents, or the anti-CD52 antibody alemtuzumab [26,[30][31][32][33][34]. More recently, several studies have reported that CLL patients with early progression under therapy with the novel agents ibrutinib, idelalisib and venetoclax can develop aggressive transformation to DLBCL (including EBV + cases), suggesting that these drugs can increase the risk of RT by permitting viral reactivation during therapy-related immunosuppression [35][36][37][38][39][40][41][42]. Because of this potentially devastating consequence, the role of EBV in the development of currently incurable EBV + DLBCL in CLL patients warrants urgent investigation, with the aim of developing strategies to monitor and prevent transformation and to define effective therapies.…”