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One of the hallmarks of chronic lymphocytic leukemia (CLL) is the uncontrolled proliferation of B cells coupled with a failure of apoptosis due to overexpression of anti-apoptotic Bcl-2. Venetoclax-based therapies targeting the Bcl-2 pathway became a standard of care for patients with CLL.1-3 However, little is known about the optimal treatment regimen after discontinuation of venetoclax or the impact of venetoclax resistance on the efficacy of subsequent therapies. This is particularly important considering the early use of venetoclax-based therapies4 in the treatment of patients with CLL supported by the data from MURANO and CLL14 clinical trials.
Anthony R. Mato, Memorial Sloan Kettering Cancer Center, New York, US, and colleagues, aimed to address those knowledge gaps in a multicenter retrospective study of patients with CLL who had discontinued venetoclax and received subsequent therapy. The results were presented during the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, US.5 Here we provide a summary of the data reported at the meeting. Data presented at the ASH meeting may supersede the data in the published abstract.
Baseline characteristics |
Results |
Available data (n) |
---|---|---|
Age at CLL diagnosis, median (range), years |
58 (32–88) |
326 |
Age at venetoclax start, median (range), years |
66 (38 –91) |
324 |
Male, (%) |
69 |
326 |
White race, (%) |
87 |
325 |
CLL characteristics, (%) Rai stage ≥ 3 Del(17p) TP53 mutated TP53 disruption (del17p or TP53 mutated) Complex karyotype (≥ 3 abnormalities) NOTCH1 mutated IGHV non-mutated |
64 47 45 56 39 18 82 |
318 312 221 312 279 103 171 |
Therapy prior to venetoclax Lines of therapy, median (range) Prior ibrutinib (%) Prior BTKi (%) Prior idelalisib (%) |
3 (0–11) 60 61 19 |
326 324 324 324 |
Allo-HSCT, allogeneic hematopoietic stem cell transplantation |
|
Overall discontinuation rate, (%) |
100 |
Reasons for discontinuation, (%) CLL progression Adverse event Richter’s transformation Patient preference Planned allo-HSCT |
38 14 14 8 6 |
Following discontinuation Treatment with next line of therapy Alive and untreated Died prior to subsequent therapy |
58 19 23 |
acalabr, acalabrutinib; BTKi, Bruton tyrosine kinase inhibitor; CAR T-cell, chimeric antigen receptor T cell; CR, complete response; Nc BTKi, non-covalent BTKi; ORR, overall response rate; PD, progressive disease, PI3Ki, phosphoinositide 3-kinase inhibitor; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease; ven, venetoclax |
||||||
Post-ven |
BTKi |
PI3Ki |
CAR T- cell therapy |
Anti-CD20 antibody |
||
---|---|---|---|---|---|---|
Agent |
Ibrutinib |
Ibrutinib |
Ibrutinib |
Idelalisib |
Anti-CD19 |
Rituximab |
Prior exposure |
BTKi-naïve |
BTKi-exposed |
BTKi- exposed |
PI3Ki- |
BTKi-exposed |
– |
Number of patients |
44 |
20 |
10 |
17 |
18 |
19 |
ORR (%) CR PR PR-L SD PD |
83.9 9 56.8 18.1 11.6 4.5 |
53 6.6 26.4 20 20 27 |
70 20 30 20 – 30 |
46.9 5.9 35.2 5.8 23.7 29.4 |
66.6 33.3 33.3 0 5.7 27.7 |
32 16 16 0 32 37 |
The data support the early use of venetoclax in the course of CLL and demonstrate the importance of prior treatment exposure and reasons for discontinuation in decision making on the subsequent line of therapy. BTKi in patients who were BTKi-naïve or previously responsive and allo-HSCT were the most effective post-venetoclax treatments.
However, the author highlighted the limitations of the study, including a more heavily pretreated patient population, with a high number of patients who received venetoclax monotherapy, which might not be representative of patients seen in everyday clinical practice. As true venetoclax discontinuation might not have been captured and the relatively short follow-up, direct comparisons between therapies should not be made.
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