There is a need for treatment for patients with chronic lymphocytic leukemia who fail both Bruton tyrosine kinase inhibitors and B-cell lymphoma 2 inhibitors.

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Patients with chronic lymphocytic leukemia (CLL) who have been “double exposed” to both Bruton’s tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, constitute a difficult population to treat, with a generally poor prognosis. dark, according to the authors of a systematic study. review of the literature on the subject published in Cancer Medicine.¹ This is the first systematic review of its kind focused on this focus, they said.

Current evidence indicates that topirtobrutinib, lisocabtagene maraleucel, and ibrutinib/venetoclax combination treatments are potentially effective in dual-exposed patients. These clinical data are, however, very limited, note the authors.

“The treatment options available for patients failing BTKi and BCL2 inhibitors highlight a significant unmet need,” they emphasized, echoing previous researchers.^2.3 “Carefully designed clinical trials with balanced treatment groups should be ordered to better understand efficacy outcomes in doubly exposed patients. »

What the literature reveals

A comprehensive database search resulted in 13 publications based on 9 different studies: 5 single-arm clinical trials (all phase I or II) and 4 retrospective observational studies. Each clinical trial included between 4 and 100 patients (usually the double exposure cohort was a subgroup) and the observational studies each included between 11 and 125.

The authors reported their results organized according to the 9 treatment classes received by doubly exposed patients with CLL or small lymphocytic lymphoma. Overall poor prognoses exist regardless of the reasons for stopping venetoclax or BTKi, the authors said. They added that because the results they presented all came from single-arm studies or observational studies, the results could be confounded based on patient characteristics.

The 9 studies covered these treatments:

Non-covalent BTKi. A clinical trial each evaluated the efficacy of pirtobrutinib and nemtabrutinib, both non-covalent BTKi. With pirtobrutinib, after a median follow-up of 18.2 months, the median progression-free survival (PFS) of patients was 16.8 months. The overall response rate (ORR) was 70%. In the nemtabrutinib trial, at 8.1 months follow-up, the median PFS of patients was 10.1 months; the ORR was 58%.

Chimeric antigen receptor (CAR T) T cell therapy. Two clinical trials and 3 observational studies have evaluated the efficacy and effectiveness of CAR T in this population. In the first clinical trial evaluating lisocabtagene maraleucel, the ORR was 80% (complete response (CR), 60%; partial response (PR), 20%). At 11 months follow-up, the median PFS was 13 months. The results of the second clinical trial showed that the ORR of patients treated with anti-CD19 CAR T cells was 50% (all PR).

No survival results were reported in the 3 observational studies. Concerning the response results, in the first, the ORR was 85.7% at 3 months of follow-up. The second reported a CR in 50% of patients. The ORR was 66.6% (CR, 33.3%; PR, 33.3%) in the third.

Reprocessing with BTKi. Two retrospective studies sought to verify the effectiveness of retreatment with drugs in this category. In one study, patients treated with BTKi comprising ibrutinib, acalabrutinib, and non-covalent BTKi had a collective ORR of 53.7%. In the other, PFS was 12 months and ORR was 53.4% ​​(CR, 10%; PR, 26.7%).

PI3K inhibitors. Two observational studies reported efficacy results. In one of them, after a follow-up of 4 months, the PFS was 5 months and the ORR was 40.9%. In the other retrospective study, the median PFS was 5 months and the ORR was 44.6% (OR: 5.9%; PR: 35.2%).

BTKi combined reprocessing. Again, 2 observational studies reported efficacy results. A retrospective study evaluated the efficacy of combined retreatment of ibrutinib and venetoclax in these doubly exposed patients. At a median follow-up of 23.8 months, median OS was 27 months and all patients had a response (CR, 55%; PR, 45%). A second retrospective study, involving only 2 patients, evaluated the effectiveness of acalabrutinib plus obinutuzumab and found that 1 patient had an objective response.

BCL2 reprocessing. In a study evaluating the effectiveness of venetoclax retreatment, the median PFS was 14 months and the ORR was 40%.

Allogeneic stem cell transplant. A study of patients who underwent this treatment found that after 6.5 months, the median PFS was 11 months and the ORR was 76.5%.

Chemo-immunotherapy. An observational study reported the effectiveness of chemo-immunotherapy in this population, revealing that after a median follow-up of 2 months, the ORR was 31.8%.

Bispecific trigger of CD3 T lymphocytes directed towards CD20. Efficacy results of subcutaneous epcoritamab were explored in a study which found that after 9.3 months of follow-up, the ORR was 53% (OR, 27%; PR, 26% ).

References

1. Zuber M, Akkala S, Li N, Veettil SK, Tan CJ, Zapata LV. Efficacy and effectiveness outcomes of treatments for patients with double exposure chronic lymphocytic leukemia and small lymphocytic lymphoma: a systematic review of the literature. Cancer Med. 2024;13(18):e70258.doi:10.1002/cam4.70258

2. Aronson JH, Skånland SS, Roeker LE, Thompson MC, Mato AR. Approach to a patient suffering from “double refractory” chronic lymphocytic leukemia: “double, double toil and trouble” (Shakespeare).Am J Hematol. 2022: 97 Supplement 2: S19-S25. doi:10.1002/ajh.26682

3. Zygmunciak P, Robak T, Puła B. Treatment of refractory double chronic lymphocytic leukemia – an unmet clinical need.Mol Sci. 2024;25(3):1589.doi:10.3390/ijms25031589