Treating Double-Exposed Patients With CLL: A Continued Unmet Need

There is a need for treatment for patients with chronic lymphocytic leukemia who fail on both Bruton tyrosine kinase 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 are a difficult population to treat, with generally poor prognoses, according to authors of a systematic literature review on the topic published in Cancer Medicine.¹ It is the first such systematic review with this focus, they stated.

Current evidence points topirtobrutinib, lisocabtagene maraleucel, and combination ibrutinib/venetoclax treatments as potentially effective in double-exposed patients. These clinical data are very limited, though, the authors noted.

“Available treatment options for patients who fail on 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 commissioned to better understand the efficacy outcomes in double-exposed patients.”

What the Literature Revealed

An exhaustive database search resulted in 13 publications based on 9 different studies: 5 single-arm clinical trials (all phase I or II) and 4retrospective observational studies. Each clinical trial included between 4 and 100 patients (generally, the double-exposed cohort was a subgroup) and the observational studies each included between11 and 125.

The authors reported their findings organized by the 9 classes of treatment received by the double-exposed patients with CLL or small lymphocytic lymphoma.The overall poor prognoses exist no matter what the reasons were for discontinuation of venetoclax or BTKi, said the authors. They added that since the results they presented were all from either single-arm or observational studies, outcomes could be confounded by patient characteristics.

The 9 studies covered these treatments:

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

Chimeric antigen receptor T-cell therapy (CAR T). Two clinical trials and 3 observational studies assessed the efficacy and effectiveness of CAR T in this population. In the first clinical trial, assessing lisocabtagene maraleucel, the ORR was 80% (complete response [CR], 60%; partial response [PR], 20%). At 11 months of follow-up, the median PFS was 13 months.The second clinical trial’s results showed that the ORR of patients treated with anti-CD19 CAR T cells was 50% (all PRs).

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

Retreatment with BTKi. Two retrospective studies sought to ascertain the effectiveness of retreatment with drugs in this category.In one, patients treated with BTKi that included ibrutinib, acalabrutinib, and noncovalent BTKi had a collective ORR of 53.7%. In the other, PFS was 12 months and theORR was 53.4% (CR, 10%; PR, 26.7%).

PI3K inhibitors. Two observational studies reported effectiveness results. In one, at 4 months follow-up, the PFS was 5 months and the ORR was 40.9%. In the other, a retrospective study, the median PFS was5 months and the ORR was 44.6% (CR, 5.9%; PR, 35.2%).

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

BCL2 retreatment. In a study assessing effectiveness of venetoclax retreatment,the medianPFS was 14 months and the ORR was 40%.

Allogeneic stem cell transplantation. A study following patients who had undergone this treatment found that after 6.5 months, the median PFS was 11 months and the ORR was 76.5%.

Chemoimmunotherapy. One observational study reported the effectiveness of chemoimmunotherapy in this population, finding that at a median follow-up of 2 months, the ORR was 31.8%.

Bispecific CD20-directed CD3 T-cell engager. Efficacy results for subcutaneous epcoritamab were explored in a study that found that at 9.3 months of follow-up, the ORR was 53% (CR,27%; PR, 26%).

References

1. Zuber M, Akkala S, Li N, Veettil SK, Tan CJ, Zapata LV. Efficacy and effectiveness outcomes of treatments for double-exposed chronic lymphocytic leukemia and small lymphocytic lymphoma patients: a systematic literature review. 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 with “double refractory” chronic lymphocytic leukemia: “double, double toil and trouble” (Shakespeare).Am J Hematol. 2022:97 Suppl 2:S19-S25. doi:10.1002/ajh.26682

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