Chronic Lymphocytic Leukemia
Novel Small-Molecule Inhibitor–Based Combinations in Development for Chronic Lymphocytic Leukemia
With the emergence of a new generation of small-molecule inhibitors and anti-CD20 therapies for chronic lymphocytic leukemia (CLL), researchers are now exploring their potential use in combination. In clinical trials, gains in efficacy will be balanced against any additional toxicities beyond that of the current standards of care.
Medical Director of Hematology Research
“An important question in the field is: Which is the better partner for venetoclax? Is it a BTK inhibitor or an anti-CD20 antibody?”
Over the last several years, exciting developments in CLL have included Bruton tyrosine kinase (BTK) inhibitors, anti-CD20 therapies, BCL-2 inhibitors, and phosphoinositide 3-kinase (PI3K) inhibitors. We are now in the position to begin seeking to determine the best way to combine or sequence these agents. Answering questions about combination vs sequential therapy is complicated in the context of clinical trials. It has been a paradigm in oncology that, if 2 drugs work well separately, they may work even better in combination. However, the questions of what to use if the patient relapses and whether additional efficacy outweighs the increase in toxicity of the combination remain, and this may be particularly true when considering novel doublet or triplet regimens.
BCL-2 inhibition offers several advantages in patients with CLL, including deep remissions that can lead to time off from therapy. Venetoclax plus obinutuzumab is approved by the US Food and Drug Administration for the first-line treatment of adults with CLL, and, in our most recent update from the German CLL14 study, the estimated progression-free survival rate at 4 years was 74% among patients who received this combination. However, there have been concerns about using a monoclonal antibody in the context of the current pandemic.
An important question in the field is: Which is the better partner for venetoclax? Is it a BTK inhibitor or an anti-CD20 antibody? We hope to address this question in the upcoming MAJIC study, in which venetoclax is being combined with either obinutuzumab or acalabrutinib, a second-generation BTK inhibitor that has lower rates of cardiovascular side effects and arthralgias than ibrutinib. I think that the BTK/BCL-2 inhibitor strategy looks very exciting. In clinical trials, we are seeing very deep remissions with this all-oral regimen, and patients are not coming in for infusions.
Another study that is underway is examining the role of PI3K inhibition together with anti-CD20 therapy, where umbralisib is being combined with ublituximab, and patients are randomly being assigned to the addition of venetoclax or no additional treatment. Studies of pirtobrutinib, a promising investigational, noncovalent, reversible BTK inhibitor, in combination with venetoclax are also on the horizon. For now, I think that the question of whether to choose between doublet or triplet therapy is unsettled. We have seen some studies in which a BTK inhibitor was added to venetoclax and then an anti-CD20 therapy was added. The jury is still out as to whether doublet or triplet therapy offers advantages.
Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. doi:10.1200/JCO.21.01181
ClinicalTrials.gov. A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations. Updated August 4, 2020. Accessed February 11, 2022. https://clinicaltrials.gov/ct2/show/NCT03226301
ClinicalTrials.gov. A study of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (MAJIC). Updated January 19, 2022. Accessed February 11, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05057494
ClinicalTrials.gov. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CAPTIVATE). Updated July 14, 2021. Accessed February 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02910583
ClinicalTrials.gov. Venetoclax and ibrutinib in treating patients with chronic or small lymphocytic leukemia. Updated January 12, 2022. Accessed February 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02756897
Davids MS, Mato AR, Hum J, et al. MAJIC: a phase 3 prospective, multicenter, randomized, open-label trial of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma [abstract 1553]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
Fürstenau M, Eichhorst B. Novel agents in chronic lymphocytic leukemia: new combination therapies and strategies to overcome resistance. Cancers (Basel). 2021;13(6):1336. doi:10.3390/cancers13061336
Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 unity-CLL study [abstract 543]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574
Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study [abstract 391]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
Rogers KA, Huang Y, Ruppert AS, et al. Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(31):3626-3637. doi:10.1200/JCO.20.00491