Safety and Future Considerations

Overall, treatment with the combination was well-tolerated. Tumor lysis syndrome occurred in 2 patients. Other common side effects were generally low-grade and included diarrhea, fatigue, and nausea or vomiting.


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“It is still unknown whether the drug combination will be successful in all subtypes of MCL, as the study only included one case of pleomorphic/blastoid disease, and the patient did not respond,” Dr Tam added.

In an interview with Cancer Therapy Advisor, Dr Fung called the results of the phase 2 study “very promising,” especially given the inclusion of patients with unfortunate features including TP53 mutations.

Of the 24 patients in the study, half had TP53 mutation or deletion. Of these 12 patients, 6 had a complete response, with 5 remaining progression-free for between 13 to 20 months.

“Having said that, this is still a small study that only included 24 patients, and follow-up was brief,” Dr Fung noted. “Further studies will be required to confirm this finding, compared with other available treatments, specifically, but not limited to, other BTK inhibitors.” 

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The relative safety and efficacy of the combination to that of single-agent ibrutinib is being evaluated in the ongoing phase 3 PCYC-1143 trial (ClinicalTrials.gov Identifier: NCT03112174). Patients will begin treatment with a run-in period to evaluate the occurrence of tumor lysis syndrome and dose-limiting toxicities.

All included patients will receive ibrutinib 560 mg once daily and venetoclax at 20 mg on day 1 with gradual increase to a target dose of 400 mg daily. The study will then transition to a randomized design with assignment to 24 months with the combination followed by single-agent ibrutinib.

References

  1. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-23. doi: 10.1056/NEJMoa1715519.
  2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-16.
  3. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-33.
  4. Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Paper presented at: American Society of Hematology Annual Meeting and Exposition; Dec 9-12, 2017; Atlanta, Georgia.