Ibrutinib, venetoclax oral combination shows promise for mantle cell lymphoma
medwireNews: Ibrutinib plus venetoclax could together be beneficial as oral treatment for mantle cell lymphoma, suggests a phase II study published in The New England Journal of Medicine.
The agents, which target different critical pathways in the malignant B cell – Bruton tyrosine kinase (BTK) by ibrutinib and B-cell lymphoma 2 protein (BCL2) by venetoclax – significantly improved outcomes compared with historical controls.
Constantine Tam (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) and colleagues say their results “are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma.”
The study included 24 patients aged 47 to 81 years who had received up to six previous treatments. Overall, 23 had relapsed or refractory disease, while one was previously untreated. Half of the patients had aberrations of TP53 and 75% had a high-risk prognostic score.
Patients commenced with oral ibrutinib 560 mg/day for 4 weeks before oral venetoclax was introduced at 50 mg/day and increased weekly to 100 mg/day, then 200 mg/day, and finally 400 mg/day, with escalation after week 16 up to 800 mg/day if a complete response had not occurred.
Patients received treatment for a median of 14.4 months, with a median follow-up of 15.9 months.
At week 16, 42% of patients had a complete response, according to computed tomography, which was higher than the 9% rate seen at this timepoint for a historical cohort from the PCYC-1104-CA phase II study who received ibrutinib monotherapy. The rate of complete response, as assessed by positron-emission tomography, was 62% at week 16 and 71% overall.
Half of the patients with TP53 aberrations had complete responses, the team emphasizes, and these were durable in most cases, but they caution that the number of patients was small.
Responses to combination therapy were unaffected by traditional risk factors, such as high levels of lactate dehydrogenase or the Mantle Cell Lymphoma International Prognostic Index score, and were seen in 60% of heavily pretreated patients. One factor that negatively affected complete response, however, was highly proliferative disease.
Clearance of minimal residual disease was documented in 67% of patients according to flow cytometry and in 38% by allele-specific oligonucleotide-polymerase chain reaction assessment in peripheral blood samples. Overall, 78% of the responses were ongoing at 15 months and 57% of the patients were alive and progression-free at 18 months, the team reports.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the researchers note, adding that a phase III study testing the superiority of combination therapy over ibrutinib monotherapy is currently underway.
They also add that the occurrence of complete response with clearance of minimal residual disease suggests response-adapted treatment cessation, where treatment is stopped in selected patients, may be feasible.
This strategy “has been effective in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab,” they explain, although they concede: “The “question remains open, given that two patients with a minimal residual disease–negative complete response in our series had a relapse.”
Serious adverse events were recorded in 58% of patients and two of the first 15 patients developed tumor lysis syndrome, a known adverse event associated with venetoclax. This prompted a reduction in the starting dose from 50 to 20 mg/day, after which there were no further cases. Common side effects were generally low grade and included diarrhea in 83%, fatigue in 75%, and nausea or vomiting in 71%.
By Anita Chakraverty
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