Study Proves Effectiveness of Dual Targeting in Mantle Cell Lymphoma

Results from a study published in The New England Journal of Medicine last week have shown consistency with previous data, concluding that dual targeting is effective in mantle cell lymphoma (MCL).

At present, younger patients without coexisting conditions are typically treated with intensive chemotherapy, which is normally combined with autologous stem-cell transplantation. Older patients or those with coexisting conditions are treated with chemotherapy and maintenance rituximab. Historically, patients with disease resistant to chemotherapy haven’t had many effective treatment options.

The study, titled “Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma,” provided further proof that dual targeting with both the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of MCL in patients who had been predicted to have poor outcomes with the current standard-of-care.

From July 2015 through September 2016, 24 patients with relapsed of refractory MCL (23) or previously untreated MCL (1) between the ages of 47 to 81 years were enrolled in the Phase 2 study of daily oral ibrutinib and venetoclax, and each had received between 0 and 6 previous treatments. Patients received ibrutinib monotherapy at a dose of 560 mg per day, and after 4 weeks, venetoclax was added with doses escalating 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events (AEs).

The primary endpoint was the rate of complete response at week 16, and minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleuotide-polymerase chain reaction (ASO-PCR) in blood. Disease reassessment was performed at weeks 4, 16, 28, 40, and 56.

Twelve patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% now point with ibrutinib monotherapy (P<0.001). Complete response rate as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67& of the patients and by ASO-PCR in 38%.

78% (n=18) of the patients with a response were estimated to an ongoing response at 15 months in a time-to-event analysis, and tumor lysis syndrome occurred in 8% (n=2) of patients.

The most common AEs were gastrointestinal in nature and generally low grade; they included: diarrhea, fatigue, and nausea or vomiting. Serious AEs were recorded in 58% (n=14) of patients. Six deaths were reported during the study, four of which were attributed to disease progression.

Overall, results of the study are consistent with the belief that the combination of ibrutinib and venetoclax is highly effective in MCL. The potential superiority of the combination therapy to single-agent ibrutinib in MCL is currently being evaluated in an ongoing Phase 3 study (NCT03112174).

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