Venetoclax/Ibrutinib Combo Impresses in MCL

Constantine S. Tam, MD

The combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) induced a 16-week complete response (CR) rate of 42% per CT imaging in patients with previously untreated or relapsed/refractory mantle cell lymphoma (MCL).

In comparison, the CR was 9% at 16 weeks in a historical cohort of patients who received ibrutinib monotherapy (P <.001), according to investigators from the phase II AIM study. The findings, where were published in the New England Journal of Medicine, showed that the CR rate as measured by PET imaging was 62% at week 16.

The single-group AIM study was conducted at 2 sites in Melbourne, Australia, from July 2015 through September 2016. The patient population included 23 patients with relapsed/refractory disease and 1 with previously untreated MCL.

The median number of previous therapies among relapsed/refractory patients was 2 (range, 1-6). The 1 previously-untreated patient could not undergo cytotoxic chemotherapy because the patient declined blood transfusions, and expressed both a TP53 mutation and deletion in the lymphoma.

The median age of the patients was 68 years (range, 47-81). Half the patients (including the previously untreated patient) had a TP53 aberration, 75% had a high-risk prognostic score, and 25% had an NF-κB pathway mutation

“TP53 mutations appear to be a critical prognostic factor in mantle cell lymphoma, being strongly associated with treatment resistance and inferior survival among patients receiving intensive chemotherapy and undergoing first-line autologous stem-cell transplantation,” lead author Constantine S. Tam, MD, department of hematology, Peter MacCallum Cancer Centre, Melbourne, and colleagues wrote.

“TP53 aberrations were present in 50% of the patients in this study, half of whom had complete responses, most of which were durable. However, the number of such patients is small, and the follow-up is less than 2 years,” added Tam et al. “Preexisting NF-κB pathway mutations appeared to have no effect on the response to combination therapy with ibrutinib and venetoclax in our study.”

All patients initiated treatment with 560 mg of ibrutinib monotherapy per day for the first 4 weeks. At 5 weeks, patients began venetoclax treatment at a daily dose of 50 mg and increased weekly in a stepwise fashion to 100 mg per day, 200 mg per day, then 400 mg per day, on the basis of the recommended dose at the time the study began for treating patients with chronic lymphocytic leukemia .

Subsequently, the recommended phase II dose in MCL was reported to be 800 mg per day and the study protocol was amended to allow escalation to a dose of 800 mg per day after week 16 if CR had not occurred.

The 42% CR rate per CT imaging without PET had a 95% confidence interval (CI) of 22% to 63%. With the inclusion of PET assessments, the overall response rate was 71% (95% CI, 49-87), comprising a CR rate of 62% and partial response rate of 8%.

Sixteen (67%) patients had absence of minimal residual disease (MRD) in bone marrow as assessed by flow cytometry. Nine (38%) evidenced absence of MRD in blood as assessed by ASO-PCR.

Among the 19 patients who could be evaluated for MRD clearance, 16 (84%) had clearance according to flow cytometry, and 9 (56%) had clearance according to ASO-PCR. Among patients with CR who could be evaluated for MRD, 14 of 15 (93%) had a negative status according to flow cytometry, and 9 of 11 (82%) had a negative status according to ASO-PCR.

The median progression-free survival (PFS) had not been reached after a median follow-up of 15.9 months. The estimated 12-month PFS was 75% (95% CI, 60-94) and 57% (95% CI, 40-82) at 18 months. At 15 months, 78% (95% CI, 59-100) of patients with a response were estimated to be progression-free.

The median duration of response had not been reached at the time of this analysis. The rate of overall survival was 79% (95% CI, 64-97) at 12 months and 74% (95% CI, 57-95) at 18 months.

Eight patients experienced disease progression, 5 who had disease that was primarily refractory to study therapy and 3 who had a relapse after CR while continuing therapy.

The most common (≥10%) grade ≥3 adverse event (AE) was neutropenia (33%), followed by thrombocytopenia (17%), anemia (12%), and diarrhea (12%). Investigators noted that diarrhea was typically transient; diarrhea of grade ≥2 lasted a median of 2 weeks (range, <1-14), and it was managed with antimotility agents or with dose reduction.

Fourteen (58%) patients experienced serious AEs. Six patients died during the study, 4 of which were due to disease progression. Of the other 2 deaths, 1 patient died from malignant otitis externa during week 6 after treatment with ibrutinib alone and the other died from cardiac failure during ongoing complete response.

Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma [published online March 29, 2018]. N Engl J Med. 2018; 378:1211-23. doi: 10.1056/NEJMoa1715519.