There was a 16-week complete response rate of 42% per CT imaging with the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) in patients with previously untreated or relapsed/refractory mantle cell lymphoma, according to results from the phase II AIM study.
Constantine S. Tam, MD
There was a 16-week complete response (CR) rate of 42% per CT imaging with the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) in patients with previously untreated or relapsed/refractory mantle cell lymphoma (MCL), according to results from the phase II AIM study.
In comparison, the CR was 9% at 16 weeks in a historical cohort of patients who received ibrutinib monotherapy (P <.001), according to investigators of the study. The findings, which where were published inThe 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.
There was a median age of 68 years (range, 47-81). Half of the patients (including the previously untreated patient) had a TP53 aberration, while 75% of the patients 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. Preexisting NF-κB pathway mutations appeared to have no effect on the response to combination therapy with ibrutinib and venetoclax in our study," added Tam et al.
At initiation, all patients were given 560 mg of ibrutinib monotherapy per day for the first 4 weeks. After 5 weeks, patients received venetoclax treatment daily at a dose of 50 mg, which was increased weekly in a stepwise fashion to 100 mg per day, 200 mg per day, then 400 mg per day, on the basis of recommended doses for treating patients with chronic lymphocytic leukemia.
The study protocol was amended to allow escalation to a dose of 800 mg per day after week 16 if CR had not occurred, per the recommended phase II dose in MCL of 800 mg per day.
The 42% CR rate per CT imaging without PET had a 95% confidence interval (CI) of 22% to 63%. The overall response rate was 71% (95% CI, 49-87) with the inclusion of PET assessments, finding a CR rate of 62% and partial response rate of 8%.
Subsequently, 16 (67%) patients were found with absence of minimal residual disease (MRD) in bone marrow as assessed by flow cytometry. Also, 9 (38%) patients had absence of MRD in blood as assessed by ASO-PCR.
Among the 19 patients with 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.
Median progression-free survival (PFS) was not reached after the 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, while at 15 months, 78% (95% CI, 59-100) of patients with a response were estimated to be progression-free.
At the time of analysis, median duration of response was not reached. Investigators found an overall survival rate of 79% (95% CI, 64-97) at 12 months and 74% (95% CI, 57-95) at 18 months.
Overall, 8 patients experienced disease progression, 5 of whom had disease that was primarily refractory to study therapy and 3 who had a relapse after CR while continuing therapy.
The most commonnly (≥10%) reported grade ≥3 adverse events (AEs) were neutropenia (33%), thrombocytopenia (17%), anemia (12%), and diarrhea (12%). Diarrhea was typically transient while diarrhea of grade ≥2 lasted a median of 2 weeks (range, <1-14). This was managed with antimotility agents or with dose reduction.
Also, 14 (58%) patients experienced serious AEs and 6 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.