Responses to Venetoclax are Durable in MCL

Article

Long-term follow-up of patients with relapsed or refractory mantle cell lymphoma treated with venetoclax monotherapy indicate that remissions are durable in a meaningful proportion and that late-onset toxicities are uncommon.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

Long-term follow-up of patients with relapsed or refractory mantle cell lymphoma (MCL) treated with venetoclax (Venclexta) monotherapy indicate that remissions are durable in a meaningful proportion and that late-onset toxicities are uncommon.

Among responders in a dose-escalation phase I study of venetoclax that included 28 patients with MCL, with a median follow-up of 27 months, the median duration of response was 15.7 months (95% CI, 4.2-30.4), reported Matthew S. Davids, MD, MMSc, at the 2018 American Society of Hematology Annual Meeting.1The overall response rate in the study was 75.0% (n = 21), with 6 patients (21.4%) achieving a complete response (CR) and 15 (53.6%) achieving a partial response (PR).

Venetoclax was previously found to be active in patients with relapsed MCL as part of the phase I M12-175 study,2said Davids, associate director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, Boston.

Median progression-free survival (PFS) was 11.3 months (95% CI, 5.4-21.0) for all patients irrespective of the response achieved. The 2-year PFS estimates were 30% among all 28 patients, 83% among those who achieved a CR, and 14% among those with a PR.

The data are from a larger study of 106 patients with relapsed/refractory non-Hodgkin lymphoma. In the MCL cohort, a stepwise ramp-up dosing regimen was employed in which venetoclax was administered 100 mg (week 1, day 1) to 800 mg (week 4, day 1), and to 1200 mg (week 5, day 1 and thereafter) to mitigate the risk of tumor lysis syndrome (TLS). Following the ramp-up, venetoclax was administered in dose cohorts ranging from a maximum dose of 300 to 1200 mg and was continued until progressive disease or unacceptable toxicity; intrapatient dose escalation was allowed.

Patients with disease progression were allowed to continue venetoclax at the same dose received when the progression occurred; for the duration of clinical benefit, an increased dose up to 1200 mg was allowed.

The median age of patients with MCL was 72 years (range, 35-85). They received a median of 3 (range, 1-7) prior lines of therapy; 5 patients received a prior PI3 kinase inhibitor but none previously received ibrutinib (Imbruvica). Some 28.6% were refractory to rituximab (Rituxan); 26.9% had relapsed post stem cell transplant. More than half of patients had bulky lymph nodes ≥5 cm.

The time from last therapy to start of venetoclax was a median of 12.9 months (range, 2.4-147.9). The median dose of venetoclax was 400 mg/day; 25 (89%) received at least 400 mg/day and 6 (21%) received the maximum dose of 1200 mg/day. Median time on study drug was 11.2 months (range, 0.2-59.2). Three patients have been on therapy for more than 4 years.

Twenty-five of the 28 patients have discontinued, 11 due to clinical disease progression, 16 due to radiographic progression, and 7 due to adverse events (AEs; 2 for thrombocytopenia, 2 for lymphoma disease progression, 1 for anemia, 1 for hemolytic anemia, 1 for pancreatic cancer, and 1 for respiratory failure [1 patient reported both hemolytic anemia and thrombocytopenia]).

Of the responders, 1 patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last follow-up (24 months after coming off study). Four patients developed progressive disease after receiving venetoclax for >2 years (time to progression: 31, 32, 33, and 36 months). Two patients with CR are continuing on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy.

“Nearly all patients had at least 1 treatment-emergent adverse event, with 68% of patients experiencing grade 3 or 4 AEs, and 46% experiencing serious AEs,” said Davids. “Laboratory tumor lysis syndrome was reported in 1 patient considered high risk for TLS on the basis of nodal bulk >10 cm, but this patient was able to continue on study drug without specific interventions.”

The most common all-grade treatment-emergent AEs in the MCL population were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%), and upper respiratory infection (25%). The most common grade 3/4 AEs were pneumonia (18%), neutropenia (14%), anemia (14%), and thrombocytopenia (11%). Serious AEs included pneumonia (n = 2) and picornavirus infection (n = 2).

AEs that appeared after 2 years of venetoclax therapy occurred at a lower rate than earlier in the course of therapy, the most common being upper respiratory infection or vomiting, at about 10%.

Of the 11 deaths, 3 occurred ≤30 days after discontinuing venetoclax because of disease progression and 8 occurred ≥30 days after discontinuation with 6 related to progression, 1 to pneumonia, and 1 to pulmonary hemorrhage.

Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including the phase III SYMPATICO randomized study comparing venetoclax plus ibrutinib versus ibrutinib alone.

References:

  1. Davids MS, Roberts AW, Wierda WG, et al. Long-term follow-up of patients with mantle cell lymphoma treated with venetoclax monotherapy. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 2883.
  2. Davids MS, Roberts AW, Seymour JF, et al. Phase 1 first-in-human study of eventioclax in patients with relapsed or refractory non-Hodgkin lymphoma.J Clin Oncol.2017;35:826-833. doi: 10.1200/JCO.2016.70.4320.
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