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Conference Correspondent - Conference Highlights ASH

New treatment options are needed for relapsed or refractory non-Hodgkin lymphoma (NHL), particularly mantle-cell lymphoma (MCL), where there are no curative options. ABT-199 is a selective, potent, orally bioavailable small-molecule, BCL (B-cell lymphoma)-2 inhibitor that could be the next treatment option for patients with MCL.

In this phase 1, dose-escalation study, conducted by Davids and colleagues, the primary objectives were to evaluate the safety and pharmacokinetics of ABT-199, and to determine its maximum tolerated dose as well as it recommended dose for the phase 2 trial.  The secondary objectives were to assess the efficacy of ABT-199 and to explore potential biomarkers of response.

Adult patients with ECOG (Eastern Cooperative Oncology Group) performance status of ≤1 and with adequate marrow function received ABT-199 on week 1, day 7, followed by continuous, once-daily dosing from week 1, day 1, until disease progression or unacceptable toxicity. A 2- to 3-week lead-in period with stepwise escalation starting with lower doses to final cohort doses of 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg was instituted.  Patients were evaluated for adverse events (AEs), pharmacokinetic parameters, and disease responses.

A total of 32 patients enrolled in the trial, including 11 (34%) with follicular lymphoma, 8 (25%) with MCL, 8 (25%) with diffuse large B-cell lymphoma (DLCBL), 1 (3%) with marginal zone lymphoma, 3 (9%) with Waldenström macroglobulinemia, and 1 (3%) with multiple myeloma. The patients’ median age was 68 years and patients received a median of 3.5 previous therapies.

Overall, 22 patients discontinued the study drug: 18 patients discontinued because of disease progression, 2 because of AEs, and 2 proceeded to stem-cell transplantation. The most common AEs of any grade were nausea, diarrhea, vomiting, fatigue, and upper respiratory tract infection. Grade 3 or 4 AEs occurring in more than 3 patients included anemia (15%), neutropenia (3%), and thrombocytopenia (13%). Of note, grade 3 or 4 thrombocytopenia was not dose-limiting. After the initial dose, grade 3 laboratory tumor lysis syndrome was observed in 1 patient with bulky MCL and in 1 patient with DLBCL. At the target dose of 600 mg, 2 of the 10 patients in cohort 5 experienced dose-limiting toxicities, including febrile neutropenia and neutropenia.

Preliminary efficacy results indicated that the overall response rate was 53%. Of note, 100% of patients with MCL achieved a partial response and 100% of patients with Waldenström macroglobulinemia achieved a partial response or complete response. Responses in DLBCL and follicular lymphoma were observed at doses of 600 mg and higher. 

Davids and colleagues concluded that ABT-199 showed antitumor activity as monotherapy for several subtypes of relapsed or refractory NHL, including MCL. The dose-escalation portion of this study is ongoing to determine the maximum tolerated dose and the phase 2 study dose of ABT-199. Biomarker studies are also underway in various NHL subtypes to explore potential correlations with response.

References:


Davids MS, Seymour JF, Gerecitano JF, et al. The single-agent Bcl-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in all mantle cell lymphoma (MCL) patients. Blood. 2013;122. Abstract 1789.

Last modified: August 30, 2021