John F. Seymour, MBBS, FRACP,
ABT-199, an orally bioavailable selective inhibitor of the Bcl-2 protein as monotherapy, induced remissions in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including adverse-risk subsets of patients, according to John Seymour, MBBS, PhD, who reported the final results from the first in-human study of ABT-199 at the 55th Annual Meeting of the American Society of Hematology (ASH).
Bcl-2 is recognized as being critical to the pathogenesis of many hematologic malignancies and is universally overexpressed in patients with CLL. Preclinical studies from the Dana Farber Cancer Institute have demonstrated that CLL is dependent upon Bcl-2 for its survival. Bcl-2 overexpression is also one of the main mediators of resistance to many forms of chemotherapy, “making Bcl-2 a very encouraging target that had not been able to be selectively inhibited until recently,” said Seymour, director, department of Hematology, Peter MacCallum Cancer Centre in Melbourne, Australia.
ABT-199 has selectivity for Bcl-2 inhibition over Bcl-xL, another member of the Bcl-2 family, which was responsible for dose-limiting thrombocytopenia observed with an earlier generation Bcl-2 inhibitor.
Previous data with ABT-199 showed encouraging clinical activity but an increased risk of tumor lysis syndrome. For this reason, modifications were made to the dose escalation schedule and tumor lysis syndrome prophylaxis and monitoring schedule.
The data presented at ASH were from a phase I, open-label, dose escalation, multicenter, international study of 67 patients with CLL/SLL. The initial dosing schema started with a single 50-mg dose of ABT-199 during week 1, followed by a two-step dose escalation to the designated cohort dose.
During the second dose escalation from 150 mg to 1200 mg, there was one death attributed to tumor lysis syndrome. The study was temporarily suspended and redesigned using a more conservative three-step dose escalation (starting with a 20-mg test dose on day 1, with escalation only allowed in the absence of biochemical tumor lysis), along with enhanced prophylactic measures.
The median number of prior therapies in the 67 patients enrolled until September 30, 2013, was four (range, 1-11), with 52% of patients having disease refractory to prior fludarabine. Of the 52 patients whose cytogenetics were analyzed by fluorescence in situ hybridization, 37% had a deletion of chromosome 17p.
Forty-three patients remain in the study and continue active drug therapy. The median time on study is 10.9 months. Reasons for discontinuation were progressive disease (n = 14), adverse events (n = 8), allogeneic transplant (n = 1), and other (n = 1).
By CT scan, 88% of patients (50/57) had at least a 50% reduction in the sum product of diameters of nodal masses. The median time to achieve a 50% reduction was 6 weeks (the time of the first CT scan stipulated per protocol). “Forty-one patients had achieved at least a partial remission at that 6-week scan, indicating that cytoreduction is rapid,” said Seymour.
Eighty-nine percent of patients (33/37) had at least a 50% reduction in bone marrow infiltrate at the first bone marrow biopsy at week 24. “The median reduction is approximately 95%,” said Seymour.
The median time to a 50% reduction in the peripheral blood lymphocyte count (for those with lymphocyte count >5 at baseline) was “quite rapid at 15 days,” Seymour reported.
The overall response rate (ORR) among all current evaluable patients was 84%, including a 23% complete response (CR) rate. The ORR among patients with del(17p) was 82% and among those with fludarabine-refractory disease, it was 89%.
Serious adverse events attributed to ABT-199 included three cases of febrile neutropenia and three cases of tumor lysis syndrome, all of which occurred before the most recent modification of the dosing schedule.
ABT-199 monotherapy and combination trials in CLL have begun enrolling patients, including a phase II monotherapy study in del(17p) with relapsed CLL.