NEW ORLEANS—The oral, selective, small molecule Bcl-2 inhibitor ABT-199 (GDC-0199) was found to have antitumor activity—including complete remission—in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), a study reported at the 55th American Society of Hematology Annual Meeting and Exposition.

“We are very encouraged by these early results and, in particular, by the high rate of complete response among patients with treatment-resistant or relapsed CLL,” said John F. Seymour, MBBS, PhD, of the Department of Haematology at the Peter MacCallum Cancer Centre in East Melbourne, Australia. “Our ongoing work will seek to improve the efficacy of this drug while carefully monitoring toxicities to deliver the maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate.”

The phase 1 dose-escalation study enrolled 56 patients in cohorts at doses from 150 to 1,200 mg. Median time on study was 10.9 months (range, 0.3-23.7 months). Patients received a single dose of ABT-199 on week 1 (day 3 or 7), followed by continuous once-daily doses until disease progression or unacceptable toxicity. After tumor lysis syndrome (TLS) was observed in some patients, modifications were made to the dose escalation scheme.

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Of the patients, 19 (37%) had del(17p) and 35 (52%) had fludarabine-refractory disease; 13 (43%) of 30 had beta-2 microglobulin levels  greater than 3 mg/L and 21 of 28 (75%) had IgVH unmutated status. Median age of the patients was 67 years (range, 36- 86 years); 76% were male.

Preliminary efficacy data showed an overall response rate of 84% for the study population; 23% had a complete response (CR) and 61%, a partial response.  Those with high-risk CLL showed similar efficacy, with a response rate of 82% in del(17p) and 89% in fludarabine-refractory disease. “No detectable minimal residual disease was observed in several patients, including those with high-risk disease, who achieved CR,” Dr. Seymour said. A total of 24 patients discontinued ABT-199, eight due to adverse events (AEs), 14 due to progressive disease, and two for other reasons (one had a pulmonary embolus requiring warfarin and one went to transplant in response).

The most common AEs were diarrhea (43%), nausea (40%), neutropenia (37%), fatigue (33%), upper respiratory tract infection (33%), and cough (22%). Grade 3/4 AEs occurring in three patients or more  were neutropenia (36%), anemia (9%) thrombocytopenia (9%), TLS (9%), febrile neutropenia (7%), hyperglycemia (7%), and hypophosphatemia (4%).

Serious AEs possibly or probably related to ABT-199 included febrile neutropenia in three patients (5%) and TLS, also in three patients (5%). There was one sudden death in the setting of TLS.

Risk of TLS is being addressed using a titrated dosing scheme combined with aggressive prophylaxis, monitoring, and management, he said. As of the latest database analysis, no additional events, either clinical or laboratory, have been reported with the new dosing scheme.

Preliminary pharmacokinetics of ABT-199 show that after a single dose with a low-fat meal, Cmax and T1/2 values were approximately 6 and 17 hours, respectively, supporting daily dosing. ABT-199 exposures (Cmax and AUC) were approximately dose proportional between 150 mg and 800 mg dose levels at steady state.

Dr. Seymour said that ABT-199 monotherapy and combination trials in CLL have begun enrolling, including a phase 2 monotherapy study in patients with relapsed del(17p)  as well as combination studies with either rituximab or obinutuzumab in those with relapsed CLL.


  1. Seymour JF et al. Abstract #872. Presented at: American Society of Hematology Meeting 2013. Dec. 7-10, 2013; New Orleans.