Bringing the Oncology Community Together

Bcl-2 Inhibitor ABT-199 Shows Promise in CLL and SLL

Wayne Kuznar
Published Online: Monday, December 9, 2013
Dr. John F. Seymour

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.

Seymour JF, Davids, MS, Pagel JM, et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 872.

<<< View more from the 2013 ASH Meeting

Related Articles
FDA Approves First-Line Ofatumumab for Fludarabine-Ineligble Patients With CLL
The FDA has approved ofatumumab plus chlorambucil for previously untreated patients with chronic lymphocytic leukemia who are considered inappropriate for treatment with fludarabine therapy.
Hitting the Target: How Druker’s Persistence Helped Launch a New Mode of Attack
Take a prognosis of three years, multiply it by 10, and what do you get? A staggering improvement in the survival of patients with chronic myeloid leukemia (CML), and a crucial steppingstone on the road to the targeted treatment of cancer.
Irregular Menstruation Linked to Higher Risk of Ovarian Cancer Death
A prospective study found that women with irregular menstrual cycles have a 2.4-fold increased risk of dying from ovarian cancer compared to women with normal menstrual cycles
Most Popular Right Now
More Reading
External Resources

American Journal of Managed Care
Pharmacy Times
Physicians' Education Resource
Physician's Money Digest
Specialty Pharmacy Times
OncLive Resources

OncLive TV
Oncology Nurses
Web Exclusives

About Us
Advisory Board
Contact Us
Forgot Password
Privacy Policy
Terms & Conditions
Intellisphere, LLC
666 Plainsboro Road
Building 300
Plainsboro, NJ 08536
P: 609-716-7777
F: 609-716-4747

Copyright OncLive 2006-2014
Intellisphere, LLC. All Rights Reserved.