Encouraging Results in Leukemia from a BCL-2 Inhibitor

Published Online:May 31, 2014
The BCL-2 family proteins are key regulators of the apoptotic process in human cells, and the family includes both pro-apoptotic and antiapoptotic/prosurvival proteins. Overexpression of prosurvival proteins is one of the mechanisms used by cancer cells to evade apoptosis, and inhibitors of the prosurvival proteins have been in development for some time now. ABT-199, the result of a collaboration between AbbVie and Genentech, is a selective, potent, orally available BCL-2 inhibitor.1 The drug is being developed in collaboration by the two companies for acute myelogenous leukemia and chronic lymphocytic leukemia (CLL).

The following posters presented at the meeting provided the current status of this promising drug moiety.

1. ABT-199 in the treatment of diffuse B-cell and follicular lymphoma.2

The objectives of this phase 1, dose-escalation study included evaluations of safety, pharmacokinetics (PK), and preliminary efficacy in patients with relapsed/refractory non-Hodgkins lymphoma (NHL). ABT-199 was administered on Week 1 Day 7 (W1D7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise dose titration was implemented. As of April 2014, ≥20% of 62 patients presented with all grade adverse events (AEs) of nausea, vomiting, anemia, and fatigue, while ≥5% presented with grade 3/4 AEs of anemia, neutropenia, and thrombocytopenia. A case-study presented showed anti-tumor activity of ABT-199 in a stage II mantle cell lymphoma patient who had previously undergone 6 cycles of R-CHOP, 2 cycles of R-ICE and IFRT. A 6-week treatment with ABT-199 showed complete clinical resolution of node after 6 weeks. The overall response rate was 48% in the evaluated NHL patients. The authors are in the process of conducting biomarker studies with ABT-199.
2. Interim results from a phase 1b trial of ABT-199 plus rituximab in CLL.3

The objective of this trial was to assess safety, pharmacokinetics (PK) and preliminary efficacy of ABT-199 plus rituximab in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), and to determine a recommended phase 2 dose. The most common treatment-emergent AEs, observed in >25% patients, were neutropenia (43%), nausea (38%), and diarrhea (30%). The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%), and anemia (11%). Two dose limiting toxicities were observed with ABT-199 + rituximab: thrombocytopenia and hemophagocytic syndrome. The addition of rituximab to ABT-199 has identified no new toxicities. The combination is active in R/R CLL with a substantial CR rate. The combination is active in R/R CLL with a substantial CR rate. Best R/R of 89% was observed in R/R patients and 39% achieved CR/Cri. Absence of minimal residual disease was observed in 6/8 patients tested who had achieved CR/Cri, along with 5 patients who have a PR. A fatal episode of tumor lysis syndrome (TLS) occurred during the ABT-199 lead-in period, but dosing modifications and increased monitoring prevented the occurrence of any further TLS events. Rituximab does not seem to affect ABT-199 exposure.

A phase 3 trial is currently ongoing in previously treated CLL patients, to evaluate ABT-199 plus rituximab compared with Bendamustine and rituximab.
3. Phase 1 study of ABT-199 in CLL and SLL patients: determine safety, PK, efficiency.4

The primary objectives of this phase I study were to evaluate the safety and pharmacokinetics (PK) and to determine the maximum tolerated dose and a recommended phase 2 dose (RPTD) of ABT-199 in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). A secondary objective was to assess preliminary efficacy. Following early events of TLS, a weekly ramp-up period to the final cohort dose (150 – 1200 mg) was implemented. Patients are now being enrolled in the safety expansion (SE) cohort. Most common AEs observed were diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 AEs (≥3 patients) were neutropenia (32%), anemia (8%), TLS (8% including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). 28 patients discontinued the study: 18 for progressive disease, 8 for AEs, and 2 for other reasons.

ABT-199 monotherapy was found active in patients with R/R CLL with a 77% RR. Patients with high-risk CLL showed similar efficacy, with OR over 75%. ABT-199 monotherapy and combination therapy in CLL are currently enrolling. This includes a phase 3 trial evaluating the combination of ABT-199 and rituximab in comparison to Bendamustine/rituximab in patients with relapsed CLL and combination studies with Bendamustine/rituximab and obinutuzumab in patients with relapsed CLL.

1.      Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.

2.      Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): Responses observed in
diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014;32(5s)suppl; abstr 8522.

3.      Ma S, Seymour JF, Lanasa MC, et al. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase 1b study. J Clin Oncol. 2014;32(5s)suppl; abstr 7013.

4.      Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete-response rate and durable disease control. J Clin Oncol. 2014;32(5s)suppl; abstr 7015.