BCL-2 Inhibitor Combo May Offer Remissions in CLL

BCL-2 protein

ABT-199

Creating new treatment options for chronic lymphocytic leukemia (CLL), particularly for high-risk patient populations such as those with fludarabine-refractory disease or with 17p deletions, is the goal of an intense effort by clinical researchers and pharmaceutical companies. Targeted therapies such as BCL-2 inhibitors offer the prospect of more durable remissions and better safety profiles in the treatment options available for patients with difficult-to-treat CLL. Promising interim results from a trial of one such agent, ABT-199, were presented at the 19th Congress of the European Hematology Association.The novel anticancer agent, ABT-199 (GDC-0199), has shown efficacy when administered to patients with relapsed/refractory CLL (R/R CLL) in combination with rituximab. No additional toxicities were observed compared with trials in which ABT-199 was administered as a monotherapy.

Anas Younes, MD, on IPI-145 and ABT-199 for Lymphoid Malignancies

Younes is the chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center.

ABT-199 is part of a class of drugs known as BH3 mimetics. In the cell, proteins made up solely of BH3 domains (eg, BAD and BIM) function as antagonists of the prosurvival proteins in the BCL-2 family (eg, BCL-2 and BCL-XL). BH3 mimetics are small molecules that function as anti-tumor agents by binding BCL-2 family proteins in a manner analogous to endogenous BH3-only proteins, and thereby inhibit their antiapoptotic functions.

Trial Data

ABT-199 is a derivative of navitoclax (ABT-737/263), a compound that binds with high affinity to BCL-2, BCL-XL, and BCL-W. ABT-199 was rationally designed to bind BCL-2 with high affinity, but not BCL-XL or BCL-W, using the x-ray crystal structure of the BCL-2/small-molecule complex.¹This binding profile was intended to avoid the dose-limiting thrombocytopenia induced by navitoclax. ABT-199 has been shown to induce BAX/BAK-dependent apoptosis in a number of hematologic tumor cell lines. In an in vivo model, ABT-199 demonstrated similar efficacy in prolonging the life of lymphoma-bearing mice without inducing thrombocytopenia.²The interim results from a phase Ib clinical trial (NCT01682616) were presented at the 19th Congress of the European Hematology Association.³The aims of the study are to evaluate safety and efficacy, as well as to establish the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the treatment combination of ABT-199 and rituximab, a chimeric monoclonal antibody targeting the B-cell antigen CD20.

The interim results included data from 37 patients with a median time in the trial of 19 weeks, a median of 2 prior therapies, and a median age of 68 years. Nine patients (24%) were refractory to fludarabine, 9 (24%) were refractory to rituximab, and 9 (24%) had del(17p). Six patients discontinued the trial, 4 of whom experienced disease progression, 1 who withdrew consent, and 1 who suffered a fatal episode of hyperkalemia caused by tumor lysis syndrome (TLS) during the initial dosing. This event was not considered to be dose-limiting.

Patients were started on a daily dose of ABT-199 of 50 mg that was subsequently reduced to 20 mg following the TLS event. The doses were then increased weekly to the final cohort dose that varied between 200 mg and 600 mg daily. The patients received rituximab at a starting dose of 375 mg/m², then increased to 500 mg/m²monthly for 6 total doses and continuation of daily ABT-199 until disease progression.

The most common adverse events (AEs) were neutropenia (43%), nausea (38%), and diarrhea (30%). The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%) and anemia (11%). Of 14 grade 4 AEs observed in 9 patients, 2 were considered dose-limiting toxicities. Both occurred in the cohort receiving 300 mg of ABT-199 daily: thrombocytopenia in a patient receiving 375 mg/m²of rituximab and hemophagocytic syndrome in a patient receiving 500 mg/m²of rituximab.

Clinical Potential

Eighteen patients had completed the combination therapy or discontinued before completion and were therefore evaluable for remission. Seven (39%) achieved complete remission (CR/CRi), including 4 (22%) who were minimal residual disease negative. Seven more patients (39%) achieved partial remission.  Jacqueline Claudia Barrientos, MD, an assistant professor at Hofstra North Shore-LIJ School of Medicine in New York and one of the investigators in this trial, explained its clinical significance and its potential impact on the treatment of R/R CLL.

Clinical Pearls

Promising interim results from a trial of ABT-199 in CLL were presented at the 19th Congress of the European Hematology Association.

Of 18 evaluable patients, 7 (39%) achieved complete remission (CR/CRi), including 4 (22%) who were minimal residual disease negative, and 7 more patients (39%) achieved partial remission.

The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%) and anemia (11%).

“ABT-199 has demonstrated significant clinical activity in CLL patients, including hard-to-treat conditions like fludarabine-refractory disease and in 17p deletion patients. Even though we now have the drug ibrutinib available to treat 17p deletion patients, at the end of the day, these are the patients that continue to do worse (compared with other patients without 17p deletion) as evidenced by the curves showing an earlier relapse compared with other groups. As a physician treating mainly hard-to-treat refractory cases, [I know that] we need these new agents to salvage our patients after each relapse. CLL is a chronic condition and there is no cure for our patients. With the advent of new therapies, our patients are living longer, but after time, patients may stop responding or may develop resistance to the drug, hence the need to get new agents approved.”

References

“With more data on its safety,” Barrientos concluded, “I believe that this drug will be a reasonable therapeutic option in the future to treat relapsed or refractory disease, including patients with high-risk disease (like 17p deletion) as a single agent or in combination strategies.”

1. Billard C. BH3 mimetics: status of the field and new developments.Mol Cancer Ther. 2013;12(9):1691-1700.
2. Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.Blood. 2013;121(12):2285-2288.
3. Roberts AW, Ma S, Kipps T, 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. In: Proceedings from the 19th Congress of the European Hematology Association; June 12-15, 2014; Milan, Italy. Abstract S703.

Financial Interest Statement