Forodesine Shows Activity in a Relapsed/Refractory Chronic Lymphocytic Leukemia Population
ORLANDO, Fla.—Patients with previously treated chronic lymphocytic leukemia (CLL) who subsequently received oral forodesine, a purine nucleoside phosphorylase (PNP) inhibitor, had a response rate of 26%, an analysis of an open-label, multicenter, phase 2 study has found.
The agent was generally safe and well tolerated by the study population, which included elderly and poor performance-status patients, Asher Chanan-Khan, MD, Roswell Park Cancer Institute, Buffalo, N.Y., and colleagues reported. Forodesine, a potent, specific transition-state inhibitor of the purine salvage pathway enzyme PNP, induces apoptosis in primary CLL cells via accumulation of deoxyguanosine triphosphate. Unlike other nucleoside analogues, forodesine is not phosphorylated, is not incorporated into DNA, and is not cytotoxic, Dr. Chanan-Khan noted during the 52nd American Society of Hematology Annual Meeting and Exposition.
Previous phase 1/2 studies have shown clinical activity of forodesine in T-cell acute lymphoblastic leukemia (IV) and cutaneous T-cell lymphoma (IV and oral). In a single institute exploratory study, 5 of 13 patients (38%) with CLL demonstrated anti-leukemic effects with oral forodesine (200 mg once daily); however, none of the patients achieved remission. Forodesine is absorbed via a saturable mechanism, and in a clinical pharmacology study in normal subjects, 200 mg bid dosing was found to partially overcome the exposure limits from once-daily dosing. The 200 mg bid regimen was used in this study.
Eligibility included patients with primary resistant (no complete/partial response) or progressive disease (PD) with CLL who had either failed at least 1 prior therapy or were treatment-naïve, providing their age was >65 years; ECOG performance status was 2 or 3; or they were unable to tolerate standard therapy. Among 27 patients enrolled, 1 was deemed ineligible and 1 did not receive the study drug.
Median age was 70 years (range, 48-92 years); 59% were male; and 74% had Rai stage 3/4 disease (high risk). Median duration from time to CLL diagnosis was 90.4 months (range, 8.4-243.5) months. Features of high-risk disease were del (17p) (n=6), ZAP70+ (n=13), and CD38+ (n=15). All patients had relapsed or refractory CLL with a median of 2 (range, 1-22) prior therapies including fludarabine (76%), alkylating agents (72%), anti-CD20 monoclonal antibodies (72%), and experimental agents (36%).
Primary analysis was performed after ≥6 months of follow-up. Partial remission was noted in 6/23 patients (26%). Mean time to response was 153 days, and median duration of response was 189 days. Additionally, 11 patients (48%) demonstrated stable disease. Serious adverse events were reported in 17 patients; PD was noted in 8 patients. Individual serious AE reports included 7 cases of febrile neutropenia, 5 cases of pneumonia, 2 cases of congestive heart failure, and 2 cerebrovascular accidents/intracranial hemorrhages.
Further studies of optimized dosing regimens of PNP inhibitors in CLL are warranted, Dr. Chanan-Khan noted, including evaluation of forodesine in combination with other antileukemic agents with different mechanisms of action; in patients intolerant of or ineligible for aggressive conventional chemotherapeutic regimens; or maintenance treatment after conventional therapy.