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Purpose A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. Patients and Methods Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. Results The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily × 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. Conclusion Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.

7542Background: Forodesine, a potent purine nucleoside phosphorylase inhibitor, induces apoptosis mainly in T cells. Forodesine at relatively low dose was feasible but the response rate was not suf...

8552 Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to T-cell selective intracellular accumulation of dGTP, resulting in apoptosis. Methods: An open-label dose escalation study of oral forodesine (40–320 mg/m2 daily) for 4 wks with extended therapy was performed to determine the maximum tolerated and/or optimal biologic dose (OBD). Additional subjects were accrued at an OBD (80 mg/m2) to further assess safety and clinical efficacy. Subjects with refractory CTCL, stages IB-IV were eligible. The primary efficacy endpoint (objective response rate [ORR]) was defined as ≥ 50% improvement by a severity-weighted assessment tool (mSWAT). Results: The overall intent to treat response rate was 17 of 64 (27%) subjects or 14 of 36 (39%) at the OBD. As of October 2008, nine of 64 subjects (14%) have received forodesine treatment for >12 months. This cohort of 9 subjects is further examined. Six discontinued treatment (median time on treatment 440 days): 4 for progressive disease, 1 withdrew consent, and 1 due to an adverse event (Diffuse Large B-cell Lymphoma). Three are continuing on therapy for 416, 710, and 863 days. Median age was 68 years (range 42, 81), and all but one was ≥ stage III. They had received a median of 3 prior systemic therapies including 8 of 9 with prior bexarotene. Five of 9 subjects had a response (2 with complete response, 3 with partial response, and 4 with stable disease). Related AEs were experienced by 7 of 9 subjects. The most frequent were nausea (44%), fatigue, peripheral edema, dyspnea, and urinary casts (all 22%). Grade 3 or higher related AEs were experienced by 2 of 9 subjects (Diffuse Large B-Cell Lymphoma as previously mentioned and peripheral edema). There were no hematologic or infection AEs related to forodesine. Grade 3 lymphopenia and CD4 count < 200 were noted in 8 of 9 and 4 of 9 subjects respectively. The risk of any infection AE regardless of cause in these 9 subjects was 15 per 100 person-months of forodesine exposure compared to 59 in all other subjects (n=55). Conclusions: Forodesine has an acceptable safety profile and efficacy in these CTCL subjects treated for 12 months or longer. [Table: see text]