Phase II Study of Forodesine, a PNP Inhibitor, in Patients with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia.

Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that has shown activity in acute lymphoblastic leukemia (ALL). Although the drug was thought to be most active in T-cell malignancies, preclinical data and results of a phase I/II trial showed clinical activity in B-lineage ALL (B-ALL).

Methods: Twelve patients with relapsed/refractory B-ALL were enrolled (median age of 10 adults, 48.5 yr; median age of 2 children, 10 yr). Three patients had relapsed after allogeneic bone marrow transplantation (BMT), and 9 patients relapsed after a median of two prior regimens. The patients were treated with a 30-minute infusion of forodesine, 80 mg/m² for 5 days/wk for a 4-week period. If the patient showed clinical improvement at 4 weeks, the drug was continued for additional cycles.

Results: Two of 12 patients achieved a complete response. One of these patients had relapsed after allogeneic BMT and restored complete donor chimerism after 16 weeks of forodesine treatment. As restoration of donor chimerism was achieved, the patient developed hepatic graft-versus-host disease (GVHD) and was treated simultaneously with dexamethasone beginning at 4 weeks; this was tapered off and restarted when GVHD again worsened. The second patient failed one prior regimen and had no leukemic blasts in the bone marrow after 4 weeks of treatment. Both these patients continue to receive therapy (5+ and 2+ months respectively). There were no patients with a partial response. Four patients presented with high white blood cell (WBC) counts; each demonstrated an initial decrease in WBCs without an increase in neutrophils while they were receiving forodesine but then developed persistent pancytopenia with residual bone marrow disease at 4 weeks. Dexamethasone was added to the treatment of 3 nonresponders, with no clinical benefit. Three patients with Ph⁺ B-ALL were treated on the study. Two rapidly progressed on the medication and were taken off the study before the end of 2 weeks; one had persistent pancytopenia and bone pain with residual marrow disease at 4 weeks and was taken off the study. Adverse events included increases in liver transaminase (grade ≥ 2, 2 patients) and alkaline phosphatase levels (grade 2,3, 2 patients), hyperkalemia (grade 2,3, 2 patients), and hypomagnesemia (grade 1, 1 patient). Two patients with increased liver transaminase levels underwent liver biopsies: 1 showed leukemic infiltration and the other GVHD. Patient accrual continues for this study.

Conclusions: Forodesine is a safe, well-tolerated drug with preliminary evidence of activity as a single agent in B-ALL.