Forodesine in Patients with Refractory/Relapsed T-ALL Can Induce Prolonged Stable Remission with Minimal Toxicity before and after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Stelljes Mattias , Kienast Joachim , Berning Björna , Gokbuget Nicola , Hoelzer Dieter , Silling Gerda , Berdel Wolfgang E. , Van Houten Dahl Gary , Schissel Debra , Hemenway Molly , Gore Lia 
Published: October 2019

Abstract
Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that elevates plasma 2′-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate (dGTP) levels, leading to T-cell apoptosis. It has shown promising clinical activity in patients with T-cell malignancies. Here we describe our experience with three patients with refractory or relapsed T-cell acute lymphocytic leukemia (T-ALL) who received IV forodesine before or after allogeneic transplant (pts. treated within an ongoing study from BioCryst Pharmaceuticals, Inc, Birmingham, Alabama, USA; ClinicalTrials.gov Identifier: NCT00095381).
Methods: Forodesine was given at 40 mg/m2 for 5 days per week (1 cycle) for ≥6 cycles. Patients 1 and 2 received forodesine at 443 and 161 days after allogeneic hematopoietic stem cell transplantation (HSCT), respectively. Patient 3 received forodesine until 4 days before conditioning therapy prior to allogeneic HSCT.
Results: Patient 1 with T-ALL was transplanted in the 2nd CR (10/10 HLA-identical sibling donor), after conditioning therapy and developed extensive wide-spread nodal relapse. After 2 weeks of forodesine, he had a very good partial response. The patient developed new-onset chronic graft-versus-host disease (GVHD) of the oral mucosa and lung during treatment. After 6 cycles, treatment was stopped and corticosteroids were given for the GVHD. This patient has been in CR3 (minimal residual disease [MRD]-negative by molecular analysis and complete donor cell chimerism) for >6 months and is no longer receiving immunosuppressives. Patient 2 is a 3-year-old girl with T-ALL who, following two induction failures, proceeded to uncomplicated 6/6 unrelated marrow transplantation in CR1. She had a bone marrow relapse 5 months after transplantation and was started on forodesine on study. After 2 weeks of treatment she achieved a CR, was MRD-negative by flow cytometry, and had 100% donor chimerism. By the middle of week 3 of treatment, she developed GVHD of the liver and was treated with cyclosporine and prednisone. Twice-weekly forodesine was restarted, and all laboratory parameters returned to normal and repeat bone marrow showed continuous CR2. This patient received forodesine twice weekly for 9 additional months and remains in CR with 100% donor chimerism for >12 months (she is no longer receiving forodesine). Patient 3, who had refractory T-ALL and disease progression shortly after relapse therapy with cladribine, cytarabine, and V16, achieved stable remission after 2 weeks of forodesine and completed 6 weeks of treatment. He then received conditioning therapy followed by an HSCT from a 10/10 HLA-identical sibling donor, and remains in CR2. No drug-specific adverse events of grade 2 or higher were seen in these patients.
Conclusions: These encouraging experiences in patients with relapsed and refractory T-ALL suggest that forodesine monotherapy can be effective before and after allogeneic HSCT with minimal toxicity and without affecting potential graft-versus-leukemia effects.
Forodesine Treatment in Patients before and after Allogeneic HSCT Patient No. Age/Gender Diagnosis HSCT (prior/post forodesine Tx) Response Disease Status 1 28/M T-ALL, relapse Prior PR CR ongoing 215+ days 2 3/F T-ALL, relapse Prior CR CR ongoing 398 + days 3 27/M T-ALL, refractory Post CR CR ongoing 180+ days