Successful usage of fludarabine for treatment of partial immunologic hematopoietic graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients

Summary

Introduction

There are no any widely accepted recommendations for management of immunologic graft rejection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A number of possible approaches increase therapeutic risk due to high toxicity and severe side effects. Our aim was to evaluate the Fludarabine-based immunodepletion therapy followed by donor lymphocytes infusion (DLI) for treatment of early immunological hematopoietic graft rejection after allo-HSCT.

Patients and methods

Efficacy of Fludarabine therapy has been tested in BMT Department of the Russian Children Research Hospital. Seven patients at early terms after allo-HSCT were selected (6 patients with non-depleted graft, and one case of haploidentical HSCT with TcR α/β/CD19-depleted graft), treated from 2008 to 2016. Diagnoses: 2 patients with acute myeloid leukemia; 2, with aplastic anemia; 1, with MPS type I (Hurler syndrome); 1, with neuromyelitis optica (Devic’s disease); 1, with osteopetrosis. Treatment indications were as follows: decreased donor chimerism (common or/and restricted by CD34+ and CD3+) less than 95% at 1…6 months after HSCT. All the patients were transfusion-dependent at the moment of therapy (four patients were transfusion-dependent permanently after HSCT, and three required transfusions after the chimerism shift). The regimen used consisted of lymphocyte depletion therapy with fludarabine (150 mg/m2 for 5 days in one patient, and 90 mg/m2 for 3 days in other patients) followed by DLI on day 3 after the fludarabine treatment. Average dose of donor lymphocytes was 7.25х105 cells/kg, number of DLIs was 1 to 6 (depending on individual patient’s characteristics). Chimerism control was performed on day +30 after DLI. The average observation period was 3.5 years (10 months to 8 years).

Results

Five patients developed complete donor chimerism 1 month after DLI, and became transfusion independent. There were no any serious complications or side effects of the therapy. All patients who responded to the treatment have maintained complete donor cell engraftment during entire observation period. Two patients rejected their grafts despite treatment and will be transplanted again.

Conclusion

Our study shows that post-HSCT monotherapy with fludarabine followed by DLI is an effective and safe approach to therapy of partial immunological graft rejection, and may resolve a transfusion dependency.

Keywords

Allogeneic hematopoietic cell transplantation, donor lymphocyte infusion, graft rejection, fludarabine