The results of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimen doses in patients with Hurler syndrome

Background. Hurler syndrome is the most severe type of mucopolysaccharidosis with central nervous system, cardio-vascular system and musculoskeletal system involvement. A unique method of radical therapy is allogenic stem cell transplantation (allo-HSCT). A question on high toxicity of HSCT is still unsolved for these patients.

Aim – to estimate effectiveness and toxicity of conditioning regimen with reduce intensity in patients with Hurler syndrome.

Materials and methods. Eight patients were enrolled to the investigation. Follow-up median was 20 (1–60) months. 6 patients received allo-HSCT from full HLA-matched unrelated donors, 2 patients received HSCT from partially HLA-matched unrelated donors with mismatch in A locus. The following conditioning regimens with reduce intensity were used as preparative therapy: Fludarabine – 150 mg/m2, Melphalan – 140 mg/m2, Antithymocyte Immunoglobulin (ATGAM) – 60 mg/kg. For graft-versus-host disease (GvHD) prevention Cyclosporine A in dose 1.5 mg/kg2 time per day with a combination with Methotrexate (10 mg/m2 in days +1, +3, +6) or Mycophenolate mofetil (MMF) (15 mg/kg 2 times per day during 30 days) was used. The most common transplant source were peripheral blood stem cells (PBSC) – 6 (75 %) patients, in 2 cases bone marrow was used. Due to high level of T-cells in PBSC at 3 patients, the immunomagnetic CD3/CD19-depletion or CD34+-cells depletion with the help CliniMACs device was performed. The following transplantation of CD3/CD19+-cells in dose 1.0 × 107/ kg
of recipients weight in case of full-matched unrelated donor or 1.0 × 106/ kg of recipients weight in case of mismatched unrelated donor was performed.

Results. Six patients are alive on a moment of analysis (median follow-up 20 (1–60) months). Overall survival of patients with Hurler syndrome after allo-HSCT is 75 %. All patients engrafted with complete donors chimerism on day +30. Alpha-L-iduronidase activity in leukocytes achieved normal level (average 61.3 nM/mg/18 h) on day +30. Activity was normal till day +100 – 77.6 nM/mg/18 h (normal indicator –61.0–175.5 nM/mg/18 h). Mixed donor’s chimerism was revealed on days +60 and +180 at two patients. No incidence of severe mucosytis III–IV gr. revealed. Two patients died due to transplant related causes. Causes of deaths: 1st patient – acute intestinal GvHD IV gr., III gr. skin GvHD, II gr. liver GvHD on day +69 from allo-HSCT, 2nd patient – TRALI-syndrome after packed red cells transfusion on day +45after allo-HSCT.

Conclusion. Allo-HSCT with reduced intensity conditioning regimen for the patients with Hurler syndrome is effective method of treatment without severe toxic complication. Immunoadoptive therapy can be used for rejection prevention in case of mixed donor’s chimerism.

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