Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman–Diamond syndrome

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS).In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/ melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m 2 / day  6), treosulfan (12 g/m 2 /day  3) and melphalan (140 mg/m 2 /day  1). CAMPATH-1H (0.1 mg/kg  2) was added in two cases, while rabbit ATG (Genzyme; 3  2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6  10 8 nucleated cells/ kg BW for the bone marrow recipients and 4.2  10 7 nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.

Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience

“…Therefore, TREO was explored increasingly in paediatric patients. [3][4][5][6][7] In general, the favourable properties of TREO, and especially the decreased acute toxicity have been confirmed in these paediatric reports. As we also observed an increasing use of TREO in paediatric patients in Germany and Austria during the last 4 years, we decided to perform a formal retrospective analysis of all patients transplanted between 2003 and 2009 and compare it wih a historical control cohort provided by the Paediatric Registry for Stem Cell Transplantation (PRST), which documents all paediatic transplantations in Austria, Switzerland and Germany.…”

“…Patients 21 and 36 with Shwachman-Diamond syndrome were previously described by Sauer et al 3 Patients 18 to 32 were included in the retrospective European Group for Bone Marrow Transplantation (EBMT) analysis of paediatric leukaemia patients conditioned with TREO. 7 The two patients with IL-10 receptor deficiency were reported by Kotlarz and Beier et al…”

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman–Diamond syndrome

“…The significant regimen-related toxicity observed during HSCT in past reports of HSCT for SDS has led to recent interest in reduced-intensity preparative regimens that might ameliorate cardiac and pulmonary toxicities. Sauer et al 36 reported three patients with SDS and BM failure transplanted using a regimen consisting of fludarabine, treosulfan and melphalan. All three patients engrafted rapidly with 100% donor chimerism.…”

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

“…However, complications from HSCT are more common in SDS patients than in patients with idiopathic blood dyscrasias [52]. However, some authors have proposed to use attenuated conditioning regimen has been proposed to limit toxicity [53].…”