Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Non Malignant Hematologic Disorders (NMHD), Using a Chemotherapy-Only Cytoreductive Regimen and T-Cell Depleted Grafts from Alternative Donors

Non-malignant hematologic disorders of childhood comprise a number of various disorders  including acquired severe aplastic anemia (SAA), and inherited marrow failure syndromes. Patients with such diseases who do not have matched related donors fare poorly with allogeneic HSCT from alternative donors and are at high risk for developing chronic GvHD. We report 14 patients aged 0.7-18 years of age (median 5.3 years) who received T-cell depleted HSCT from alternative donors between April 2005 and May 2013. Diseases included acquired SAA including PNH (N=6), severe chronic neutropenia (SCN)(N=2), congenital amegakaryotycic thrombocytopenia (N=2), Shwachman Diamond syndrome (N=1), autoimmune hemolytic anemia (N=1), chronic granulomatous disease (N=1) and hemophagocytic lymphohistiocytosis (N=1). Two patients with SAA had constitutional abnormalities and were therefore thought to have possibly genetic diseases despite negative testing for defined disorders. Ten patients had long standing symptomatic disease for > 1 year prior to transplant. Patients with Fanconi anemia and dyskeratosis congenita were treated with reduced intensity regimens and were not included.  Patients received one of 3 myeloablative regimens: Busulfan Melphalan and Fludarabine (N=2), Cyclophosphamide Thio Flu (N=3) or Mel, Thio Flu (N=9). Patients received rabbit ATG pre-transplant and filgrastim post transplant to promote engraftment. Donors were unrelated HLA-matched donors (N=5), unrelated HLA-mismatched donors (N=6) or related HLA-mismatched donors (N=2), and related phenotypic matched donor (N=1). Grafts included soybean agglutinin negative, E-rosette negative bone marrow grafts (N=5), Isolex CD34+ E-rosette- peripheral blood stem cell grafts  (N = 4), or CliniMACS CD34+ PBSC grafts (N=5).

All 13 evaluable patients engrafted. Neutrophil engraftment occurred on day +12 and platelet engraftment to 20,000 on day +20 post transplant. Four patients died from multi-organ failure and/or infection (three of whom had a duration of their disease of 2-7 years). One patient with SAA fully engrafted with donor cells developed a pancytopenia post transplant with secondary MDS in donor cells; this patient is alive. Excluding one patient who is too early post transplant and with a median follow-up of 2 years, 8 of 13 patients are alive (OS 61%). None of these patients has evidence of GvHD.

These results should encourage proceeding to transplant with chemotherapy-only cytoreductive regimens and T-cell depleted stem cell transplants from alternative donors for patients with non malignant hematologic disorders earlier in the course of their disease.