Durable Engraftment, Correction of Genetic Defects and Prevention of Veno-Occlussive Disease, Following Blood and Marrow Transplantation with an HLA-Matched Sibling DONOR, Using a Reduced Toxicity Conditioning Regimen with Busulfan, Reduced Dose Cyclophos

Background: Genetic lymphohematopoietic diseases have been effectively cured by performing allogeneic blood and marrow transplant (BMT) from a histocompatible sibling, following a standard conditioning regimen with busulfan (BU), cyclophosphamide (CY), and antithymocyte globulin (ATG). However, the high levels of transplant related mortality (TRM) and morbidity with this regimen limits its more widespread use as curative therapy. Objective: To determine the safety, donor chimerism and complications associated with de-escalation of CY, in a reduced toxicity conditioning regimen with fludarabine and alemtuzumab, prior to HLA-matched sibling donor transplantation among pediatric recipients with genetic lymphohematopoietic diseases. Methods: Eligible patients were consented at Children’s Hospital Los Angeles, Stanford Hospital and Lucile Packard Children’s Hospital between 2008 and 2013. The conditioning regimen consisted of Busulfan 16 mg/kg, Cyclophosphamide 105 mg/m2 Fludarabine 105 mg/m2, and Alemtuzumab 52 mg/m2. Graft versus host disease prophylaxis consisted of steroids and a calcineurin inhibitor. Results: The study population was 68% female with a median age of 5.25 (± 5.9 years). Patients pre-transplant diagnoses included Sickle Cell Disease (n=7), Thalassemia (n=4); Kostmann’s Syndrome (n=2), Chronic Granulomatous Disease (n=1), Chediak Higashi syndrome (n=1), hemophagocytic lymphohistiocytosis (n=2), Cartilage Hair Hypoplasia (n=1), Diamond Blackfan Anemia (n=2), and Hurler’s syndrome (n=2). The median total nucleated cell count (TNC) and CD34 dose was 4.6x108 (± 2.26x108) cells/kg and 8.5x106 (± 5.2x106) cells/kg respectively. All patients had an initial donor chimerism >90% (median 99%). The median time to neutrophil engraftment (>500 cells/µL) and platelet engraftment (>20K cells/microliter) were 19 (±9.7) and 23.5 (± 26.2) days respectively. One patient required a stem cell boost on day +83 (poor count recovery due to CMV). There were no cases of veno-occlussive disease or Grade III/IV acute or extensive chronic GVHD. Infectious complications (Figure 2) included CMV viremia (n=5), EBV viremia (n=1), mucoromycosis (n=1) and adenoviremia (n=1); two patients expired, one from pneumonitis (EBV viremia) and the other from mucormycosis. Overall survival (OS) at 100 days was 95%; with a median follow up of 1 (± 2.05) years, the OS is 90%, with all patients sustaining high-level donor chimerism and a median Lansky/Karnofsky score of 100. Conclusion: A reduced toxicity conditioning regimen with reduced doses of CY achieves durable engraftment of stem cells from related donors among patients with genetic lymphohematopoietic diseases and low rates of transplant related mortality and morbidity. Longer follow-up is required to assess for a potential reduction in late effects associated with this regimen.