Case number# PHHY2015US027243, is an initial literature case report received on 04 Mar 2015. The authors discussed using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning. This report refers to a female patient of unknown age with Hgb SS type of sickle cell disease (SCD). The concomitant medications included levetiracetam to prevent busulfan and cyclosporine induced seizures, amlodipine to prevent cyclosporine induced hypertension and supplemental magnesium beginning on day -2 was recommended to prevent cyclosporine-induced hypomagnesemia. On an unknown date, the patient underwent hematopoietic cell transplantation (HCT) at the age of 8 from the bone marrow of 25-year-old female and the indication was abnormal transcranial Doppler ultrasonography (TCD). For post-transplant immune suppression, cyclosporine (manufacturer unknown) and methotrexate (manufacturer unknown) and were administered. Cyclosporine administration commenced on day -2 using the intravenous formulation and subsequently converted to oral as patients were able to tolerate; doses were adjusted to maintain a level of 200 to 300 ng/mL by the TDx method (or equivalent level for other cyclosporine testing methods). Methotrexate was administered at a dose of 15 mg/m2 intravenous (based on actual weight) on day +1 and at 10 mg/^2 intravenous on days +3 and 6 and 11. The stratum (dose de-escalation schema) was level two which included total dosage conditioning regimens of fludarabine at a dose of 105 mg/m2, busulfan at a dose of 12.8 mg/kg, the percentage decrease was 0. The cyclophosphamide total dosage was 90 mg/kg with a % decrease of 55 from the initial 200mg/kg; horse ATG total dosage was 90 mg/kg. The cytomegalovirus (CMV) serostatus was negative for both recipient/donor (R/D). Total nucleated cell (TNC) was 1.6 x 108/kg and CD34+/kg was 9.0 x 106/kg. The estimated average AUC (per dose) was 973. The length of follow-up was 18 months. The patient had neutrophil engraftment on +22 day and platelet engraftment on +33 day. There was no grade three-fourth regimen-related toxicity (RRT). The chimerism on day +28 was 68/100%. The patient developed stage 2 skin, grade 1 acute GVHD that responded to treatment. She was placed back on immune suppression, shortly after discontinuation, because she developed moderate chronic GVHD. Her GVHD progressed and was severe. Of interest, the chronic GVHD occurred after receiving an influenza vaccine. The patient developed posterior reversible encephalopathy syndrome shortly after initiating treatment (cyclosporine and prednisone) for her chronic GVHD. All clinical and acute radiographic (by magnetic resonance imaging) abnormalities resolved. For seizure prophylaxis they used levetiracetam instead of phenytoin and other older anticonvulsants used in previous studies. The most recent hemoglobin (g/dL) was 10.0 and hemoglobin S was 40.3% (donor had sickle cell trait). The number of transfusions post-transplant for packed red blood cell (PRBC) was 2 and for platelet were 17. Seriousness assessment of the events (acute skin GVHD, chronic GVHD and PRES) was upgraded as per NVS-IME list. The authors concluded that the results of the dose de-escalation trial demonstrate that by adding fludarabine to BU-CY-ATG, it was feasible to reduce the dose of cyclophosphamide needed to achieve donor engraftment in children with SCD receiving matched related donor transplants. A full-scale multi-institutional clinical trial was needed to confirm that this 4-drug regimen can maintain disease-free survival at 95%.