Targeting Busulfan to Concentration Steady State of 600–700 ng/Ml Is Associated with Robust Engraftment and Decreased Toxicity in Patients with Sickle Cell Disease Receiving An HLA Identical Donor Transplant
Authors: Domm Jennifer , Yang Elizabeth , Ho Richard , Kassim Adetola a , Frangoul Haydar 
Published: October 2019

Abstract
Abstract 1966
Sickle cell disease is a chronic illness with significant morbidity and mortality. The most frequent adverse events are painful vaso-occlusive crises (VOC) that often require hospitalization. VOC are recurrent and unpredictable and associated with higher mortality. Adults frequently suffer from the consequences of cumulative organ damage. The life expectancy of patients with sickle cell disease is still in the 40s by the most recent evaluation. The only curative therapy is allogeneic hematopoietic stem cell transplant. The major complication related to transplant includes transplant related mortality and graft rejection. We used the previously described regimen of busulfan, cyclophosphamide and ATG. Concentration steady state (CSS) of busulfan <600 ng/ml has been associated wth graft rejection and a CSS >900 ng/ml is associated with increased risk of regimen related toxicity. We targeted busulfan to a CSS of 600–700 ng/ml in an attempt to decrease regimen related toxicity and achieve donor engraftment.
Between 2004 and 2011 14 patients underwent allogeneic bone marrow transplant from HLA identical siblings. Preparative regimen consisted of intravenous busulfan 0.8–1 mg/kg/dose for 16 doses, cyclophosphamide of 50 mg /kg daily for 4 doses, and equine ATG 30 mg/kg daily for 3 doses. Busulfan levels were measured after the first dose busulfan and subsequent doses were adjusted to provide a total exposure of concentration steady state of 600–700 ng/ml. Graft versus host disease prophylaxis was with cyclosporine starting on day −3 and short course methotrexate. Indications for transplantation included stoke or abnormal transcranial doppler (n=2), acute chest syndrome (n=1), renal disease (n=1), history of vaso-occlusive crisis in (n=10) and availability of HLA identical donor.
The median age at time of transplant was 6.1 years (range 1.2–19 years). All patients received anti-seizure prophylaxis and antihypertensive therapy until all immune suppression was discontinued. All patients received a bone marrow graft from HLA identical siblings. The median busulfan steady state exposure was 648 ng/ml (range 607–670). Only 3 patients (21%) developed mucositis requiring parentral nutrition and none of the patients developed sinusoidal obstructive syndrome post transplant. All patient achieved neutrophil and platelet engraftment at a median of 18 and 22 days respectively. Grade II acute graft versus host disease developed in 2 patients (14%) and none of the 13 evaluable patients developed chronic GVHD (one patient is <100 days from transplant). Median donor engraftment is 100% (range 85–100) and all patients have achieved a hemoglobin profile identical to their donor's. None of the patients experienced sickle cell related complications post transplant. With a median follow up of 600 days (range 70–2644), the event free and overall survival are both 100%. All patients who are beyond one year post transplant are off all immune suppression.
We conclude that targeting of busulfan between 600 and 700 ng/ml in combination with cyclophosphamide and ATG can result in excellent and sustained engraftment with low risk of toxicity in young patients with sickle cell disease.

Disclosures:
No relevant conflicts of interest to declare.