Curative Allogeneic Stem Cell Transplantation Is Safe and Feasible in Adult Patients with Sickle Cell Disease Despite Lack of Matched Sibling Donor and Presence of Sickle Cell-Related Co-Morbidities
Authors: Assal Amer , George Diane , Bhatia Monica , Gordillo Christian , Howard Nicole , Reshef Ran , Mapara Markus Y 
Published: October 2019

Abstract
Introduction:
Sickle cell disease (SCD) affects 300,000 annual births globally, and about 100,000 individuals in the United States. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only cure. HSCT risks necessitate a risk-benefit analysis in each case. Excellent long-term overall survival (OS) of 91-95% has been described with matched-sibling (SIB) HSCT, but fewer than 15% of SCD patients have a SIB donor. Matched unrelated donor (MUD) availability is limited for ethnic groups afflicted with SCD. Alternative donor HSCT from mismatched unrelated donors (MMUD) or haploidentical donors improves donor availability but increases toxicity and risk of graft failure. SCD-induced organ damage is another limitation to HSCT. In this study, we review our experience with HSCT for SCD and demonstrate that most patients can receive a curative HSCT despite lack of SIB donor and presence of significant co-morbidities.
Methods:
All adult SCD patients who received HSCT at our center since 2014 were included. Patients had at least 2 hospitalizations per year for pain crises despite hydroxyurea compliance and evidence of end-organ damage. Patients with a SIB donor (n=6) received conditioning with alemtuzumab and 3Gy TBI (per Hsieh et al, 2009). Patients with MUD/MMUD (n=4) or haploidentical (n=1) donors received conditioning with alemtuzumab, fludarabine, melphalan, and a CD34+ selected graft with CD3+ cell add back on an ongoing clinical trial for non-malignant hematologic diseases. One patient s/p kidney transplant and liver failure requiring TIPS procedure was conditioned with alemtuzumab and 4Gy TBI, received a 10/10 MUD graft, and given post-HSCT cyclophosphamide (50 mg/kg d+3) along with sirolimus continuation as GVHD prophylaxis. GVHD prophylaxis otherwise consisted of sirolimus (n=10) and tacrolimus (n=1). All patients received a G-CSF mobilized peripheral blood stem cell (PBSC) graft and underwent RBC exchange to achieve Hgb S <30%.
Results:
Twelve patients are included in this analysis. Median age was 28.7 (18.5 - 44.2) years with 6 males and 6 females. Median follow up was 13.6 months (range 1.4 - 51.3). Two patients had stage V renal disease with one patient on active dialysis. Two patient were s/p kidney transplant with one patient awaiting a 2nd kidney transplant. Median CD34 cell dose in SIB and MUD/MMUD HSCT was 14.8 and 8.5 x 10e6 CD34/kg respectively. Median T cell add back in CD34-selected M/MMUD recipients was 2.5 x 10e5 CD3/kg. No G-CSF was used. All patient engrafted with no cases of graft failure or treatment related mortality (TRM). Median time to neutrophil engraftment for SIB and M/MMUD recipients was 24.5 and 19 days respectively. Median time to platelet engraftment was 19 days for M/MMUD recipients and 2 of 6 SIB recipients required only 1 platelet transfusion each. The patient s/p kidney allograft and TIPS for liver failure engrafted neutrophils and platelets on day +22 and +26 respectively. All patients are alive and free of SCD. Available chimerism analysis at 6 months (n=8) shows median myeloid chimerism to be the same in SIB and M/MMUD recipients (99.7%) where median T Cell chimerism was 35% and 65% for SIB and M/MMUD recipients respectively. Chimerism at 1 year shows stable myeloid engraftment and median T cell chimerism of 61.5% for SIB recipients.
Two cases of PRES were noted after HSCT, one in a patient on tacrolimus after which the CD34-selected protocol was modified to include sirolimus as GVHD prophylaxis. Another case of PRES was noted on sirolimus which was switched to prednisone and mycophenolate mofetil. Two patients discontinued sirolimus due to myalgias and were switched to tacrolimus on days +44 and +58 with resolution of symptoms.
Acute/Late acute GVHD occurred in 4 patients. Three cases were noted in patients treated on the CD34-selected protocol; two MMUD (Grade III and Grade I) and one haploidentical (Grade III) graft recipients. One case of late acute liver GVHD, evident in elevation of liver enzymes and alkaline phosphatase with evidence of hepatitis on biopsy, occurred in a SIB recipient (Grade I). All cases responded to corticosteroid therapy.
Conclusion:
SCD patients with or without a SIB donor can be offered a curative HSCT that is safe without TRM. SCD patients with severe SCD-related organ damage can also be offered HSCT however further research is warranted to identify optimal conditioning and GVHD prophylaxis regimens for these patients.

Disclosures
Reshef: Kite Pharma: Consultancy; Atara Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.