Long-Term Follow-up of Adults with Severe Sickle Cell Disease After Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning
Authors: Biernacki Melinda A , Okam Maureen , Shenoy Shalini , Krishnamurti Lakshmanan , Horwitz Mitchell E. , Neuberg Donna , Antin Joseph H. , Wu Catherine J 
Published: October 2019

Abstract
Abstract 261
Despite advances in care, sickle cell disease (SCD) continues to be associated with considerable morbidity and premature mortality, particularly in adulthood. Myeloablative hematopoietic stem cell transplantation (HSCT) in children 16 years or younger with matched sibling donors is effective, well-tolerated, and controls SCD-mediated damage. In adults, HSCT after myeloablative conditioning carries unacceptable transplant-related mortality. Several recent studies suggest the feasibility of using reduced intensity conditioning regimens (RIC) in adults. However, these reports were generated with few patients, using different regimens, and with short follow-up periods. To determine the common features of these regimens, and to assess the long-term outcomes of RIC-HSCT in adults (16 years or older), we reviewed all reports published on the subject as manuscripts or abstracts from 2002 to 2010. Six distinct RIC-HSCT regimens were used (see table). All included fludarabine and/or alemtuzumab. Twenty previously reported adult patients (age 16–45, median 21 years) and 4 new adult patients were identified. Nine of the 24 patients received bone marrow stem cells, while the rest received peripheral blood stem cells. All had HLA-matched donors. From reported outcomes, RIC-HSCT was well-tolerated with minimal transplant-related toxicity. At a median of 2.5 years, overall survival was 95% and disease-free survival was 85%. Two patients developed acute graft-versus-host disease (GvHD), and 2 developed limited chronic GvHD. To determine long-term outcomes of RIC-HSCT in adults, we obtained follow-up information on 12 of the 24 adult patients from 3 of the 6 centers. At follow-up of up to 6 years, 11 of 12 patients were alive with stable donor chimerism (median 100%, range 0–100%) and no new SCD symptoms. Two developed acute GvHD progressing to chronic extensive GvHD. One had limited chronic GvHD but expired from an embolic event 9 months after HSCT. A fourth developed limited chronic GvHD that resolved off steroids. Six patients were able to discontinue all immunosuppressive medications. In summary, our review of published data and report of subsequent follow-up demonstrate that adult patients with SCD tolerate a variety of RIC. Conditioning regimens combining immunosuppressive agents with moderate ablation appear sufficient to generate sustained donor engraftment and disease control. Though GvHD was common, a majority of patients (6 of 11) eventually discontinued immune suppression. These data together provide compelling rationale for formal clinical trials of RIC-HSCT in adults with severe SCD.
Center (Reference) Preparative regimen GvHD prophylaxis Total # subjects in published report Age (years) of adult subjects Published outcomes Latest follow up Follow up (yrs) Death (months) Complications Most recent follow up (yrs) On IS GvHD % donor chimerism University of Pittsburgh (Krishnamurti, 2008) BU 8 mg/kg, Flu 135 kg/kg, ATG 120 mg/kg, TLI 500 cGy CsA, MMF 7 16, 16, 18, (18) 2, 1.5, 3.5 None Pancreatitis (n=1) Graft loss from IS nonadherence (n=1) 5, 5, 6, (1) 1 of 4 1 of 4 (limited cGvHD) 100, 90, 0, (70) Washington University (Shenoy-multicenter, 2008) Mel 140 mg/kg, Alem 48 mg, Flu 150 mg/kgTLI 200 cGy CsA, methylpred, MTX 5 18, 17, (17), 17, (18), (22) 0.6, 0.75, 0.9 One patient, embolus (9) TAM, pancreatitis, hemolytic anemia, pulmonary process (n=1) 3, 1.5, (0.75), -, (0.6), (0.9) 4 of 5 3 of 6 (1 limited cGvHD, 2 aGvHD/extensive cGvHD) 100, 100, (100), -, (56), (96) Duke University (Horwitz, 2007) Cy 2000/m2, Alem 100 mg, Flu 120 mg/kg CsA, MMF 2 21, 27 1.3, 2.0 None Dilated cardiomyopathy (n=1) 4.3, 5.0 0 of 2 0 of 2 91, 60 Munich (Schleuning, 2008) Cy 120/kg, Flu 120 mg/kg CsA, MMF 1 22 1 None None U/A U/A U/A U/A NHLBI (Hsieh, 2009) Alem 1mg/kg,TBI 300 cGy Sirolimus 10 16, 21, 21, 24, 26, 26, 26, 27, 40, 45 1.3-4.5 None Graft loss (n=1), 2nd HSCT successful U/A U/A U/A U/A Columbia University (Bhatia, 2008) BU 16 mg/kg, Alem 62 mg/m2, Flu 180 mg/kg +/- rATG CsA, MMF 7 16 1 None None U/A U/A U/A U/A Alem, alemtuzumab; ATG, antithymocyte globulin; Bu, busulfan; Cy, cyclophosphamide; Flu, fludarabine; Mel, melphalan; TBI, total body irradiation; TLI, total lymphoid irradiation; TAM, transplant-associated angiopathy; HTN, hypertension; IS, immunosuppressive medications; U/A, unavailable. Parentheses indicate previously unreported patient.

Disclosures:
No relevant conflicts of interest to declare.