Long‐term outcomes after unrelated donor transplantation for severe sickle cell disease on the BMT CTN 0601 trial
Authors: Mary Eapen, Jianqun Kou, Martin Andreansky, Monica Bhatia, Joel Brochstein, Sonali Chaudhury, Ann E. Haight, Hilary Haines, David Jacobsohn, Jennifer Jaroscak, Kimberly A. Kasow, Lakshmanan Krishnamurti, John E. Levine, Kathryn Leung, David Margolis, Lolie C. Yu, Mary M. Horowitz, Naynesh Kamani, Mark C. Walters, Shalini Shenoy
Journal: American Journal of Hematology (2024)

HLA-matched sibling donor transplantation accounts for the majority of transplants performed for sickle cell disease (SCD). However, only about 18% of patients in the United States with SCD will have unaffected human leukocyte antigen (HLA)-matched siblings or one with sickle trait, limiting applicability. A Blood and Marrow Transplant Clinical Trials Network phase II trial of HLA-matched unrelated donor bone marrow transplantation (URD BMT) for severe SCD was conducted between 2008 and 2014 and enrolled patients aged 3–19 years (BMT CTN 0601, NCT00745420).1 A reduced intensity immunosuppressive conditioning regimen (RIC) of alemtuzumab (45 mg; days −22 to −19), fludarabine (150 mg/m2; day −8 to −4), and melphalan (140 mg/m2; day −3) was employed using alemtuzumab early to provide recipient immune suppression to overcome a higher risk of graft rejection (GR) with URD BMT in SCD patients while also limiting toxicities associated with myeloablative agents.1 The trial met a pre-specified primary endpoint of 75% 1-year event-free survival (EFS). However, as previously reported, the incidence of 1-year acute and extensive chronic graft-versus-host disease (GVHD) were unacceptably high at 17% and 38%, respectively. This report details long-term outcomes in this previously reported cohort as an important consideration for therapeutic trials as follow-up is usually limited to early time points. Follow-up information beyond 2 years post-BMT was available for 20 of 21 survivors described in the initial report through the Center for International Blood and Marrow Transplant Research (CIBMTR) database, which collects patient-level data from transplant centers annually for 5 years and then every 2 years for as long the center maintains contact with the patient (www.cibmtr.org). Median follow-up was 97 months (range 11–144). Six patients were lost to follow-up at 11 months, 4.0, 4.5, 5.5, 5.5, and 6 years after transplantation. For this report, GR, GVHD, EFS, and overall survival (OS) were examined similar to the initial report.1 The incidence of GR and chronic GVHD was calculated using the cumulative incidence estimator to accommodate competing risks. Probabilities of EFS and OS were calculated using the Kaplan–Meier estimator. Surviving patients were censored at the last follow-up or death. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). The median age of this cohort at transplant was 13 years (range: 6–18); 5 were 6–9 years old, 10 were 10–15 years old, and 6 were 16–19 years old (Table S1). Median donor age was 34 years (range: 21–53). Indications included stroke (N = 11), vaso-occlusive episodes (N = 5), acute chest syndrome (N = 3), and high transcranial Doppler velocity (>200 cm/s) (N = 2). The median age of recipients at the current time is 21 years (range: 11–25). Eighteen (86%) had ≥5 years of follow-up. Three patients died beyond 2 years post-transplant. Two deaths were secondary to complications of chronic GVHD at 2.6 and 3.9 years. A third patient who had primary GR (reported in the initial report), underwent a second myeloablative URD umbilical cord blood transplant 27 months after the first and died at 2.5 years after the first transplant of grade IV acute GVHD that developed following the second transplant. Consequently, the 5- and 8-year probabilities of OS were 68% (95% CI: 48%–82%) (Figure 1A). With a single secondary GR 5 years after transplantation, the 5- and 8-year probabilities of EFS were 61% (95% CI: 41%–76%) and 57% (95% CI: 37%–73%), respectively (Figure 1B). The 8-year GR rate is 14%, similar to that previously reported after myeloablative or reduced intensity alternative donor transplantation.2 At last follow-up, performance scores for 19 of 20 patients were reported as 90–100 (n = 13) and 70–80 (n = 6). There were no central nervous system (CNS), pulmonary, or vaso-occlusive events reported after successful donor engraftment. No patient reported pulmonary, cardiac, hepatic, renal, or CNS toxicity beyond a year post-transplant. Details of immune reconstitution were available in 12 patients, and all reported normalization of CD4+ and CD8+ T cell numbers at 2 years. Four patients reported gonadal dysfunction of which two patients (male aged 13 years and female aged 18 years at transplantation) were receiving hormone replacement therapy. Two others did not (male aged 10 years and female aged 15 years but now deceased). Fifteen patients are ≥18 years of age and none have reported pregnancies or history of having fathered children. However, the cohort is still young at a median age of 21 years (range: 18–25) and longer follow-up will be necessary to report on fertility. Apart from the conditioning agents, additional disease-related factors that impede fertility in SCD patients include vascular complications affecting the gonads, transfusional iron-overload and related toxicity, and hydroxyurea use.3 The level of contribution of each of these factors is difficult to evaluate unless future trials incorporate such data collection. Other complications beyond 1 year after transplantation were reported in nine patients. New-onset avascular necrosis was reported in 4 patients, 1.3, 2.4, 2.9, and 3.4 years post-transplantation. Two patients had pancreatitis 1.7 and 2.2 years post-transplant, adrenal insufficiency was reported at 3 years in one patient, and severe depression and anxiety in one patient each, 1.8 and 5 years post-transplant. Patients with SCD and progressive age-related vasculopathy are predisposed to all these complications that could have been exacerbated by GVHD prophylaxis or therapy with corticosteroids.4-6 Four patients were lost to follow-up 4–6 years after transplantation and one declined consent for data collection upon age of maturity. The reasons for loss of follow-up are not known but previous reports have noted obstacles to transition of care, perceived discrimination and consequent nonadherence to physician recommendations, communication barriers regarding the impact of participation in clinical trials, and concerns regarding maintenance of privacy. We have also experienced limitations that impact outcomes such as medication compliance especially in adolescent patients. The small sample size was inadequate to formally examine risk factors for late mortality. The two deaths beyond 2 years after transplantation occurred in patients aged 15 and 19 years at the time of transplant and was GVHD associated. This extends the observation reported in the primary manuscript1 that all GVHD-associated deaths occurred in patients who were transplanted beyond 13 years of age. A higher mortality in SCD patients transplanted beyond the first decade of life (presumably with more advanced disease) and an increasing GVHD risk with age and associated mortality have been previously reported.7 Calcineurin inhibitor and short-course methotrexate-based GVHD prophylaxis that was used in this trial is a common regimen that is used with T-depleting antibody-based conditioning where the latter helps provide additional GVHD prophylaxis. In this study, however, in vivo T-cell depletion with alemtuzumab was used 3 weeks prior to transplant targeted immune ablation of the recipient while sparing donor cells to facilitate engraftment due to the higher risk for GR in this non-malignant disorder. As hoped, this supported sustained engraftment despite the RIC regimen. The alemtuzumab however was unable to provide a GVHD sparing benefit. The regimen had previously been used in other non-malignant disorders and in HLA-matched sibling donor transplantation for SCD with EFS and OS rates of 90% and 93%, respectively.8 In that setting, chronic GVHD again occurred only in recipients >13 years of age and GVHD-related mortality was noted only in patients >17 years of age at the time of transplant similar to GVHD patterns previously described and encountered in the current study.1, 9 Safety was compromised by the high rate of GVHD and associated mortality in older recipients drawing attention to the need for more effective GVHD prophylaxis for this transplant approach. In summary, extended follow-up demonstrated that engraftment and cure were achievable with a RIC regimen following unrelated donor transplantation. The GVHD prophylaxis, however, was inadequate especially in recipients over 13 years of age, compromising outcomes and increasing mortality. Since completion of BMT CTN 0601 and the recognition of the GVHD-related complications, successful application of novel GVHD prophylaxis, including extended duration abatacept, has been reported with this conditioning regimen in HLA matched and minimally mismatched unrelated transplants.10 This progress has paralleled with the successful use of RIC regimens in haploidentical transplantation with post-transplantation cyclophosphamide to offset chronic GVHD in older recipients thus helping advance alternate donor transplantation for SCD.11 These efforts are proceeding in parallel with gene therapy efforts that have successfully achieved engraftment of gene-modified autologous cells following myeloablative conditioning. It is encouraging that the results from these collective curative efforts are now approaching those previously described only after HLA-matched sibling donor transplantation and serve to expand curative options for SCD patients over a wide age and therapeutic range. Importantly, these curative therapies require long-term follow-up via registries as described here to ensure that short-term success is sustained and pros and cons are tracked. Mary Eapen and Shalini Shenoy designed the study, interpreted the data, and drafted the manuscript. Mary Eapen and Jianqun Kou assembled and prepared the data set and analyzed the data. All remaining authors critically reviewed the manuscript. All authors approved the final manuscript. Support for this study was provided by grant #U10HL069294 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute, along with funding by the National Marrow Donor Program, the Sickle Cell Disease Clinical Research Network, and the National Center on Minority Health and Health Disparities. The Center for International Blood and Marrow Transplant Research is supported primarily by grant #U24-CA76518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases and contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the above mentioned parties. Authors declare none for this study. Data available on request due to privacy/ethical restrictions. Table S1. Patient and donor characteristics at transplantation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.