Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure—albeit with full host haemopoietic recovery—occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2–70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day −9 and 2 mg/kg on days −8 and −7, intravenous fludarabine 30 mg/m 2 on days −6 to −2, intravenous cyclophosphamide 14·5 mg/kg on days −6 and −5, and total body irradiation 400 cGy administered as a single fraction on day −1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5–15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6–31, IQR 7·7–27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2–4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355–1294; IQR 398–943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure—the main problem previously reported—might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.
Bibliographical noteFunding Information:
We thank the patients involved in this study, their families, and their caregivers. This study was funded in part by MSCRF/TEDCO (grant no 2013-MSCRFII-0082 to RAB), and by National Institutes of Health grants ( no P01 CA015396 to RJJ, and no P30 CA006973 to William Nelson (Principal Investigator of the core grant from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins). This study was presented in part at the Late Breaking Abstracts session (LBA-3) at the American Society for Blood and Marrow Transplantation 2018 BMT Tandem Meeting, Salt Lake City, UT, USA, Feb 21–25, 2018.
SAA reports consulting and research funding from Celgene, consulting fees, advisory board fees, and research funding from Aduro Biotech, advisory board fees from Bristol-Myers Squibb, advisory board fees from Amgen, and advisory board fees from Takeda, all outside the submitted work. JB-M reports data and safety monitoring board fees from Incyte Corporation, outside the submitted work. RAB reports grants from MSCRF/TEDCO, during the conduct of the study; and scientific advisory board and research funding from Alexion Pharmaceuticals and Achillion Pharmaceuticals, outside the submitted work. KRC reports grants from MSCRF and grants from the National Institutes of Health, during the conduct of the study. LL reports advisory board fees from AbbVie, speaking engagement fees from Merck, grants from Genentech, and advisory board fees from Pharmacyclics, ouside the submitted work. HJS reports belonging to the speaker's bureau for Jazz Pharmaceuticals regarding Defitelio (Jazz Pharmaceuticals; Dublin, Ireland), and helped create a slideset, and spoke about veno-occlusive disease pathophysiology and treatment. SAT reports a scientific grant from ASELL and a scientific grant from Elekta, outside the submitted work. NW-J reports advisory board fees from Gilead, Bayer, JUNO, ADC Therapeutics, and Janssen, outside the submitted work. All other authors declare no competing interests.
PubMed: MeSH publication types
- Journal Article
- Clinical Trial