Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study

Abstract

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of Busulfan (13.2 mg/kg), Fludarabine (175 mg/m2) and Thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17–36) were enrolled at 8 centers. Seventeen patients received marrow from an HLA-identical sibling donor and 5 patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grade II-III acute GVHD (18%) and 6 developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68–98%) and 86% (95% CI, 63–95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).

Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease

“…Based on the acute and chronic complications that lead to greater morbidity and mortality in SCD, several guidelines have been proposed for when to consider allogeneic HSCT [34,35,36,37]. Most of the earlier guidelines focused on acute complications (e.g., stroke, recurrent hospitalizations for VOC or acute chest syndrome), chronic organ complications (e.g., impaired neurocognitive function with abnormal brain MRI scan, early stages of sickle lung disease, nephropathy, retinopathy, or avascular necrosis of multiple joints), or red blood cell alloimmunization during long-term transfusion therapy [37].…”

“…More recent guidelines have included an elevated TRJV, removed sickle lung disease, and bilateral proliferative retinopathy as indications for HSCT. Table 1 provides criteria that have been proposed for HSCT using either HLA-matched related or alternative donors in SCD [34,35,36,37]. Due to the concern of greater HSCT-related complications when using an alternative donor as the graft source, guidelines recommend that hydroxyurea or chronic red blood cell transfusion therapy be tried prior to HSCT using an unrelated or haploidentical donor source [34].…”

“…In a retrospective study of 20 SCD adults (mean age of 33 years) undergoing HSCT using HLA-matched related donors at the University of Baskent, all 20 had stable engraftment at the last follow-up and 11 of 12 patients who completed one year of follow-up were off all immunosuppression [50]. In the prospective, multicenter STRIDE study of 22 adolescents and young adults (median age: 23 years) undergoing HSCT using either HLA-matched related or unrelated donors, two patients had secondary graft failures and two deaths were observed [35].…”

Chimerism in the Realm of Hematopoietic Stem Cell Transplantation for Non-malignant Disorders—A Perspective

“…Myeloid lineage chimerism is a good surrogate for erythropoiesis in the absence of red cell chimerism (CD71) evaluation. Lymphoid engraftment can remain low or increase over time but there are no threshold levels necessary to maintain myeloid engraftment (21,22).…”

Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

“… 43 Since that first transplant using cyclophosphamide and fractionated whole body irradiation, outcomes for HSCT have improved with the introduction of other conditioning regimens, including busulfan, fludarabine, and anti-thymocyte globulin. 44 , 45 Despite being potentially curative, HSCT is optimized in individuals with a matched sibling donor, which is not universally available. Furthermore, the risks of HSCT, including infertility and graft- versus -host disease, have dampened enthusiasm as a universal cure.…”