The widespread adoption of stem cell transplantation, the longest studied transformative therapy for people with sickle cell disease (SCD), has been limited by the availability of fully matched bone marrow donors and by transplant-related morbidity and mortality.1 In light of improvements in conditioning therapies and post-transplant supportive care, haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with nonmyeloablative conditioning has become a feasible therapy for many individuals with SCD, as it increases the eligible donor stem cells up to 90% for all individuals.2 Haplo-HSCT with nonmyeloablative conditioning regimens have been historically associated with lower rates of engraftment,3 higher rates of graft-versus-host disease (GVHD), and mixed chimerism (the latter being associated with a higher risk of secondary myeloid neoplasms compared to fully matched sibling HSCT with myeloablative conditioning).4,5 The evolution of transformative therapies for SCD during the past two decades reflects an effort to maximize the benefit of these interventions while minimizing their risk. Thiotepa, for example, was introduced in response to the prohibitively low engraftment rates.3,6 Other examples include increasing doses of total body irradiation (TBI),7 in vivo T-cell depletion with alemtuzumab,8 and use of pretransplant immunosuppressive therapy.9
In this article, Adetola A. Kassim, MD, and colleagues from the multicenter Vanderbilt Global Haploidentical Bone Marrow Transplant Learning Collaborative present the results of their prospective, phase II study of haplo-HSCT for SCD. Eight sites participated, with a total of 70 children and young adults with SCD without a human leukocyte antigen (HLA)-matched sibling donor or an available first- or second-degree haploidentical relative. Notably, patients with a history of stroke and end-organ damage were included. Conditioning was achieved with the Johns Hopkins University nonmyeloablative regimen of antithymocyte globulin, fludarabine, cyclophosphamide, and 200 centigray of TBI. Thiotepa was added after three of the initial five participants (60%) developed graft failure, with these individuals subsequently excluded from the final analysis. GVHD prophylaxis was achieved with post-transplant cyclophosphamide (PTCy). The primary endpoint of the study was the rate of two-year, event-free survival (EFS), defined as not resulting in graft failure or death. Secondary objectives included overall survival (OS), engraftment rate, chimerism, and GVHD.
Overall, two-year EFS was 82.6%, exceeding the prespecified 80% EFS threshold. OS at one and two years was 95.7% and 94.1%, respectively, with all five deaths (7.1%; all females) attributed to infectious complications. Although there were no differences in OS among patients of different age groups, all eight graft failures (11.4%; four primary and four secondary) occurred among participants less than 18 years old, all of whom had autologous reconstitution and went on to receive a second haploidentical transplant. Among participants who engrafted, blood donor chimerism was 100% by post-transplant day 180, suggesting long-term stability of the graft. Those with SCD trait donors had less than 50% sickle hemoglobin at six months post-transplant, while those with donors without SCD had no hemoglobin S at the same time point. Both the one-year rate of grades 3 and 4 acute GVHD and the two-year rate of moderate-to-severe chronic GVHD were 10%, with no differences between children and adults, similar to other nonmyeloablative protocols with PTCy as GVHD prophylaxis.2
Although these initial results are promising, there are a few limitations to consider. It is unclear why children had higher rates of graft failure, which will require a follow-up clinical trial with a modified conditioning regimen. The paucity of older adults in this study limits generalizability. Additionally, the impact on SCD-related outcomes, such as vaso-occlusive pain crisis, health care use, and quality of life (QOL) are unavailable. These endpoints are critical in comparing the results of this study to those of gene therapy, especially as chronic GVHD may have an outsized negative impact on QOL and drive health care use.
In Brief
This study is the culmination of years of trial and error, collaboration between multiple SCD centers, and the brave contribution of hundreds of patients with SCD. The strengths of this study include the low rates of graft failure in adults, high overall survival with acceptable toxicity, the use of less toxic nonmyeloablative conditioning regimens compared to prior SCT efforts in SCD, and expanded availability with haploidentical donors. Furthermore, the inclusion of individuals with a history of stroke (largely excluded from the gene therapy trials) extends the availability of transformative therapy for those with severe SCD manifestations. The results of these studies must be interpreted in the context of improving maximum medical therapy outcomes and evolving transformative (yet costly) genetic therapies, while accounting for other nonquantifiable endpoints such as disease burden and QOL.10 Selecting a treatment approach for patients with SCD presents many challenges: the uncertainty of long-term outcomes and complications, the issue of standardizing protocols among treatment centers, and the difficulty capturing other QOL and treatment endpoints that affect the patient and provider decision-making process. With continuous multicenter collaboration, the SCD community will develop progressively better transformative therapies and improve the lives of those living with SCD.
Disclosure Statement
Drs. Caceres-Nazario and Wilson indicated no relevant conflicts of interest.
