Non‐myeloablative allogeneic HSCT in adult patients with sickle cell disease: Multiple take‐home points from the Saudi Arabia experience
Authors: Damiano Rondelli
Journal: American Journal of Hematology (2024)

Allogeneic hematopoietic stem cell transplantation has been the only curative option for patients affected by sickle cell disease (SCD), and over a thousand patients have undergone this procedure over the last decades. The initial results of innovative clinical trials utilizing autologous transplantation of gene-edited CD34+ hematopoietic stem cells1, 2 suggest that this could become another potentially curative strategy in the next future. Because allogeneic HSCT with standard myeloablative conditioning regimens carries a higher risk of transplant-related toxicity, adult patients with SCD have not been offered a curative transplant as much as pediatric patients.3 The study of allogeneic HSCT in SCD from matched-related donors presented in this issue of the American Journal of Hematology by Damlaj M and Colleagues4 utilized a pre-transplant chemotherapy-free conditioning regimen, based on immunosuppressive agents such as alemtuzumab and low-dose total body irradiation (TBI) at 3Gy, followed by graft-versus-host disease (GVHD) prophylaxis with sirolimus. This regimen was initially introduced in 20095 and then validated in other centers in adult or pediatric patients,6, 7 all with relatively small number of cases in each center. The results of this new study add relevance to the field for at least two main reasons. The first is that it is the study with the largest number of SCD patients (n = 200) receiving an allogeneic HSCT with a non-myeloablative protocol, thus validating this transplant approach both in adult and pediatric SCD patients. The second is that it addressed a significant need in a region where they estimated approximately 61 000 SCD patients over a general population of only 36 million individuals, whereas in the United States, there is an estimated number of 100 000 patients over 340 million inhabitants. This raises the importance of establishing international partnerships to have world regions with very high incidence of SCD, such as West Africa, other areas in the Middle East and in South Asia (particularly Northern India, Nepal, or Pakistan) build human and infrastructure capacity and offer HSCT at an affordable cost to currently undeserved patients. Multiple take-home points can be highlighted from this study. First, (a) in a single center experience a non-myeloablative HSCT was very effective in a large number of patients with advanced SCD with an estimated EFS of 88.2% at 3 years. The success of HSCT was also due to the control of the disease prior to transplant using hydroxyurea, iron chelation, red cell exchange, and a strict transfusion policy during the post-transplant cytopenia. Another important point (b) was that by utilizing a primarily immunosuppressive conditioning regimen with alemtuzumab and low dose TBI, fertility is likely to be preserved in a high number of patients, as demonstrated by 26 pregnancies from patients transplanted in the study. This seems extremely important since it is common to have young patients with SCD inquire about transplant due to the challenging experience of frequent venous-occlusive crises (VOC), but then holding on the decision because of their desire to carry on with their life and have a family, despite a chronic and limiting condition. A third point (c) highlighted in the study was the reduced healthcare utilization of SCD patients after allogeneic HSCT, especially because of the reduction or disappearance of VOC requiring hospital admission and transfusions. This was also previously shown by prospectively analyzing the healthcare utilization for 2 years of a group of SCD patients referred to transplant, and comparing those receiving an HSCT vs those who for different reasons were not transplanted.8 Because of the non-myeloablative preparative regimen, it is not surprising that this study further demonstrates a high tolerability of the procedure without major organ toxicity. However, the non-myeloablative approach may also be one of the causes of an 8.5% rate of graft failure. Among multiple measures to address this complication, the authors correctly suggested: optimization of HU therapy prior to HSCT, or use of G-CSF post-HSCT, or limiting the use of drugs that can concur in myelosuppression post-HSCT. Based on the experience reported using a different non-myeloablative approach in haploidentical HSCT,9 it is conceivable that increasing the dose of TBI from 3 Gy to 4 Gy could facilitate a complete donor cell engraftment and reduce the risk of graft failure. However, this would also increase the risk of GVHD. A note of caution may be raised on the assessment of risks and benefits of a second, or even a third HSCT for patients experiencing graft failure. In fact, three out of 11 patients who underwent a second HSCT, and one of two who underwent a third HSCT in this study died of sepsis. This large study from Saudi Arabia provides a solid confirmation that non-myeloablative allogeneic HSCT from MRD results in very high rates of long-term EFS, and possible cure in SCD, as well as in a cost-effective strategy since it reduces or abrogates very high healthcare costs often associated with the management of SCD. Similar encouraging results are also seen in HSCT from haploidentical donors,9, 10 suggesting that non-myeloablative HSCT can be a game changer in SCD, especially in adult more vulnerable patients. The accessibility to HSCT and its affordability in many underserved areas of the world remain the challenges that we hope to see improving in the next future. Honoraria from Vertex (clinical trial steering committee). Not applicable.