Applicability of and potential barriers preventing allogeneic stem cell transplant in sickle cell patients treated outside a sickle cell program
Authors: Arun Kumar, Jibran Ahmed, Asad Anwar, Michael Fanucchi, Seah H. Lim
Journal: American Journal of Hematology (2018)

Despite improvement in the life-expectancy of children with sickle cell disease (SCD), there has been little change in the mortality rate among adult patients in the last few decades.1, 2 Cardiopulmonary complications remain the major causes of death in these patients. Although hydroxyurea reduces the acute sickle-related events, it does not appear to protect against the cardiopulmonary complications.3 Whether newer agents such as crizanlizumab and l-glutamine change the outcome of the disease remain to be determined. Allogeneic hematopoietic progenitor cell transplant (HPCT) is currently the only cure available to patients with SCD. However, its applicability was limited by the lack of related human leukocyte antigen (HLA)-matched donors. Only 18% of SCD patients have HLA-identical related donors.4 The use of post-transplant high dose cyclophosphamide to eradicate allo-reactive T cells and reduce graft-versus-host disease has expanded the donor pool. The majority of SCD patients are managed outside a comprehensive sickle cell program, in the real world. The applicability of and barriers preventing allogeneic HPCT from being offered to these SCD patients remain to be determined. We, therefore, carried out a survey of a random cohort of adult patients who received their care at a medical center that does not have a dedicated sickle cell program. A total of 99 adult patients were identified. The distribution of the SCD was: 75 HbSS, 19 HbSC, and 5 unknown. There were 49 males and 50 females. Median age was 26 years (range 17–65). Forty-two (42.4%) of these patients received hydroxyurea. To determine how many SCD patients would be eligible for allogeneic HPCT, we first used the five SCD-related medical indications adopted for three multicenter studies (Clinicaltrials.gov Identifiers: NCT01565616, NCT02766465, and NCT03263559). These criteria, in addition to a diagnosis of SCD, were as follows: A history of stroke, at least two acute chest syndromes within two years, multiple hospitalization for painful crisis (>3 a year for two years), blood transfusion need of >8 units a year, and presence of pulmonary hypertension. The proportion of patients who were eligible for allogeneic HPCT based on these indications was 54.5% (95% confidence interval (CI): 44.75-64). This proportion increased to 58.6% (95% CI: 48.7–67.8) when we included two more criteria that have also been included in many single-center studies: A history of multiple priapism and multiple osteonecrosis. These data, therefore, indicate that a large proportion of adult SCD patients treated in the real world could potentially be candidates for allogeneic HPCT. By far, the SCD-related criteria most commonly met for these studies were multiple hospital admissions for painful crisis and high blood transfusion requirements, followed by pulmonary hypertension, multiple osteonecrosis, and stroke (Figure 1A). A previous study found that mortality among adult SCD patients was higher in those with >4 pain crises a year or a high organ severity score,1 arguing for the utilization of allogeneic HPCT, particularly, in patients with frequent pain crises and end-organ damage. SCD-related indications for allogeneic HPCT and their influence on the risks for the development of transplant-related mortality. A, Distribution of the SCD-related indications for transplant. B, Correlation between the number of SCD-related indications met by the patients and their hematopoietic cell transplant-specific comorbidity score. C, Patients in the low- and intermediate-risk groups had less number of SCD-related indications for transplant than those in the high-risk group Patients with high SCD-related comorbidities are more susceptible to transplant-related mortality after allogeneic HPCT. To determine the impact of SCD-related comorbidities on the applicability of allogeneic HPCT, we used the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)5 to estimate the 2-year transplant-related mortality in these patients if they were to undergo allogeneic HPCT. The 2-year transplant-related mortality estimated by HCT-CI has been adjusted for age and transplant preparative regimen. A correlation was observed between the number of SCD-related comorbidities and the HCT-CI scores (R = 0.3; 95% CI: 0.04-0.52) (P = .024) (Figure 1B). This correlation persisted even when recurrent priapism and multiple osteonecrosis were added to the five SCD-related complications used in the multicenter studies (data not shown). Based on the HCT-CI scores, these patients were divided into low-risk, intermediate-risk, and high-risk groups. Less than half of the patients (41.4%; 95% CI: 29.6–54.2) belonged to the low-risk, 24% (95% CI: 15–36.5) intermediate-risk, and 34.5% (95% CI: 23.6–47.3) high-risk groups. Patients in the low- and intermediate-risk groups had less number of SCD-related medical indications for the allogeneic HPCT studies than those in the high-risk group (P = .01) (Figure 1C). Therefore, the more an adult is affected by the complications of SCD, the higher is the transplant risk. The 2-year transplant-related mortality for low-risk, intermediate-risk, and high-risk groups were estimated at 14%, 21%, and 41% respectively.5 When the transplant-related mortality is weighed against death in those managed conservatively with hydroxyurea, it has been suggested that only adult SCD patients with a 2-year mortality after allogeneic HPCT of approximately 20% would benefit from allogeneic HPCT.6 Therefore, high SCD-related comorbidities would prevent more than one-third of the adult patients treated outside a sickle cell program and are eligible for allogeneic HPCT from receiving the transplant. This group of adult SCD patients experienced a very high unemployment rate (63.8%; 95% CI: 50.9–75). The payors for more than half of the patients (53%; 95% CI: 40.8–65.7) were Medicaid, suggesting that most adult SCD patients requiring allogeneic HPCT and treated outside a comprehensive sickle cell program were from a socio-economically disadvantaged background. These factors could pose further barriers to allogeneic HPCT being recommended to the patients. In conclusion, although many adult SCD patients treated outside a sickle cell program have SCD-related medical indications for allogeneic HPCT transplant, they will unlikely be offered this potentially curative therapeutic option. It is likely that the under-usage of allogeneic HPCT in this group of patients is due to the prevailing assumption that the risks associated with allogenic HPCT outweigh the benefits for these patients. This may be the case for those with many SCD-related comorbidities who fall into the group of patients at high risks for 2-year transplant-related mortality. However, more than 40% of the adult patients belong to low- or intermediate-risk group and these patients could benefit from allogeneic HPCT. Anxiety about possible suboptimal social supports following transplant, based on the socio-economic situation of the patients, may also pose barrier. Early referral for transplant before these patients develop too many SCD-related comorbidities, combined with improved social support, will increase the applicability of allogeneic HPCT to adult SCD patients treated in the real world. All authors declare no conflict of interest.