Abstract
Background:
Hematopoietic cell transplant for sickle cell disease is curative but is associated with life threatening complications most of which occur within the first 2 years after transplantation. In the current era with interest in gene therapy and gene editing we felt it timely to report on sickle cell disease transplant recipients who were alive for at least 2-year after transplantation, not previously reported.
Objectives:
Our objectives were to 1) report the conditional survival rates of patients who were alive for 2 or more years after transplantation 2) identify risk factors for death beyond 2 years after transplantation and 3) compare all-cause mortality risks to those of an age-, sex- and race-matched general population in the United States. By limiting to 2-year survivors, we exclude deaths that occur as a direct consequence of the transplantation procedure.
Design:
De-identified records of 1149 patients were reviewed from a publicly available data source and 950 patients were eligible (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). The validity of the public database was confirmed by reproducing results from an earlier publication. Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age, race and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using age, race and sex-specific US mortality rates.
Results:
The median follow up was 5 years (range 2 – 20) and 300 (32%) patients were observed for more than 7 years. Among those who lived for at least 7 years after transplantation the 12-year probability of survival was 97% (95% CI 92 – 99). Compared to an age-, race- and sex-matched US population, the risk for late death after transplantation was higher as late as 7 years after transplantation (HR 3.2, p=0.020) but the risk receded over time. Risk factors for late death included age at transplant and donor type. For every 10-year increment in patient age, an older patient was 1.75 times more likely to die than a younger patient (p=0.0004). Compared to HLA-matched siblings the use of other donors was associated with higher risk for late death (HR 3.49, p=0.003). Graft failure (beyond 2-years after transplantation) was 7% (95% CI 5 – 9) and graft failure was higher after transplantation of grafts from donors who were not HLA-matched siblings (HR 2.59, p<0.0001).
Conclusion:
Long-term survival after transplantation is excellent and support this treatment as a cure for sickle cell disease. The expected risk for death recedes over time but the risk for late death is not negligible.
Graphical Abstract
INTRODUCTION
Hematopoietic cell transplant is potentially curative but is associated with mortality risks from the treatment procedure and most deaths are expected to occur within 2 years after transplantation. Unlike in children, the life expectancy of adults with sickle cell disease in the United States is shortened by at least two decades compared to the general population.1–3 Thus, a question that is often asked is whether hematopoietic cell transplant offer extended survival especially in young adults and after transplantation of grafts from donors other than HLA-matching siblings. By selecting 2-year survivors we exclude most deaths that occurred as a direct consequence of the transplantation procedure and allow us to focus on survival beyond 2 years after transplantation. The aims of this study included the following: 1) estimate conditional survival rates of patients who survived for 2 or more years after hematopoietic cell transplantation stratified by time survived since transplantation, 2) risk factors for death beyond 2 years after transplantation and 3) compare all-cause mortality risks to those of an age, sex, and race-matched general United States population. In 2018, the National Heart Lung and Blood Institute (NHLBI) began work on BioData Catalyst, a secure shared virtual space (cloud-based platform) where biomedical researchers and the public at large can access NHLBI data and work with the digital objects needed for biomedical research (www.nhlbi.nih.gov/science/biodata-catalyst).4 The first available datasets in BioData Catalyst include data from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) Program, the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) and the Cure Sickle Cell Initiative. As we used this publicly available data source, we first demonstrated reproducibility of a published report5 that utilized data that is now available in the public domain. The ability to reproduce biomedical research is a cornerstone of science advancement and will support interpretation and reporting for the current analyses.
MATERIALS AND METHODS
Data source
De-identified records were reviewed from a publicly available data source https://picsure.biodatacatalyst.nhlbi.nih.gov/ after approval of Data Access Request. The data were retrieved from Bio Data Catalyst and all analyses were performed using the Jupyter Hub, a secure cloud environment using unique authorized credentials. Statistical software package(s) are available in the cloud environment.
Outcomes
Overall survival was the primary outcome of interest. Death from any cause was considered an event and surviving patients were censored at their last follow up time. Graft failure was defined as loss of donor chimerism (<5%; whole blood) or second transplantation.
Statistical Methods
Risk factors associated with overall survival were examined using the Cox proportional hazards model.6 The variables examined for their association with survival included age, donor type, performance score, cytomegalovirus serostatus, conditioning regimen (myeloablative vs. reduced intensity vs. non-myeloablative), graft type and transplant period. Models were built using stepwise forward selection and variables that met a significance level ≤0.05 were held in the final model. All variables met the assumption of proportional hazards and there were no first order interactions between the variables held in the final models. The probability of overall survival by donor type was generated from final Cox regression model adjusted for variables retained in the final model.7
Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. If S(x) is the unconditional (traditional) survival probability at time x, then the conditional survival probability S at any time y > x is S(y/x)=S(x + y)/S(x). The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after hematopoietic cell transplantation and compared to age, race- and sex-matched general United States population (https://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_03.pdf)8. Person-years at risk were calculated from an anchor date after transplantation until date of death or date or date last known alive. The expected number of deaths was calculated using sex, race and age-specific United States mortality rates.9,10 The equality of SMRs was tested and two-sided 95% confidence intervals (CI) were calculated.10 The incidence of graft failure was calculated using the cumulative incidence estimator to accommodate competing risks.11 All p-values are two-sided. Analysis was performed using R 4.0.3 statistical package.
RESULTS
Reproducibility of a published report to validate public data source
The patient and transplant characteristics of the cohort from an earlier publication are as previously published (Supplemental Table 1).5 In brief, this cohort included data on 910 transplantations for sickle cell disease in the United States between 2008 and 2017. Sixty-one percent (n=558) received grafts from an HLA-matched sibling, 15% (n=137) from an HLA-haploidentical relative, 12% (n=111) from an HLA-matched unrelated donor and 11% (n=104) from an HLA-mismatched unrelated donor. The median age at transplant for HLA-matched sibling and HLA-matched and mismatched unrelated donor transplant were 11 years, 14 years and 10 years, respectively. Those who received HLA-haploidentical relative transplant were older with a median age of 19 years. Bone marrow was the predominant graft for HLA-matched sibling and HLA-matched unrelated donor transplant. Umbilical cord blood was the predominant graft for HLA-mismatched unrelated donor transplant. Bone marrow and peripheral blood were equally likely to be used for HLA-haploidentical relative transplant. The predominant condition regimen intensity was myeloablative (478/910; 53%). Twenty-seven percent (250/910) received reduced intensity conditioning and the remaining patients (181/910, 20%) received non-myeloablative conditioning regimens. Table 1 shows risk factors associated with overall survival from the publication,2 and results reproduced with an additional 3 years of follow up, Figure 1A, 1B. The additional follow up resulted in 6 new events (deaths). Consistent with the primary publication, older age at transplantation, reduced intensity or myeloablative conditioning regimens and use of donors other than HLA-matched siblings are risk factors for lower overall survival.
Table 1.
Demonstration of reproducible results
| Published Results | |||
|---|---|---|---|
| Overall survival | Events/Evaluable | Hazard Ratio (95% confidence interval) | p-value |
| Age | |||
| ≤12 years | 22/491 | 1.00 | |
| 13 – 49 years | 54/419 | 3.15 (1.86 – 5.34) | <0.0001 |
| Regimen intensity | |||
| Non-myeloablative | 7/181 | 1.00 | |
| Myeloablative | 41/478 | 4.62 (1.87 – 11.44) | 0.0009 |
| Reduced intensity | 28/251 | 3.79 (1.46 – 9.84) | 0.006 |
| Donor type | |||
| HLA-matched sibling | 21/558 | 1.00 | |
| Haploidentical relative | 13/137 | 2.94 (1.26 – 6.87) | 0.013 |
| HLA-matched unrelated | 26/111 | 5.12 (2.79 – 9.40) | <0.0001 |
| HLA-mismatched unrelated | 16/104 | 4.88 (2.22 – 10.75) | <0.0001 |
| Results from Public Database with Additional Follow up for Published Cohort | |||
| Overall survival | Events/Evaluable | Hazard Ratio (95% confidence interval) | p-value |
| Age | |||
| ≤12 years | 23/491 | 1.00 | |
| 13 – 49 years | 59/419 | 3.50 (2.16 – 5.79) | <0.0001 |
| Regimen intensity | |||
| Non-myeloablative | 9/181 | 1.00 | |
| Myeloablative | 44/478 | 3.59 (1.57 – 8.21) | 0.002 |
| Reduced intensity | 29/251 | 3.08 (1.29 – 7.39) | 0.012 |
| Donor type | |||
| HLA-matched sibling | 25/558 | 1.00 | |
| Haploidentical relative | 13/137 | 2.70 (1.29 – 5.67) | 0.009 |
| HLA-matched unrelated | 27/111 | 4.36 (2.47 – 7.70) | <0.0001 |
| HLA-mismatched unrelated | 17/104 | 3.55 (1.90 – 6.65) | <0.0001 |
Figure 1:
Overall Survival
Figure 1A: Original publication: The 3-year probability of overall survival after A: HLA-matched sibling (96%, 95% CI 93–97), B: Haploidentical relative (87%, 95% CI 76–93), C: HLA-matched unrelated (81%, 95% CI 73–88) and D: HLA-mismatched unrelated (82%, 95% CI 70–90) donor transplantation, adjusted for age and transplant conditioning regimen intensity.
Figure 1B: Reproduced from Public Data Source: The 5-year probability of overall survival after A: HLA-matched sibling (95%, 95% CI 93–97), B: Haploidentical relative (87%, 95% CI 79–93), C: HLA-matched unrelated (80%, 95% CI 71–86) and D: HLA-mismatched unrelated (82%, 95% CI 73–89) donor transplantation, adjusted for age and transplant conditioning regimen intensity.
Characteristics of patients who survived 2 or more years after transplantation
One thousand one hundred and forty-nine transplantations for sickle cell disease were reported between 2000 to 2017 from 94 centers in the United States. Of these, race was reported for 1096 (95%) transplantations. The 1-,2- and 10-year survival rate for the 1096 patients were 94% (95% CI 93 – 96), 92% (95% CI 90 – 93) and 88% (95% CI 86 – 90), respectively. Nine hundred and fifty of 1096 patients were alive for at least 2 years after their transplantation and the population of interest for conditional survival and standardized mortality risk. Their characteristics are shown in Table 2. Characteristics of patients who died within 2 years after transplantation are shown in Supplemental Table 2. The median age at transplantation with HLA-matched sibling donor was 10 years (range, 1 – 55) and alternative donors, 13 years (range 1 – 56). Two hundred and sixteen (23%) of patients were aged ≥18 years at transplantation. Twenty-one patients were aged 40 – 49 years and 6 patients, aged 50 – 57 years. The predominant donor was an HLA-matched sibling (66%) and the predominant graft was bone marrow (70%). Approximately 70% of transplantations occurred after 2010. 750 of 950 (79%) transplant recipients were included in an earlier publication.5
Table 2.
Characteristics of patients who were alive 2-years after transplantation.
| Characteristic | Number (percent) |
|---|---|
| Number | 950 |
| Age at transplant, years | |
| ≤10 | 458 (48%) |
| 11 – 17 | 276 (29%) |
| 18 – 29 | 142 (15%) |
| 30 – 39 | 47 (5%) |
| 40 – 49 | 21 (2%) |
| ≥ 50 | 6 (1%) |
| Sex, male/female | 531(56%)/419(44%) |
| Disease type, Hemoglobin SS/SP-thalassemia | 917(97%)/33(3%) |
| Performance score | |
| ≤ 80 | 187 (20%) |
| 90 – 100 | 711 (75%) |
| Not reported | 52 (5%) |
| Donor type | |
| HLA-matched sibling | 627 (66%) |
| Haploidentical relative | 124 (13%) |
| HLA-matched unrelated | 95 (10%) |
| HLA-mismatched unrelated | 104 (11%) |
| Graft type | |
| Bone marrow | 669 (70%) |
| Peripheral blood | 167 (18%) |
| Umbilical cord blood | 114 (12%) |
| Conditioning regimen intensity | |
| Myeloablative | 496 (52%) |
| Reduced-intensity | 237 (25%) |
| Non-myeloablative | 173 (18%) |
| Not reported | 44 (5%) |
| In vivo T-cell depletion | |
| None | 67 (7%) |
| Yes | 864 (91%) |
| GVHD prophylaxis | |
| Ex vivo T-cell depletion | 15 (2%) |
| CD 34 selection | 34 (4%) |
| Post-transplant cyclophosphamide/CNI/other | 92 (10%) |
| CNI/mycophenolate or methotrexate | 643 (68%) |
| CNI/prednisone | 63 (7%) |
| Other | 103 (11%) |
| History of grade II-IV acute GVHD | |
| None | 777 (82%) |
| Yes | 146 (15%) |
| Not reported | 27 (3%) |
| History of chronic GVHD | |
| None | 727 (77%) |
| Yes | 217 (23%) |
| Not reported | 6 (1%) |
| Transplant period | |
| 2000 – 2005 | 101 (11%) |
| 2006 – 2010 | 182 (19%) |
| 2011 – 2015 | 443 (47%) |
| 2016 – 2017 | 224 (24%) |
| Follow up, median (range), months | 62 (24 – 244) |
Abbreviation:
CNI = calcineurin inhibitor
GVHD = graft versus host disease
Conditioning regimen intensity
Myeloablative: busulfan was administered orally at a concentration greater than 8 mg/kg or intravenously at a concentration greater than 6 mg/kg, or melphalan was administered at concentrations greater than 150 mg/m2
Reduced intensity: lower doses of busulfan or melphalan
Non-myeloablative: Total body irradiation regimens (dose 200–400 cGy) alone or with cyclophosphamide and/or fludarabine
Conditional survival of patients who survived 2 or more years after transplantation and risk factors for death beyond 2 years after transplantation
Among the 950 patients who were alive 2-years after transplantation, the probability of surviving for another 5 and 8 years was 97% (95% CI 95 – 98) and 96% (95% CI 94 – 98), respectively Figure 2, (i.e., 7 and 10 years after transplantation). The probability of surviving for 5 more years for those who already survived 5- and 7-years after transplantation were 98% (95% CI 96 −99) and 97% (95% CI 92 – 99), respectively, Figure 2 (10- and 12-years after transplantation, respectively). Results of multivariate analysis of risk factors for late death (i.e., beyond 2-years after transplantation) confirmed higher mortality with older age at transplant and transplantation of grafts from alternative donors compared to HLA-matched siblings, Table 3. Among the alternative donors we did not observe differences between Haploidentical relative, HLA-matched, HLA-mismatched unrelated donors and umbilical cord blood (p=0.26). We did not observe a difference between HLA-mismatched unrelated adult donor and umbilical cord blood transplantation (HR 0.68, 95% CI 0.11 – 4.14, p=0.67). The effect of age at transplantation and donor type on late death are independent of each other (p=0.89). Conditioning regimen (myeloablative vs. reduced intensity vs. non-myeloablative) was not associated with late deaths (p=0.22) and the effect of age on late death is independent of conditioning regimen (p=0.22). History of acute graft versus host disease (HR 1.45, 95% CI 0.55 – 3.92, p=0.45) was not associated with late mortality. Although the risk for mortality was twice as high for patients with a history of chronic graft versus host disease this did not reach the level of significance for the study (HR 2.18, 95% CI 0.89 – 5.30, p=0.08).
Figure 2:
Overall Survival
The 10-year probability of overall survival of patients who lived for at least 2- (A), 5- (B) and 7- (C) years after transplantation were 96% (95% CI 94 – 98), 98% (95% CI 96 −99) and 97% (95% CI 92 – 99), respectively.
Table 3.
Relative risk of late death for sickle cell disease
| Variable | Hazard Ratio (95% confidence interval) | p-value |
|---|---|---|
| Age (10-year increment) | 1.75 (1.29 – 2.40) | 0.0004 |
| Donor type | ||
| HLA-matched sibling | 1.00 | |
| Alternative donor | 3.49 (1.53 – 7.96) | 0.0030 |
| Sex | ||
| Male | 1.00 | |
| Female | 1.01 (0.47 – 2.15) | 0.98 |
| Performance score | ||
| 90 – 100 | 1.00 | |
| ≤ 80 | 1.31 (0.53 – 3.22) | 0.56 |
| CMV serostatus | ||
| Negative | 1.00 | |
| Positive | 1.74 (0.68 – 4.42) | 0.25 |
| Conditioning regimen intensity | ||
| Myeloablative | 1.00 | 0.22 |
| Reduced-intensity | 1.55 (0.58 – 4.12) | 0.38 |
| Non-myeloablative | 0.44 (0.11 – 1.74) | 0.24 |
| Graft type | ||
| Bone marrow | 1.00 | 0.44 |
| Peripheral blood | 1.46 (0.59 – 3.61) | 0.41 |
| Umbilical cord blood | 0.59 (0.16 – 2.24) | 0.44 |
| Transplant period | ||
| 2011 – 2017 | 1.00 | |
| 2000 – 2010 | 1.12 (0.43 – 2.91) | 0.82 |
Graft failure
Among 2-years survivors, the overall incidence of graft failure that occurred beyond 2-years after transplantation was 7% (95% CI 5 – 9). When examined by donor type, the risk of graft failure beyond 2 years after transplantation was higher after alternative donor (HR 2.59, 95% CI 1.94 – 3.46, p<0.0001; 12% [95% CI 8–18]) compared to HLA-matched sibling transplantation (4% [95% CI 3–6]). Twenty-six of 53 patients with graft failure were evaluable for consecutive chimerism in the first year after transplantation. Nineteen of 26 (73%) recorded mixed chimerism within the first year after transplantation with donor chimerism that varied between 17% and 80%. In our population, graft failure led to recurrent disease. Seventeen of 53 patients, (33%) patients, a second transplantation. Sixteen of 17 patients are alive after second transplantation. Fourteen transplants used the same donor for both transplants, 8 received myeloablative, 2 reduced intensity and 7 non-myeloablative regimens. None received donor leukocyte infusion or CD34 boost.
Standardized mortality risk compared to an age-, race- and sex-matched US population
An examination of the SMR for patients who survived at least 2 years after transplantation was 7-fold higher compared to an age, sex and race-matched general US population (Table 4). For patients who survived 5 and 7 years after transplantation, the SMR was also 4- and 3-fold higher compared to an age, sex and race-matched general United States population (Table 4).
Table 4.
Relative mortality rate for death compared to an age-, sex- and race-matched population in the United States
| Survival time after transplantation | Relative Mortality Rate (95% confidence interval) | p-value |
|---|---|---|
| 2- years | 6.9 (4.9 – 9.6) | <0.0001 |
| 5- years | 3.8 (2.1 – 6.2) | <0.0001 |
| 7- years | 3.2 (1.4 – 6.4) | 0.020 |
Causes of death
There were 27 deaths that occurred beyond 2-years after transplantation. Five of 27 deaths occurred in patients who were aged ≤12 years at transplantation and the remaining 22 deaths in older patients. Nine deaths occurred after HLA-matched sibling, 5 deaths after HLA-haploidentical relative and 13 deaths after unrelated donor transplantation. The primary causes of death are shown in Table 4. Twelve of 27 (44%) of deaths were due to chronic graft-versus-host disease and the most common cause of death. Four of these deaths occurred after HLA-matched sibling transplant, 2 after Haploidentical relative and 6 after HLA-matched unrelated donor transplantation. Seven transplants used peripheral blood and 5, bone marrow graft. Graft vs. host disease prophylactic regimens included a calcineurin inhibitor with methotrexate, mycophenolate or sirolimus for 10 transplantations and mycophenolate and sirolimus for one transplant. The prophylaxis regimen was not reported for one transplant. The 15-year incidence of new malignancy (N=22) for the whole cohort (N=1096) was 2.3% (95% CI 0.9 – 4.2) and for acute myeloid leukemia (N=7) or myelodysplastic syndrome (N=5), 2.1% (9% CI 0.8 – 3.9). Other malignancy included: central nervous system tumor (N=2), embryonal rhabdomyosarcoma (N=1), other sarcoma (N=3), other leukemia (N=3) and hepatic myofibroblastic tumor (N=1). Median time to onset of malignancy was 40 months (range 9 – 196) after transplantation.
DISCUSSION
Hematopoietic cell transplantation is associated with highest risk of death during the first 2 years after transplantation and thereafter, the risk of death diminishes but may persist longer. This is well documented after transplantation for hematologic malignancy and severe aplastic anemia.12,13 The current analysis focused on sickle cell disease, a disease for which transplantation is increasingly offered as a curative option. Yet, little is known on long term survival except after HLA-matched sibling transplantation.14,15 Therefore, in the current analyses, we studied late deaths, risk factors for late deaths and compared standardized mortality rates to an age, sex and race-matched United States population for patients with sickle cell disease who were alive for at least 2 years after hematopoietic cell transplantation. By limiting to 2-year survivors, we exclude deaths that occur as a direct consequence of the transplantation procedure. To our knowledge this is the first report of this kind that has focused on sickle cell disease, included patients across the lifespan and donor types. As we utilized a publicly available data source (https://picsure.biodatacatalyst.nhlbi.nih.gov/), reproducibility of an earlier publciation5 was intended to support interpretation and reporting for the current analysis.
Our analysis recorded excellent 10-year probability of survival for patients who were alive for at least 2 years after their transplantation. Compared to an age-, sex- and race-matched general United States population, the expected risk for death after transplantation receded over time but the risk for late death is not negligible even as late as 7-years after transplantation. For 7-year survivors of transplantation, their risk of death is three times higher compared to an age-, sex- and race-matched United States general population. This is comparable to the risk reported after transplantation for severe aplastic anemia compared to an age-, sex- and race-matched general population and lend support to offering transplantation as a curative treatment for sickle cell disease.12 Two risk factors were identified for late mortality, older age and transplantation of grafts from donors other than HLA-matched siblings. For every 10-year increment in patient age, an older patient is 1.75 times more likely to die than a younger patient. Access to transplantation has increased with use of donors who are not HLA-matched siblings16–19 but the risk for late mortality (in 2 years survivors) is 3.5 times higher with donors who are not HLA-matched siblings. Amongst the alternative donors we did not observe an advantage for one donor type over another. Thus, our observations support early referral for transplantation with the best available donor for sickle cell patients with stroke or recurrent vaso-occlusive episodes. We acknowledge the ideal comparison cohort for long term survival would have been those with sickle cell disease who meet criteria for transplantation (disease severity and adequate cardio, pulmonary and renal function) but did not receive transplantation. Such a cohort is particularly challenging to assemble outside of a planned prospective study.
Our study recorded overall incidence of graft failure beyond 2-years after transplantation at 7% and the risk was 3 times higher compared to HLA-matched sibling transplantation (12% versus 4%). Our definition of graft failure did not consider low levels of donor chimerism (5 – 20%), levels associated with symptomatic disease. Although it is acknowledged that graft failure is higher after HLA-mismatched alternative donor transplantation2,20,21 most graft failure is expected to occur within 1–2 years after transplantation. Mixed donor chimerism after transplantation for sickle cell disease is also documented and these patients may progress to graft failure.2,15,22 The management of mixed chimerism is highly variable and determined by treating physician and/or transplant center practice. Therefore, definitive management guidance requires conducting carefully designed interventional prospective studies and beyond the scope of the current analysis. The public data source we used identified recurrent disease as a consequence of graft failure and no deaths were attributed to marrow aplasia. Further analysis of graft failure is not supported by the quality of data that is available and we acknowledge this as a limitation.
Chronic graft versus host disease is a debilitating complication of transplantation and an obstacle to long-term survival.12,13,23–25 In the current analysis, chronic graft versus host disease accounted for ~45% (12 of 27) of deaths and the risk for late deaths was higher although this did not reach the level of significance set a priori for this study. The median age at transplantation of patients who died of chronic graft versus host disease was 17 years (range 9.5 – 24), a relatively young cohort. Approximately 60% of these patients received peripheral blood graft, a known risk factor for graft vs. host disease and death after transplantation for severe aplastic anemia.26,27 Chronic graft versus host disease has also been attributed to higher risk of death in African Americans after transplantation for aplastic anemia.28 Although all patients in our study received graft versus host disease prophylaxis considered “standard of care”, we hypothesize that studying novel approaches like the inclusion of high dose cyclophosphamide post-transplant for prophylaxis for all donor types may mitigate the risk for graft versus host disease. Post-transplant high dose cyclophosphamide prophylaxis regimens have been incorporated successfully for HLA-matched sibling and HLA-matched unrelated donor transplantations for hematologic malignancy.29,30
As with any observational study ours has limitations. We showed the relative risk for mortality compared to an age-, sex- and race-matched general United States population is higher after curative treatment for SS/Sβ-thalassemia. Our cohort did not include SC or other genotypes and included only about a quarter of adult transplantations. The age distribution of transplant recipients reflects clinical practice, and we anticipate later studies will include greater numbers of adult survivors. The causes of death were reported by the transplant center. Without access to source documents, we cannot ascertain the sickle-related complication to which a patient succumbed after recurrence of disease or organ failure that may be associated with chronic immune suppression for treatment of chronic graft versus host disease. We conclude durable survival is likely in the majority of 2-year survivors of transplantation and may inform emerging novel curative treatment options like gene therapy and gene editing for sickle cell disease.31,32 We also observed deaths several years after transplantation underscoring the need for surveillance long term after transplantation.
Supplementary Material
Table 5.
Causes of death
| Causes of death | Number |
|---|---|
| Total number of deaths | 27 |
| Chronic graft versus host disease | 12 |
| Infection without chronic graft versus host disease | 2 |
| Recurrent sickle cell disease | 6 |
| Pulmonary hypertension* | 1 |
| Intracranial hemorrhage* | 1 |
| Multi-organ failure* | 1 |
| Acute myeloid leukemia* | 2 |
| Not reported | 2 |
Graft failure with recurrence of sickle cell disease prior to death
Highlights.
The 10-year survival for patients surviving ≥ 2 years after transplantation was 96%
Older age and donors other than HLA-matched siblings increased risk for death
Risk for death receded over time but remains high many years after transplantation
Funding:
This research was, in part, funded by the National Institutes of Health (NIH) Agreements OT3HL147741 (Medical College of Wisconsin) and 3OT3HL142480 (The Biodata Catalyst Program). The views and conclusions contained in this document are those of the authors and should not be interpretated as representing the official policies, either expressed or implied, of the NIH.
Footnotes
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Conflict of Interest: The authors declare none
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