A machine learning-based workflow for predicting transplant outcomes in patients with sickle cell disease.

Allogeneic haematopoietic cell transplantation (HCT) with HLA-matched sibling donor remains the most established curative therapeutic option for patients with sickle cell disease (SCD). However, it is not without risks, highlighting the need for a risk stratification system. Utilizing a machine learning (ML) approach that combines clinical and imaging variables, we identified red cell distribution width and renal organ damage as important risk factors for patients undergoing HCT. This ML-based algorithm, similar to an approach previously reported for predicting mortality in patients with SCD, should be applicable to risk factor discovery in similar studies.

Improvement in Cardiac Morphology Demonstrated by Cardiac Magnetic Resonance Imaging and Echocardiography after Haploidentical Hematopoietic Cell Transplantation in Adults with Sickle Cell Disease.

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. Although HLA-matched sibling hematopoietic cell transplantation (HCT) offers a potential cure, less than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at 1 year after HCT. Here we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who underwent nonmyeloablative haploidentical peripheral blood HCT at the National Institutes of Health. Patients underwent noncontrast CMR at 3 T, echocardiography, and laboratory studies. At 1 year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass (70.2 to 60.1 g/m2; P = .02) and volume (114.5 to 90.6 mL/m2; P = .001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are needed to determine the roles of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

Pulmonary Function after Nonmyeloablative Hematopoietic Cell Transplant for Sickle Cell Disease.

Rationale: Sickle cell disease (SCD) is a monogenetic condition with recurring vasoocclusive events causing lifelong pulmonary morbidity and mortality. There is increasing access to curative therapies, such as hematopoietic cell transplant (HCT), for people living with SCD. However, more information on pulmonary function in adults with SCD after HCT is needed to best guide decisions for HCT and post-HCT care. Objectives: To test the hypothesis that forced expiratory volume in 1 second (FEV1) and other pulmonary function testing (PFT) parameters remain stable 3 years after HCT. Methods: People living with SCD undergoing nonmyeloablative HCT in a prospective cohort at the NIH Clinical Center from 2004 to 2019 were evaluated for enrollment. Global Lung Function Initiative reference equations and descriptive statistics were calculated before HCT and annually for 3 years. Six-minute-walk distance (6MWD) testing was performed. Generalized estimating equations were employed to evaluate interindividual changes in PFT parameters and 6MWD. Results: Of 97 patients with SCD undergoing HCT, 41 (42%) were female with median (25th, 75th percentile) age 31.8 (24.8, 38.0) years. Each year of measurement included the following numbers of subjects available for analysis with PFTs: baseline (n = 97), Year 1 (n = 91), Year 2 (n = 72), and Year 3 (n = 55); and the following numbers of subjects available for analysis with 6MWD: baseline (n = 79), Year 1 (n = 73), Year 2 (n = 57), and Year 3 (n = 41). Pre-HCT FEV1 was median (25th, 75th percentile) 68.3% (61.3%, 80.3%) and 69.2% (60.8%, 77.7%) 3 years after HCT, and pre-HCT diffusing capacity of the lung for carbon monoxide (DlCO) was 60.5% (53.0%, 66.3%) and 64.6% (55.1%, 73.4%) 3 years after HCT. Generalized estimating equations estimated that DlCO percent predicted increased significantly by 3.7% (95% confidence interval, 1.0%, 6.3%), and the 6MWD significantly increased by 25.9 (6.6, 45.2) meters 3 years after HCT, whereas there was no significant change in percent predicted FEV1 or FVC compared with before HCT. Conclusions: Overall, PFT results remained stable and there was an improvement in DlCO and 6MWD in this predominantly adult cohort undergoing nonmyeloablative HCT for SCD. Allogeneic HCT for SCD may cease the cycle of vasoocclusive pulmonary injury and prevent continued damage. Multicenter studies are needed to evaluate the long-term lung health effects of HCT for SCD in adults and children.

Proteomic analyses of urinary exosomes identify novel potential biomarkers for early diagnosis of sickle cell nephropathy, a sex-based study.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2 months (without albuminuria) and 4 months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, ß-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN.

Thyroid and Adrenal Dysfunction in Hemoglobinopathies Before and After Allogeneic Hematopoietic Cell Transplant.

Purpose: To determine the rate and clinical characteristics associated with abnormal thyroid and adrenal function in recipients of nonmyeloablative hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) and beta-thalassemia. Methods: We retrospectively reviewed patients who enrolled in 4 nonmyeloablative HCT regimens with alemtuzumab and total body irradiation (TBI). Baseline and annual post-HCT data were compared, which included age, sex, sickle phenotype, thyroid panel (total T3, free T4, thyroid stimulating hormone, antithyroid antibodies), cortisol level, ACTH stimulation testing, ferritin, medications, and other relevant medical history. Results: Among 43 patients in haploidentical transplant and 84 patients in the matched related donor protocols with mostly SCD, the rate of any thyroid disorder pre-HCT was 3.1% (all subclinical hypothyroidism) and post-HCT was 29% (10 hypothyroidism, 4 Grave's disease, and 22 subclinical hypothyroidism). Ninety-two (72%) patients had ferritin >1000 ng/dL, of which 33 patients (35.8%) had thyroid dysfunction. Iron overload was noted in 6 of 10 patients with hypothyroidism and 12 of 22 patients with subclinical hypothyroidism.Sixty-one percent were on narcotics for pain control. With respect to adrenal insufficiency (AI) pre-HCT, 2 patients were maintained on corticosteroids for underlying rheumatologic disorder and 8 had AI diagnosed during pre-HCT ACTH stimulation testing (total 10, 7.9%). Post-HCT, an additional 4 (3%) developed AI from corticosteroid use for acute graft vs host disease, Evans syndrome, or hemolytic anemia. Conclusion: Although iron overload was common in SCD, thyroid dysfunction pre-HCT related to excess iron was less common. Exposure to alemtuzumab or TBI increased the rates of thyroid dysfunction post-HCT. In contrast, AI was more common pre-HCT, but no risk factor was identified. AI post-HCT was infrequent and associated with corticosteroid use for HCT-related complications.

Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease.

Hematopoietic stem cell transplantation (HSCT) is potentially curative for patients with sickle cell disease (SCD). Patients with stable donor engraftment after allogeneic HSCT generally do not experience SCD-related complications; however, there are no published data specifically reporting the change in vaso-occlusive events (VOE) after HSCT. Data regarding the number of VOEs requiring medical attention in the 2 years before allogeneic HSCT were compared with the number of VOEs in the 2 years (0-12 months and 12-24 months) after allogeneic HSCT in patients with SCD. One-hundred sixty-three patients with SCD underwent allogeneic HSCT between 2005 and 2019. The average age at the time of HSCT was 21 years (range, 7 months - 64 years). Most patients underwent nonmyeloablative conditioning (75% [N = 123]) and had a matched sibling donor (72% [N = 118]). The mean number of VOEs was reduced from 5.6 (range, 0-52) in the 2 years before HSCT to 0.9 (range, 0-12) in the 2 years after HSCT (P < .001). Among the post-HSCT events, VOE was more frequent during the first 12 months (0.8 [range, 0-12]) than at 12 to 24 months after HSCT (0.1 [range, 0-8) (P < .001)). In patients who had graft rejection (12%, N = 20), VOEs were reduced from 6.6 (range, 0-24) before HSCT to 1.1 (range, 0-6) and 0.8 (range, 0-8) at 0 to 12 months and 12 to 24 months after HSCT, respectively (P < .001). VOEs requiring medical care were significantly reduced after allogeneic HSCT for patients with SCD. These data will inform the development of novel autologous HSCT gene therapy approaches.

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease.

One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD.

Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease.

In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with SCD over the past two decades. Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with SCD. While human leukocyte antigen (HLA) matched sibling HSCT has been successful, its availability is extremely limited. This review summarizes various conditioning regimens that are currently available. We explore recent efforts to expand the availability of allogeneic HSCT, including matched unrelated, umbilical cord blood, and haploidentical stem cell sources. We consider the use of nonmyeloablative conditioning and haploidentical donor sources as emerging strategies to expand transplant availability, particularly for SCD patients with complications and comorbidities who can undergo neither matched related transplant nor myeloablative conditioning. Finally, we show that improved conditioning agents have improved success rates not only in the HLA-matched sibling setting but also alternative donor settings.

Reversal of a rheologic cardiomyopathy following hematopoietic stem cell transplantation for sickle cell disease.

Cardiac complications have been well-described in sickle cell disease; however, it has been rare to see improvements in cardiac abnormalities following any interventions. Previous work has shown no significant structural changes after treatment with hydroxyurea. The cardiac effects of red blood cell exchange transfusion (RBCx) and hematopoietic stem cell transplantation (HSCT) have not been well described. We studied 56 patients undergoing HSCT (41 HLA-matched, 15 haploidentical), of whom 32 had RBCx within 3 months before HSCT. Echocardiograms and laboratory parameters were obtained at baseline, and at 3, 6, and 12 months following HSCT. Although hemolytic parameters and anemia improved following RBCx, there was a small increase in left ventricular volume index. Following successful HSCT, however, there were significant improvements in cardiac size, function, and diastolic filling parameters at 3 months followed by continued smaller improvements up to 1 year. There was a significant improvement in N-terminal pro B-type natriuretic peptide levels and a trend toward improvement in 6-minute walk time 1 year after HSCT. The magnitude of cardiac improvement seen following HSCT was comparable to that observed following correction of a volume overload state as seen in pregnancy or after repair of chronic valvular regurgitation. Further studies in sickle cell disease patients will help delineate which cardiac complications and what level of severity should be considered indications for HSCT.