Sickle cell disease (SCD) is associated with early mortality. We sought to determine the incidence, cause, and risk factors for death in an adult population of patients with SCD. All patients aged ≥18 years seen at the Adult Sickle Cell Center at Duke University Medical Center between January 2000 and April 2005 were enrolled. Forty‐three patients (21 males and 22 females) died during the study period. The median age of survival was 39 years for females (95% CI: 34–56), 40 years for males (95% CI: 34–48), and 40 years overall (95% CI: 35–48). Cardiac causes of death accounted for 25.6% (11/43 patients); pulmonary, 14.0% (six patients); other SCD related, 32.6% (14 patients); unknown, 14.0% (six patients); and others, 14.0% (six patients). Pulseless electrical activity arrest, pulmonary emboli, multiorgan failure, and stroke were the most frequent causes of death. Among the deceased patients, the most common premorbid conditions were cardiopulmonary: acute chest syndrome/pneumonia (58.1%), Pulmonary hypertension (pHTN; 41.9%), systemic HTN (25.6%), congestive heart failure (25.6%), myocardial infarction (20.9%), and arrhythmias (14.0%). Tricuspid regurgitant jet velocity was significantly higher (3.1 m/sec vs. 2.6 m/sec, P < 0.001) and hemoglobin significantly lower (8.3 g/dL vs. 9.2 g/dL, P < 0.05) in deceased patients when compared with patients who lived, respectively. With improved preventive and therapeutic advances, including hydroxyurea therapy, acute complications such as infection are no longer the leading cause of death; instead, causes of death and premorbid conditions are shifting to chronic cardiopulmonary complications. Further, arrhythmia leading to premature death is under‐recognized in SCD and warrants further investigation. Am. J. Hematol., 2010.

Key Points: Results based on our allogeneic model suggest genetic strategies aimed at correcting at least 20% of HSCs are necessary to reverse SCD. A minority of donor myeloid cells is adequate because of the vast differences in RBC survival between donor and recipient.

Background: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. Methods: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. Conclusions: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

Key Points: Patients with SCD and severe organ damage can tolerate nonmyeloablative conditioning with no transplant-related mortality. Posttransplant cyclophosphamide prevents severe GVHD, increases engraftment, and improves the success rate for haploidentical HSCT.

PURPOSE: To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. METHODS: Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. RESULTS: The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. CONCLUSION: Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Recent studies suggest that plerixafor mobilization and apheresis in patients with sickle cell disease (SCD) is safe and can allow collection of sufficient CD34+ hematopoietic stem cell (HSC) collection for clinical gene therapy applications. However, the quantities of plerixafor-mobilized CD34+ cells vary between different SCD patients for unknown reasons. Twenty-three participants with SCD underwent plerixafor mobilization followed by apheresis, processing, and HSC enrichment under a phase 1 safety and efficacy study conducted at 2 institutions. Linear regression or Spearman's correlation test was used to assess the relationships between various hematologic and clinical parameters with total CD34+ cells/kg collected. Median CD34+ cells/kg after 2 or fewer mobilization and apheresis cycles was 4.0 × 106 (range, 1.5-12.0). Similar to what is observed generally, CD34+ yield correlated negatively with age (P < .001) and positively with baseline (P = .003) and preapheresis blood CD34+ cells/µL (P < .001), and baseline white blood cell (P = .01) and platelet counts (P = .03). Uniquely for SCD, CD34+ cell yields correlated positively with the number of days hydroxyurea was held (for up to 5 weeks, P = .01) and negatively with markers of disease severity, including hospitalization frequency within the preceding year (P = .01) and the number of medications taken for chronic pain (P = .002). Unique SCD-specific technical challenges in apheresis were also associated with reduced CD34+ cell collection efficiency and purification. Here, we describe factors that impact plerixafor mobilization success in patients with SCD, confirming known factors as described in other populations in addition to reporting previously unknown disease specific factors in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03226691.