Incremental Eligibility Criteria for the BMT CTN 1507 Haploidentical Trial for Children with Sickle Cell Disease.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 leadership and the Data Safety Monitoring Board (DSMB) established incremental entry criteria for children aged 5-14.99 years with sickle cell disease (SCD) enrolling on a phase 2 trial of HLA-haploidentical hematopoietic stem cell transplantation (clinicaltrials.gov #NCT032635590). First, enrollment was limited to overt stroke in the first 10 participants (Stage 4). Subsequently, the DSMB reviewed the interim results and expanded eligibility to include children with silent cerebral infarcts or abnormal transcranial Doppler velocities with magnetic resonance angiography-defined cerebral vasculopathy (Stage 3). A third cohort was enrolled after the DSMB reviewed the clinical outcomes in these cumulative initial enrollments (n=18). Additions to the entry criteria included non-neurologic morbidities (Stage 2). Eligibility criteria included: a) life-threatening acute chest syndrome requiring exchange transfusion, b) right heart catheterization confirmed pulmonary hypertension, c) persistent systemic hypertension despite maximum medical therapy, d) acute pain despite maximum medical therapy in the absence of psychosocial factors and unmanaged asthma after adjudication, or e) 2 major priapism episodes in 12 months or 3 in 24 months. Children with SCD who did not meet the criteria for stages 4, 3, and 2 were not eligible. For the first time, we introduce a staged strategy to eligibility for a curative therapy trial for children with SCD concordant with 45 CFR § 46.405(b). The research governance-mandated eligibility strategy used within the BMT CTN 1507 phase 2 study may apply to future pediatric SCD curative therapy trials.

Digital Cognitive Behavioral Therapy vs Education for Pain in Adults with Sickle Cell Disease.

Despite the significant burden of chronic pain in sickle cell disease (SCD), non-pharmacological approaches to manage pain in SCD are lacking. Behavioral interventions incorporating digital cognitive-behavioral therapy CBT) for pain should be compared to available education efforts. To compare a CBT intervention tailored for adults with SCD to a digital pain/SCD education intervention (Education) on improving pain and associated symptoms. Multisite randomized comparative effectiveness trial. Seven comprehensive SCD centers and virtual recruitment through community organizations in the United States. Adults (age 18+) with SCD-related chronic pain and/or daily opioid use randomized to CBT or Education. Over 12 weeks, the CBT arm received an app-based intervention for pain management; the Education arm received digital pain/SCD education. Both groups received interactive chatbot lessons plus personalized health coach support. Changes in pain interference scale (primary); and other patient-reported outcomes (secondary), including pain intensity, depression, anxiety, quality of life, and self-efficacy over 6 months. 453 participants completed screening, 359 (79%) were randomized to CBT (n=181) or Education (n=178), 332 (92%) were Black African American, 238 (66.3%) female. At 6 months, 250 (70%) participants (n=125 per arm) completed follow-up assessments, 93 (26%) missed their follow-up window, 16 (4%) withdrew. Engagement with the chatbot content was variable (76% connected, 48% completed ≥1 lesson). However, 80% of participants completed ≥1 session with a health coach via phone, video, or text. The 6 month change in pain interference for CBT (-2.13; 95% CI, -3.42 to -0.84) and Education (-2.66; 95%CI, -3.97 to -1.36) was not significantly different (mean difference: 0.54; 95%CI, -1.30 to 2.37; *P=*0.57). Daily pain intensity ratings did not change for either group. There were no between-arm differences in depression, anxiety, and quality of life. CBT and Education did not differ in their effect on pain and mental health in SCD when combined with health coaching. Variable engagement with digital components and high engagement with health coaching may explain the lack of between-group differences, but these findings also provide insights into delivering digital interventions in racial minority and hard-to-reach populations. Trial Registration: ClinicalTrials.gov NCT04419168.

The use of abstract animations and a graphical body image for assessing pain outcomes among adults with sickle cell disease.

Painimation, a novel digital pain assessment tool, allows patients to communicate their pain quality, intensity, and location using abstract animations and a paintable body image. This study determined the construct validity of pain animations and body image measures by testing correlations with validated pain outcomes in adults with sickle cell disease (SCD). Analyses used baseline data from a multisite randomized trial of 359 adults with SCD and chronic pain. Participants completed questionnaires on demographics, pain severity, frequency and interference, catastrophizing, opioid use, mood and quality of life, plus the Painimation app. Participants were categorized by selected pain animations, and were split into groups based on the proportion of painted body image. The "shooting" pain animation and greater body image scores associated with poorer pain outcomes in univariate analyses, except "happy" mood days. Potential confounding was evaluated by age, gender, race, education, disability, site, depression, and anxiety. Only depression scores significantly covaried in multivariate models, accounting for the effect of greater body image score and shooting animation on all outcomes except daily pain intensity. Both pain animations and body image measures correlated with validated pain outcomes, quality of life and mental health measures. This demonstrates animations and body image data can assess SCD pain severity, potentially with more accuracy than a 0-10 scale. In exploratory analyses, depression scores accounted for the association between Painimation and other pain outcomes. Future research will explore whether Painimation can differentiate biological and psychosocial pain components. PERSPECTIVE: This article presents the preliminary construct validity of Painimation in sickle cell disease (SCD) by examining the associations of "pain animations" and body area image data with daily e-diary and traditional self-report pain outcomes.

A Novel Newborn Screening Program for Sickle Cell Disease in Nigeria.

Newborn screening for sickle cell disease (SCD) is sparse in sub-Saharan Africa. The leadership of the Aminu Kano Teaching Hospital (AKTH) in Kano, Nigeria, with the support of local religious authorities, established a groundbreaking SCD newborn screening program that has become the standard of care for pregnant women and their newborns. Our program includes (1) prenatal genetic counseling for all pregnant women in the antenatal clinic, (2) newborn screening, (3) postnatal genetic counseling for parents of newborns diagnosed with SCD and SCT, and (4) referral of newborns with SCD for follow-up in the SCD Comprehensive Care Clinic by 3 months of age. From September 2020 to December 2023, the team screened 7530 infants for SCD at the AKTH, identifying 126 (1.7%) infants with SCD and 1546 (20.5%) with SCT. Of these, 93 (73.8%) newborns with SCD received individualized genetic counseling, and 43 (46%) were referred to the SCD Comprehensive Care Clinic before 3 months. Group genetic counseling was provided to the parents of 778 (50.3%) of newborns identified with SCT. The SCD newborn screening at the AKTH is now standard care, indicating the viability of sustaining an SCD newborn screening program that provides pre- and postnatal genetic counseling and comprehensive SCD care within a low-income setting.

Incidence and Risk Factors for New and Recurrent Infarcts in Adults With Sickle Cell Disease.

BACKGROUND: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults. METHODS AND RESULTS: This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow-up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time-to-event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow-up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient-years (6.17-20.88) versus 3.74 per 100 patient-years (1.21-8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 [95% CI, 1.05-11.39]; P=0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 [95% CI, 1.16-9.51]; P=0.025). CONCLUSIONS: Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.

Distribution of Silent Cerebral Infarcts in Adults With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones. METHODS: Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors. RESULTS: Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model. DISCUSSION: When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease-related organ complications: A systematic review and meta-analysis.

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.

Transcranial doppler velocity in iron-deficient Nigerian children with sickle cell anemia.

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery.

Impact of maternal depression on malnutrition treatment outcomes in older children with sickle cell anemia.

BACKGROUND: Malnutrition and sickle cell anemia (SCA) result in high childhood mortality rates. Although maternal depression is an established risk factor for malnutrition in younger children, little is known about its impact on treatment response in children with malnutrition. We aimed to determine the relationship, if any, between maternal depression scores and malnutrition treatment outcomes in older children with SCA. METHODS: We conducted a planned ancillary study to our randomized controlled feasibility trial for managing severe acute malnutrition in children aged 5-12 with SCA in northern Nigeria (NCT03634488). Mothers of participants completed a depression screen using the Patient Health Questionnaire (PHQ-9).We used a multivariable linear regression model to describe the relationship between the baseline maternal PHQ-9 score and the trial participant's final body mass index (BMI) z-score. RESULTS: Out of 108 mother-child dyads, 101 with maternal baseline PHQ-9 scores were eligible for inclusion in this analysis. At baseline, 25.7% of mothers (26 of 101) screened positive for at least mild depression (PHQ-9 score of 5 or above). The baseline maternal PHQ-9 score was negatively associated with the child's BMI z-score after 12 weeks of malnutrition treatment (ß=-0.045, p = 0.041). CONCLUSIONS: Maternal depressive symptoms has an impact on malnutrition treatment outcomes. Treatment of malnutrition in older children with sickle cell anemia should include screening for maternal depression and, if indicated, appropriate maternal referral for depression evaluation and treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (#NCT03634488) on January 30, 2018, https://clinicaltrials.gov/study/NCT03634488 .

Barriers and facilitators to a task-shifted stroke prevention program for children with sickle cell anemia in a community hospital: a qualitative study.

BACKGROUND: Children with sickle cell anemia (SCA) are at high risk for stroke. Protocols for stroke prevention including blood transfusions, screening for abnormal non-imaging transcranial Doppler (TCD) measurements, and hydroxyurea therapy are difficult to implement in low-resource environments like Nigeria. This study aimed to examine the contextual factors around TCD screening in a community hospital in Nigeria using qualitative interviews and focus groups. METHODS: We conducted a descriptive qualitative study in a community hospital in Kaduna, Nigeria, using focus groups and interviews. Interview guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR) framework and the Theory of Planned Behavior. Transcripts were coded and analyzed using an iterative deductive (CFIR)/Inductive (transcribed quotes) qualitative methodology. RESULTS: We conducted two focus groups and five interviews with health care workers (nurses and doctors) and hospital administrators, respectively. Themes identified key elements of the inner setting (clinic characteristics, resource availability, implementation climate, and tension for change), characteristics of individuals (normative, control, and behavioral beliefs), and the implementation process (engage, implement, and adopt), as well as factors that were influenced by external context, caregiver needs, team function, and intervention characteristics. Task shifting, which is already being used, was viewed by providers and administrators as a necessary strategy to implement TCD screening in a clinic environment that is overstressed and under-resourced, a community stressed by poverty, and a nation with an underperforming health system. CONCLUSION: Task shifting provides a viable option to improve health care by making more efficient use of already available human resources while rapidly expanding the human resource pool and building capacity for TCD screening of children with SCD that is more sustainable. TRIAL REGISTRATION: NCT05434000.

Cerebral hemodynamic changes after haploidentical hematopoietic stem cell transplant in adults with sickle cell disease.

ABSTRACT: Preliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.