Kevin H. M. Kuo

Background: Pregnant people with sickle cell disease (SCD) experience high morbidity and mortality, even when RBC transfusion is safe and available. There is a lack of consensus on transfusion use partly due to concern for alloimmunization. This study examined alloimmunization in SCD pregnancies managed with chronic transfusion therapy (CTT) versus on‐demand transfusion (ODT). A secondary aim was to quantify the proportion of SCD pregnancies that met guideline indications for CTT that received CTT in pregnancy. Study Design: This is a two‐center, retrospective study of pregnancy in SCD over two decades. We compared alloimmunization between those who received CTT versus ODT by examining the Sickle Cell Pregnancy and Reproductive Knowledge Syndicate database. A secondary analysis applied American Society of Hematology (2020) and/or British Society for Haematology (2021) criteria for CTT in pregnancy to calculate guideline compliance. Results: Among 145 subjects, 26 received CTT and 119 received ODT. Alloimmunization incidence was 4%, with no significant difference by transfusion group (1/26 CTT vs. 5/119 ODT, p = 1.0). Five ODT subjects became alloimmunized (5/46). One CTT subject was alloimmunized (1/26) after receiving an unplanned ODT. Of all pregnancies, 87% met ASH criteria and 65% met BSH criteria for CTT, while 20% received CTT. Discussion: For patients with SCD in pregnancy, CTT may not pose a greater alloimmunization risk than ODT. CTT may be underutilized for SCD in pregnancy. Our study is limited by incomplete data and variable antigen matching practices. Prospective research will help establish the appropriate role of CTT in SCD pregnancies.

Neurocognitive disorders (NCD) are frequent yet underrecognized in adults with sickle cell disease (SCD), and practical strategies for routine cognitive assessment remain limited. We evaluated the psychometric properties of the Rowland Universal Dementia Assessment Scale (RUDAS) in the cognitive evaluation of adults with SCD.Between 2018 and 2023, adults with SCD were recruited from three comprehensive centers in Canada and France. Participants completed either the French or English version of the RUDAS. A prespecified subset underwent comprehensive multidisciplinary neurocognitive evaluation to establish a clinical diagnosis of minor or major NCD. The diagnostic performance of clinically relevant RUDAS cutoffs was assessed against a multidisciplinary reference diagnosis of minor or major NCD.A total of 440 adults with SCD were included (median age, 34 years; 56.4% female). The median RUDAS score was 26 (range, 16-30). A RUDAS cutoff score <27 demonstrated a specificity of 83% for detecting NCD. Adjustment for educational attainment increased specificity to 89%, with corresponding reduction in sensitivity from 50% to 45%. Latent class analysis identified two distinct cognitive profiles; individuals in the lower-performing group were older and more likely to have a history of prior stroke, vascular risk factors, impaired kidney function, lower educational attainment, and unemployment.In adults with SCD, the RUDAS provides a pragmatic and accessible approach to support brief cognitive assessment in routine clinical care. While its role in isolation is limited by moderate sensitivity, its high specificity may facilitate targeted referral for comprehensive neurocognitive evaluation and interventions.

Outside of pregnancy, placental growth factor (PlGF), is produced by erythroid cells in typically undetectable levels. In pregnancy, PlGF is strongly expressed by the trophoblast layer covering the placental villi. PlGF levels rise progressively due to placental growth, peak at 28 to 30 weeks gestation, and then slowly decline toward term. Low PlGF has emerged as a powerful diagnostic test for preterm preeclampsia. However, its interpretation in context of sickle cell disease (SCD) is potentially confounded by upregulation of cellular PlGF expression in nonpregnant individuals with SCD, and higher third trimester circulating PlGF levels documented in healthy Black compared with White individuals. Primary objectives were to determine the distribution of PlGF at midtrimester in pregnant individuals with SCD compared with unaffected Black controls and to explore the diagnostic accuracy of PlGF in the context of suspected preeclampsia in pregnancies of individuals with SCD. Secondary objective was to examine the relationship between low PlGF and placental disease in pregnancies of individuals with SCD. Pregnant individuals with SCD at Mount Sinai Hospital in Canada (January 2017 to September 2021) with at least 1 PlGF measurement 20+0 to 35+6 weeks gestation, and pregnant Black controls without SCD with suspected preeclampsia or growth restriction, were included in this retrospective study. Maternal and neonatal outcomes were extracted from medical records. For early-onset, but not late-onset, preeclampsia, a PlGF cutoff of <100 pg/mL demonstrated 100% sensitivity and specificity at 20 to 24 weeks gestation. This study is, to our knowledge, the first to demonstrate the utility of PlGF in predicting early-onset preeclampsia in pregnancies of individuals with SCD, allowing clinicians to anticipate and mitigate adverse pregnancy outcomes.

Transfusion-dependent β-thalassemia (TDT) can have negative impacts on a patient’s health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo CRISPR-Cas9 gene–edited cell therapy for TDT shown in a phase 3 clinical trial to result in transfusion independence in most participants. Here, we describe changes in patient-reported outcome (PRO) measures after exa-cel infusion in 54 participants (adults, n = 35; adolescents, n = 19), who had ≥16 months of follow-up. In adults, PRO measures included the EuroQol Quality of Life Scale-5 dimensions-5 levels of severity (EQ-5D-5L) and the Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT). In adolescents, the EuroQol Quality of Life Scale-5 dimensions-youth (EQ-5D-Y) and Pediatric Quality of Life Inventory (PedsQL) instruments were used. At baseline, mean EQ-5D-5L visual analog scale (VAS) and US and UK health utility index scores in adults were in line with baseline scores reported for adults with TDT. After exa-cel infusion, all 3 scores improved, exceeding established minimal clinically important differences (MCIDs) at month 48. Mean FACT-General (FACT-G) score and bone marrow transplant subscale score improved through month 48, also exceeding MCIDs, with improvements in all 4 FACT-G subscales (physical, social/family, emotional, and functional well-being). Consistent with HRQoL improvements in adults, adolescents had increases from baseline at month 24 in mean EQ-5D-Y VAS score and PedsQL total score, with sustained improvements in both physical and psychosocial health subcomponents. These results indicate exa-cel leads to broad, durable, and clinically meaningful improvements in HRQoL in adults and adolescents with TDT. These trials were registered at www.ClinicalTrials.gov as #NCT03655678 and #NCT04208529.

Severe sickle cell disease (SCD), an inherited blood disorder characterized by recurrent vaso-occlusive crises (VOCs), significantly impairs health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel), a one-time, ex vivo CRISPR/Cas9 gene-edited cell therapy, eliminated VOCs in 97% of participants with severe SCD in the phase 3 CLIMB SCD-121 trial. Here, we describe changes in patient-reported outcomes (PROs) in 30 adults and 12 adolescents with ≥16 months follow-up. Adult PROs include EuroQol Quality of Life Scale–5 dimensions–5 levels of severity (EQ-5D-5L), Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT), Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), and 11-point pain Numerical Rating Scale (NRS). In adolescents, EuroQol Quality of Life Scale–5 dimensions–youth (EQ-5D-Y), Pediatric Quality of Life Inventory (PedsQL), and pain NRS were used. Adult EQ-5D-5L US and UK healthy utility index and EQ visual analog scale (VAS) scores, which were lower than general population norm at baseline, substantially improved by month 6 after exa-cel infusion and were sustained through month 36, with similar improvements in FACT-General (FACT-G) total and bone marrow transplant subscale. All FACT-G (physical, social/family, emotional, functional well-being) and ASCQ-Me (emotional, social functioning, stiffness, sleep impact) subscales showed clinically meaningful improvement, including ASCQ-Me pain subscales (impact, episode frequency, severity), with substantial decreases in pain episode frequency by month 6. Mean pain NRS score decreased by month 6 and was sustained. Consistent with adults, adolescents had improvements in mean EQ-5D-Y VAS score, PedsQL score, and pain NRS. Exa-cel led to broad and clinically meaningful HRQoL benefits in adults and adolescents with SCD. The CLIMB SCD-121 and CLIMB-131 trials were registered at www.clinicaltrials.gov as #NCT03745287 and #NCT04208529, respectively.