Prevalence of autoimmune diseases in patients with sickle cell disease: a single center retrospective analysis.

Not available.

Withholding transfusion therapy in children with sickle cell disease with abnormal transcranial doppler and normal magnetic resonance angiography: a retrospective analysis.

Not available.

Hematopoietic cell transplantation for older acute myeloid leukemia patients in first complete remission: results of a randomized phase III study.

Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.

Bleeding assessment following central venous catheter placement, a direct comparison of prospective and retrospective analyses.

BACKGROUND: Reported bleeding incidences following central venous catheter (CVC) placement highly depend on methods of bleeding assessment. To determine the direction and magnitude of the bias associated with retrospective data collection, we used data from the PACER randomized controlled trial and a previous retrospective cohort study. STUDY DESIGN AND METHODS: A patient-level comparison of CVC-related bleeding severity was made among (1) the prospectively collected clinical bleeding assessment of the PACER trial, (2) centralized assessment of CVC insertion site photographs, and (3) retrospective chart review. Interrater reliability for photographic bleeding assessment and retrospective chart review was assessed using Cohen's κ. The magnitude of underreporting of both methods compared to prospective clinical bleeding assessment at different cutoff points of clinically relevant bleeding was assessed using McNemar's test. RESULTS: Interrater reliability was acceptable for both methods (κ = 0.583 and κ = 0.481 for photographic assessment and retrospective chart review, respectively). Photographic bleeding assessment led to significant underreporting of bleeding complications at all cutoff points. Retrospective chart review led to significant underreporting of minor bleeding complications, with an odds ratio (95% CI) of 0.17 (0.044-0.51) for the cutoff point grade 1 (i.e., self-limiting or requiring at most 20 min of manual compression) or higher. There was no significant underreporting of major bleeding complications with retrospective chart review. DISCUSSION: Centralized photographic bleeding assessment and retrospective chart review lead to biased bleeding assessment compared to prospective clinical bleeding assessment.

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.

Neutrophils in sickle cell disease: Exploring their potential role as a therapeutic target.

Factors influencing the activation of neutrophils in SCD and the potential neutrophil-mediated ameliorating effects of therapies in SCD.

Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Macular neurodegenerative and vascular changes on OCTA in sickle cell disease are not related to its ocular and systemic complications.

PURPOSE: To evaluate macular abnormalities in sickle cell disease (SCD) with OCT-Angiography (OCTA) and to determine associations with sickle cell retinopathy (SCR) and clinical and laboratory characteristics. METHODS: Complete ophthalmic examination was performed in consecutive SCD patients (HbSS, HbSC, HbSß0 or HbSß+ genotype), including fundoscopy and macular SD-OCT/OCTA scans. SCR stage was based on fundoscopic examination (without fluorescein angiography) instead of the Goldberg classification, since fluorescein angiography was only used in case of tentative diagnosis. Medical/ophthalmological history and hematologic characteristics were retrieved from medical records. RESULTS: 249 eyes of 137 patients were analyzed. The mean age was 33.3 ± 12.4 years (range 15-70). Non-proliferative SCR was present in 57 eyes (22.9%) and proliferative SCR in 36 eyes (14.5%). Macular thinning was present in 100 eyes (40.2%) and was associated with lower foveal vessel density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) and with enlargement of the foveal avascular zone (FAZ) area, perimeter and acircularity index (AI). Age and female sex were associated with lower (para)foveal VD in the SCP and DCP. No associations were found between SCR presence/severity and macular thinning or VD. CONCLUSION: Macular abnormalities were common, but did not result in visual impairment. No relation with SCR presence/severity was found. While OCTA-imaging is suitable for detecting maculopathy, it appears to have no diagnostic value in identifying patients at risk for SCR.

Development and Validation of a Prediction Model for 1-Year Mortality in Patients With a Hematologic Malignancy Admitted to the ICU.

OBJECTIVES: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU. DESIGN: A retrospective cohort study. SETTING: Five university hospitals in the Netherlands between 2002 and 2015. PATIENTS: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers (C-statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model (C-statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality. CONCLUSIONS: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations.

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling.

BACKGROUND: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. AIM: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. METHODS: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. RESULTS: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13-3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08-7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95-1.91], p = 0.10), which did not translate into a significant survival benefit. CONCLUSION: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease.

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p < 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p < 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.