By stimulating the expression of fetal hemoglobin (HbF), hydroxyurea helps patients with sickle cell disease (SCD). Improved clinical outcomes are correlated with higher HbF levels. The long-term response to the medication, however, varies significantly. The effects of hydroxyurea treatment on the quantitative alterations in hematopoietic stem and progenitor cells (HSPCs) are still poorly understood. 

This study aimed to identify the HSPC profiles linked to hydroxyurea response and ascertain the incidence and clinical significance of decreasing hydroxyurea response in pediatric SCD patients. The study was presented as a poster at the 65th American Society of Hematology Annual Meeting & Exposition.

 Study Design and Characteristics  

Data from 760 pediatric SCD patients at Texas Children’s Hematology Center were retrospectively analyzed (2010–2021). Patients with more than 5 years of hydroxyurea use were chosen. They were classified as sustained response (HbF >20%) or decreased response (HbF <10%) based on each patient’s unique HbF response. The hydroxyurea treatment and clinical data were gathered.

Levels of Fetal Hemoglobin in Children With Sickle Cell Disease

The analysis included 208 children with HbSS or HbSβ0-thalassemia; 148 (71%) showed a sustained response to hydroxyurea, and 60 (29%) showed a decreased response. The hydroxyurea sustained response group subjects had stable values of HbF >20%. In comparison, subjects with a decreased response had a median initial hydroxyurea-induced HbF of 23.9%, which decreased to 9.8% over time (p<0.001). When adjusted for age, these differences persisted. 

Adverse Events During the Treatment  

Patients with a decreased response to hydroxyurea were found to have a significantly higher incidence of clinical complications than those with a sustained response, such as the number of emergency visits (153.3 vs. 120.3 events per 100 patient-years), transfusions (37.4 vs. 11.9), and hospitalizations related to SCD (57.7 vs. 42.0). Vaso-occlusive events requiring admission (27.7 vs. 21.1 events per 100 patient-years), acute chest syndrome (13 vs. 9.9), splenic sequestration (6.4 vs. 3.5), and surgical procedures (7.47 vs. 3.02) were the causes of hospitalizations related to SCD.

Proportions of Hematopoietic Cells

From 40 patient peripheral blood mononuclear cell samples (20 with sustained response, 20 with decreased response), differences emerged: sustained responders showed increased levels of multipotent cells (51.75% vs. 43%), CD49F⁺⁺ HSCs (20.5% vs. 13.55%), and CD235a+/CD71⁺ (11.55% vs. 4.54%) cells. Conversely, decreased responders exhibited increases in percentages of committed megakaryocyte erythroid progenitors and unipotent hematopoietic progenitors (38.55% vs. 52.9%).

Source
Luisanna, S. V. (2023, December 9). Clinical and Hematopoietic Profiles Associated with Sustained Hydroxyurea Response for Patients with Sickle Cell Disease. https://ash.confex.com/ash/2023/webprogram/Paper187335.html 

Damage from hypoxia results in abnormal blood vessel formation in sickle cell disease (SCD), which affects bone marrow and red blood cell production. Erythropoiesis is impeded by a dysfunctional bone marrow environment, which can also harm hematopoietic stem cells (HSCs). The strong polymerization inhibitor GBT021601 raises hemoglobin levels by up to 3 g/dL without causing iron overload or alloimmunization hazards that come with long-term red cell transfusions.

The study investigated the potential of GBT021601 treatment to improve sickle cell disease by restoring bone marrow health, reducing proangiogenic factors, and maintaining hematopoietic stem cell activity. This study was presented as a poster at the 65th American Society of Hematology Annual Meeting and Exposition.

 Study Protocol and Characteristics

Humanized Townes HbSS SCD mice were divided into three cohorts (n = 8 per group: 4 male, 4 female) and fed either standard chow (control) or chow containing 0.1% or 0.2% GBT021601. The mice were phlebotomized and killed after 12 weeks. Spleens were taken and weighed. Centrifugation was used to obtain whole bone marrow from both tibias and one femur; the other was retained for later 3D confocal imaging. Flow cytometry examined the bone marrow for erythroid cell maturation (Annexin V, TER119, and CD44) and HSC markers (Lin, Sca-1, and c-kit). An immunoblot examination of peripheral plasma assessed hypoxia-induced signaling and angiogenesis markers (VCAM-1, VEGF-A, ANG-1, and -2).

Increased Hemoglobin Counts and Reduction of Spleen Size Noted

Hb increased by 3 g/dL on average after GBT021601 administration, and spleen weights decreased significantly (P = 0.0023 and P = 0.0015 for control vs. 0.1% and 0.2%, respectively). Mature red blood cells (RBCs) significantly outnumbered erythroid progenitors at all stages, according to flow cytometry analysis of the removed bone marrow.

 No Significant Changes Observed in Hematopoietic Stem Cells

Dysfunctional bone marrow affects red blood cell production and harms HSCs. Despite GBT021601 treatment, HSC counts showed no notable differences between groups. Further research aims to assess GBT021601’s potential for normalizing bone marrow and protecting edited HSCs.

Changes in Angiogenesis Markers After Administration

VCAM-1 and ANG-1 levels are greater in HbSS mice than in HbAA mice. Treatment with GBT021601 reduced factors leading to pathogenic blood vessel growth. ANG-2 and VEGF-A levels, on the other hand, remained unchanged, with VEGF-A levels being similar between HbSS and HbAA mice.

Source
Hernandez, B. (2023, December 9). Evaluation of GBT021601 as a therapeutic agent to restore bone marrow health and effective erythropoiesis in a sickle mouse model. https://ash.confex.com/ash/2023/webprogram/Paper175022.html 

For those diagnosed with sickle cell disease (SCD), allogeneic hematopoietic stem cell transplantation (HCT) and ex vivo autologous gene therapies (GT) are among the most promising treatment approaches. However, a key challenge lies in defining what constitutes a cure, specifically in terms of donor chimerism and functional hemoglobin levels. 

Currently, information on red cell function post-HCT/GT and its correlation with donor chimerism and the resolution of SCD complications is limited. This study, presented at the proceedings of the 65th ASH Annual Meeting & Exposition, aimed to address this gap by providing insights into rheology and whole blood viscosity data in patients with the hemoglobin SS genotype (HbSS) following HCT or GT.

Defining Cure Based on Myeloid Donor Chimerism Is Insufficient

Conducted under IRB-approved protocols at Baylor College of Medicine and Emory University School of Medicine, the study involved the analysis of various parameters, including elongation index (EL) maximum (EI[max]) and minimum and (EI[min]), point of sickling (PoS), hematocrit–viscosity ratio (HVR) at different shear rates (HVR45 and HVR225), and dense red blood cell percentage (DRBC%). These parameters were assessed using a laser-assisted optical rotational red cell analyzer (LORCA) and other validated methods. 

Results from the study, involving 29 patients with a median age of 6.6 years at HCT/GT and a median follow-up of 2.4 years, indicated that while myeloid donor chimerism was generally high (median 94%), the percentage of sickle hemoglobin (HbS%) varied, ranging from 28.9% to 45.2% with HbAS donors and 0% with HbAA donors. Notably, two HbAS HCT patients exhibited myeloid chimerism ≤50%, prompting consideration of the follow-up period and associated parameters. 

The study determined improvements in RBC function over time post-HCT/GT, particularly in patients with HbAA donors, with EI[max] showing a trend toward statistical significance. Patients with HbAS donors displayed significantly higher point of sikcling (PoS) values and a trend toward lower HVR225 compared to HbAA donors.

The study identified a subset of patients (24%) with abnormal red cell function test values post-HCT/GT despite achieving myeloid donor chimerism of >25–30%, a commonly accepted threshold in clinical practice. These findings challenge existing notions and prompt a reconsideration of defining a cure based solely on myeloid donor chimerism.

The Bottom Line

In conclusion, the study advocates for the inclusion of red cell function tests in the follow-up care of HCT/GT patients until values normalize, acknowledging their potential significance in assessing the clinical relevance of these therapeutic interventions. The findings underscore the complexity of defining a cure in the context of SCD and advocate for a comprehensive approach that considers both hematological parameters and functional outcomes.

Source

Patel, A. (2023, December 9). Red Cell Rheology and Blood Viscosity in Pediatric Individuals Having Received Allogenic Hematopoietic Stem Cell Transplantation or Ex Vivo Autologous Gene Therapy for Sickle Cell Disease. https://ash.confex.com/ash/2023/webprogram/Paper188045.html 

Priapism, defined as a painful, sustained erection of the penis, is observed in 35% of adult male sickle cell disease (SCD) patients. Priapism is thought to be mediated by vaso-occlusion in SCD. Crizanlizumab, a monoclonal antibody, has been approved by the Food and Drug Administration (FDA) to reduce vaso-occlusive crises in SCD patients.

This study is a primary analysis of the phase 2 clinical trial SPARTAN, which evaluated the safety and efficacy of crizanlizumab in treating priapism in SCD patients for a duration of 26 weeks. The study findings were presented as a poster at the 65th American Society of Hematology Annual Meeting and Exposition.  

Study Protocol

The clinical trial included male SCD patients 12 years of age or older. The eligible patients had experienced ≥4 priapic episodes over a 14-week period before the screening and ≥3 priapic episodes over the 12-week screening period. The outcome-related data was acquired from the patients via electronic self-reporting tools. The patients were administered 5 mg/kg intravenous infusions of crizanlizumab on the 1st week, 3rd week, and every 4th week after that.   

Baseline Characteristics

A total of 36 patients were enrolled in the SPARTAN trial, with a median (range) age of 29 (14–58) years. Most of the patients had the HbSS genotype of SCD, and approximately 58.3% were taking hydroxyurea. The majority of patients reported having priapic episodes for a duration of 1–5 hours.

Reduction in Frequency of Priapic Events

The median percent decline in the priapic events from the baseline was 46%. Approximately 77.8% of the patients experienced a reduction in priapic events after treatment with crizanlizumab. The percent reduction was significantly greater among patients with ≥22 baseline priapic episodes.

Treatment-Emergent Adverse Events

Headache was the most common treatment-emergent adverse event (TEAE) among the study participants. The treatment was found to be safe and well-tolerated.

Source:

Idowu, M. (2023, December 9). Primary Analysis of Spartan: A Phase 2 Trial to Assess the Efficacy and Safety of Crizanlizumab in Patients with Sickle Cell Disease Related Priapism. https://ash.confex.com/ash/2023/webprogram/Paper179042.html 

Many men with sickle cell disease experience reproductive health issues. Pubertal delay is linked to sickle cell disease (SCD), although little is known about puberty onset among male SCD patients. Infertility is frequently observed in men who do not undergo hydroxyurea (HU) therapy; less than 10% of these men exhibit normal semen analysis results per the World Health Organization’s guidelines. Notably, HU therapy may worsen infertility issues in many people. 

Due to these issues, male SCD patients prescribed HU therapy have several fertility preservation options. These include cryopreserving sperm before HU therapy for adolescent boys and adults and temporarily stopping HU therapy when therapy begins in infancy for sperm banking. Adding monthly transfusions throughout the HU-free time should improve fetal preservation. This study was presented as a poster at the 65th American Society of Hematology Annual Meeting and Exposition.

Baseline Characteristics

The study had enrolled 1860 patients as of June 28, 2023, with a total of approximately 2000 participants expected to participate over 5 years. The current median age at inclusion was 24 [IQR: 14-40] years, 44.4% of whom are male. The HbSS genotype was observed in 87% of the subjects. The median length of HU exposure at the time of study was 8.5 years.

Pubertal Onset in Males With Sickle Cell Disease

The mean age at Tanner V stage was not significantly different between males who underwent puberty before initiating hydroxyurea (HU) and those who experienced puberty after HU initiation (15.0 years [IQR: 14.0-16.0] versus 15.2 years [IQR: 14.0-16.0], respectively).

Cryopreservation Patterns in Pubescent Male Participants 

Out of the 527 pubescent males, 293 started HU at the age of 17 years or later. Among these individuals, 117 out of 240 (49%) underwent cryopreservation. Out of the 234 individuals who began HU before the age of 17, 23 out of 207 (11%) underwent cryopreservation. The median age at cryopreservation was 26.0 [IQR: 21.0-33.0] years.

Semen Analysis Pre- and Post-Hydroxyurea Treatment

A total of 104 semen analyses were recorded in the database, of which 66 were carried out before the start of HU treatment and 24 afterward. Notably, prior to the sampling, nine of these analyses were carried out with no breaks in HU therapy.

Pre-Treatment Assessment of Patients Initiating Hydroxyurea

Out of the 66 patients who were assessed before starting hydroxyurea (HU) treatment, data was not accessible for 34 individuals. Out of the available findings, 78% (25 out of 32) were within normal ranges, while 22% (7 out of 32) showed abnormalities. These abnormalities included four cases with qualitative anomalies, two cases of azoospermia, and one presenting with both quantitative and qualitative anomalies.

Semen Analysis Post Hydroxyurea

Out of the 24 patients who had their semen analyzed after starting hydroxyurea (HU), 11 patients temporarily stopped the treatment for the procedure. Out of these individuals, three showed normal results and seven showed abnormal results, and data was unavailable for one case. Significantly, a patient with oligospermia effectively employed previously frozen semen to impregnate his girlfriend. In contrast, nine patients continued taking HU before the surgery, leading to seven abnormal findings, one normal result, and data unavailability for one case. Information about HU interruption during cryopreservation was not available for four patients.

Source:

Mariane, D. M. (2023, December 9). Puberty Onset and Preservation of Fertility in Male Patients with Sickle Cell Disease Treated with Hydroxyurea: Data from the European Sickle Cell Disease Cohort – Hydroxyurea Extension (ESCORT-HU Extension) Study. https://ash.confex.com/ash/2023/webprogram/Paper178219.html 

Stress erythropoiesis (SE) occurs when the physiological process of erythropoiesis is insufficient to fulfill the required production of functional red blood cells (RBCs), resulting in heightened activity in extramedullary sites. SE is present in disorders such as sickle cell anemia (SCA) and polycythemia vera (PV), hence affecting the functioning of red blood cells (RBCs). 

The objective of this study, presented as a poster at the 65th American Society of Hematology Annual Meeting and Exposition, was to determine whether the increased phagocytic activity observed in monocytes (MCs) of these individuals is affected by changes in MC phenotype or red blood cell (RBC) features, and also to investigate the consequences related to iron metabolism following phagocytosis.

Mononuclear cells (MCs) derived from peripheral blood were subjected to incubation with labeled red blood cells (RBCs), facilitating the process of phagocytosis. The implications of iron metabolism were examined using flow cytometry analysis using anti-intracellular heme-oxygenase-1 (HO-1) and anti-membrane ferroportin (FPN) antibodies. The statistical analysis utilized the paired Student t-test with a significance level of P<0.05.

High Phagocytic Capacity in Sickle Cell Anemia

Mononuclear cells (MCs) from both SCA patients and healthy individuals, upon exposure to SCA RBCs, demonstrated a heightened phagocytic capacity in comparison to the same cells exposed to RBCs from healthy controls (mean corpuscular hemoglobin concentration  (MCHC 22.9±8 vs 9.4±1.1, **P=0,0099; MCSCA 33.6±11.4 vs 16.4±11, **P=0,0054; respectively)

Enhanced Phagocytosis in Polycythemia Vera and Healthy Control Mononuclear Cells With Exposure to Polycythemia Vera Red Blood Cells

The phagocytic activity of MCs derived from individuals with polycythemia vera (PV) and healthy controls (HC) when exposed to PV RBCs revealed that the presence of PV RBCs led to a significant increase in phagocytic activity compared to the presence of HC RBCs (MCHC 9.3±4.4 vs 2.8±4.7, **P=0.0065; MCPV 21.3±6.1 vs 11±6.8, *P=0.0146; respectively).

Sickle Cell Anemia Mononuclear Cells Exhibited a Phagocytic Pattern Similar to That of Healthy Control Mononuclear Cells

The SCA MCs displayed a phagocytic pattern that was comparable to the HC MCs (P=0.0699); however, the PV MCs revealed considerably greater phagocytic capability in comparison to the HC MCs (**P=0.0022). Moreover, across all the studied groups, the MCs that engaged in phagocytosis exhibited increased levels of both HO-1 and ferroportin FPN, underscoring their pivotal involvement in this process.

Source:

Marina, D. B. (2023, December 10). Erythrophagocytosis mediated by circulating monocytes is induced by distinct mechanisms depending on the disease. https://ash.confex.com/ash/2023/webprogram/Paper189370.html 

For pediatric patients with sickle cell disease (SCD), ophthalmologic complications include nonproliferative retinopathy (NPR) and proliferative retinopathy (PR), which occur in 33 and 6 percent, respectively, according to a study presented at the annual meeting of the American Academy of Ophthalmology, held from Nov. 3 to 6 in San Francisco.

Barbara Smith, M.D., and Mary Ellen Hoehn, M.D., from the University of Tennessee Health Science Center, describe ophthalmologic manifestations among pediatric patients with SCD who had a dilated eye exam from October 2010 to September 2022. A total of 652 patients were included who underwent eye exams during 2,240 visits.

The researchers found that 33 percent of the patients had NPR and 6 percent had PR. Panretinal photocoagulation was received by 33 eyes, most commonly for PR stage 3 (43 percent). Five eyes, all with PR, received intravitreal anti-vascular endothelial growth factor therapy. Retinal detachment and retinal artery occlusion occurred in two patients each. Following complications from SCD, vision loss (final best corrected visual acuity 20/60) was seen in one patient with a central retinal artery occlusion.

“Our data underscores the need for patients — including pediatric patients — with sickle cell disease to get routine ophthalmic screenings along with appropriate systemic and ophthalmic treatment,” Hoehn said in a statement.

Press Release

More Information

Sickle cell disease (SCD) is more likely to affect people of African descent. Additionally, it is known that SCD significantly increases the risk of pregnancy-related complications like sepsis, venous embolism, intrauterine growth restriction, and other issues. Early studies have shown that maternal mortality rates are much higher in SCD patients than in the general population. Between 1998 and 2008, the U.S. maternal mortality rate in SCD was 7.2 to 16 deaths per 10,000 SCD pregnancies, whereas this rate was 1.3 deaths in the general population. However, a new study published in JAMA Network Open shows significantly higher maternal morbidity and mortality rates in Black women due to racial disparities.

Racial Disparities Cause Higher Maternal Morbidity and Mortality in Blacks

This cross-sectional study included data from 5,401,899 deliveries, including 3901 among those living with SCD. Of the total deliveries, 742,164 were among Black patients. Generally, Black patients were younger and more likely to have public insurance. The study found that the maternal mortality rate among Black pregnant people with SCD was 26 times higher than in the non-Black control group and 10 times higher than that of Black people without SCD.

The study concluded that, on average, racial disparities increased the risk of adverse pregnancy outcomes in Black people by 28.9%. Racial disparities increased the risk of acute kidney failure by 40–50%, intrauterine fetal demise by 47.8%, and eclampsia by 42.1%. 

The Bottom line

The study found that racial disparities are causing much higher maternal mortality among Black people living with SCD than among their Black counterparts without SCD and non-Black counterparts. They are more likely to experience severe maternal mortality and life-threatening complications. There is an urgent need to find ways to reduce these racial disparities. It is vital to carry out further studies to understand the reasons for these racial disparities and make appropriate changes to the healthcare system.

Source:

Early, M. L., Eke, A. C., Gemmill, A., Lanzkron, S., & Pecker, L. H. (2023). Severe maternal morbidity and mortality in sickle cell disease in the National Inpatient Sample, 2012-2018. JAMA Network Open, 6(2), e2254552. https://doi.org/10.1001/jamanetworkopen.2022.54552 

A new study finds that Black patients have a lower life expectancy when living with sickle cell disease compared to Non-Blacks. This is despite being insured by Medicare and Medicaid, and might point to healthcare disparities requiring further investigation.

Sickle Cell Disease (SCD) affects about 100,000 individuals in the United States. However, this genetic disorder disproportionately affects people of African descent and other ethnic minorities. SCD predisposes individuals to wide-ranging life-threatening complications like stroke, severe anemia, chronic pain, and organ damage. Thus, these individuals require regular medical attention. Consequently, most of those living with the condition in the US are beneficiaries of Medicare and Medicaid. The present study, published in the journal Blood Advances, focused on the long-term survival of SCD patients with Medicare and Medicaid coverage.

Blacks Have Lower Life-Expectancy Than Non-Blacks

The study analyzed Medicare and Medicaid claims data between 2008 and 2016 for beneficiaries living with SCD, covering 50 states. The final data analysis included 94,616 individuals. The study confirmed that SCD patients have a life expectancy of 52.6 years. Moreover, the study also found that those with dual coverage of Medicare and Medicaid had worse survival, which is explained by the fact that these individuals live with more severe disease and its complications. 

However, there were some surprising findings in the study that pointed to health disparities. The study additionally analyzed the life expectancy of Blacks vs. Non-Blacks when living with SCD. This secondary data analysis demonstrated that, at birth, the life expectancy of Black individuals living with SCD was 52.2 years vs. 55.1 years for Non-Black individuals. 

The Bottom line

Though the study did not explicitly focus on health disparities, its data clearly indicate poor health outcomes and a lower life expectancy among Blacks despite adequate insurance coverage. This indicates that the reasons for worse health outcomes and disparities are not essentially related to poor access to healthcare alone. There could be other factors like worse care, poor communication, differences in managing the disease-related complications, and so on. Further, studies are needed to determine the causes for different outcomes and lower life expectancy of Blacks vs. Non-Blacks when living with SCD, since overcoming health disparities may significantly help  enhance overall life expectancy for the population group.

Source:

Jiao, B., Johnson, K. M., Ramsey, S. D., Bender, M. A., Devine, B., & Basu, A. (2023). Long-Term Survival with Sickle Cell Disease: A Nationwide Cohort Study of Medicare and Medicaid Beneficiaries. Blood Advances, 7(13), 3276–3283. https://doi.org/10.1182/bloodadvances.2022009202