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Key Points Cardiac abnormalities in children and young adults with sickle cell anemia are common.Timely initiation of treatment with hydroxyurea may lead to reverse cardiac remodeling and improvement in these cardiac abnormalities., Visual Abstract, Cardiac abnormalities such as left ventricular hypertrophy, left ventricular dilation, and pulmonary hypertension in sickle cell anemia have been previously described. Hydroxyurea, a disease-modifying therapy for sickle cell anemia, has been used for several decades. Longitudinal assessment of echocardiographic abnormalities in children and young adults with sickle cell anemia receiving hydroxyurea therapy is lacking. The goal of this retrospective study was to determine the prevalence of echocardiographic abnormalities in children and young adults with sickle cell anemia and to examine the effects of hydroxyurea on reverse cardiac remodeling. We reviewed the records of patients with sickle cell anemia who underwent routine cardiac screening at Cohen Children’s Medical Center between 2010 and 2017, followed by retrospective longitudinal analysis of echocardiograms performed on patients receiving treatment with hydroxyurea. Data on a total of 100 patients with sickle cell anemia were analyzed; 60 (60%) were being treated with hydroxyurea. Twenty-five (41.6%) of the patients on hydroxyurea had been treated for 1 year. Serial echocardiograms of patients receiving hydroxyurea were then analyzed. Left ventricular dilation and hypertrophy improved significantly with hydroxyurea treatment. In addition, the left ventricular volume and mass correlated negatively with duration of treatment with hydroxyurea. Our study provides evidence that prolonged hydroxyurea therapy may lead to reverse cardiac remodeling. Future studies should attempt to follow up this patient cohort for a longer duration.

This retrospective study investigates the relationship between the presence of a documented viral infection in children with sickle cell disease during their first splenic sequestration crisis and their odds of recurrence. Forty-eight children were admitted to our hospital between 2008 and 2018 with a splenic sequestration crisis. Thirty-six had respiratory viral panels done on admission, 13 of whom were positive. Two additional children were diagnosed with parvovirus B19 infection by serology. The recurrence rate was 52% (17/33) for those deemed negative for viral illness compared with 33% (5/15) among those with a positive documented viral illness, which was not statistically different (P=0.35). HbSC genotype decreased, and reticulocytosis increased the odds of recurrence. Further research is needed to substantiate these findings.

Patients with sickle cell disease (SCD) are living longer and subsequently more apt to develop cardiopulmonary dysfunction. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels have been used in adults with SCD to assess for pulmonary hypertension and mortality. While the incidence of PH is low in pediatrics, it is reasonable to presume that NT-proBNP levels can be used to assess risk for the development of cardiopulmonary morbidity. We hypothesized that NT-proBNP levels would be increased in patients with SCD compared to age-adjusted healthy children; additionally, these levels would be associated with labs indicative of hemolysis and would demonstrate evidence of obstructive lung disease and cardiac dysfunction. We retrospectively evaluated patients with SCD, 8-18 years old, at a large, tertiary care children's hospital. NT-proBNP levels were assessed in correlation with hemolytic lab work, spirometry, and echocardiographic data. The age group 8-14 years old, 75% of our cohort's population, had a median NT-proBNP of 70 pg/ml, greater than their age-adjusted counterparts (52 pg/ml). NT-proBNP levels were associated with an increased degree of hemolysis when compared with hemoglobin (Hb) (r = -0.43, p < .0001), reticulocyte count (r = .25, p = .01) and lactate dehydrogenase levels (r = .47, p < .0001). An inverse trend was found between NT-proBNP and spirometric data. Finally, a positive correlation was found between NT-proBNP and diastolic left ventricular size (r = .28, p = .047]. The correlations found suggest that NT-proBNP may be used prospectively to identify patients with SCD at increased risk for the development of cardiopulmonary dysfunction.

Youth with sickle cell disease (SCD) and their caregivers are susceptible to stress and depression, perhaps exacerbated by pandemic-associated health and economic concerns. Most of the 50 youth-caregiver dyads enrolled in the multisite trial, Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT), took an online survey of self-reported mental health symptoms and food insecurity during the 2020 COVID-19 pandemic. Compared to largely pre-pandemic results, prevalence of mental health symptoms in dyad members appeared to have shifted: fewer youth and more caregivers were affected during the pandemic; many of both groups lacked optimism. Pandemic/post-pandemic screening of youth with SCD for mental health symptoms and food insecurity appears warranted.

Adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have had high rates of thrombosis. A novel condition in children infected with SARS-CoV-2, multisystem inflammatory syndrome in children (MIS-C), has limited data on their prothrombotic state or need for thromboprophylaxis.We aimed to analyze the prothrombotic state using coagulation profiles, rotational thromboelastometry (ROTEM) parameters and clinical outcomes, to determine if this could aid in risk stratification for thromboprophylaxis.This analysis included patients (21 years of age) with a diagnosis of MIS-C (n = 40) and controls (presenting with suspicion of MIS-C but later ruled out; n = 26).MIS-C patients had higher levels of inflammatory markers including D-dimer (p .0001), compared with controls, along with evidence of hypercoagulability on ROTEM with elevated evaluation of fibrinogen activity (FIBTEM) maximum clot firmness (MCF) (p .05). For MIS-C patients with D-dimers1000 ng/ml, there was a significant correlation of FIBTEM MCF (p .0001) with a mean value of 37.4 (standard deviation 5.1). D-dimer2144 ng/ml was predictive of intensive care unit admission (area under the curve [AUC] 0.80; 95% confidence interval, 0.60-0.99; p .01; sensitivity: 82%, specificity: 75%), and elevated FIBTEM MCF (AUC 1 for2500 ng/ml). MIS-C patients (50%) received enoxaparin thromboprophylaxis (in addition to aspirin) with significant improvement in their inflammatory and ROTEM parameters upon outpatient follow-up; none developed symptomatic thrombosis.Despite an observed prothrombotic state, none of the MIS-C patients (on aspirin alone or in combination with enoxaparin) developed symptomatic thrombosis. ROTEM, in addition to coagulation profiles, may be helpful to tailor thromboprophylaxis in critically ill MIS-C patients.

Introduction: Youth with sickle cell disease (SCD) and their families are susceptible to stress and depression associated with chronic illness and social factors disproportionately affecting under-resourced U.S. communities. The COVID-19 pandemic has adversely impacted psychosocial and economic well-being, especially in some of these same communities. Our concurrent HABIT multi-site randomized trial aims to improve hydroxyurea adherence in youth with SCD ages 10-18 years through an intervention led by community health workers(NCT03462511). Subjects enrolled as youth-primary caretaker dyads; adults were mostly parents. We hypothesized that some HABIT subjects had depressive symptoms at baseline, and many had additional stressors during the pandemic. Methods: Two self-reported assessment tools were used, with options of English or Spanish: 1) PROMIS® pediatric (8a, v1.0) or adult (4a, v1.0) depression measures, completed at HABIT enrollment, nearly all between May 2018 - March 2020 ("baseline"); 2) A pandemic-related open-access survey originated by Johns Hopkins University on established core adult mental health assessed risks and behaviors.[1] Questions were closely adapted for use by youth. The pandemic survey assessed recent mental health symptoms and substance or domestic abuse. Two validated food insecurity screening questions were added.[2] Of 92 HABIT subjects, 84 were offered survey participation between May - July, 2020. Participants completed both assessment tools via electronic linkage to REDCap data capture. Analyses used chi square or Fisher exact test. Results: In all, 75% (63 of 84) responded to the pandemic survey; 31 were youth-parent dyads and one unpaired parent. Baseline demographics were: Youth (N=31): mean age 12.9±1.9 years, 48.4% female, 80.6% grade 6-12, 45.3% hospitalized within the prior 12 months; Caretakers (N=32): mean age 44.0±9.6 years, 87.5% Black, 18.8% Latinx, 37.50% married or living with a partner, 59.4% with at least some college education. At baseline, youth mean PROMIS® Depression T-Score was 49.9±10.1 (normal Conclusions: In this sample of subjects from the HABIT Trial, at baseline a higher proportion of youth had depressive symptoms compare to their primary caretakers. During the initial pandemic peak in the Northeast, disrupted work arrangements and especially school cancellation were widespread. Fewer youth but similar proportions of caretakers reported feeling depressed and/or anxious. Both groups commonly reported loneliness or not feeling hopeful for the future. History of mental health conditions, current substance use/abuse or verbal abuse were uncommon. Concordant with concerns for under-resourced communities, a sizeable minority of families reported food insecurity. Under the limitations of using 2 different assessment tools, in this modest sample the majority of youth with SCD but not caretakers were mildly-moderately depressed at baseline and that, during the pandemic, the 2 groups reported similar proportions of mental health symptoms. These findings suggest that screening for mental health symptoms, social disruption and food insecurity may be warranted in this high-risk group overall and during the pandemic. References: 1) COVID-19 and mental health measurement working group, Johns Hopkins Bloomberg School of Public Health, March 18, 2020 2) Barnidge E., et al., Screening for Food Insecurity in Pediatric Clinical Settings. J. Community Health 42(1):51-57, 2017 The HABIT Trial is supported by 5R01NR017206-04 (Green, Smaldone). The authors have no conflicts to disclose. Disclosures Smith-Whitley: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees. Aygun:bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding.

The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time found to be strong predictors of mortality, and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk assessment for thromboprophylaxis in SARS-CoV-2 is warranted.

Background The Spectra Optia allows automated performance of red blood cell reduction and isovolemic hemodilution (IHD) prior to standard red cell exchange (RCE), and is primarily intended for patients with sickle cell disease (SCD) undergoing chronic RCE. Data on the safety of inducing transient further anemia and the benefits of IHD-RCE is limited and occasionally contradictory. Study design and methods In this retrospective crossover analysis of six patients with SCD who underwent chronic exchange with standard RCE (Cobe Spectra) followed by IHD-RCE (Spectra Optia), we compared safety and benefit outcomes with IHD-RCE vs standard RCE. Results There were statistically but not clinically significant drops in blood pressure in the post-IHD phase. With IHD-RCE, there were significant reductions in red blood cell (RBC) usage and/or lower fraction of cells and significant increases in postprocedure hematocrit (Hct) associated with increased preprocedure Hct. There were no differences achieved in the time interval between procedures or in the net RBC gain with IHD-RCE. Overall, there were also no significant differences in pre- and postprocedure percentage of hemoglobin S, reticulocyte count, interval daily hemoglobin A decrement, or postprocedure white blood cell, neutrophil, or platelet counts. Conclusions Our study supports that IHD-RCE can be safely used in patients with stroke risk and compared to standard RCE, results in benefits of lower RBC usage and/or fraction of cells remaining and higher postprocedure Hct associated with higher preprocedure Hct. These findings support wider use of IHD-RCE, especially in the current environment with reduced availability of minority units.

Background Children with sickle cell disease (SCD) are at risk for neurocognitive deficits, which can lead to effects on academic performance and later job attainment. However, screening in children at high risk for poor academic performance (PAP) in a clinic setting has been limited. The goal was to identify young children with SCD at high risk for PAP via administration of a standardized screening tool at the clinic visit. Procedure Parents of 20 patients were asked to complete the Behavior Assessment System for Children, 3rd edition (BASC-3) Parent Rating Scale. Children ages six to nine years and all SCD genotypes were included. Those patients who scored at least 1 standard deviation below the mean were considered high risk. Statistics was used to associate demographic, academic, and laboratory data with risk status (RS). Results Four of 20 patients (20%) were found to be at risk by the BASC-3. A significant association was found between those with a history of PAP and RS (P = 0.001). A trend toward association was found between baseline hemoglobin, reticulocyte count, and RS. Children not at risk had a higher hemoglobin level and lower reticulocyte count (P = 0.37 and P = 0.20, respectively). Those on hydroxyurea were significantly less likely to score as at risk (P = 0.014), whereas those with siblings may be at greater risk (P = 0.037). Conclusion(s) A parent-directed screening tool may identify children with SCD in need of additional school support. Further prospective studies are necessary to understand correlations found between hemoglobin, reticulocyte count, and hydroxyurea treatment and risk for PAP.

Acute vaso-occlusive episodes (VOE) are the most common reason for presentation to the Emergency Department (ED) and inpatient admission in people living with sickle cell disease (SCD). The goal of this study was to compare the hospital admission rate for VOE from our centre's day hospital (Pediatric Ambulatory Chemotherapy and Transfusion Unit; PACT) versus the ED, and to determine which factors influence admission rate. The study included a total of 370 visits involving 140 children with SCD with a mean age of 10·9 ± 5·5 years. The timing from triage to the first analgesic was significantly different between the PACT and the ED (median, 32 vs. 70 min, P < 0·0001). The initial choice of opioid dosage adhered to our centre's guidelines 84% of the time in the PACT v. 45% in the ED for morphine (P = 0·0003) and 100% in the PACT vs. 43% (P = 0·002) for hydromorphone. The admission rate from the ED (57%) was significantly higher than that of the PACT (29%) even when accounting for differences in baseline variables (P = 0·0001). In conclusion, the odds of being admitted were 3·8 times higher if the patient was treated in the ED. Timely administration and appropriate dosing of intravenous opioids may change this outcome in the future.

The intracellular parasites Babesia microti and Babesia duncani can be transmitted by blood transfusion and cause severe life-threatening hemolytic anemia in high-risk patients, including those with sickle cell disease. The rarity of the diagnosis, as well as its similar clinical presentation to delayed hemolytic transfusion reaction, may lead to a delay in diagnosis, as well as inappropriate treatment with steroids or other immunosuppressive agents. The morbidity caused by this disease in especially vulnerable populations justifies the need for a universal blood-screening program in endemic areas.

Background: Isovolemic hemodilution (IHD-RCE), an add-on to standard red cell exchange (RCE), was recently FDA-approved on select apheresis devices. Equipoise exists as to the degree of red cell unit reduction and time interval extension between procedures with IHD-RCE. Also, concern has been raised that the transient hematocrit (Hct) decrease and potential hypotension with IHD-RCE causes ischemic brain injury, especially with Moya Moya disease. Again, there is equipoise, with only one of 4 studies reporting increased hypotension and no studies of ischemic brain injury with IHD-RCE. We therefore conducted a retrospective crossover study of efficacy and safety of IHD-RCE in our sickle cell disease patients, three of whom had Moya Moya, and report follow-up brain MRI/MRA data, heretofore not reported in the literature. Study design: This was a retrospective review of patients who crossed over from standard RCE (Cobe Spectra) to IHD-RCE (Spectra Optia). The IHD phase used normal saline for replacement fluid. Minimum (post-IHD) hematocrits (Hcts) and post-procedure Hcts were based upon pre-procedure Hcts as per Matevosyan et al, JCA 2012. Pre-procedure CBCs, reticulocyte counts, and serum ferritins were drawn within 72 hours of the procedure and post-procedure CBCs drawn immediately post-procedure. All red cell units were leuko-reduced, CEK matched, and less than 15 days old when possible. Methods: The same number of procedures were analyzed for standard RCE and IHD-RCE, with the RCE procedures most recent to crossover to IHD-RCE used for comparison. Means of continuous variables were calculated for each patient; means and standard deviations of the patient means are shown, unless otherwise indicated. Paired t-testing was used to compare IHD-RCE to RCE († in tables indicates p-value < 0.05) Results: Patients: All 6 patients (3 M, 3 F) were black; 5 had HbSS and 1 had SB+thal. The indication for RCE was stroke prophylaxis in four, 3 of whom had Moya-Moya disease, and frequent vaso-occlusive crisis (VOC) in two. Mean patient age at the time of first IHD-RCE was 15 ± 2 years, and a mean 26 ± 12 procedures of each procedure type was analyzed for IHD-RCE to RCE comparisons. Patient total blood volume (TBV) significantly increased from the RCE to IHD-RCE periods and was accounted for in the analysis. Procedure-centric measures (Table 1). Despite increasing TBV, red cell unit usage did not increase, and the volume of donor red cells transfused per mL TBV significantly decreased with IHD-RCE. There was no increase in inter-procedural interval. Patient-centric efficacy measures (Table 2): Despite the decreased volume of donor red cells transfused per mL TBV, and similar post- and pre-procedure HbS %s between IHD-RCE and RCE, the pre-procedure Hct was slightly (5%) increased with IHD-RCE. Procedural safety-related measures (Table 3): Although there were statistically significant drops in systolic and diastolic blood pressures (BP) post-IHD compared to pre-procedure BP, the degrees (about -6%) were mild. By procedure end, there were no overall significant differences in BP from pre-procedure BP. In addition, there was no overall significant change in heart rate post-IHD or post-procedure. Actual patient adverse events (Table 4): One patient had a single possibly IHD-related Grade 2 symptomatic (dizziness) vasovagal event, occurring at procedure end and resolved with normal saline bolus. All 4 patients on IHD-RCE for stroke prophylaxis had follow-up MRI/MRA after switching to IHD-RCE. One patient showed new silent strokes and vasculopathy but her prior MRI/MRA predated her standard RCE period. One patient who had progressed on standard RCE had no progression on IHD-RCE. The other two patients had stable MRI/MRA. Conclusion: When reducing pre-procedure Hct by 20-24% during the IHD phase, our data confirm the 11-13% reduction in red cell unit usage with IHD-RCE reported by Sarode et al, JCA 2011 and Hequet et al, Transfusion 2019, but do not support an increased inter-procedural interval of 16 days as per Sarode et al. Most patients had a mild (< 15%) and asymptomatic drop in systolic and diastolic BPs with IHD-RCE; a minority also had a very mild ( Disclosures No relevant conflicts of interest to declare.

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.

Alpha thalassemia due to nondeletional mutations usually leads to more severe disease than that caused by deletional mutations. Devastating outcomes such as hydrops fetalis can occur with two nondeletional mutations, therefore warranting DNA-based workup for suspected carriers with subtle hematological abnormalities for family counseling purposes. We describe three cases with hemoglobin (Hb) Adana, a nondeletional alpha chain mutation, compounded with an alpha globin gene deletion resulting in thalassemia intermedia. We review the literature, draw genotype-phenotype correlations from published cases of Hb Adana, and propose that this correlation can be used by clinicians to help direct diagnostic studies and urge hematologists to thoroughly workup high-risk patients.

Sickle cell disease (SCD) represents a major challenge in hematology, with approximately 100,000 Americans afflicted and the annual number of newborns with SCD set to rise over the next 40 years worldwide. Current treatment approaches rely on increasing levels of fetal hemoglobin (HbF) to prevent painful vaso-occlusive crises and hemolysis secondary to red cell sickling. Hydroxyurea remains the only pharmacologic intervention approved for SCD; however, it has limited efficacy and carries significant side effects such as myelosuppression. Thus, there is a critical need to develop drugs that enhance HbF production without similar dose limiting side effects. Second generation immunomodulatory drugs, such as pomalidomide, are a class of emerging HbF inducers both in vitro and in vivo. Recent work from our laboratory revealed that hydroxyurea and pomalidomide differentially regulate HbF production in CD34+ cells undergoing erythroid differentiation using a 3-phase culture system. Pomalidomide, but not hydroxyurea, was found to decrease BCL11A expression through a yet to be defined mechanism. In the present study, we sought to characterize erythropoiesis and the expression of key transcription factor networks in this 3-phase culture system to determine the mechanisms underlying pomalidomide’s effect. Following a four day expansion period, isolated CD34+ cells from the peripheral blood of SCD or normal individuals were differentiated along erythroid lineage in the presence of pomalidomide (1μM) or DMSO (vehicle) for 14 days. As an additional control, CD34+ cells were also treated with hydroxyurea (10μM). Proliferation and erythroid differentiation were assessed at 7, 11 and 14 days of culture. Although a 50% decrease in cell growth was noted in cells treated with hydroxyurea, no such decrement was found in control, DMSO and pomalidomide-treated cells. Moreover, pomalidomide produced a transient delay in erythroid differentiation between days 6 and 11 of culture phenotypically documented by flow cytometric analysis using glycophorin-A, α-4 integrin and band 3 as surface markers monitoring erythroid differentiation as well as morphologically by May-Grunwald Giemsa staining. In contrast, cells treated with hydroxyurea demonstrated accelerated differentiation, compared to the control cultures. However, by day 14 of culture, no significant difference was observed under any condition, suggesting that the delayed cells eventually finished terminal differentiation. In terms of HbF induction, we confirmed elevated production in the cultures with pomalidomide by measuring the number of F-cells by flow cytometry. We also evaluated the production of γ-globin chains by qRT-PCR and western blot at D4 and D11 and found a dramatic increase in the production of γ-globin, in both SCD and normal samples treated with pomalidomide. We posited that pomalidomide might foster changes in transcription factors known to play a role in both erythropoiesis and globin switching. To this end, we evaluated the expression kinetics of BCL11A, SOX6, KLF1, MI2β, GATA1 and FOG1 via qRT-PCR and western blot analyses. In DMSO-treated cultures the above transcription factors were maximally expressed between days 6-8, and their levels diminished during the remainder of the culture. Conversely, pomalidomide markedly decreased BCL11A, SOX6, KLF1 and MI2β between days 4 and 6 in cultures of both SCD and normal samples. In line with our results, MI2β acts as a positive regulator of BCL11A and KLF1, and previous studies have shown that its knock down in CD34 cells leads to decreased levels of BCL11A and KLF1. Western blot analyses confirmed the qRT-PCR data. Further, the divergent expression patterns correlated temporally with the differentiation delay suggesting that pomalidomide modulates expression of members of the BCL11Atranscription factor complex, thereby augmenting γ-globin production. Taken together, these data provide evidence that pomalidomide influences erythropoiesis by modulating transcription factor expression in CD34+ cells differentiated in the 3-phase culture system, leading to a decrease in BCL11A and activation of γ-globin production. Importantly, further exploration of these pathways that function to regulate erythropoiesis and promote HbF silencing, may help elucidate the mechanism of action of pomalidomide as well as identify additional druggable molecules. Disclosures No relevant conflicts of interest to declare.

Fetal hemoglobin (HbF) is a known modifier of sickle cell disease (SCD) severity. KLF-1 is a regulator of the globin switch. It does so by increasing beta-globin production and up-regulating BCL11A, a repressor of HbF synthesis. Pomalidomide, a second generation immunomodulatory drug (IMiD), regulates HbF and F-cell production during erythropoiesis in human CD34+ cells. The mechanism by which pomalidomide enhances F-cell production is not well understood. In this study, CD34+ cells were obtained after purification of peripheral blood and positive selection and cultured using a three-phase in vitro liquid culture system which recapitulates erythropoiesis, including terminal differentiation and enucleation, in the presence of no drug, pomalidomide, hydroxyurea, or dimethyl sulfoxide (DMSO; vehicle control). Erythroid differentiation was assessed morphologically and by flow cytometry using the transferrin receptor and glycophorin A as markers of erythroid maturation. Flow cytometry was used to quantify F-cells. RT-qPCR was used to quantify mRNA expression of BCL11A, KLF-1, and gamma-globin. Western blot was used to measure the total expression levels of BCL11A. In this culture system pomalidomide increased F-cells more than hydroxyurea in both SCD and normal control erythroid cultures. There was a significant decrease in BCL11A expression levels, a repressor of HbF synthesis, with pomalidomide but not with hydroxyurea. This decrease was seen in both SCD and normal samples. KLF-1 was not affected by pomalidomide. These findings suggest a very different mechanism of action for pomalidomide versus hydroxyurea in increasing F-cell production. Pomalidomide appears to target the erythroid specific BCL11A but not the more pleiotropic transcription regulator KLF-1. Since the F-cell production was augmented in the presence of pomalidomide in controls as well as SCD erythroid cultures this study suggests a role for pomalidomide in the pharmacologic augmentation of fetal hemoglobin levels, perhaps in addition to hydroxyurea, not only in SCD but in any beta-hemoglobinopathy. Disclosures: Chan: BioTheryX Inc: Employment.