X-linked sideroblastic anemia (XLSA) (MIM 300752) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. It is due to mutations of the erythroid-specific enzyme ALAS2, the first enzyme of the heme biosynthetic pathway. Herein, we report a novel 11-bp deletion in exon 11 leading to a frameshift in the C-terminal region of the ALAS2 gene with a non-functional longer polypeptide of 614 amino acids leading to a loss-of-function mutation manifested as an X-linked sideroblastic anemia phenotype. The proband was a 29-year-old man with moderately severe microcytic hypochromic anemia with splenomegaly and increased ring sideroblasts in the bone marrow with considerable iron overload. Sanger sequencing documented a missense mutation leading to a frameshift with an elongated polypeptide of 614 AA instead of the normal 587 AA protein c.1743_1753 del (p.Gln581Hisfs*35). This mutation affected the interaction with cofactor pyridoxal 5 '-phosphate since the patient's hemoglobin improved with oral administration of pyridoxine tablets. His iron overload also responded to sustained oral iron chelation therapy with deferasirox. The screening of the entire family's kindred revealed that two other male siblings were also hemizygous for the same mutation with hypochromic microcytic anemia and tissue iron overload, whereas, three female siblings and their mother were heterozygous for the mutant allele. They did not have anemia or iron overload.

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Non-traumatic fat embolism syndrome (FES) affecting brain, lung and hematopoietic system is a rare, but a serious complication of sickle cell disease (SCD), resulting from bone marrow necrosis. SCD-related FES is rare, with the spectrum of clinical, laboratory, radiological manifestations and patient outcome is not fully understood. After medical research & ethics committee approval, retrospectively, SCD-FES patients at our centre, were reviewed between January 2006 to December 2023. 27 patients (17 males, 10 females) with a median age of 24 years and length of hospital stay of 24 (16-38) days were enrolled. They had fever, chest/back pain, cough and crepitation in 100%, 96%, 56% and 100% respectively, with neurological manifestations in 96%. Abnormal chest X-rays and CT scans were observed in 96%, and 100% respectively. Patients had significant anemia, reticulocytopenia, and thrombocytopenia, with raised WBC (p < 0.05). There was a significant rise in LDH, ALP, Ferritin and C-reactive protein levels. All patients received antibiotics, and exchange transfusions, whereas 24%, 76% required non-invasive ventilation (NIV) and mechanical ventilation respectively, with 18.5% mortality. FES is a rapidly progressive respiratory and neurological syndrome, characterized by hypoxia, and cytopenia, with raised inflammatory markers, raised LDH and ALP, with distinctive multiple cerebral microbleeds.

Sickle cell disease (SCD) is an inherited disorder characterized by abnormal mutation leading to formation of sickle red blood cells. The initial step is the formation of polymers and precipitation of Hemoglobin within the cell. voxelotor is a novel anti-polymerization drug approved for treatment of patients with SCD, resulting in improved hemoglobin level. Recently its clinical development was suspended, as concerns were raised regarding its safety and efficacy. We have evaluated 11 patients who were stable, on voxelotor for a mean period of 191 weeks (range, 8-369). We observed that upon its withdrawal, 8 patients (73%) showed a rapid onset of vaso-occlusive crisis, within a median of 4.7 days, precipitating hemolysis, with a significant drop of Hb, raised reticulocytes, bilirubin, and lactic dehydrogenase. Also, one patient (9.1%) developed acute chest syndrome, whereas five (45.5%) patients needed blood transfusions. Our data confirms that rapid withdrawal of voxelotor could precipitate severe SCD-related crisis.

This systematic review aims to summarise the clinical outcomes of l-glutamine, crizanlizumab, and voxelotor in the treatment of sickle cell disease (SCD) based on clinical trials and real-world data and to identify any gaps in the observations. The review identified 97 studies reporting data until 31 May 2024. A pivotal phase III study of l-glutamine showed that patients treated with l-glutamine had a 25 % reduction in pain crises and 33 % fewer hospital days compared to placebo. l-glutamine was generally well tolerated with minimal side effects. Real-world studies of l-glutamine emphasize patient adherence and obstacles to medication accessibility and approval as key concerns. In the SUSTAIN study, a 5-mg/kg dose of crizanlizumab reduced the occurrence of vaso-occlusive crises (VOCs) and hospitalizations by 45 % and 41 %, respectively. Real-world studies of crizanlizumab showed a reduction in complicated VOC events. The high discontinuation rate and results of the STAND trial led to a significant decrease in the use of crizanlizumab. The HOPE trial demonstrated a 51 % improvement in hemoglobin response and a reduction in hemolytic markers in patients treated with voxelotor. While some real-world studies have reported a decrease in VOCs and hospitalizations, the results are inconsistent and not conclusive. Further studies are needed to assess the impact of these novel therapies on end-organ-specific complications of SCD.

BACKGROUND:Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity. METHODS:A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT. RESULTS:The median age at transplant was 11.0 months (4.6-61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40-100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2-13.6), 0.9 × 109/L 0.6-1.2), and 0.5 × 109/L (0.2-0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0-14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4-11.5). The 10-year overall probability of survival is 84.3%. CONCLUSION:Monitoring IRC is important in ensuring adequate disease-free survival.

The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001–2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd–3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.

Sickle cell disease (SCD) is a major public health burden worldwide with increasing morbidity and mortality. The study evaluates the risk factors associated with mortality in SCD patients, between the years 2006 and 2020 at three hospitals in Oman. The analysis includes clinical manifestations, haematological, biochemical, and radiological parameters, use of antibiotics, and blood and exchange transfusions. Our cohort included 123 patients (82 males, 41 females), with a median age of 27 (Interquartile Range 21–35 years). SCD related complications included acute chest syndrome (ACS) in 52.8%, splenic sequestration in 21.1%, right upper quadrant syndrome in 19.5%, more than > 6 VOC/year in 17.9%, and stroke in 13.8%. At the terminal admission, patients had cough, reduced O2 saturation, crepitation and fever in 24.4%, 49.6%, 53.6% and 68.3% respectively. Abnormal chest X-ray and chest CT scan were seen in 57.7%, and 76.4% respectively. Laboratory parameters showed a significant drop in hemoglobin (Hb) and platelet counts from baseline, with a significant rise in WBC, LDH and CRP from baseline (p < 0.05, Wilcoxon Signed Ranks test). All patients received antibiotics, whereas, 95.9% and 93.5% received simple blood transfusions, and exchange transfusions respectively, and 66.6% required non-invasive ventilation. Among the causes of death, ACS is seen in 32 (26%), sepsis in 49 (40%), and miscellaneous in 42 (34%). Sudden death was seen in 32 (26%) of patients. Male gender, with low HbF, rapid drop in Hb and platelet, and increased in WBC, LDH, ferritin, and CRP, correlated significantly with mortality in this cohort.

This systematic review and meta-analysis aimed to provide guidance on preoperative blood transfusion strategies for patients with sickle cell disease (SCD).We included all randomized controlled and observational studies exploring the clinical outcomes of preoperative blood transfusion among patients with SCD compared to the conservative transfusion strategy until 14/09/2022.Sixteen studies involving 3486 participants were analysed.The findings revealed a significantly higher bleeding rate in patients who received preoperative transfusion than those who followed a conservative strategy (RR = 4.32, 95% CI 1.75-10.68,P = 0.002, I2 = 0%).However, the two strategies had no significant differences in other clinical outcomes, such as acute chest syndrome, painful crisis, fever, neurological complications, thrombosis, ICU admission, and mortality.It is important to note that all the included studies had a moderate risk of bias.Preoperative transfusion in SCD was associated with a higher bleeding risk but a similar risk in other outcomes compared to conservative strategies.Notably, the increased bleeding risk observed seldom had clinical significance.We recommend individualizing management strategies, considering the overall positive impact of transfusions in reducing complications.Further high-quality studies are needed to refine recommendations.

Studies on chronic myeloid leukemia (CML) in the Gulf region are scarce, consisting of a survey and expert meeting that included 15 experts in 2023 which discussed CML diagnosis, testing, treatment objectives, toxicities, and discontinuation in the Gulf region. Most patients were reported to be in first-line therapy, and the most common treatments were imatinib/imatinib generic in first-line and dasatinib in second- and third-lines. Mutation analysis was not reported to be routinely performed at the time of diagnosis but rather in case of progression to accelerated/blast phase or any sign of loss of response. While all participants were aware that BCR-ABL should be monitored every three months during the first year of treatment, 10% reported monitoring BCR-ABL every six months in practice due to test cost and lab capability. The most important first-line therapy objective was “achievement of major molecular response” (MMR) in younger patients and “overall survival” in older ones. The most important treatment objectives were “MMR” and “early molecular response followed by prolongation of overall survival” in the short term and “treatment-free remission” in the long term. The current practices in CML in the Gulf region appear to be similar to global figures.

Abstract Presentation Date: 6/9/2024 Presentation Start Time: 1:33:00 PM Background In patients with sickle cell disease (SCD), polymerization of sickle hemoglobin (HbS) results in red blood cell sickling and leads to hemolysis, chronic anemia, and vaso-occlusive crises. Voxelotor, a first-in-class HbS polymerization inhibitor, is approved in the United States and Europe for the treatment of patients with SCD aged ≥4 years and ≥12 years, respectively. To assess the safety and efficacy of long-term voxelotor use, we report an updated interim analysis of an open-label extension (OLE) of the HOPE phase 3 trial (NCT03036813). Methods Patients who completed the HOPE trial were eligible to enroll in the multicenter, global OLE study (NCT03573882) and received ongoing treatment consisting of once daily voxelotor 1500 mg if they continued to derive clinical benefit. Adverse event (AE) data were collected through 28 days after voxelotor discontinuation, and measurements of hemoglobin and clinical markers of hemolysis were summarized through 168 weeks of treatment in the OLE. Data are based on an interim data cut (December 31, 2022). Results Of 199 patients who completed the HOPE trial, 178 (89.4%) were enrolled and dosed in the OLE. Median age at enrollment was 25 years. The median duration of voxelotor exposure in the OLE was 124.0 weeks, and 81 patients were treated for ≥168 weeks. Of these, 52 had received voxelotor in the HOPE trial, for a combined duration of exposure of ≥ 240 weeks. Patients previously treated with placebo in the HOPE trial had a mean (SD) hemoglobin change from baseline (start of OLE) of 1.1 (1.51) g/dL at Week 168. The mean (SD) hemoglobin change from baseline for patients who previously received voxelotor 1500 mg was 0.5 (1.49) g/dL (n = 18), indicating durability of response with continued treatment. Markers of hemolysis (indirect bilirubin, reticulocyte percentage) improved in patients who received placebo in the HOPE trial and were stable for patients who previously received 1500 mg voxelotor in the HOPE trial. Non-SCD-related treatment-emergent AEs (TEAEs) were reported in 88.2% of patients; no new safety signals were identified. Most TEAEs were grade 1 or 2 in severity. Eight deaths occurred, none deemed related to voxelotor treatment. Conclusions In this updated analysis from the HOPE OLE, long-term use of voxelotor was effective at improving hemoglobin and clinical markers of hemolysis in patients with SCD. The safety profile in the OLE was consistent with findings from the HOPE trial, and no new safety signals were identified with exposure through a combined 240 weeks of treatment. © American Society of Hematology (2023). Reused with permission.

Introduction Chez les patients atteints de drépanocytose, la polymérisation de l’hémoglobine S (HbS) entraîne une falciformation des globules rouges, une hémolyse, une anémie chronique et des crises vaso-occlusives (CVO). L’hémolyse et des taux d’Hb bas exposent à un risque d’atteinte d’organes cibles, à une augmentation de la morbidité et à une mortalité précoce. Voxelotor est un inhibiteur de polymérisation de l’HbS initiant une nouvelle classe thérapeutique, approuvé en Europe pour le traitement de l’anémie hémolytique due à la drépanocytose chez les patients âgés de ≥12ans. Afin d’évaluer l’innocuité et l’efficacité de l’utilisation à long terme de voxelotor, nous rapportons les résultats intermédiaires d’une étude d’extension en ouvert (EEO) de l’essai HOPE. Patients et méthodes Les patients ayant terminé l’essai HOPE étaient éligibles à l’inclusion dans l’EEO (NCT03573882) pour recevoir voxelotor 1500mg une fois par jour. Les événements indésirables ont été recueillis jusqu’à 28jours après l’arrêt de voxelotor et les mesures de l’Hb et des marqueurs d’hémolyse ont été recueillies jusqu’à 168 semaines. Le taux annualisé de CVOs a été calculé à partir d’événements rapportés en « anémie falciforme avec crises » ou « syndrome thoracique aigu ». Les données présentées sont issues d’une analyse intermédiaire réalisée au 31 décembre 2022. Résultats Sur les 199 patients ayant terminé l’essai HOPE, 178 (89,4 %) ont été inclus dans l’EEO et ont reçu une dose unique de voxelotor de 1500mg/jour. L’âge médian à l’inclusion était de 25ans. La durée médiane (intervalle) d’exposition au voxelotor était de 124,0 semaines (1,9–205,9) et 81 patients avaient été traités pendant ≥168 semaines. Parmi eux, 52 patients avaient déjà reçu voxelotor dans le cadre de l’étude HOPE, pour une durée cumulée d’exposition de ≥240 semaines (4,6ans). Les patients précédemment traités par placebo dans l’essai HOPE présentaient une variation moyenne (ET) de l’Hb par rapport à la valeur de base (début de l’EEO) de 1,1 (1,51) g/dL à la semaine 168 (n=17). La variation moyenne (ET) de l’Hb par rapport à la valeur de base chez les patients ayant déjà reçu 1500mg de voxelotor était de 0,5 (1,49)g/dL (n=18), ce qui indique une persistance de la réponse avec la poursuite du traitement. Les marqueurs d’hémolyse (bilirubine indirecte, pourcentage de réticulocytes) se sont améliorés chez les patients ayant reçu du placebo dans l’essai HOPE et étaient stables chez les patients ayant reçu voxelotor 1500mg. Le taux d’incidence annualisé de CVOs était de 1,1 (IC95 % : 1,0–1,2) événements par an chez tous les patients. Au total, 88,2 % des patients (157/178) ont signalé un événement indésirable survenu au cours du traitement, non lié à la drépanocytose. La plupart étaient de grade 1 ou 2. Des effets indésirables ayant conduit à l’arrêt du traitement sont survenus chez 16 patients (9,0 %). Huit décès sont survenus et aucun n’était lié au voxelotor. Conclusion Dans cette analyse actualisée de l’étude d’extension de l’essai HOPE, le traitement à long terme avec voxelotor s’est avéré efficace pour maintenir l’amélioration des paramètres d’hémoglobine et d’hémolyse chez les patients atteints de drépanocytose. Le profil de tolérance de voxelotor était conforme aux résultats de l’essai HOPE et aucun nouveau signal n’a été identifié sur une période cumulée de traitement de 240 semaines. Un faible taux d’incidence annualisé de CVOs a également été observé chez les patients atteints de drépanocytose au cours de l’EEO.© Société américaine d’hématologie (2023). Réutilisé avec autorisation.

β-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent β-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

Background: Sickle cell disease (SCD) is a major public health issue worldwide with high morbidity and mortality. SCD SD Punjab is the third most common genotype of SCD in Oman and is associated with several serious complications. The aim of the study is to establish the clinical and laboratory features of SCD patients with SD double heterozygotes and study the impact of haemoglobin F, hydroxyurea, and other modulators on the disease severity. Methods: We analyzed the electronic medical records of 52 consecutive SCD patients who were diagnosed as double heterozygote SD Punjab between 2006 and 2022. The study was approved by the local medical research and ethics committee. The data captured included SCD-related complications and current clinical and laboratory indices. Data from other studies on other SCD genotypes were used as historical controls. Results: 52 patients (31 males, 21 females) who formed this cohort had a median age of 32 years with an interquartile range (IQR) of 21-39.8 years. 37(71.2%) had <3 VOC per year, whereas 15 (28.8%) patients had >3 vasooclusive (VOC) episodes per year. SCD-related complications included Acute Chest Syndrome (ACS) (48%), Gall stones (26.9%), Avascular necrosis (AVN) (28.8%), Stroke (13.5%) and splenic sequestration (7.7%), whereas 5 (9.6%) patients of this cohort died. Surgical and Autosplenectomy were seen in 18 (34.6%). These findings were similar to other SCD genotypes in this community.19 (57.6%) were taking Hydroxyurea (HU) amongst the 33 patients who were prescribed HU. Haematological parameters showed a median (IQR) Hb (g/dl), MCV (fl), Retic count (%), WBC count(X109/L) and Platelet count(X109/L) of 9.7 (8.5-11.3), 74.9 (68.4-79.8), 4 (3.2-5.7), 9.9 (8.1-12.6) and 309 (239-428) respectively. The haemoglobin electrophoresis showed an elevated HbF, whereas serum bilirubin and LDH were elevated amongst the biochemical parameters. The use of hydroxyurea showed no impact on VOC, ACS, AVN, Stroke or mortality. Conclusion: SD Punjab is the third most common SCD genotype in Oman and was associated with recurrent VOC, ACS, AVN, and gall stones comparable to other SCD genotypes. Patients with > 3 VOC/year had significantly increased incidence of Stroke, AVN, and gallstones. However, HU was not associated with improved prognosis and better survival in this cohort of patients. Keywords: Sickle Cell Disease; Haemoglobin SD Punjab; vaso-occlusive crises; acute chest syndrome; Avascular Necrosis; HbF; hydroxyurea.

Many Omani patients with sickle cell disease (SCD) undergo red blood cell (RBC) transfusions that are only matched for ABO and D, making RBC alloimmunization a significant concern in this population. Currently, the integration of molecular assays and hemagglutination testing helps to determine RBC phenotypes and genotypes, facilitating the provision of compatible blood and minimizing additional alloimmunization risks in patients with SCD. Based on this finding, our objective was to use molecular methods to predict the extended antigen profile of Omani patients with SCD across various blood group systems including Rh, Kell, Duffy, Kidd, Colton, Lutheran, Dombrock, Diego, Cartwright, and Scianna. This approach aims to implement RBC matching strategies and enhance daily transfusion practices for these patients. Molecular methods encompassed multiplex polymerase chain reaction for RHD, BeadChip arrays for variants of RHD and RHCE, and ID CORE XT for the primary allelic variants of RBCs. This study enrolled 38 patients with SCD, comprising 34 patients with homozygous HbSS, 1 patient with HbSC, and 3 patients with HbS Oman. The predominant ABO blood group was group O, observed in 44.7 percent of patients, followed by group A in 21.1 percent and group B in 13.2 percent. The most prevalent Rh phenotype predicted from the genotype was D+C+E-c+e+, identified in 34.2 percent of patients. All patient samples were K-, exhibiting the k+ Kp(b+) Js(b+) phenotype, with 81.6 percent demonstrating Fy(a-b-) due to the homozygous FY*02N.01 genotype and 28.9 percent displaying Jk(a+b-). RH variant alleles were detected in five patients (13.2 %), with only one type of RHD variant (RHD*DIIIa) and one type of RHCE variant (RHCE*ceVS.02.01) identified. Alloantibodies were present in 26 patients (68.4%). This study presents the initial comprehensive report of extended RBC antigen profiling in Omani patients with SCD, revealing disparities in the prevalence of RBC phenotypes compared with SCD patients from other regions and countries. Furthermore, our findings underscore a high rate of alloimmunization in these patients, emphasizing the need to implement antigen-matching programs to improve daily transfusion practices.

BackgroundSickle cell disease is an inherited disorder characterized by the presence of sickle hemoglobin (HbS). The process of Hb molecule polymerization is a pivotal step in the sickling process. Voxelotor, a recently approved novel therapeutic agent, is known to interfere with polymerization. We aim to study the impact of Voxelotor on Hb variants analysis using high performance liquid chromatography (HPLC).Material and methodsWe are reporting the impact of Voxelotor on Hb variants analysis using HPLC after an informed consent and medical research committee approval. Data was collected from eight patients who are enrolled in the GBT440-034OL study using electronic medical records, to evaluate the Hb levels, hemolytic markers and the clinical response.ResultsOur patients were well-balanced for gender, with a mean age of 31.1 years (19–50). Six patients showed a significant improvement in the Hb level, with reduced reticulocytes, bilirubin, LDH and an improved clinical outcome. Interestingly, these patients showed the appearance of a split band of Hb S and D on HPLC impacting significantly on HbS level. Two patients did not show any improvement on laboratory parameters, and no changes on their HPLC analysis.ConclusionsWe report here eight patients on Voxelotor therapy, six of which showed improved hemolytic markers and anemia and demonstrated the appearance of HbD peak on the HPLC chromatogram. Therefore, the absence of HbD on HPLC or other laboratory methods for estimating HbS in patients on Voxelotor therapy, gives the clinician a possible hint regarding the patient's compliance with the drug.

Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (p<0.01). IAPCs produced more PTN than MK (p<0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (p<0.05) and in MDDCs by TLRs 7/8 (p<0.05). TLR4 induced a stronger MK production than NAS TLRs (p≤0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (p<0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.