Transfusion Independence Research Articles

Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia.

Luspatercept, a ligand-trapping fusion protein, binds select TGF-β superfamily ligands implicated in thalassemic erythropoiesis, promoting late-stage erythroid maturation. Luspatercept reduced transfusion burden in the BELIEVE trial (NCT02604433) of 336 adults with transfusion-dependent thalassemia (TDT). Analysis of biomarkers in BELIEVE offers novel physiological and clinical insights into benefits offered by luspatercept. Transfusion iron loading rates decreased 20% by 1.4 g (~7 blood units; median iron loading rate difference: -0.05 ± 0.07 mg Fe/kg/day, p< .0001) and serum ferritin (s-ferritin) decreased 19.2% by 269.3 ± 963.7 μg/L (p < .0001), indicating reduced macrophage iron. However, liver iron content (LIC) did not decrease but showed statistically nonsignificant increases from 5.3 to 6.7 mg/g dw. Erythropoietin, growth differentiation factor 15, soluble transferrin receptor 1 (sTfR1), and reticulocytes rose by 93%, 59%, 66%, and 112%, respectively; accordingly, erythroferrone increased by 51% and hepcidin decreased by 53% (all p < .0001). Decreased transfusion with luspatercept in patients with TDT was associated with increased erythropoietic markers and decreasing hepcidin. Furthermore, s-ferritin reduction associated with increased erythroid iron incorporation (marked by sTfR1) allowed increased erythrocyte marrow output, consequently reducing transfusion needs and enhancing rerouting of hemolysis (heme) iron and non-transferrin-bound iron to the liver. LIC increased in patients with intact spleens, consistent with iron redistribution given the hepcidin reduction. Thus, erythropoietic and hepcidin changes with luspatercept in TDT lower transfusion dependency and may redistribute iron from macrophages to hepatocytes, necessitating the use of concomitant chelator cover for effective iron management.

A-150 Abo Subgroup Incompatibility Leading to Red Cell Engraftment Failure and Fatal Outcome: A Rare But Preventable Complication in Related Allogeneic HSCT

Abstract Background Pre-allogeneic hematopoietic stem cell transplant (HCST) testing includes, among others, ABO and HLA typing and testing for anti-HLA antibodies. ABO subgroup typing is not routinely performed, as A2 subgroup representes 1% of the total group A population and only 0.4% of A2 individuals have anti-A1 in their serum. ABO antigens are also found on the platelet surface. We describe a case of alloHSCT performed between siblings, the donor A1 and the recipient A2, with a fatal outcome caused by red cell and platelet engraftment failure due to anti-A1 antibodies, and emphasize the need to routinely investigate subgroup incompatibility in the pre-alloHSCT workup. Methods Patient data was collected from hospital and laboratory electronic records. Blood typing and immunohematological investigation was performed at the hospital blood bank using gel cards for ABO typing, DAT and antibody screening panels (Grifols, Barcelona). Tube method was used for A subgroup typing (Fresenius, Germany). Bone marrow analysis and other blood tests were performed at local hospital laboratory. HLA typing and antibody screening (Luminex, USA) were sent to a specialized laboratory. Results A 51 year-old male with Non-Hodgkin lymphoma underwent a full-match ABO compatible allogeneic HSCT, both brother/donor and recipient group A. Pre-transplant anti-HLA or ABO antibodies were negative. WBC recovery was achieved on D + 22. The patient had a catheter infection on D + 15 (Permcath removed), CMV infection on D + 24 (treated with gancyclovir) and received several blood transfusions. On D + 22, he had a hemolytic transfusion reaction with fever (38.5°C), chills and a decline in hemoglobin (7.3 g/dL to 6.6 g/dL in the following day), low haptoglobin and increased indirect bilirrubin levels. Immunohematological investigation revealed a positive DAT with an anti-A antibody in the eluate. Subgroup incompatibility was suspected and the patient was found to be subgroup A2, whereas the donor typed A1. Three days later the DAT became negative and anti-A1 was no longer detected. Other RBC antibodies were also excluded. Only group O RBCs and A / AB platelets were transfused thereafter to prevent further hemolysis. On D + 35 the patient was diagnosed with GI-GVHD, which responded to corticosteroids. He never achieved transfusion independence and received RBC and platelet transfusions on a regular basis. Failure of RBC and platelet engraftment was confirmed by a bone marrow aspirate on D + 45, showing only 20% erythroid lineage and absence of megakaryocytes. Marrow chimerism revealed 83% of donor origin. Sepsis by S. aureus ensued on D + 57 and three days later he had fever (38.2°C) and dyspnea after a platelet transfusion. Despite entubation and mechanical ventilation, he evolved to RCP and died on D + 60. Conclusion ABO subgroup typing is a simple and low-cost technique routinely available in the blood bank. Detection of A subgroup incompatibility impacts on key decisions, such as donor choice (if more than one candidate) and the need for erythrocyte depletion of donor stem cells and recipient plasmapheresis if the anti-A1 titer is high. Since graft failure due to ABO subgroup incompatibility can be hazardous, we recommend routinely ABO subgroup typing in the pre-alloHSCT workup to increase donor safety.

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

Treatment of refractory or relapsed myelodysplastic neoplasms with luspatercept: a multicenter Chinese study.

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67years: range 29 to 80years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9weeks (9.0-32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement-erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84g/L, and patients had significantly higher hemoglobin concentrations after 12weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment.

POSTER: MPN-383 Healthcare Resource Utilization and Costs Associated With Transfusion Dependence and Anemia Severity in Patients With Myelofibrosis: A Retrospective Analysis of the Medicare Fee-for-Service Claims Data

POSTER: MPN-383 Healthcare Resource Utilization and Costs Associated With Transfusion Dependence and Anemia Severity in Patients With Myelofibrosis: A Retrospective Analysis of the Medicare Fee-for-Service Claims Data

MPN-383 Healthcare Resource Utilization and Costs Associated With Transfusion Dependence and Anemia Severity in Patients With Myelofibrosis: A Retrospective Analysis of the Medicare Fee-for-Service Claims Data

MPN-383 Healthcare Resource Utilization and Costs Associated With Transfusion Dependence and Anemia Severity in Patients With Myelofibrosis: A Retrospective Analysis of the Medicare Fee-for-Service Claims Data

Neutrophil Gelatinase Associated Lipocalin: A Possible Role in β Thalassemia Syndromes

Abstract Background Beta Thalassemia is a group of inherited blood disorders that caused by reduced or absent synthesis of the beta chains of hemoglobin resulting in variable outcomes ranging from severe anaemia to clinically asymptomatic individuals. Neutrophil gelatinase-associated lipocalin (NGAL), is a protein which is encoded by the LCN2 gene. NGAL is involved in innate immunity by sequestrating iron that in turn limits bacterial growth. It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and the alimentary tracts. It also plays a key role in the physiology and pathophysiology of red blood cells, particularly in anemia. Aim of the Work The aim of the present work is to assess plasma level of NGAL in Beta thalassemia syndromes and correlate with laboratory hematological data and iron profile. Patients and Methods A Case-Control study conducted on Beta Thalassemia patients of both sexes attending the outpatient clinic of Ain Shams University Hospitals, this Pilot study of 50 previously diagnosed Beta Thalassemia patients and 30 sex and age matched healthy control subjects. Results The results were correlated with clinical and laboratory parameters. Comparative analysis of the results showed that all groups were homogeneous in terms of size and demographic characteristics. This can explain our results that shows that there is a highly statistically significant difference (p-value &amp;lt; 0.001) between the cases subgroups regarding the inter-transfusion interval with longer intervals among the thalassemia intermedia subgroup. While by comparing the Hb electrophoresis parameter between the 2 groups HbA% levels were higher is the group of serum ferritin &amp;lt;1000 ng/ml and HbF% where higher in group of serum ferritin &amp;gt;1000 ng/ml with (p-value &amp;lt; 0.05) for both of them. On conducting a linear regression analysis we found that the intertransfusion interval was the only independent parameter to have an effect on NGAL level on our patient group with regression coefficient -5.78 and this complies with our results of correlation between NGAL and those parameters mentioned and discussed previously. Conclusion The relationship between NGAL and iron level in Egyptian β-TM patients proved in our results has confirmed the proposed regulatory role played by NGAL on erythropoiesis and iron metabolism in β-thalassemia, NGAL at a cutoff value of &amp;gt; 100 proved to be an efficient predictor of increased serum ferritin &amp;gt; 1000 ng/ml. we believe that incorporating NGAL testing in the work up of β-TM patients in the early phases of iron transfusion dependency would provide a promising sensitive and predictive tool for early iron accumulation. We recommend further studies β-TM patients with larger samples size to clarify the co-regulatory role of erythropoiesis and iron metabolism played by NGAL.

Long-term clinical efficacy and safety of thalidomide in patients with transfusion-dependent β-thalassemia: results from Thal-Thalido study

Regular blood transfusion is the mainstay of treatment in transfusion-dependent β-thalassemia (TDT); however, transfusions culminate in an array of serious complications. Therefore, a single-arm, non-randomized clinical trial was conducted in hydroxyurea refractory TDT patients to explore the long-term safety and efficacy of thalidomide. The primary outcomes for efficacy were rise in hemoglobin (Hb) level and changes in transfusion frequency. Whereas, several clinical and laboratory parameters were assessed for safety of thalidomide. Secondary outcomes included changes in serum ferritin, serum lactate dehydrogenase (LDH), serum uric acid, red blood cell indices, and size of liver and spleen. A total of 532 patients were followed for a period of 30 months. Significant increase in mean Hb level was identified at 6 months (1.4 g/dL, p ≤ 0.001) and 30 months (2 g/dL, p ≤ 0.001) in comparison with baseline. A total of 408 (76.7%) patients responded to thalidomide therapy (excellent responders 25.8%, good responders 31%, and partial responders 19.9%) and attained transfusion independence within 6 months of therapy. A significant decline in mean ferritin, LDH level, liver size, and spleen size was observed. No unfavorable effects were observed on kidney and liver functions. Mild adverse events were reported in 48 (9%) patients and serious adverse events, including cerebral vascular accident and portal vein thrombosis were reported in two patients each. This study concludes that thalidomide is an effective and well-tolerated drug that can improve Hb levels and reduce transfusion burden in hydroxyurea refractory TDT patients.Trial registration: This trial is registered at http://www.clinicaltrial.gov as # NCT03651102.

Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis

AbstractIn patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib’s inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.

Systemic inflammatory indices for predicting prognosis of myelofibrosis

The impact of inflammatory markers such as systemic immune-inflammation (SII) index and systemic inflammation response index (SIRI) on myelofibrosis (MF) prognosis was evaluated for the first time in this study. Data from 60 patients diagnosed with MF between March 2011 and September 2022 were retrospectively analyzed. In addition to disease-related markers, the impact of SII and SIRI on prognosis was evaluated. In our study, the overall median survival (OS) was 64 months. OS was significantly shorter in patients older than 65 years, with high ferritin and lymphocyte levels, transfusion dependence at diagnosis, platelet count below 100 × 109/L, Hb level below 8 g/dl, and high risk according to the dynamic international prognostic scoring system (DIPSS)-Plus score. When these variables were included in the multivariate Cox regression model, it was found that being older than 65 years, having a high ferritin value, being at high risk according to the DIPSS-plus score and Hb values below 8 increased the risk of death. Platelet-to-lymphocyte ratio (PLR) and SII index were lower in patients with a fatal outcome. No statistically significant relationship was found between SIRI and mortality. The findings of this study showed that low PLR and high ferritin were associated with poor prognosis in MF. Elevated SII and SIRI, evaluated for the first time in patients with myelofibrosis, did not predict prognosis. Since non-inflammatory variables play a role in the pathogenesis of MF, bone marrow indicators and systemic inflammation indicators derived from hematologic parameters may not be accurate.

Prevalence and treatment of anemia and secondary iron overload in patients with a myelodysplastic syndrome: real-world data from a multicenter cohort study.

anemia is the most common finding in patients with a myelodysplastic syndrome (MDS). Repetitive red blood cell (RBC) transfusions and disease-related low hepcidin levels induce secondary iron overload. Real-world data on the prevalence and treatment strategies of anemia and secondary iron overload in MDS patients, is limited. three years of data on MDS diagnosis, anemia and ferritin management was collected in 230 MDS patients from seven non-academic hospitals in the Netherlands. Descriptive statistics and linear mixed models were used to analyze the data. transfusion dependent (TD) patients (n=49) needed 1-3 RBC transfusions per month. Serum hemoglobin remained stable in both TD and transfusion-independent (TI) patients over 3 years. In the TD patients, serum ferritin increased 63 pmol/L/month. Overall, 19 (39%) were diagnosed with secondary hemochromatosis, of which 13 (68%) received chelation therapy with a heterogeneous response. mean hemoglobin remains stable over time in both TD and TI MDS patients. Approximately 40% of TD patients develop secondary hemochromatosis. Treatment and monitoring of secondary hemochromatosis as well as the response on chelation therapy varies substantially.

Clinical Outcomes in Patients With COVID-19 and Hematologic Disease.

Patients with hematologic diseases are at higher risk of the SARS-CoV-2 infection and more severe clinical outcomes of the coronavirus disease. CHRONOS19 is an observational prospective cohort study with the aim to determine the short and longer-term clinical outcomes, risk factors for disease severity and mortality, and rates of postinfectious immunity in patients with malignant and nonmalignant hematologic diseases and COVID-19. Overall, 666 patients were enrolled in the study, of which 626 were included in the final data analysis. The primary endpoint was 30-days all-cause mortality. Secondary endpoints included COVID-19 complications, rates of ICU admission and mechanical ventilation, outcomes of a hematologic disease in SARS-CoV-2 infected patients, overall survival, and risk factors for disease severity and mortality. Data from 15 centers were collected at 30, 90, and 180 days after COVID-19 was diagnosed and were managed using a web-based e-data capture platform. All evaluations were performed in the pre-omicron period of COVID-19 pandemic. Thirty-days all-cause mortality was 18.9%. The predominant cause of death (in 80% of cases) were COVID-19 complications. At 180 days, the majority (70%) of additional deaths were due to hematologic disease progression. At a median follow-up of 5.7 [0.03-19.04] months, 6-months overall survival was 72% [95% CI: 0.69-0.76]. One-third of patients had severe SARS-CoV-2 disease. The rate of ICU admission was 22% with 77% of these patients requiring mechanical ventilation, with poor survival rate. A univariate analysis revealed that older age (≥ 60 years), male sex, malignant hematologic disease, myelotoxic agranulocytosis, transfusion dependence, refractory disease or relapse, diabetes among comorbidities, any complications, especially ARDS alone or in combination with CRS, admission to an ICU, and mechanical ventilation were associated with higher risks of mortality. Treatment of the hematologic disease was changed, postponed, or canceled in 63% of patients. At a longer follow-up (90 and 180 days), the status of the hematologic disease changed in 7.5% of patients. Patients with hematologic disease and COVID-19 have high mortality rates, predominantly due to COVID-19 complications. At a longer-term follow-up, no significant impact of COVID-19 on the course of a hematologic disease was revealed.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study

The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48. MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete. Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia). Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia. Sierra Oncology, a GSK company.

Lenalidomide treatment of Japanese patients with myelodysplastic syndromes with 5q deletion: a post-marketing surveillance study

Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.

Interim analysis of post-marketing surveillance of ravulizumab for paroxysmal nocturnal hemoglobinuria in Japan.

Ravulizumab is a long-acting C5 inhibitor available for treating paroxysmal nocturnal hemoglobinuria (PNH). Post-marketing surveillance (PMS) was implemented following its approval in September 2019 in Japan. We report safety data obtained through to December 2021 for 218 patients and effectiveness data for 194 patients (182 switched from eculizumab and 12 complement inhibitor-naïve). Over a median follow-up of 74.4weeks, 193 adverse events (AEs) were reported in 66/218 patients (30.3%; incidence 72.73/100 patient-years). The two most frequent AEs were anemia and pyrexia (each 3.01/100 patient-years). The incidence of serious AEs was 36.93/100 patient-years. In patients who switched from eculizumab, lactate dehydrogenase (LDH) and hemoglobin (Hb) levels were maintained over 26weeks of ravulizumab treatment. In complement inhibitor-naïve patients, LDH decreased significantly and Hb increased significantly over 26weeks of ravulizumab treatment. These data for Japanese patients with PNH who were naïve to complement inhibitors and patients who switched from eculizumab show that the safety and effectiveness of ravulizumab are consistent with the published clinical trial data. However, transfusion independence was less likely in patients with bone marrow failure. Further follow-up data from this PMS will help to elucidate the long-term clinical safety and effectiveness of ravulizumab for treating PNH.

Correlation of Transfusion Dependence and Its Associated Sequelae to Hematological and Biochemical Parameters in Patients With Sickle Cell Disease and Beta Thalassemia Major in Khobar: A Retrospective Study.

Sickle cell disease (SCD) and beta thalassemia major (βTM) are multisystemic, genetically inherited diseases. They are caused by mutations of hemoglobin, which ultimately cause abnormal functioning of the red blood cells. The morbidity and mortality rates of these diseases are significant, as they may result in severe complications, some of which are quite fatal; hence, early diagnosis and treatment are crucial. The purpose of this study is to collect patients' data in terms of their manifestations and overall clinical picture and correlate them to the laboratory parameters with emphasis on their transfusion dependence and its sequelae in King Fahd Hospital of the University (KFHU), Al-Khobar, Saudi Arabia. After obtaining ethical approval from the institutional review board and in collaboration with the blood bank, patients' data were retrospectively collected from the hospital's database and categorized into two disease groups. Accordingly, data related to the biological and demographic information, clinical picture pattern, laboratory investigations, and therapeutic measures, with emphasis on blood transfusion as a treatment option, were gathered and analyzed. Eventually, the aforementioned data aspects were assessed for the probability of correlations, which were proven to be present to some level as an answer to our cohort study's question. Such findings, which will be depicted later in this study, might represent a ground for having a more comprehensive and extensive approach in terms of the general evaluation of patients with SCD and βTM based on the established level of correlation. During the course of conducting our research, we encountered some limitations, including the sample size and scarce data available during the process of data collection.

Genomic and computational analysis of four novel variants of MPL gene in Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.

Understanding the Intricacies of Iron Overload Associated with β-Thalassemia: A Comprehensive Review

β-thalassemia, a congenital genetic hematological disorder characterized by the decrease or absence of β-globin chains, leads to a decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia also exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications that arise due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, the therapeutic efficacy of different iron chelators in managing iron overload complications is mentioned briefly, along with the guidelines for their usage in India. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia.

Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML.

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9months. The median duration of overall response was 11.7months, and the median overall survival was 11.6months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n= 31; 20% each), thrombocytopenia (n= 25; 16%), and neutropenia (n= 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.