Target Platelet Research Articles

Splenectomy in Thalassemia: The Role of Surgery as an Adjunct to Medical Management.

Introduction Beta thalassemia is a hemoglobinopathy characterized by defective production of the beta chain of hemoglobin, leading to irreversible destruction of RBCs, splenomegaly, pancytopenia, and a requirement for multiple transfusions. This condition necessitates iron chelation therapy, and splenectomy is often performed to manage hypersplenism. Methods This report includes a series of seven diagnosed cases of beta thalassemia with hypersplenism, all of whom underwent open splenectomy. Preoperative transfusions were administered to achieve target hemoglobin and platelet counts of 9 g/dL and 50,000/µL, respectively. Results The study included seven patients diagnosed with beta thalassemia, all of whom underwent open splenectomy. Among these, three patients also had concomitant cholecystectomy due to the presence of gallstones. The primary indication for performing splenectomy was hypersplenism. Preoperative transfusions were administered to ensure target hemoglobin levels of 9 g/dL and platelet counts of 50,000/µL. All patients were successfully discharged with minimal morbidity and no reported mortality. The longest follow-up period observed in this series was 10 months post-splenectomy, which limited the assessment of long-term effects. Conclusion Open splenectomy for hypersplenism in patients with beta thalassemia appears to be a safe and effective procedure with minimal short-term morbidity and no mortality observed in this series. However, due to the limited follow-up duration, the long-term effects of splenectomy in these patients could not be evaluated. Further studies with longer follow-up are needed to assess the long-term outcomes of splenectomy in beta thalassemia patients.

Phase 3 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with essential thrombocythemia (ET).

TPS6596 Background: ET is a myeloproliferative neoplasm (MPN) driven by mutations in JAK2, CALR, and MPL that is characterized by thrombocytosis and megakaryocyte hyperplasia. Currently available treatments can prevent thrombotic complications but do not substantially alter the natural history of ET. LSD1 is an enzyme that regulates hematopoietic stem and progenitor cell proliferation and is overexpressed in MPNs. In a phase 2 study, the LSD1 inhibitor bomedemstat was generally well tolerated and improved symptoms, durably reduced platelet and white blood cell counts, and reduced mutation burden in patients with ET. Here, we describe the methods for a randomized, open-label, phase 3 study (NCT06079879) that has been designed to evaluate bomedemstat versus best available therapy in patients with ET who had an inadequate response to or were intolerant of hydroxyurea. Methods: Key eligibility criteria include age ≥18 years, a diagnosis of ET per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, a platelet count of >450 x 109/L, and an absolute neutrophil count of ≥0.75 x 109/L. All patients must have a history of inadequate response to or intolerance of hydroxyurea per modified European LeukemiaNet (ELN) criteria. Patients will be randomly assigned 1:1 to bomedemstat 50 mg/day by mouth (starting dose) or investigator’s choice of best available therapy (anagrelide, busulfan, interferon alfa/pegylated interferon alpha, or ruxolitinib). Bomedemstat dose will be titrated to a target platelet count of ≥150 to ≤350 x 109/L. After 52 weeks, patients receiving best available therapy can cross over to bomedemstat at the investigator’s discretion and patients in the bomedemstat arm can continue on treatment (maximum of 156 weeks on study). Randomization will be stratified by hydroxyurea history (inadequate response vs intolerance) and MFSAF v4.0 baseline score (≥4 vs <4). Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE v5.0 criteria and monitored for up to 30 days after last dose of study drug. The primary end point is durable clinicohematologic response rate per modified ELN criteria. Secondary end points are duration of clinicohematologic response, duration of hematologic remission, change from baseline in total symptom and fatigue score per MFSAF v4.0 criteria, change from baseline in total fatigue score per the PROMIS Fatigue SF-7a scale, incidence of thrombotic or major hemorrhagic events, transformation to post-ET myelofibrosis or myelodysplastic syndrome/acute myeloid leukemia, event-free survival, and safety. Exploratory end points include pharmacokinetics, the proportion of patients reporting stability or improvement versus decline on the MSAF v4.0 and PROMIS Fatigue SF-7a domains, and molecular biomarkers. Approximately 300 patients will be enrolled. Clinical trial information: NCT06079879 .

A practical guide to the management of immune thrombocytopenia co-existing with acute coronary syndrome.

Immune thrombocytopenia (ITP) management with co-existing acute coronary syndrome (ACS) remains challenging as it requires a clinically relevant balance between the risk and outcomes of thrombosis and the risk of bleeding. However, the literature evaluating the treatment approaches in this high-risk population is scarce. In this review, we aimed to summarize the available literature on the safety of ITP first- and second-line therapies to provide a practical guide on the management of ITP co-existing with ACS. We recommend holding antithrombotic therapy, including antiplatelet agents and anticoagulation, in severe thrombocytopenia with a platelet count < 30 × 109/L and using a single antiplatelet agent when the platelet count falls between 30 and 50 × 109/L. We provide a stepwise approach according to platelet count and response to initial therapy, starting with corticosteroids, with or without intravenous immunoglobulin (IVIG) with a dose limit of 35 g, followed by thrombopoietin receptor agonists (TPO-RAs) to a target platelet count of 200 × 109/L and then rituximab. Our review may serve as a practical guide for clinicians in the management of ITP co-existing with ACS.

Platelet Implication in Atherosclerosis Pathogenesis

Atherosclerosis is a prevalent cardiovascular disease that leads to serious complications like myocardial infarction and ischemic stroke. Platelets play a pivotal role in thrombosis and contribute to the development of atherosclerosis through interactions with the cellular environment. Consequently, platelets have emerged as a potential therapeutic target. This review explores the normal functioning of platelets and their involvement in atherosclerosis progression, highlighting their participation in inflammatory responses within the arterial wall. Platelets activate and release mediators that promote vascular inflammation and endothelial dysfunction, key features of atherosclerotic plaque formation. They also interact with circulating immune cells, exacerbating the inflammatory milieu and fostering disease progression. Targeting platelets presents a promising approach for therapeutic interventions in atherosclerosis. Antiplatelet agents aim to impede platelet activation and aggregation, reducing thrombosis risk. Novel strategies that target platelet interactions with inflammatory cells and modulate platelet-derived inflammatory mediators are also being investigated. Further research is needed to fully exploit the potential of platelet-targeted therapy. Understanding the precise role of platelets at different stages of atherosclerosis and their interactions with immune cells and the inflammatory milieu will enhance our understanding of disease pathogenesis and guide the development of more effective therapeutic approaches. In conclusion, platelets significantly influence atherosclerosis by contributing to thrombus formation and promoting inflammatory processes. Recognizing platelets as a therapeutic target opens up new possibilities for mitigating the consequences of atherosclerosis and improving patient outcomes.

Raman spectra simulation of antiplatelet drug-platelet interaction using DFT

The paper reflects the results of molecular docking and mathematical DFT simulation for antiplatelet drugs and the target platelet receptor/ferment interaction in the limited area. The results of Raman spectra simulation are implemented and obtained from the interaction of the clopidogrel metabolite of the P2Y12 receptor. The interaction of aspirin with the COX-1 enzyme was also investigated. As a result, theoretical Raman spectra of the drug-receptor area were obtained. The theoretical data were compared with the experimental SERS results. The characteristic bands corresponding to metabolite/ferment and antiplatelet drug vibrations were clarified. The prospects of obtaining results for pathologies based on platelet conformations during cardiovascular diseases have been demonstrated.

Efficacy and safety of QL0911 in adult patients with chronic primary immune thrombocytopenia: A multicenter, randomized, double-blind, placebo-controlled, phase III trial.

QL0911, a recombinant human thrombopoietin mimetic peptide-Fc fusion protein, is a romiplostim (Nplate®) biosimilar used to treat primary immune thrombocytopenia (ITP). This phase III study aimed to assess the efficacy and safety of QL0911 in adult patients with chronic primary ITP over a 24-week treatment period. We conducted a double-blind, placebo-controlled, phase III study in patients diagnosed with primary ITP for at least 12 months who had received at least one first-line ITP treatment with no response or recurrence after treatment, or who relapsed after splenectomy at 44 sites in China. Patients were randomly allocated (2:1 ratio) to QL0911 or placebo injection subcutaneously once weekly at an initial dose of 1 μg/kg for 24 weeks. The doses were adjusted to maintain the target platelet counts from 50 × 109/L to 200 × 109/L. Patients and investigators were blinded to the assignment. The primary endpoints were the proportion of patients who achieved a durable platelet response at week 24 (platelet count, ≥ 50 × 109/L during 6 of the last 8 weeks of treatment) and safety. The study was registered at ClinicalTrials.gov (NCT05621330). Between October 2019 and December 2021, 216 patients were randomly assigned (QL0911,144; placebo,72). A durable platelet response was achieved by significantly more patients in the QL0911 group (61.8%, 95% CI: 53.3-69.8; P < 0.0001) than in the placebo group (0%). The mean duration of platelet responses was 15.9 (SE: 0.43) weeks with QL0911, and 1.9 (SE:0.26) week with placebo. Consistent results were achieved in subgroup analyses categorized by baseline splenectomy status (yes/no), concomitant ITP treatment (yes/no), and baseline platelet count (≤ 10 × 109/L, > 10 × 109/L, ≤ 20 × 109/L, > 20 × 109/L, and < 30 × 109/L). The incidence of TEAEs was comparable between the QL0911 and the placebo groups (91.7% and 88.9%, respectively). The most common adverse events overall were ecchymosis (28.5% for QL0911 vs. 37.5% for placebo), upper respiratory tract infections respiratory tract infections (31.9% for QL0911 vs. 27.8% for placebo), and gingival bleeding (17.4% for QL0911 vs. 26.4% for placebo). QL0911 was well-tolerated and increased and maintained platelet counts in adults with ITP. QL0911, a biosimilar to romiplostim (Nplate®), may be a novel treatment option for patients with ITP who have failed or relapsed from first-line treatment in China. Ongoing studies will provide further data on long-term efficacy and safety in such patient populations.

Effects of Intermittent Fasting on Patients with Immune Thrombocytopenia (ITP) Receiving TPO-RA : Multicenter Mixed-Design Study

Introduction The thrombopoietin receptor agonists (TPO-RAs), such as Avatrombopag (AVA), Eltrombopag (ELT), and Romiplostim (ROM), have, in recent years, changed ITP treatment, showing that there is both increased platelet destruction and suboptimal platelet production in ITP. ELT and AVA are oral drugs, while ROM is subcutaneous, and studies have shown that absorption of ELT can be affected by meals. Thus, for optimum absorption, patients are counseled to take it on an empty stomach at least 1 hour before or 2 hours after a meal and at least 2 hours before and 4 hours after calcium-containing meals. However, in Muslim countries where the 16/8 type of intermittent fasting is practiced by religion, the scheduling of drug consumption can be affected. Objective The aim of this study is to evaluate the effect of fasting on patients with ITP receiving different Thrombopoietin receptor agonists (TPO-RAs) brands. Methods A Multicenter, mixed design study was performed in which we interviewed Muslim patients (n = 100) who were 18 years of age or older in Qatar, Kuwait, and Saudi Arabia and fasted Ramadan while receiving TPO-RA treatment between the years of 2015 and 2023. Clinical and biological parameters are recorded using using a standardized patient form. Fasting status was confirmed by a telephone call to each patient. Patients' responses were retrospectively evaluated before, during, and after Ramadan. A statistically significant result was identified with a P-value of &amp;lt; 0.05. Bleeding tendency was also evaluated as either no bleeding, minor cutaneous and mucosal bleeding, or life-threatening bleeding involving major organs (i.e., central nervous system, gastrointestinal, or genitourinary). Results A hundred patients were identified who matched our inclusion criteria for this study. Platelet responses were different among the 3 products, and statistical significance was attributed to the product's compromised efficacy due to disturbed meal schedules and decreased absorption. For patients on AVA, the drug efficacy was not directly affected by meal schedule and absorption but instead was affected by patient compliance. The mean platelet count before Ramadan was estimated at 146.11 ± 111.76, while during Ramadan it dropped to 131.7 ± 107.6. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference 146.11 ± 111.76 vs. 134.17 ± 60.9. For patients on ELT, the mean platelet count before Ramadan was estimated at 120.02 ± 59.7, while during Ramadan it dropped to 100.8 ± 68.16. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference 120.02 ± 59.7 vs. 136.04 ± 74.86. For patients on ROM, the mean platelet count before Ramadan was estimated at 122.68 ± 80.57, while during Ramadan it was 130.94 ± 84.96. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference but an increase in platelet count 122.68 ± 80.57 vs 212.0 ± 113.72. Only 3% (3 patients on ELT) of the patients fasting during Ramadan experienced bleeding episodes. 2 of which experienced minor bleeding (ecchymosis and gingival bleeding), and 1 had major bleeding episodes (Lt. hemorrhagic infarction). 47% of the patients experienced a complete response (PLT&amp;gt;100x10 9) among the three products, and 17% experienced a partial response (PLT 51-100x10 9) 36.6% of the patients on AVA showed a complete response, 46.15% of patients on ELT, and 63.15% of patients on ROM. Conclusion TPO-RAs achieve target platelet counts in adult ITP patients. However, the absorption of ELT is highly affected by food consumption, and thus it is critical to adhere to the instructions given on how the dose should be adjusted and consumed on an empty stomach. AVA absorption didn't show compromise with food consumption, and its efficacy may depend only on patient's compliance. ROM showed better adherence to the medication schedule compared to ELT, contributing to its subcutaneous form and a tailored home visit program given weekly by trained nurses, enhancing patient compliance. The general tolerability and efficacy of TPO-RAs may be reflected on incidence of no major bleeding and the better efficacy of AVA and ROM, which are not affected by fasting.

The Combination of Iguratimod and Danazol Versus Danazol As a Treatment of Corticosteroid-Resistant/Relapse Immune Thrombocytopenia: A Randomized, Controlled, Multicenter, Open-Label Trial

Introduction: The treatment of choice in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) is still controversial due to the unclear mechanism and unpredictable efficacy of available therapies. The small molecule compound iguratimod is widely used as a novel antirheumatic drug to treat several autoimmune diseases. According to studies involving ITP mice, iguratimod may represent a new approach for the prevention and treatment of anti-platelet antibody-mediated ITP by modulating T-cell differentiation. Since iguratimod and danazol share disparate mechanisms in treating ITP, a combination of iguratimod and danazol may work synergistically based on a “double-hit” mechanism targeting both platelet production and destruction. The aim of this study was to evaluate the efficacy and safety of iguratimod and danazol versus danazol alone in patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. Methods: Across seven tertiary medical centers in China, adult ITP patients from this randomized, controlled, multicenter, open-label trial participated. Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count &amp;lt;30×10 9/L or bleeding symptoms at enrollment were randomlyallocated by masked statisticians in a 1:1 ratio to receive oral iguratimod at 25 mg twice daily plus oral danazol at 200 mg twice daily or oral danazol monotherapy at 200 mg twice daily for 12 weeks. The group assignment was not masked for clinicians or patients. Following the first eight weeks of treatment, patients were assessed every two weeks thereafter. The primary endpoint was a 6-month sustained response (SR), defined as a platelet count of 30×10 9/L or more and at least a doubling of the baseline platelet count (partial response) or a platelet count of 100×10 9/L or more (complete response) and the absence of bleeding without rescue medication. This trial was registered with ClinicalTrials.gov (NCT05281068). Results: From September 1, 2021, to December 31, 2022, a total of 106 patients were screened for eligibility; 35 were excluded, and 71 were randomly assigned: 37 to the iguratimod plus danazol group and 34 to the danazol group. The median age of the patients was 41 years, and 69.0% (49/71) of them were females. All patients enrolled failed to respond to the first-line treatment with corticosteroids, and 21 (29.6%) of all patients had received three or more therapies. The data cutoff for the analyses was July 1, 2023. The median follow-up was 14 months (IQR 11-15) in the iguratimod plus danazol group and 12.5 months (11-15) in the danazol group. Six-month follow-up results showed that iguratimod plus danazol was more likely to produce SR than danazol alone (20 [54.1%] of 37 vs. 9 [26.5%] of 34; odds ratio 1.82, 95% CI 1.22-2.70, p = 0.003). The combination group had 25 (67.6%) patients with at least one response (overall response), and 13 (35.1%) patients had a complete response by the end of the follow-up; whereas 15 (44.1%) of 34 patients in the monotherapy group had an overall response, and three (8.8%) had a complete response. A target platelet count of 30×10 9/L was achieved in 18 (48.6%) of 37 patients given iguratimod plus danazol after 4 weeks and five (14.7%) of 34 patients given danazol monotherapy, indicating that the combination therapy significantly increased the initial response rate ( p = 0.002). Both groups experienced similar serious adverse events (AEs), rescue treatment, and treatment side effects, and all patients tolerated the treatment well, without any grade 4 AEs or treatment-related deaths reported. Conclusions: Patients with corticosteroid-resistant or relapsed ITP responds well to iguratimod plus danazol. This regimen achieved a rapid and long-lasting response. It is necessary to conduct further studies to determine the optimal dosage and a variety of combination therapies using several immune-suppressing agents, including iguratimod, to achieve a sustained response in patients with corticosteroid-resistant or relapsed ITP.

Phase 2 Study to Assess the Safety and Efficacy of Bomedemstat (MK3543) in Combination with Ruxolitinib in Patients with Myelofibrosis

Background Approximately 50% of patients with myelofibrosis (MF) discontinue ruxolitinib after 3 years, mostly due to disease progression, suboptimal response or cytopenia. Outcome after ruxolitinib discontinuation is poor with a median overall survival (OS) of approximately 14 months. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal of malignant hematopoietic stem cells and for maturation of progenitor cells. Bomedemstat is an oral LSD1 inhibitor clinically active in patients with myeloproliferative neoplasms (MPN) and has shown clinical activity as a single-agent in patients with MF. Aims This is an ongoing, open-label, Phase 2 study of the combination of bomedemstat and ruxolitinib in treatment-naïve patients with MF or those with a sub-optimal response to ruxolitinib. The objectives of this are to evaluate the safety and tolerability of the combination, the optimal dosing of bomedemstat in this regimen, and to assess the efficacy of the combination as assessed by spleen size reduction and symptom reduction using the Myelofibrosis Symptom Assessment Form (MFSAF). Methods Cohort A is comprised of patients with a sub-optimal response to an adequate trial of ruxolitinib defined as splenomegaly not reduced by &amp;gt;35% from baseline or symptoms scores that have not improved by &amp;gt;50%. Cohort A patients must have been on a stable dose of ruxolitinib for ≥8wks. Cohort B is comprised of treatment-naïve patients with MF who require treatment per guidelines. Patients in Cohort A remain on the entry dose of ruxolitinib while Cohort B patients received a starting ruxolitinib dose of 10 mg BID throughout the study. All patients received concomitantly, a starting dose of bomedemstat of 0.4mg/kg/d. Dose adjustments up were allowed every 4 weeks to achieve a target platelet count of 50 x 10 9/L (40-90 x 10 9/L range) Down titrations could be made at any time in the interest of patient safety. Results At the data cut-off of 30 June 2023, 16 men and 16 women with a median age of 64 (range: 47-81) years were enrolled. Case distribution was PMF, N=19 (59.4%); PPV-MF, N=7 (21.9%); and PET-MF, N=6 (18.8%). Mutational profile of driver genes was JAK2 V617F, N=24 (75%); JAK2 exon 12, N=1 (3.1%); and CALR mutations, N=7 (21.9%). Six patient (18.8%) harbored high-molecular risk (HMR) mutations ( ASXL N =4; EZH2, N=2). At enrollment, the median white blood cell count (WBC), hemoglobin (Hb), platelet count, and lactate dehydrogenase (LDH) were 10.21 x 10 9/L (2.4-50.8 x 10 9/L), 9.4 g/dL (6.7-12.1g/dL), 215 x 10 9/L (100-906 x 10 9/L) and 504 IU/L (107-2174 UL), respectively. Ten patients (31.2%), 19 patients (59.4%) and 3 patients (9.4%) belonged to the Dynamic International Prognostic Scoring System (DIPSS) high, intermediate-2 and intermediate-1 risk categories, respectively. The median spleen size was 5cm (5-16cm) below left costal margin (BLCM). Twenty-four patients were enrolled in Cohort A with a median treatment duration of ruxolitinib of 128 (13-668) weeks. Cohort B has enrolled 8 patients. The median duration of ruxolitinib + bomedemstat was 12 (1-26) weeks. In 20 evaluable patients at Week 12 (Cohort A, N=17; Cohort B, N=3), 12 patients (60%) had stable ( ∆&amp;lt;± 1.0 g/dL) or improved Hb (&amp;gt;1.0 g/dL) (Cohort A: 11/17, 64.7%; Cohort B: 1/3, 33.3%), 5 patients (25%) had ≥50% reduction in MF-SAF Total Symptom Score (TSS) (Cohort A: 4/17, 23.5%; Cohort B: 1/3, 33.3%) and 18 patients (65%) had ≥ 30% spleen length reduction (Cohort A: 15/17, 88.2%; Cohort: 3/3, 100%) (Figure 1A-C). In six patients evaluable for molecular responses by droplet-digital polymerase chain reaction at Week 12, 4 patients (67%) had reductions in JAK2 V617F allele frequencies with 1 patient (17%) having ≥50% reduction. The most common non-hematologic adverse events (AEs) were diarrhea (Grade 1-2, N=16; Grade 3-4, N=0); malaise (Grade 1-2, N= 6; Grade 3-4, N=0); oedema (Grade 1-2, N=7; Grade 3-4, N=0) and dysgeusia (Grade 1-2, N=5; Grade 3-4, N=0). There were no safety signals, dose-limiting toxicities, or deaths related to drug. Conclusions These early results suggest that the addition of bomedemstat to a ruxolitinib regimen is well tolerated, improves splenomegaly and symptom scores, and stabilizes hemoglobin both in the frontline and second-line setting. Enrollment in ongoing.

Successful renal transplantation following hemodialysis as bridging therapy in a patient with Fechtner syndrome: a case report and literature review

BackgroundFechtner syndrome, also referred to as nonmuscle myosin heavy chain 9-related disease (MYH9-RD), is an autosomal-dominant genetic disorder. It is caused by abnormalities in the MYH9 gene, which encodes the nonmuscle conventional (class II) myosin heavy chain A (NMMHC-IIA). Its clinical manifestations include mild macrothrombocytopenia with leukocyte inclusions, hearing loss, cataracts, and renal failure.Case presentationWe present the case of a 34-year-old female patient with Fechtner syndrome in whom end-stage renal disease (ESRD) developed. During childhood, she presented with the typical symptoms of MYH9-RD, including thrombocytopenia, leukocyte inclusion bodies, onset of nephropathy, sensorineural hearing loss, and cataracts, wherein a clinical diagnosis of Fechtner syndrome was established. Her renal function deteriorated during adolescence. Furthermore, the patient underwent renal biopsy at the age of 18 years, which revealed focal segmental glomerulosclerosis. She was started on hemodialysis at the age of 33 years, followed by a living-donor renal transplantation after 5 months. She achieved a target platelet count of 50 × 109/L for arteriovenous fistula creation and 100 × 109/L for renal transplantation via platelet transfusions. Heparin use was avoided as an anticoagulant during hemodialysis. Since the patient expressed a desire for childbearing, genetic testing was performed, revealing an in-frame deletion of 21 nucleotides at 3195–3215 in exon 25 (A1065_A1072 del) of NMMHC-IIA, which has been reported to correlate with mild renal dysfunction. Our patient’s condition progressed into ESRD. Although genetic testing techniques have made great strides in recent years, our case clearly presents the difficulty in assuming an association between genetic abnormalities and clinical manifestations.ConclusionsOur case may provide further understanding of the management of ESRD in patients with MYH9-RD-related thrombocytopenia based on the results of genetic testing.

Longitudinal analysis of annual national hemovigilance data to assess pathogen reduced platelet transfusion trends during conversion to routine universal clinical use and 7-day storage.

France converted to universal pathogen reduced (PR; amotosalen/UVA) platelets in 2017 and extended platelet component (PC) shelf-life from 5- to 7-days in 2018and2019. Annual national hemovigilance (HV) reports characterized longitudinal PC utilization and safety over 11 years, including several years prior to PR adoption as the national standard of care. Data were extracted from published annual HV reports. Apheresis and pooled buffy coat [BC] PC use was compared. Transfusion reactions (TRs) were stratified by type, severity, and causality. Trends were assessed for three periods: Baseline (2010-14; ~7% PR), Period 1 ([P1] 2015-17; 8%-21% PR), and Period 2 ([P2] 2018-20; 100% PR). PC use increased by 19.1% between 2010 and 2020. Pooled BC PC production increased from 38.8% to 68.2% of total PCs. Annual changes in PCs issued averaged 2.4% per year at baseline, -0.02% (P1) and 2.8% (P2). The increase in P2 coincided with a reduction in the target platelet dose and extension to 7-day storage. Allergic reactions, alloimmunization, febrile non-hemolytic TRs, immunologic incompatibility, and ineffective transfusions accounted for >90% of TRs. Overall, TR incidence per 100,000 PCs issued declined from 527.9 (2010) to 345.7 (2020). Severe TR rates declined 34.8% between P1-P2. Forty-six transfusion-transmitted bacterial infections (TTBI) were associated with conventional PCs during baseline and P1. No TTBI were associated with amotosalen/UVA PCs. Infections with Hepatitis E (HEV) a non-enveloped virus resistant to PR, were reported in all periods. Longitudinal HV analysis demonstrated stable PC utilization trends with reduced patient risk during conversion to universal 7-day amotosalen/UVA PCs.

Morphologic evaluation of megakaryocytes in immune thrombocytopenia patients older than 80 years.

In immune thrombocytopenia (ITP), which is a common acquired bleeding disorder, cytotoxic T-cell-mediated cellular immune response against both circulating platelets and bone marrow megakaryocytes are the most important mechanisms in the pathogenesis. In our study, we evaluated the features of 33 patients with ITP, over 80 years of age. The median age of the patients was 90, 15 patients were female (45.4%). The mean platelet count of the patients was 39×109/L and the mean mean platelet volume was 10,33fL. Twelve patients had a target thrombocyte count greater than 30×109/L, while 20 patients had a target platelet count of 75×109/L or greater with an absolute indication of antiaggregation. In the environmental spread, 18 dysplasia findings were observed. Morphologic observations suggesting dysplasia including micromegakaryocytes and a non-dysplastic but dysmegakaryopoietic finding, multiple segmented nuclei may be related to the degree of thrombocytopenia and response to treatment. Likewise, nondysplastic features including immature forms, emperipolesis, bare nucleus, hypolobulation, and hypersegmented nucleus were related to the degree of thrombocytopenia.

A Phase 2 Study of the LSD1 Inhibitor Bomedemstat (IMG-7289) for the Treatment of Essential Thrombocythemia (ET)

Many patients with ET are intolerant of or have an inadequate response to current standards of care (SOC) - hydroxyurea (HU), interferon, or anagrelide. Lysine-specific demethylase-1 (LSD1) is an enzyme critical for the self-renewal potential of malignant cells and hematopoietic differentiation, e.g., LSD1 licenses progenitors to mature into megakaryocytes, a cell central to ET pathogenesis. Bomedemstat is an orally active LSD1 inhibitor that reduced peripheral cell counts, splenomegaly, inflammatory cytokines, mutant cell burdens and improved survival in mouse models of MPNs (Kleppe et al. 2015; Jutzi et al. 2018). IMG-7289-CTP-201 is a global, open-label, Phase 2b study of bomedemstat taken once daily for 24+ weeks in patients with ET who are resistant to or intolerant of at least one SOC treatment (NCT04254978). Key eligibility criteria include the need for cytoreduction (age >60 or history of thrombosis), platelet count >450 x 109/L and hemoglobin ≥10 g/dL. Key objectives are safety and response, defined as platelets (plt) ≤400 x 109/L without new thromboembolic events. Exploratory endpoints include durability of response, reduction in WBCs, changes in mutant allele frequencies (MAF), and symptom improvement. Patients receive a starting dose of 0.6 mg/kg/d followed by dose titrations if necessary to a target platelet count of 200-400 x 109/L. At data cut-off (20Jun2022), 73 patients had enrolled. Median age was 66 (42-92) yrs; median time since diagnosis was 81 months (N=71), and 60 patients had previously been treated with HU. Of the patients most recently treated with HU (N=51), 90% met ELN criteria for resistance/intolerance. 64% (47/73) received 1 prior cytoreductive therapy with 36% (26/73) receiving between 2 and 4. The Day 1 mean (range) platelet, WBC and Hb values were 809 x 109/L (457-2220), 8.8 x 109/L (3.7-43.1), and 13.0 g/dL (9.4-16.5), respectively. Median (range) MPN-SAF TSS at baseline was 16 (0-74). 32% (23/73) and 11% (8/73) of patients had a history of bleeding or thromboembolic events respectively. Extended sequencing of 261 genes in 53 patients identified mutations in JAK2 (51%), CALR (36%), and MPL (4%). 32% had more than one mutation of which 41% were high molecular risk mutations (U2AF1, IDH1/2, NPM1, RUNX1, EZH2, ASXL1, TP53). Median time on treatment was 23 weeks (0.1-84). For patients treated ≥24 weeks, 94% (34/36) achieved a platelet count response ≤400x109/L, without new thromboembolic events, in a median time of 8 weeks (Figure). One patient was diagnosed with a pulmonary embolism. 83% of patients (30/36) treated for ≥24 weeks maintained their platelet count response for ≥12 weeks. Of the 7/36 (19%) patients with Day 1 WBC count >10x109/L, 100% of those treated for ≥24 weeks had a reduction in WBC count to ≤10x109/L (Figure); mean hemoglobin remained stable at ≥10 g/dL. In patients with baseline MPN-SAF TSS >20 (28/73), at Week 24, 79% (11/14) experienced an improvement with 64% (9/14) improving ≥10-points. The median baseline score for worst fatigue was 4.0 (N=73). By Week 24, the median fatigue score had improved to 3.0 (N=35). At Week 24, 67% (N=24) had a decrease in allele frequencies. No new mutations were found. In the safety population (N=73) the most common AEs (% patients, % patients with grade 3/4) regardless of causality were dysgeusia (43%, N/A), constipation (27%, 1%), fatigue (23%, 0%), thrombocytopenia (23%, 6%), arthralgia (21%, 3%), contusion (16%, 0%), and diarrhea (15%, 1%). Seventeen patients reported serious AEs (SAE), with related events (per the PI) in 2 patients. Fifteen patients discontinued treatment, 9 due to AEs (3 for dysgeusia), 3 subject decision, 1 investigator decision, 1 disease progression to MF, and 1 unrelated death due to aspiration pneumonia. There have been no safety signals or deaths related to drug. At the data cut-off date, 80% (58/73) of patients remain on study. With this additional follow-up data, bomedemstat, in this ET patient population, continues to be generally well-tolerated, improves symptoms, reduces the mutation burden and, importantly durably reduces platelets and WBCs without adversely affecting hemoglobin. Based on these data, a Phase 3 study of bomedemstat for the treatment of ET is being planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eltrombopag in Pediatric Patients with Previously Untreated or Refractory/Relapsed Severe Aplastic Anemia: The Phase II Escalate Trial

Background: Severe aplastic anemia (SAA) is a rare, life-threatening disease characterized by pancytopenia and hypocellular bone marrow (BM). Immunosuppressive therapy (IST) is the standard of care for pediatric patients (pts) who lack a matched sibling donor. Approximately one-third of pts do not respond to IST or relapse following treatment. Therefore, effective and well-tolerated therapies are needed to improve outcomes of IST in pediatric pts with untreated or refractory/relapsed SAA. Aims: ESCALATE (CETB115E2201; NCT03025698) is a multi-institutional Phase II dose-escalation study to evaluate the pharmacokinetics (PK), safety, efficacy, and acceptability of the thrombopoietin receptor agonist eltrombopag (ETB) in pediatric pts who have refractory/relapsed SAA after IST for SAA (Cohort A) or who have previously untreated SAA (Cohort B). Methods: Patients (1 to <18 years [y] of age) received ETB as tablets or powder for oral suspension. Cohort A pts received ETB with IST (horse antithymocyte globulin [hATG] + cyclosporin A [CsA]) or ETB + CsA, based on investigator choice. Cohort B pts received ETB + hATG + CsA. The ETB starting dose was 50 mg/day (25 mg/day in pts aged <6 y) and was adjusted to achieve a target platelet count of 50-200×109/L. The maximum allowed daily dose was 150 mg. ETB was administered for 26 weeks and initiated together with CsA (duration of ≥104 weeks) +/- hATG (Days 1-4). Study follow-up included an additional 52 weeks during which ETB could be continued (data to Week 52 included here). ETB PK were the primary endpoint; secondary endpoints included safety/tolerability, overall response rate (ORR), BM cellularity, morphology, cytogenetics, paroxysmal nocturnal hemoglobinuria (PNH) clonal evolution, and acceptability/palatability (full data to be presented). ORR was defined as the proportion of pts with a complete (CR) or partial (PR) response (see Table 1 footnote). Results: Fifty-one pts (14 in Cohort A, 37 in Cohort B) were enrolled. The ORRs at Week 26 were 71% (95% CI 42-92) and 46% (30-63), respectively, for Cohorts A and B, and 57% (95% CI 29-82) and 51% (34-68) at Week 52 (Table 1). The most common ETB/hATG/CsA-related adverse events (AEs) (>20%) over the study period were increased bilirubin (43%), increased ALT (41%), increased creatinine (39%), increased AST (33%), hypertension (31%), hypomagnesemia (26%), and increased blood urea (24%). The most common serious AE was pyrexia (29%). Twenty-six pts discontinued ETB treatment, including 11 pts due to physician decision, 7 pts due to AEs (increased ALT/AST/blood bilirubin), 4 pts due to pt/guardian decision, 3 pts no longer requiring treatment, and 1 pt due to progressive disease. Two pts had BM chromosomal abnormalities post baseline (1 with 47XY+Y[2]/46XY[18] at Week 26 [normal at baseline and at Weeks 12 and 52]; 1 with 46,XY,t(2,3)(p23,q12)[2]/46,XY[18] at Week 182 [normal at baseline]). One pt evolved to PNH and 1 pt progressed to acute myeloid leukemia. Most pts reached the maximum daily dose of 150 mg regardless of age. The median dose intensity was 116.6 mg/day in pts aged <6 y and 94.8 mg/day in those aged 6 to <18 y. In pts who maintained the highest dose achieved for ≥14 days, the geometric mean (CV%) AUCtau was μg⋅h/mL (43%, n=8) and 733 μg⋅h/mL (63%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 71.6 μg/mL (33%, n=9) and 36.2 μg/mL (62%, n=22). Dose-adjusted (to 50 mg) geometric mean AUCtau was 447 μg⋅h/mL (54%, n=8) and 321 μg⋅h/mL (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 25.8 μg/mL (46%, n=9) and 16.6 μg/mL (52%, n=22). The higher ETB exposure in younger pts was a consequence of slower clearance: geometric mean CLss/F was 0.112 L/h (54%, n=8) and 0.156 L/h (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. This age effect on ETB PK is supported by data in adult SAA pts (dose-adjusted AUCtau and Cmax of 257 μg⋅h/mL and 13.4 μg/mL, respectively). Conclusion: The overall response rate to ETB in pediatric refractory/relapsed SAA pts was encouraging. ETB exposure was higher in pts aged 1 to <6 y than in those aged 6 to <18 y because of the age-related increase in ETB clearance. Despite the higher exposure in the younger pts, the daily dose achieved was generally 150 mg in both the 1 to <6 y and 6 to <18 y groups. The observed AEs reflected the disease itself and the safety profiles of hATG, CsA, and ETB. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Prospective Randomized Study for Optimal Red Blood Cell Use Patients with Acute Myeloid Leukemia Receiving Dose Intensive Chemotherapy

Background: Although blood transfusion is fundamental throughout the course of hematologic malignancy, acute myeloid leukemia (AML) patients requiring intensive chemotherapy are left at the edges of patient blood management programs because current guidelines do not have established recommendations for a transfusion threshold in patients treated for hematological disorders nor for those with severe thrombocytopenia who are at risk of bleeding. Especially in the past 2 years, patient blood management programs gained more popularity with the spread of COVID-19. Due to blood inventory shortages, majority of the institutions lowered the hemoglobin (Hb) threshold to 7g/dL and this hit patients with hematologic malignancies especially hard. To close the gaps in inconsistencies of RBC transfusion care, we conducted a prospective trial focusing on newly diagnosed AML patients undergoing intensive chemotherapy. To the best of our knowledge, this is the first trial focusing on this unique subpopulation of patients. Also by doing so, we were able to shed some light on RBC transfusion optimization for patients with thrombocytopenia. Methods: This was a randomized trial of newly diagnosed AML diagnosed and treated between September 2018 and February 2022. Figure A outlines the study design. Patients were randomized into 4 groups using 2 by 2 factorial design, according to trigger (Hb 7 vs 8g/dL) and quantity (single-unit vs double-unit). In case patients became hemodynamically unstable due to major bleeding, severe infection, ischemic heart disease, stroke or any other compromising conditions, liberal RBC transfusion was allowed regardless of the grouping to ensure patients’ safety. Platelet transfusion was done liberally to maintain target platelet count between 10 - 20 x 109/L. Non-acute promyelocytic leukemia AML aged between 19 to 70 years old, undergoing cytarabine ± anthracycline chemotherapy were considered eligible for enrollment. The primary objective of the study was to compare the differences in the number of RBC units per case across the groups. The secondary outcomes included major bleeding and clinical relevant non-major bleeding (CRNM) according to ISTH, AML treatment outcomes according to International Working Group, platelet transfusion, RBC transfusion adherence rates (events of out of specification transfusion), transfusion related adverse events (AE), and infection complications Results: Initially 91 patients were randomized into 4 groups, but the protocol adherence rate was 90.1% (Figure B). As whole, patients received a median of 4 units of RBC (range 0-24) and AE rate associated with RBC transfusion was 16.9% (13/77). All 13 cases of AE were mild allergic and non-hemolytic reactions. There were no cases of fatal AEs such as anaphylaxis, acute hemolysis or transfusion-associated lung injury. Hemoglobin trigger did not affect the amount of RBC transfusion required during treatment. Patients receiving RBC transfusion at Hb < 7 g/dL used a median of 4 units of RBC (range 0-12), and those receiving transfusion at Hb < 8g/dL also used a median of 4 units of RBC (range 0-24) (P=0.305). The AE rates associated with RBC transfusion were similar between the 2 groups (P=0.286). As for platelet transfusion, there were no differences regards to transfusion frequency (P=0.256) or amount (P=0.258) between the 2 groups. Quantity of RBC per transfusion did not affect the total amount of RBC transfusion required during treatment. Patients receiving 2 units of RBC per transfusion used similar amount of RBC as patients receiving 1 unit of RBC per transfusion. There were no differences in platelet transfusion frequency (P=0.256) or amount (P=0.258) between the 2 groups. Overall, treatment outcomes did not differ across the 4 groups. There were 3 cases of major bleeding: 2 cases of gastrointestinal bleeding and 1 case of muscle hematoma. There was 1 case of CRNM: the patient had grade 1 epistaxis that did not require intervention. There were 4 deaths during the follow-up: 2 due to uncontrolled AML and 2 due to infection. Conclusion: This study establishes feasibility for restrictive RBC transfusion in AML patients undergoing chemotherapy. For stable patients without significant medical history, RBC transfusion can be safely initiated when Hb < 7g/dL and 1 unit is adequate. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Longitudinal trends of peripheral blood counts in polycythaemia vera and essential thrombocythemia patients in the UK.

There is sparse evidence of how well haematological targets are met in practice for essential thrombocythemia (ET) and polycythaemia vera (PV) patients. Patient data was collected between 2008 and 2020 from two UK NHS Trusts for ET and PV patients. Longitudinal changes in peripheral blood counts, including the proportion of patients meeting peripheral blood count remission, was modelled. Relative risk of cardiovascular‐related events for patients achieving remission within 3‐months was estimated. A total of 620 ET and 429 PV patients were analysed. For high‐risk patients, haematological parameters decreased in the first months of observation then stabilised within normal reference ranges until year 5. Total time spent in peripheral blood count remission was 39.2% for ET and 29.1% for PV. A lower proportion of ET patients reached target platelet counts (48.3%) compared to WBC (79.1%), whilst PV patients were less likely to reach target haematocrit levels (56.9%) compared to platelets (77.3%) or WBC (74.6%). There was no statistically significant association between reaching target blood counts within 3‐months and cardiovascular risk. Complete haematological remission remains a challenging target in managing PV and ET, however this study was unable to show statistically‐significant evidence that this was associated with increased risk of cardiovascular events.

Eltrombopag in pediatric chronic and refractory ITP: data from a retrospective multicenter study from Lebanon.

About 20% to 30% of pediatric patients with immune thrombocytopenia (ITP) develop chronic or refractory disease lasting 12months or more that can be challenging to treat. Eltrombopag is being used after failure of previous lines of therapy with good results at tertiary healthcare centers in Lebanon, a developing country with available multidisciplinary treatment modalities. This is a retrospective multicenter observational study that analyzed data on pediatric patients with chronic or refractory ITP who were given eltrombopag as second- or third-line therapy in 6 large referral hospitals in Beirut (country capital located in mid Lebanon), South, North, and Mount Lebanon between October 2016 and May 2020. The primary end point of the study was a proportion of patients achieving platelet counts of ≥ 50 × 109/L for at least 6weeks without requiring rescue therapy during the observation period. Data from 36 patients treated for chronic and refractory ITP, 20 (55.6%) males and 16 (44.4%) females, were analyzed. The median age at the eltrombopag dose was 11years (2-18years). All the patients had failure of the first-line therapy with steroids, 3 patients received eltrombopag as second-line therapy, and the remaining patients had failure of at least 2 previous lines of therapy, including steroids. The primary end point was achieved in 21 (58.3%) of 36 patients. The treatment was discontinued in 3 patients due to no response. Hepatotoxicity and all other adverse events (headache, weakness, and diarrhea) were mild and transient. All the patients who achieved the target platelet count of ≥ 50 × 109/L maintained the response for the treatment duration, which was a minimum of 5months up to 3years, with median/mean observation periods of 12months and 14months, respectively. This study confirms the findings of randomized controlled trials that eltrombopag as second- or third-line therapy in pediatric patients with chronic and refractory ITP is effective and safe, reinforcing its role in the real-world management of these patients.

2021 Chinese consensus on the diagnosis and management of primary immune thrombocytopenia in pregnancy.

2021 Chinese consensus on the diagnosis and management of primary immune thrombocytopenia in pregnancy.

How do I implement pathogen-reduced platelets?

Several risk mitigation steps have improved the safety of platelets in regard to bacterial contamination, but this continues to be a concern today. A Food and Drug Administration (FDA) Guidance issued in December 2018 aims to further limit this risk. The guidance offers multiple pathways for compliance, and hospital blood banks will have to collaborate with blood donor centers to assess various factors before deciding which method is most appropriate for them. Our institution considered several factors before moving forward with pathogen reduction technology. This included an assessment of platelet shelf-life, bacterial testing requirements, the efficacy of low-yield platelets, and managing a mixed platelet inventory. The decision to transition to pathogen-reduced platelets was associated with complex collection and processing limitations that resulted in either an increase in platelets that were over-concentrated or products with a low platelet yield. Through trials of various collection settings with unique target volumes and target platelet yields, our blood donor center was able to optimize the production. At the hospital end, this transition required a thorough review of low-yield platelet products and their clinical efficacy. Additionally, this implementation necessitated collaboration with clinical colleagues, comprehensive education, and training. Pathogen-reduced platelets would be the most efficient way for our institution to be compliant. This summary may serve as a roadmap for other institutions that are considering which FDA prescribed method to use and provide support for those that have decided on pathogen reduction technology but need to optimize their collections to best utilize low-yield products.

A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Essential Thrombocythemia (ET)

A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Essential Thrombocythemia (ET)