Transfusion Independence Research Articles

Predictive Biomarkers of Response to Luspatercept in Patients with Myelofibrosis- (MF) Associated Anemia: Biomarker Analysis from the ACE-536-MF-001 Study

Introduction: MF is a clonal myeloproliferative neoplasm that results in fibrosis of the bone marrow and impaired hematopoiesis. Among other clinical manifestations, ineffective erythropoiesis leads to anemia resulting in poor quality of life and reduced overall survival (Passamonti et al., Blood 2010). Current treatment options for MF-associated anemia with most agents lack optimal efficacy and durability of response (Cervantes et al., Expert Rev Hematol., 2016). Luspatercept is a transforming growth factor-β (TBF-β) family ligand trap that inhibits the TGF-β-Smad signaling axis and promotes late-stage erythropoiesis. Luspatercept is approved in low-risk MDS with ring sideroblasts and β-thalassemia requiring red blood cell (RBC) transfusion. The ACE-536-MF-001 study investigates the safety and efficacy of luspatercept in the treatment of MF-related anemia. Here, through mutational and cytokine analysis of ACE-536-MF-001 biomarker samples, we sought to identify mutational and cytokine profiles associated with response. Methods: Eligible patients were divided into 4 cohorts based on transfusion dependence (TD) and treatment with ruxolitinib (RUX). Cohorts 1 and 3A were non transfusion dependent (NTD) while cohorts 2 and 3B were TD patients receiving 4-12 RBC units/84 days up to C1D1. Cohorts 3A and 3B received a stable dose of RUX. All patients received 1.0 mg/kg of luspatercept (1.33 mg/kg for cohort 3B) with titration up to 1.75 mg/kg once every 21 days. Primary endpoint was anemia response (defined as an increase of ≥ 1.5 g/dL hemoglobin (Hgb) from baseline for cohorts 1/3A or RBC transfusion free for ≥ 12 consecutive weeks for cohorts 2/3B). Secondary endpoint was mean Hgb increase ≥ 1.5 g/dL from baseline for ≥ 12 consecutive weeks for cohorts 1/3A, or ≥ 50% decrease in RBC transfusions from baseline for ≥ 12 consecutive weeks and duration of RBC transfusion-free period for cohorts 2 and 3B. Mutational analysis was performed in DNA from peripheral blood mononuclear cells using a panel targeting 74 genes. Rules-Based Medicine's Human Inflammation panel was used to measure changes in 54 serum cytokines. Nexelis custom panel was used for detection of GDF8, GDF15, erythroferrone, soluble transferrin receptor 1 (sTfR1) and hepcidin. Changes in soluble factors from cycle 1 to end of week 24 (day 169) were examined for correlation with clinical response. Results: All 4 cohorts (N = 95) displayed improvement in anemia and TD patients receiving RUX had the greatest benefit (Gerds et al. EHA 2023 S167). In the biomarker cohort (n = 63 across all 4 cohorts), mutational analysis revealed that most patients carried the JAK2 V617F mutation, and patients with SF3B1 or SF3B1 with co-occurring DTA mutations ( DNMT3A, TET2 or ASXL1) had a favorable prognosis related to anemia response (p= 0.0260, 0.0495; OR= 3.54, 3.86). In addition, JAK2 V617F patients in cohort 3B showed clinical benefit with luspatercept (OR= 6.75, p= 0.0445). Across cohorts and endpoints, the general trend of responders was low baseline (2-3-fold lower relative to nonresponders) levels of key inflammatory cytokines. Low levels of IL-10 (TD patients) and VCAM-1, TNFR2, CRP and IL-18 (NTD patients) were significant ( P < 0.01) predictors of response. Paired analysis between cycle 1 and week 24 revealed increases in alpha-2-macroglobulin, haptoglobin, TIMP1, and decrease in C3, vitamin D-binding protein, hepcidin and sTfR1 associated with anemia response. When transfusion burden reduction was used as a response criterion, ferritin, hepcidin, thrombopoietin, von Willebrand Factor, sTfR1, and beta-2-microglobulin were significantly ( P < 0.05) associated with response (Figure). In addition, Hgb increase was associated with increased TGF-β1 and VEGF levels and decreased GDF-15 and ERFE. These cytokines are implicated in iron metabolism (ferritin, hepcidin, alpha-2-macroglobulin), Hgb catabolism (haptoglobin), anemia (vitamin D-binding protein, C3), and luspatercept-target engagement (hepcidin, sTfR1). Conclusions: Our analysis identifies unique predictors of response to luspatercept treatment in patients with MF. While the data describe our findings across cohorts, cohort 3B (TD, receiving RUX), which had the highest response rate, also had higher levels of RANTES and TPO at baseline in responders. The ongoing phase 3 study, INDEPENDENCE (NCT04717414), would validate these observations in a larger cohort of patients

Ghosal Hematodiaphyseal Dysplasia: Implications of Late Diagnosis and Unusual Presentation in Adults

Ghosal Hematodiaphyseal Dysplasia (GHDD) is a rare autosomal recessive disorder characterized by bone modeling failure, resulting in thickening of bone cortices with predominant diaphyseal involvement and responsive anemia to steroids. Late diagnosis of GHDD in adulthood can lead to significant morbidity and suboptimal response to steroids. Moreover, GHDD often mimics more common hematological disorders like myelodysplastic syndrome and myelofibrosis, leading to treatments such as transfusions, splenectomy, and hematopoietic stem cell transplantation. Early diagnosis is critical to enable the patient to receive the appropriate treatment. We present a case series of three Indian patients from different families with genetically proven GHDD. Despite experiencing symptoms from early childhood, all patients were diagnosed in adulthood. None of them were born out of a consanguineous marriage . Two of them, aged 43 and 56, are the oldest reported GHDD patients to date. They initiated steroid treatment in their 5th and 6th decades of life, respectively. Unlike previously reported cases, these two patients required additional drugs like Thalidomide along with steroids, and their response to treatment was not as rapid. The first patient, a 43-year-old male, had a history of anemia since childhood and became transfusion dependent after 15 years of age. He developed bicytopenia and later pancytopenia with hypocellular bone marrow , along with splenohepatomegaly and extramedullary hematopoiesis in the paravertebral and presacral areas, a novel finding in GHDD cases. Whole exome sequencing revealed a missense mutation in the TBXA2 gene. The second patient, a 56-year-old male, had a history of anemia since childhood and underwent splenectomy at 46 due to massive splenomegaly and transfusion dependency. However, his transfusion dependency persisted, and bone marrow biopsy suggested myelofibrosis. However he was negativefor myeloid mutations including JAK2. Subsequently, genetic testing revealed a homozygous missense mutation in the TBXAS1 gene. He also developed paraplegia and bladder incontinence, attributed to extramedullary hematopoiesis, which improved with steroid treatment The third patient a 23 year old man with history of anemia, lower limb tenderness and ecchymosis at 14 months of age. Evaluation then had shown hyperostosis of diaphysis of long bones of lower limbs with sparing of metaphysis and bicytopenia. Was on regular transfusions till 9 years. Re-evaluation with bone marrow studies at 9 years revealed a varying cellular marrow with dysplastic megakaryocytes and diagnosed as pediatric myelodysplatic syndrome ,He was on steroids till 13 years and he did not require further transfusions.He stopped steroids for 1 year following which there was a fall in Hb levels and recurrence of pain in both lower limbs with inability to squat. In view of history of steroid responsive anemia and thickening of diaphysis in X-rays GHDD was suspected and confirmed by genetic testing. He was restarted on steroids and there was a good response to steroids within 4 week with normalisation of hemoglobin levels . Late diagnosis of GHDD in adulthood can lead to severe complications and suboptimal treatment response. These cases highlight the importance of early diagnosis to prevent unnecessary interventions and improve patient outcomes. Unusual presentations, like extramedullary hematopoiesis, can further complicate the diagnostic process. Clinicians should maintain a high index of suspicion for GHDD in cases of refractory anemia or myelofibrosis-like features, especially in adults with an earlier history of anemia. Early recognition and appropriate management are crucial to mitigate morbidity and improve patients' quality of life

Metabolic Syndrome Among Patients with Myelodysplastic Syndrome: A Population Analysis

Introduction: Metabolic syndrome (MS) comprises a cluster of cardiovascular risk factors, including central obesity, dysglycemia, elevated blood pressure (BP), increased triglyceride levels (HyperTG), and low HDL cholesterol levels. Epidemiologic and clinical data suggest that MS may be an important etiologic factor in the progression of certain cancer types. These studies have excluded patients with myelodysplastic syndromes (MDS), but MS may be relevant in these patients owing to the link between cardiovascular disease and MDS derived from clonal hematopoiesis. We conducted a population-based analysis to define the prevalence of MS and its components among patients with MDS and explore the effect of MS on MDS outcomes. Methods: We identified patients aged 66 and older diagnosed with MDS between 2007 and 2017 using the SEER-Medicare database. Preexisting MS was identified using ICD-9/10 codes in claims from at least 12 months before MDS diagnosis. MS was defined as the presence of 3 or more of the 5 MS components. MDS histologic risk was defined based on ICD-O-3 morphology codes. Transfusion dependence, defined as 2 or more transfusions within 8 weeks of MDS diagnosis date, and therapy with hypomethylating agents (HMA), lenalidomide and erythropoietin stimulating agents (ESA) were defined from HCPCS codes and prescription records. Other variables defined included age, sex, race/ethnicity, rurality (using RUCC codes), marital status, and socioeconomic status [SES] (using the Yost index). Descriptive statistics were used to define the frequency of MS and its components. MDS outcomes of interest were transformation to acute myeloid leukemia (AML), defined from ICD-9/10 codes for AML, and overall survival (OS), defined as the time between MDS diagnosis and death from any cause. Cox proportional hazards regression was used to determine the association between MS and AML transformation and OS, through adjusted hazard ratios (HR). Results: A total of 15,227 cases diagnosed with MDS between 2007 and 2017 were analyzed, including 3,402 (22.3%) with baseline MS. High BP was present in 72.2%, HyperTG in 47.8%, dysglycemia in 35.5%, central obesity in 4.6% and 0.5% had low HDL cholesterol. The prevalence of MS and the distribution of its components did not significantly differ based on MDS histologic risk (Table 1). The prevalence of hyperTG was notably higher in patients with MDS, especially in the high histologic risk category (50.4%). Compared to other MDS patients, those with preexisting MS were predominantly male (55.5% vs 53.3%, p=0.03) of non-White race (6.7% vs 4.8% non-Hispanic Black, p<0.01, and 2.1% vs 1.5% Hispanic, p<0.01), from urban/metropolitan areas (87.7% vs 86%, p=0.01) and lower SES quintiles 1 and 2 (34.2% vs 31.5%, p<0.01). In a model adjusting for age, sex, race/ethnicity, rurality, marital status, SES, MDS risk, transfusion dependence and MDS therapies (HMA, lenalidomide and ESA), baseline MS at the time of MDS diagnosis was not associated with a significant effect on the risk of AML transformation (HR=1.0, 95%CI 0.9-1.2) or the risk of death from any cause (HR=1.0, 95%CI 0.9-1.1) (Table 2). In models assessing the effect of MS subcomponents on MDS outcomes, high BP (HR=1.0, 95CI% 1.0-1.1) and obesity (HR=1.1, 95CI% 1.0-1.2) were associated with an increased risk of mortality. Obesity was also associated with an increased risk of transformation to AML (HR=1.3, 95CI% 1.0-1.6). Conclusions: The overall prevalence of MS among patients with MDS appears similar to that reported in the general population and does not differ based on the histologic risk category. The observed prevalence of HyperTG was higher than expected, particularly in high-risk MDS patients. Older males of non-White race from urban/metropolitan areas of lower SES are more likely affected across all groups. Though preexisting MS is present in an important proportion of MDS patients, it was not significantly associated with an increased risk of mortality or AML transformation after adjusting for confounders. Obesity was associated with higher mortality and linked to increased transformation to AML. Given recent data suggesting that statins may improve survival and decrease AML transformation in MDS, future studies should investigate the potential association between other metabolic parameters and MDS outcomes.

Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HR-MDS: Update from Higher Dose Levels

Background: RVU120, a first-in-class CDK8/19 kinase inhibitor, showed antileukemic activity mediated by inhibition of STAT5 phosphorylation in AML cell lines and patient-derived cells.Clinical activity in a population of patients with relapsed/refractory AML and HR-MDS with poor prognostic factors was shown in a currently ongoing phase 1 dose escalation study (NCT04021368) consistent with the preclinical evidence of both cytotoxic and erythroid and myeloid differentiation effects in cell and mouse models. Aims: The primary objective of the study is to determine the safety profile and the recommended phase 2 dose (RP2D) of RVU120 as a single agent in R/R AML and HR-MDS. Secondary objectives include the characterization of PK, antitumor activity, and exploratory pharmacodynamic (PD) effects. Methods: CLI120-001 is an open-label, multi-center, dose escalation study. RVU120 is administered orally every other day, for a total of 7 doses, in a 3-week treatment cycle until disease progression or unacceptable toxicity. Adverse events are graded according to NCI-CTCAE v.5.0. DLTs are assessed at the completion of Cycle 1. Disease evaluation is performed according to Dohner 2017 and Cheson 2006 response criteria for AML and MDS respectively. Pharmacodynamic assessments (PD) include a flow cytometry assay to assess target engagement by evaluating changes in phosphorylated STAT5. Results: As of 26 Jul 2023, 31 patients received RVU120 at doses between 10 and 175 mg, median age 71 years, median of 3 prior lines of therapy. ECOG PS was 2 in 8 pts, 1 in 20 pts, and 0 in 3pts. No severe drug reactions, no DLT have been reported, with manageable nausea and vomiting being the most frequent treatment-emergent adverse events. Twelve out of the 24 evaluable patients showed clinically relevant benefit. Four patients achieved a reduction of blasts to <5% in the BM: One patient with NPM1 and FLT3 mutated AML, achieved a CR, 3 patients with HR-MDS had a marrow CR, one of those had G3 BM fibrosis and is currently in C3 of treatment. 3 additional patients treated across different dose levels experienced a sustained BM blast reduction: 2 patients with TP53+ AML with 37% and 74% BM blast reduction, 1 patient with AML-MRC and monosomy 7 with 28% blast reduction; 1 patient with AML-MRC failing 4 lines of therapy received allogeneic BM transplantation after 6 cycles of RVU120 treatment. 5 patients achieved hematology improvement including: 1 patient with HR-MDS failing 2 lines of therapy, 1 patient with AML secondary to MF, became RBC transfusion independent (TI) and is still ongoing after >18 months with nearly normal Hgb and Plts values. 2 patients with AML-MRC, with baseline RBC and Plt transfusion dependance (TD), became TI and reached normal Plts values. 1 patient with AML-MRC with RBC and Plt TD and severe neutropenia showed RBC and Plt TI and ANC recovery and is currently in C7 of treatment. A correlation between pSTAT5 inhibition and RVU120 exposure was observed. Conclusion: In the ongoing phase 1 trial, RVU120 shows clinical activity in both AML and HR-MDS, inducing RBC transfusion independence and blast reduction with a tolerable safety profile. Clearance of BM blasts including a formal CR were observed in patients treated at different dose levels. Relevant target inhibition is achieved from 110 mg onwards with expected higher pSTAT 5 inhibition with further dose escalation.

The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes

Background and Significance: Anemia is a common and debilitating symptom in patients with myelodysplastic syndromes (MDS), frequently leading to dependence on red blood cell (RBC) transfusions. Transfusion-dependent (TD) patients have worse overall survival and quality of life, and repeat transfusions are associated with complications, including iron overload. Erythropoiesis-stimulating agents (ESAs) are the standard treatment for anemia in patients with lower-risk (LR)-MDS, but many patients are ineligible for or refractory to ESAs, and responses are limited. Luspatercept, a late-stage erythroid maturation agent, is approved to treat TD patients with LR-MDS after ESA failure. In the phase 3 COMMANDS study, in ESA-naive patients with LR-MDS requiring transfusions, a significantly higher proportion of patients receiving luspatercept than epoetin alfa achieved RBC transfusion independence for ≥ 12 weeks with concurrent hemoglobin (Hb) increase ≥ 1.5 g/dL (weeks 1-24) (Platzbecker U, et al. Lancet 2023. doi: 10.1016/S0140-6736(23)00874-7). The potential of luspatercept to improve moderately severe chronic anemia and reduce RBC transfusion dependence has not yet been investigated in the majority non-transfusion-dependent (NTD) LR-MDS patient population. Preventing transfusion dependence is crucial for improving LR-MDS patient outcomes. The aim of this actively enrolling, phase 3, randomized, multicenter study is to compare the safety and efficacy of luspatercept versus epoetin alfa in reducing progression to RBC transfusion dependence in ESA-naive, NTD adult patients with anemia due to LR-MDS. Study design and methods: The ELEMENT-MDS study includes a 5-week screening period, a 96-week treatment period, an extension phase, and a post-treatment follow-up period (Figure). Target enrollment is 360 patients with anemia due to Revised International Prognostic Scoring System (IPSS-R) Very low-, Low-, or Intermediate-risk MDS. Eligible patients are ≥ 18 years of age with a confirmed MDS diagnosis, baseline serum erythropoietin (sEPO) levels ≤ 500 U/L, and symptomatic anemia defined as a score of moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness). Participants must be RBC transfusion-independent per International Working Group 2018 criteria (no RBC transfusions within 16 weeks prior to randomization) and have baseline Hb ≤ 9.5 g/dL. Patients will be excluded if they have a del(5q) cytogenetic abnormality, unclassifiable MDS or myelodysplastic/myeloproliferative neoplasms, anemia due to reasons other than MDS, bleeding disorders, low absolute neutrophil or platelet counts, uncontrolled hypertension, previous acute myeloid leukemia diagnosis, or history of recent malignancies, among other reasons. Participants will be randomized 1:1 to receive luspatercept or epoetin alfa. Stratification factors include baseline sEPO levels, ring sideroblast status, and IPSS-R risk category. Patients will receive luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg (escalation up to 1.75 mg/kg allowed) or epoetin alfa once a week at a starting dose of 450 IU/kg (escalation up to 1050 IU/kg allowed). The primary endpoint will compare the proportion of patients becoming TD (defined as requiring ≥ 3 RBC units/16 weeks) during any continuous 16-week interval in weeks 1-96. The key secondary endpoint is a Hb increase ≥ 1.5 g/dL sustained for ≥ 16 weeks during weeks 1-48. Additional secondary endpoints include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence ≥ 24 weeks, and quality of life assessment. Safety endpoints include type and severity of adverse events and relationship to treatment, overall survival, and progression to high-risk MDS and acute myeloid leukemia. Summary: The results of this phase 3 study will determine the efficacy and safety of luspatercept as a therapy for ESA-naive NTD patients with LR-MDS, who have limited treatment options for anemia. The study is registered at ClinicalTrials.gov (NCT05949684) and EudraCT (2022-500430-29-00).

British Columbia Experience in Allogeneic Stem Cell Transplantation for Myelofibrosis with or without Pre-Transplant Ruxolitinib

Introduction Allogeneic stem cell transplantation (AlloHSCT) remains the only potentially curative treatment for myelofibrosis (MF). It confronts many challenges stemming from the older age of the typical patients and their age-related comorbidities, as well as disease-specific factors such as splenomegaly and hostile marrow microenvironment, which raise concerns for delayed engraftment and graft failure. Methods We performed a retrospective review of the 58 adult patients who received AlloHSCT for MF in British Columbia, Canada, in the 20-year period between January 2001 and December 2020. Data pertaining to patient demographics, disease characteristics, treatment/transplant details and clinical outcomes were gathered from the available paper and electronic records. Relapse-free survival (RFS) was defined as the time between the day of the transplant and the day of disease relapse or death from any cause. Overall survival (OS) was defined as the time between the day of the transplant and death from any cause. Patients who did not have an event during follow up were censored at the time of the last known follow up. Survival analysis was performed by Kaplan-Meier survival estimator and log-rank test, using Stata version 16.1 (Texas, USA). Results The median age of the cohort was 56 years (range 26-68), with 36% being 60 years old or older. The male to female ratio was 1.6:1. The median Karnofsky Performance Status index was 80 (range 70-100) and the median age-adjusted HCT-specific Comorbidity Index was 2 (range 0-5). The pre-transplant DIPPS plus risk category was: high in 13 patients (22%); intermediate-2 in 29 (50%); intermediate-1 in 15 (26%); and low in 1 (2%). 19/58 (33%) had a peripheral blast percentage greater than 2%. 51/58 (88%) had grade 3 fibrosis seen on the pre-AlloHSCT bone marrow biopsy. 27/57 (47%) patients were transfusion-dependent for pRBC and/or platelets. 28/54 (52%) evaluable patients had a normal karyotype and 6/54 (11%) a complex karyotype. Sixteen patients (28%) had a myeloid gene panel performed by PCR; the most commonly seen variants were ASXL1 (10 patients) and TET2 (5 patients). The median number of variants seen in a single patient was 3 (range 0-5). 42/58 (72%) patients received myeloablative conditioning before AlloHSCT. The donor type was: a volunteer unrelated donor in 54%; a matched sibling in 42%; and an alternative source (double cord or haploidentical donor) in 4%. Peripheral blood stem cells were used in 93% of the AlloHSCT. 24/58 (41%) patients received ruxolitinib pre-AlloHSCT (starting in June 2012) for a median duration of 10 months (range 1-44); 17/24 (71%) of the recipients had a clinical response to ruxolitinib but 3 had lost the response before their AlloHSCT. One patient had stopped ruxolitinib due to cytopenia. During a median follow up period of 41.7 months (range 0.5-260.7), 24/58 (41%) experienced acute graft-versus-host disease (GVHD) and 33/49 (67%) evaluable patients developed chronic GVHD. Graft failure was seen in 2 patients - one primary and the other secondary. MF relapse was seen in 13/58 (22%) after a median time of 1.1 years post-AlloHSCT (IQR 0.7-2.4). The transplant-related mortality (TRM) was 25% at 1 year and 28% at 3 years post-AlloHSCT. The most common causes of death were infection (7 patients), disease relapse (6 patients), and multiorgan failure (5 patients). Transfusion independence was achieved in 45/58 (78%) patients by day +100 and in 40/44 (90%) by 1-year post-AlloHSCT. 17/48 (35%) evaluable patients had persistent grade 3 fibrosis on their day+100 bone marrow biopsy. The estimated 1-year, 5-year and 10-year RFS rates were 66% (95% CI 52-76), 55% (95% CI 41-67) and 47% (95% CI 42-61) respectively. The estimated 1-year, 5-year and 10-year OS rates were 72% (95% CI 59-82), 63% (95% CI 49-74) and 54% (95% CI 37-68) respectively. There were no differences in RFS (p=0.40) and OS (p=0.23) between those who received ruxolitinib pre-transplant vs. those who did not. Conclusion In our cohort, approximately half the AlloHSCT recipients achieved long-term survival, many in remission (10-year OS 54%; 10-year RFS 47%). TRM was seen in 25% within the first year after AlloHSCT, with patients most commonly succumbing to infections. The graft failure rate was low at 3%. An increasing number of patients received pre-AlloHSCT ruxolitinib in the recent years but we were unable to demonstrate improved transplant outcomes with its use in this single centre cohort.

Thrombocytosis and Megakaryocyte Changes Associated with Pure Red Cell Aplasia

J.A., R.G.W, and G.R. contributed equally to this abstract. Introduction: Acquired pure red cell aplasia (PRCA) is a rare hematological disorder characterized by normocytic, normochromic anemia with severe reticulocytopenia and a notable absence of identifiable erythroid precursors in the bone marrow. PRCA is often without a clear etiology and can be associated with conditions such as Large Granular Lymphocytic (LGL) Leukemias, B-cell dyscrasias, thymomas, immunodeficiencies or infections. Discovery of an IgG inhibitor in primary autoimmune pure red cell aplasia (PRCA) has been an immensely significant breakthrough. This finding has not only shed light on the critical role of IgG inhibitors in the pathophysiology of PRCA but has also underscored the importance of aberrant T cell activity in this condition. Thrombocytosis refers to an elevation in platelet count of >450,000/μL, which is not a typical feature associated with PRCA. Based on observations in our clinical practice of patients with PRCA with concomitant thrombocytosis, we screened our cohort for the combination of these features to discover potential mechanisms underlying this phenomenon. Methods: In order to address this objective, we conducted a retrospective analysis of medical records from 90 patients diagnosed with acquired PRCA at the University of Texas Southwestern and Cleveland Clinic Foundation between 2000 and 2022. Our primary goal was to determine the frequency of thrombocytosis among these patients. For those in the subset displaying thrombocytosis, longitudinal hemoglobin and platelet counts before and after treatment of the condition were also collected for relevant comparisons utilizing paired t-tests after assessing for normality with Shapiro-Wilk test. Results: Among a cohort of 90 patients diagnosed with acquired PRCA, 12 individuals exhibited thrombocytosis at the time of PRCA diagnosis (Table 1). Demographically, this subset of individuals had a median age of 53.5, and a 3:1 ratio of women to men. 66.7% of those with thrombocytosis also exhibited megakaryocyte hyperplasia on bone marrow biopsy. Molecular analysis ruled out the presence of myeloproliferative neoplasms, and blood work was obtained ruling out iron deficiency. Patients were treated for PRCA with a variety of medications including prednisone, cyclosporine, tacrolimus, rituximab, and cyclophosphamide. After treatment, 8 of the 12 patients demonstrated complete resolution of their PRCA, defined as transfusion independence with hemoglobin levels above 10. Further examination of those 8 patients with resolution of PRCA revealed statistically significant differences in mean hemoglobin and platelet counts before and after treatment (Figure 1). Specifically, the mean hemoglobin count increased from 7.9 (SD 2.5) g/dL to11.6 (1.8) g/dL (p=0.0168), while the platelet count decreased from 557,300 (SD 104,700) /μL to 414,400 (SD 109,600) /μL (p=0.0049). Conclusion: Our report is the most comprehensive case series to date reporting on thrombocytosis in patients with acquired PRCA. We speculate that the arrest of erythropoiesis generating PRCA may lead to skewing of precursors towards the megakaryocytic lineage. Alternatively, EPO production secondary to PRCA could stimulate TPO receptors and thus stimulate platelet production. Clinicians should be aware of this particular PRCA presentation. Further investigations will aid in elucidating whether one of these mechanisms may also be playing a role in PRCA-related thrombocytosis. The significance of thrombocytosis or megakaryocyte alterations in PRCA remains enigmatic, necessitating further investigations to elucidate their role in disease pathophysiology, as well as their utility as biomarkers for treatment response prediction. The limitations of this study encompass a small sample size and the absence of post-treatment bone marrow biopsy results, which would have facilitated the visual assessment of any resolved megakaryocyte abnormalities. Future directions include examining megakaryocyte hyperplasia and other megakaryocyte abnormalities such as hyper- and hypo-lobation associated with PRCA.

Treosulfan Based Haploidentical Αß T Cell Depleted HSCT Represents a Curative Alternative in Pediatric and Adult Patients with Transfusion Dependent Thalassaemia

Background: Quality of life remains severely compromised in patients suffering from Transfusion Dependent Thalassemia (TDT) despite optimal supportive care. HSCT with a MSD, the current curative option, achieving a 92.1% 2y-OS in children and 84.4% in adults (EBMT registry). Unfortunately, availability of MDs is limited, so that haploidentical HSCT is increasingly explored. Methods: 13 TDT patients (median age: 11 years; range: 2-23) received either a CD3 +/CD19 + (n=4; all class II/III) or αß/CD19 + (n=10; 7 class II, II/III) T-haplo-HSCT and were compared with 8 TDT-patients (7 class II, II/III, III) receiving a BM graft from a MSD (median age: 11 years; range: 4-22). Indication for T-haplo HSCT patients was severe iron overload/ transfusion-associated complications. All patients received an identical conditioning regimen consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to d0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF. Results: The OS and DFS for MSD and T-haplo-HSCT was 100%/100% and 100%/92%, respectively (Table 1). The median follow-up was 30 months for MSD (range 4-72) and 38 months for T-haplo-HSCT (range 4-86). Neutrophil engraftment was achieved after a median of 31 days for MSD patients and 17 days for T-haplo-HSCT with a median of 5 x 10 8 TNC/kg (range: 3.28-7.88) and 15 x 10 6 CD3 +/CD19 + or αβ/CD19 + depleted CD34 + cells/kg (range: 9.2-24.2), respectively. One patient received two T-haplo HSCT, due to primary graft failure partly due to a major AB0 incompatibility. A mixed chimerism was observed in 3/7 MSD-HSCT (median 92%; range 27.5-100%) and in T-haplo-HSCT in 2/13 patients (median 99%; range: 45.3 -100%). Transfusion independence was achieved in all MSD and in all but one T-haplo patient. In MSD and in T-haplo-HSCT, IST was terminated after a median of 173 days and 226 days (range: 112-347), respectively. MSD patients reached CD4 counts >50/µl on day +43 (median; range: 25-125) and T-haplo-HSCT patients on day +114 (median; range: 33-173). The treosulfan-based conditioning regimen was well tolerated with no VOD/SOS observed in this high-risk population. No case of acute or chronic Graft-versus-Host disease (GvHD) was observed in the MSD population. In T-haplo-HSCT, 3 patients experienced grade I acute GvHD (skin) which resolved with prednisolone and in 2 cases with additional extracorporeal photopheresis. Only the oldest patient experienced mild chronic skin GvHD, which resolved by day +580. No severe infectious complications occurred despite a prolonged chimerism-triggered weaning of the IST. Conclusions: Independent of donor availability, graft rejection and iron-overload related organ damage (VOD/SOS) are major pitfalls in transplanting advanced stage TDT patients. Treosulfan demonstrated to be an excellent alternative to busulfan in this setting reflected in the safety and efficacy data of this pilot series. Overall, outcomes of T-haplo-HSCT in TDT are very encouraging with a competitive OS, so that a transplant indication in pediatric and AYA TDT patients lacking a MD is feasible.

A Novel Beta Globin Frameshift Mutation Causing Autosomal Dominant Beta Thalassemia

Background: Dominantly inherited β-Thalassemia (β-thal) is a rare condition that results from a heterozygous mutation in the β-globin gene ( HBB), leading to the synthesis of an unstable β-globin chain, most frequently an elongated protein. Although heterogeneous, it presents not as β-thalassemia trait but rather with a more severe phenotype, resembling β-thal major or intermedia, with chronic hemolytic anemia and splenomegaly. There are approximately 150 known dominantly inherited α- and β-globin gene mutations (http://globin.cse.psu.edu/). We present a case of a novel HBB mutation leading to a dominant form of β-thalassemia, outlining our approach to attaining an appropriate diagnosis and management leading to transfusion independence. Case: A 32-year-old Caucasian female was referred to our center with a diagnosis of congenital dyserythropoietic anemia type II (CDA-II), based on bone marrow studies at 12 years of age which had demonstrated a hypercellular marrow with erythroid hyperplasia and 10% binucleated red cells. Molecular testing had not been performed. Her history was negative for developmental delay, growth retardation, or family history of anemia. She had presented to medical attention at age 11 with symptomatic anemia. Prior treatments included steroids, IVIG, and erythropoietin, with no significant improvement of her anemia. She underwent splenectomy at 19 years of age due to the hemolytic component of her anemia with the clinical diagnosis of CDA-II, with a mild improvement in baseline hemoglobin from 70-80g/L to 80-90g/L. Spleen pathology demonstrated splenomegaly (weight of 1kg) and mild iron deposition. At the time of presentation at our centre, her predominant symptom was fatigue, for which she was initiated on a chronic transfusion protocol, to maintain a pretransfusion hemoglobin of 90 g/L; she received a total of 53 units from October 2018 to November 2022. She subsequently developed worsening iron overload (ferritin 888, TSAT 80%, and LIC of 8.1mg of iron per gram of liver dry weight) requiring initiation of iron chelation therapy. Given her presumptive diagnosis of CDA-II she was later enrolled in the Congenital Dyserythropoietic Anemia Registry (CDAR) for North America (https://www.clinicaltrials.gov/study/NCT02964494). Molecular testing by next generation sequencing (NGS) on a CDA gene-panel at that time failed to identify a causative CDA mutation. Further testing with whole exome sequencing revealed a one base-pair deletion in exon 2 of the β-globin gene, creating a frameshift variant at codon 96 and ending in a premature STOP, 63 codons downstream p.(Lys 96Asnfs*63) (Figure 1). This mutation led to an elongated β-globin chain and an unstable hemoglobinopathy predicted to be the cause of her presentation. Hemoglobinopathy screen revealed HBF 8.7%, HBA 87.5%, and HBA2 3.8%. Based on the above testing, a diagnosis of dominant β-thalassemia intermedia due to HBB NM_00518.4, c.288delG, p.K96fs, recognizing that she had been previously misdiagnosed with CDA-II. Based on the revised diagnosis, the patient was initiated on Luspatercept 1mg/kg SC q3 weeks, with rapid improvement in her pre-transfusion hemoglobin to >100g/L as well as in her symptomatology and quality of life (Figure 2), rendering her transfusion independent. Discussion: This case report, to our knowledge, demonstrates a novel β-globin gene mutation leading to dominant β-thalassemia, with the phenotype of β-thal-intermedia. The latency between presentation and diagnosis demonstrates the challenges associated with diagnosing rare hemolytic anemias and highlights the importance of molecular testing to confirm the diagnosis, especially before proceeding to splenectomy which may predispose to vasculopathies in some of these diseases, such as congenital dyserythropoietic anemia type I and unstable hemoglobinopathies.

Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress

Background and Significance: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs that promotes production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. Therefore, inhibition of IRAK1/4 is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases that inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the phase 1 trial results supported the further study of R289. An open-label phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently recruiting patients. Study Design and Methods: The R289 phase 1b study (NCT05308264) is an open label, single arm, multi-center study, which includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of low-risk MDS (International Prognostic Scoring System-R ≤3.5) and ≤5% bone marrow myeloblasts. Patients must be relapsed or refractory/resistant or intolerant to prior MDS therapies. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment, clinically significant anemia (from iron deficiency, hemolysis, or GI bleeding), and chronic myelomonocytic leukemia. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 500 mg qd with dose limiting toxicity (DLT) assessed at both doses. The DLT evaluation period will be 28 days. After completion, patients not experiencing DLTs may remain at their respective dose levels as long as they demonstrate continued clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled, with R289 administered to all patients at a dose not exceeding the MTD determined in the dose escalation phase. The primary endpoint of the study is safety and tolerability of R289, assessed by incidence of AEs, discontinuation/interruption of R289 due to AEs, and incidence of DLTs. Secondary endpoints include preliminary efficacy, assessed by red blood cell transfusion independence by Week 24 (% achieving ≥50% reduction in transfusions), and pharmacokinetics of R289. Change from baseline in plasma biomarkers, including C-reactive protein and TNFα, and bone marrow biomarkers will be assessed. Statistical analyses will be primarily descriptive. Tabulations will be produced for disposition, demographics, disease characteristics, safety, pharmacokinetics, pharmacodynamics, and clinical activity. For analyses of clinical activity, such as proportion of patients with RBC transfusion independence, complete responder rate, overall response rate, and proportion of subjects with hematologic improvements, the summary will be produced separately for the dose escalation phase and dose expansion phase. For the dose escalation phase, data will be summarized by dose level and overall. The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.

Identification, Monitoring and Reversibility of PARP Inhibitor Associated Clonal Haematopoiesis and Myelodysplastic Syndrome: A Case Series

Background: Poly ADP ribose polymerase inhibitors (PARPi) are widely used as maintenance treatment for ovarian cancer (OC) after response to platinum chemotherapy in the first line setting and recurrent disease. Their use has significantly improved outcomes, particularly in patients with BRCA mutations in whom first-line PARPi maintenance therapy increases progression-free survival from 13.8 to 56.0 months (Hazard Ratio, 0.33; 95% CI, 0.25-0.43). However, a recent meta-analysis of clinical trial adverse events and pharmacovigilance data showed that PARPi therapy significantly increases the risk of therapy related myeloid neoplasms (tMN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia with poor outcomes. Platinum based chemotherapy is the mainstay of OC treatment and is associated with clonal haematopoiesis (CH) with mutations in DNA damage response genes. CH is recognised as a premalignant myeloid state but real world data on clonal dynamics during PARPi therapy are lacking. We present a case series of OC patients receiving PARPi-therapy referred for haematological review for beyond-expected HT or unexplained full blood count (FBC) abnormalities with serial FBC and myeloid next generation sequencing (mNGS) clonal monitoring in relation to PARPi therapy. Methods: Seven patients with stage III/IV high-grade OC were referred to haematology at the discretion of the treating oncologist between February 2017 and May 2022 (mean age (SD): 68 (7.0) years, median PARPi duration: 18 months (range: 4-86)). All patients had received prior platinum-based chemotherapy and were screened with mNGS in peripheral blood (PB) or bone marrow aspirate and trephine (BMAT) at initial assessment. Results: Reasons for referral are detailed in Table 1 and include two patients with isolated elevated nucleated red blood cell (NRBC) counts. Six patients had clonal pathology (CP), five of whom had single-nucleotide variants typical of platinum-exposure defined by the involved gene or platinum-associated mutational signatures. Clinical details including BRCA-status, haematological diagnosis and mNGS results are detailed in Table 1. PARPi-therapy was discontinued in four patients with CP, with resolution or improvement of FBC and m-NGS abnormalities (variant allele frequencies (VAFs) and/or copy number variations (CNVs)) in three patients. These findings were most marked in Patient 1, referred with grade 3 thrombocytopenia and transfusion dependence and in whom PARPi cessation resulted in transfusion independence and resolution of morphological and cytogenetic abnormalities (clinical course including BMAT results and haematological parameters illustrated in Figure 1), and Patient 3, who demonstrated selective regression of a TP53 mutated clone on PARPi cessation. Two patients with germline BRCA mutations continued PARPi therapy with 3 monthly PB mNGS monitoring after discussion at multidisciplinary team meetings. Conclusions: We show using sequential molecular and haematological monitoring before and after PARPi cessation that morphological, FBC and clonal abnormalities can be reversed on PARPi discontinuation, potentially mitigating the risk of life-threatening tMNs in some patients. We also highlight that, in addition to cytopenias, persistently elevated NRBCs may be an indicator of clinically relevant CP not well described in pharmacovigilance data based on common terminology criteria for adverse events criteria. Large scale prospective data on clonal dynamics in PARPi therapy are needed to inform mNGS screening and tMN risk stratification as scoring systems based on age associated clonal haematopoiesis of indeterminate potential may not be applicable. Until these data are available we demonstrate the value in MDT discussion and serial PB mNGS monitoring in formulating case-by-case therapeutic decisions regarding CP and PARPi therapy, particularly patients with high risk BRCA mutated OC.

Ker-050 Treatment Reduced Iron Overload and Increased Bone Specific Alkaline Phosphatase in Participants with Lower-Risk MDS Supporting Potential to Restore Balance to the Osteohematopoietic Niche

Background: Iron overload (IO) in myelodysplastic syndromes (MDS) contributes to the deterioration of the osteohematopoietic niche (OHN), where hematopoietic and osteogenic precursors interact to regulate hematopoiesis and bone metabolism. Excess iron exacerbates ineffective hematopoiesis, inflammation, and bone loss via direct effects on resident hematopoietic and osteogenic precursors. Iron chelation therapy (ICT) is associated with improved event-free survival in patients with MDS but does not address the underlying cause of IO and introduces patient burden due to tolerability and cost. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) and promote differentiation and maturation of erythroid and megakaryocytic precursors. KER-050 has potential to reduce dependence on red blood cell transfusions and increase iron utilization via erythropoiesis, possibly mitigating IO at its source. As previously reported from an ongoing Phase 2 study (NCT04419649), KER-050 treatment in participants with lower-risk (LR) MDS resulted in rates of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) of 51.4% and 42.3%, respectively, with a mean decrease in ferritin (322 ng/mL at Week 24) among HI-E and/or TI responders. KER-050 treatment also demonstrated effects on osteogenic precursors, including prevention of bone loss in a mouse model of MDS and dose-dependent increases in bone specific alkaline phosphatase (BSAP), a marker of bone formation, observed in healthy postmenopausal women. Thus, KER-050 has potential to address the multifaceted pathogenesis of MDS, including IO. Here, we present new data from the ongoing Phase 2 study in MDS, exploring the potential of KER-050 to provide benefit beyond hematologic responses and to ameliorate IO in MDS. Methods: This ongoing Phase 2 study is evaluating KER-050 in participants with LR MDS. Data from exploratory assessments of markers of IO, hematopoiesis, and bone turnover are presented as of a cutoff date of April 3, 2023, for all participants who had received the recommended Part 2 dose (RP2D; 3.75-5 mg/kg q4wks). Results: Baseline ferritin levels in RP2D participants (N=59) were generally elevated, while levels of mean corpuscular hemoglobin and reticulocyte hemoglobin were in the normal range (Table 1). After KER-050 treatment, sustained decreases in serum ferritin were observed among participants with baseline levels ≥1000 ng/mL (Figure 1), likely driven in part by reduced transfusion burden in responders. Concomitant increases observed in soluble transferrin receptor (sTfR; Figure 1) suggest that increased erythropoiesis may also have contributed. Mean decreases in ferritin observed in non-transfused (NT) participants (-228 ng/mL at Week 24, n=7) indicate potential for KER-050 to affect iron homeostasis by mechanisms other than transfusion reduction. In 1 NT participant receiving ICT, the baseline ferritin of 1632 ng/mL decreased to <500 ng/mL over 32 weeks, leading to ICT discontinuation and coinciding with an increase in hemoglobin (Hgb) from 9.2 g/dL at baseline to 11.3 g/dL over the same period. In another NT participant not receiving ICT, ferritin decreased from 1094 ng/mL at baseline to 884 ng/mL and 583 ng/mL at Weeks 24 and 68, respectively, while Hgb gradually increased from 9.94 g/dL at baseline to 10.7 and 12.2 g/dL at Weeks 24 and 68. KER-050 treatment was also associated with increases in BSAP, a new finding in this MDS population that is consistent with prior observations in preclinical and healthy volunteer studies. Despite some heterogeneity, mean increases of 8.47% (n=23) and 10.4% (n=13) were observed at Weeks 24 and 48, respectively; 3 participants with erythroid responses had increases in BSAP of ≥30% at these time points. Summary: Exploratory data indicate potential for KER-050 to drive meaningful decreases in ferritin in participants with LR MDS, particularly among those with IO. While transfusion reduction likely contributes, observations in NT participants highlight the potential for enhancement of erythropoiesis to improve IO, irrespective of transfusions. Observed changes in BSAP suggest that KER-050 is also acting on osteogenic precursors, with the potential to provide functional improvements within the OHN. Updated results will be provided at the presentation.

Efficacy and Safety of Recombinant Thrombopoietin Combined with Immunosuppressive Therapy for Primary Treatment of Severe Aplastic Anemia: A Single-Center, Open-Label, Randomized, Clinical Trial

Standard immunosuppressive therapy (IST) combined with eltrombopag is the first-line treatment regimen for severe aplastic anemia patients who are ineligible for allo-hematopoietic stem cell transplantation (allo-HSCT). However, there was no second-generation TPO receptor agonist available in China before 2019, and only a first-generation TPO preparation was available for clinical treatment. Although rhTPO and eltrombopag act on different receptor binding sites, the differentiation pathways are similar, so rhTPO can theoretically also stimulate hematopoietic stem cells and promote hematopoietic recovery in AA. In 2015, we used rhTPO combined with IST as the first-line treatment for SAA. The results showed that the OR and quality of response in the rhTPO group were significantly higher than those in the control group. Multivariate analysis showed that the application of rhTPO was an independent prognostic factor affecting the efficacy of IST. Based on these results, we performed a single-center, randomized, open-label, parallel-controlled clinical trial to assess the hematologic response rate and long-term safety 3, 6, and 12 months after treatment. The study was conducted between 2015 and 2019 with 188 patients with primary SAA who were randomly assigned to the control or rhTPO group (95 with IST alone and 93 with rhTPO). For rhTPO, 15000 IU was administered subcutaneously starting on day 14 after p-ATG administration and then once every other day for a total of 14 injections. The median age of the 93 patients in the rhTPO group was 33 years (range 16-67). These included 58 patients with SAA and 35 patients with very severe aplastic anemia (VSAA), which were comparable to the control group. There were no significant differences in baseline clinical parameters between groups. No significant differences were observed in the overall hematologic response rates at 3, 6, and 12 months between the rhTPO and control groups (3 months: 40.9% vs 41.1%, P = 0.979; 6 months: 52.7% vs 52.6%, P = 0.994; 12 months: 65.6% vs 63.2%, P = 0.782, respectively). The median time of platelet transfusion independent was 49 (0-376) days in the rh-TPO group and 47 (0-195) days in the control group, which was not different between the two groups ( P = 0.757). The median time of RBC transfusion independence was 47 (5-404) days and 49 (0-295) days, respectively ( P = 0.592). The median follow-up time was 64 (1.3-86.2) months. The 5-year overall survival was 86.4% (95% confidence interval [CI], 77.2-92.0%) in the rh-TPO group and 84.1% (95% CI, 74.5-90.3%, P = 0.898) in the control group. The 5-year event-free survival was 51.7% (95% CI, 41.0-61.5%) and 54.1% (95% CI, 43.5-63.6%, P = 0.947) in the two groups, respectively. No significant differences were observed in the relapse rate and clonal evolution rate between the two groups (11.5% vs. 11.7%, 4.3% vs.3.2%, repectively). Subcutaneous rhTPO injection was well tolerated by patients, with no significant adverse effects other than mild localized pain at the injection site. The patients in the rhTPO group did not have concomitant thrombotic or embolic complications; moreover, reticulo-fibrillary or collagen fibrillary hyperplasia in bone marrow was not detected in any patients at three and six months after IST. Ten patients had anti-TPO antibodies at the end of TPO treatment, with no positive anti-TPO antibodies. In conclusion, our study is the only prospective randomized controlled clinical trial in China of rhTPO combined with IST for the treatment of SAA, with no difference in the hematologic response rate of the 28-day rhTPO combination regimen compared to standard IST; however, we did confirm the safety of rhTPO at this dose. Further clinical studies are required to determine the most effective dosage and duration of rhTPO treatment.

OMS906, a Novel Alternative Pathway MASP-3 Inhibitor, Normalizes Hemoglobin Levels and Increases Clone Size in Treatment-Naïve PNH Patients

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disorder characterized by hemolytic anemia in combination with various degrees of marrow failure. PNH is driven by dysregulation of the complement system where the absence of CD55 and CD59 cell surface proteins leads to red blood cell (RBC) lysis. Untreated PNH can lead to debilitating anemia, thrombosis, fatigue, and increased mortality. Terminal complement inhibition attenuates intravascular hemolysis (IVH) but inevitably leads to extravascular hemolysis (EVH). Proximal and alternative pathway (AP) inhibition block both IVH and EVH, as demonstrated with C3, Factor B, and Factor D inhibitors. Mannan-binding lectin-associated serine protease-3 (MASP-3) activates pro-Factor D, thus activating the AP upstream of Factor D. OMS906 is a highly selective humanized mAb that binds to and inhibits MASP-3. In a Phase 1 study in healthy subjects, OMS906 was well tolerated and provided substantial MASP-3 inhibition. In the present study, safety and efficacy of OMS906 were evaluated in complement-inhibitor treatment-naïve patients with PNH. Methods: This is an ongoing, single-arm, open-label, Phase 1b proof-of-concept clinical trial (NCT05889299; EudraCT 2022-002450-22) evaluating safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OMS906 in adults with PNH. Eligibility criteria include: confirmed PNH diagnosis by flow cytometry (RBC clone size >10%); complement-inhibitor treatment-naïve or inadequate response to C5 inhibitors; and baseline hemoglobin (Hgb) <10.5 g/dL. Patients received 5 mg/kg subcutaneous (SC) OMS906 every 4 weeks, the lowest exposure cohort in this study. Primary endpoints are safety and tolerability. Secondary endpoints include changes from baseline in Hgb and lactate dehydrogenase (LDH) levels, RBC clone size, and absolute reticulocyte count; achievement of Hgb ≥12 g/dL or an increase of ≥2 g/dL; and transfusion independence. Planned enrollment was approximately 10 patients. Results: This pre-specified interim analysis included data available as of July 20, 2023. All patients (N=11) included in this analysis were complement-inhibitor treatment-naïve (55% female; mean age 41 years [range 27-72]). The majority of patients (64%) received RBC transfusions in the 12 months prior to OMS906 treatment. Co-existing conditions included iron deficiency (n=6), chronic renal failure (n=3), aplastic anemia (n=2), and myelodysplastic syndrome (MDS; n=2). At baseline (N=11), mean Hgb was 7.0 g/dL (median 6.4 g/dL, range 3.9-10.4 g/dL) and LDH was 1835 U/L (median 1831 U/L, range 905-3480). To date, all patients have received ≥2 doses of OMS906 with 4 patients having received ≥6 doses. OMS906 was well tolerated. The most common adverse events (AEs) in ≥20% of patients were increased thrombocytopenia (36%), neutropenia (27%), and itching (27%). No patients experienced clinical breakthrough hemolysis. There were no major adverse vascular events, treatment-related serious AEs, discontinuations, or deaths. Following initiation of OMS906, mean Hgb increased from baseline by 3.1 g/dL ( P<0.001) at 4 weeks (N=11), and by 9.5 g/dL ( P=0.016) at the latest timepoint of 24 weeks (n=3) [Figure 1]. Among patients receiving ≥2 doses, all but 3 experienced gender-specific normalization of Hgb levels. The remaining patients had MDS (n=2) or marrow failure (n=1). No patients required transfusions following OMS906 treatment. Mean LDH levels decreased from baseline by 1483 U/L (>80%; P<0.001) at 4 weeks (N=11) and by 1939 U/L ( P=0.004) at 24 weeks (n=3). Three patients had increases in LDH, suggesting initiation of hemolysis at the end of a dosing period. Mean absolute reticulocyte counts decreased from baseline by 87,000-122,000 ×10 9/L at all timepoints. Mean PNH RBC clone size increased by up to 38.6% (n=6; P=0.016) versus baseline. Conclusion: In this interim analysis, MASP-3 inhibitor OMS906 was well tolerated with no safety signals of concern. Once-monthly SC OMS906 resulted in clinically meaningful, beneficial effects on Hgb, LDH, and RBC clone size in treatment-naïve PNH patients. OMS906 dose escalation guided by occurrence of subclinical hemolysis is being evaluated with the goal of achieving quarterly dosing.

Chronic Myelomonocytic Leukemia (CMML) with AML Typical Mutations ( NPM1, FLT3 or CEBPA) Identify a High-Risk CMML Group Independent of Molecular-Cpss

CMML is rarely associated with AML typical mutations such as NPM1, FLT3, CEBPA and IDH1/2 (mutAML-CMML). It is unknown what its clinical meaning is and if its presence should change our management into an AML-type treatment. The aim was to describe the characteristics, prognosis and treatment of mutAML-CMML patients. We studied 83 CMML patients of Hospital Clinic diagnosed between 1998-2022, with Next Generation Sequencing (NGS). We included 53 patients with mutAML-CMML from other institutions. We identified 31 patients with mutated IDH2 (all c.419G>A p.(Arg140Gln)), 13 with IDH1, 14 with NPM1,7 with CEBPA (4 bZIP) and 11 with FLT3 (3 FLT3-ITD and 7 FLT3-TKD: 6 TKD1 and 2 TKD2 variants, all different from p.(Asp835Tyr) except one). Patient characteristics and outcome of the group with mut IDH1/2 was not significantly different from wt IDH. Those patients with mut NPM1, FLT3 and/or CEBPApresented adverse characteristics and worse prognosis. Therefore, we grouped the patients with these mutations into a category named mutCFN (n=26) (Table 1). The mutCFN incidence in our series was 9%. The mutCFN patients (n=26) vs wtCFN (n=96) were younger (63 vs 71 years, p=0.004), had more leucocytes (16 vs 7.7x10 9/L, p=0.015), monocytes (2.9 vs 1.7x10 9/L, p=0.006), anemia (9.1 vs 11.2 g/L, p<0.001) and bone marrow blasts (11.5 vs 4%, p<0.001). They belonged more frequently to myeloproliferative variant (57.7 vs 30.2%, p=0.012), CMML-2 (69.2 vs 14.7%, p<0.001), high risk CPSS and CPSS-Mol (72 vs 31%, p<0.001; 88.2 vs 44.9%, p=0.001). They showed more transfusion dependence (69.2 vs 22.9%, p<0.001). Co-mutational representation is shown in Figure 1. mutCFN patients have a different co-mutational pattern from wtCFN with more frequently mutated DNMT3A (42.9 vs 6.3%, p<0.001), SF3B1 (15.8 vs 2.3%, p=0.04), WT1 (10 vs 0%, p=0.03), and less TET2 (24 vs 58.3%, p=0.003) . mutCFN patients received treatment more frequently than wtCFN (84.6 vs 36.5%, p<0.001) and earlier (0.97 vs 4.6 months, p=0.005). They were more frequently treated with chemotherapy (53.8 vs 7.3%, p<0.001) and alloSCT (61.5 vs 11.5%, p<0.001). The median follow-up was 9.3 years (95% CI, 8-11). The 2-year cumulative incidence of AML (CIR-AML) transformation was higher in mutCFN patients (44% vs 13%, p<0.001) and overall survival (OS) was shorter (25 vs 38 months, p=0.057). Besides, when those who received and alloSCT were censored at time of alloSCT, mutCFN showed an inferior survival (9.6 vs 35.7 months, p<0.01). Multivariate analysis confirmed mutCFN as an adverse prognostic factor independent of age and CPSS-Mol (HR 2.42, IC 95% 1.23-4.76, p=0.011). Because CFN mutation showed independent prognostic value not captured by CPSS-Mol, we added to CPSS-Mol 1 point if patient had mutCFN. We derived a modified CPSS-Mol-CFN score and identified five groups with different median OS of 85 (95% CI, 54-117) vs 74 (95% CI, 53-94) vs 40 (95% CI, 17-63) vs 22 (95% CI, 11-33) vs 15 (95% CI, 5-25) months, p<0.001with a better predictive capacity than CPSS-Mol (C-index 0.66 vs 0.64). Nowadays, there is no consensus between the two recent 2022 ICC and WHO classifications, but the identification of NPM1 or CEBPA mutations in cases of CMML could define AML. We analysed the group of patients who harboured bZIP- CEBPA or NPM1 mutations (“mutCN”) (n=17) and we found that these patients retained its chemosensitivity (90%CR) and those treated with chemotherapy had better OS (27 vs 9 months, p<0.001). 10 mutCFN patients received alloSCT with a median OS post-alloSCT of 21 months (95% CI, 16-26) and a 2year-CIR-AML of 37.5% (95% CI, 15-61). 5 patients received targeted therapy for a post-transplant relapse: 3 received sorafenib after a molecular relapse with prolonged responses and 2 received an IDH inhibitor, one of them persisting with a complete response after 4 years. We analyzed 5 paired samples (diagnostic CMML-AML transformation). All of the AML related mutations were retained at AML transformation and emerged new mutations in genes of signaling ( FLT3, NRAS), transcription ( RUNX1, CEBPA) and splicing ( STAG2) pathways. Independently of CPSS-Mol, mutCFN CMML patients have a different profile, closer to AML and with worse prognosis. They could benefit from more aggressive AML-treatment based on chemotherapy and alloSCT when possible. Interestingly, some patients may benefit from approved targeted therapy for AML FinancingISCIII PI19/01476 PI22/01660, co-financed EU, Emili-Letang HCPB

Disease Management and Outcomes in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Analysis of Observational Data from the United States

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic disease characterized by complement-mediated hemolysis, thrombophilia, bone marrow failure (BMF), and renal disease. PNH is clinically heterogeneous, and hospitalization and regular blood transfusions may be needed. Treatment with currently approved C5 inhibitors (C5i), eculizumab and ravulizumab, have shown efficacy in intravascular hemolysis control and reduction in thrombosis risk. Yet, in routine clinical practice, a limited number of patients receive C5i in the United States. Moreover, less than 70% of patients treated with eculizumab continue to receive treatment 1 year following PNH diagnosis. If the disease is managed inadequately, patients may experience prolonged morbidity, increased frequency and severity of symptoms, and early mortality. There is limited real-world evidence available on PNH disease management. Aim: To better understand the disease management and consequences of PNH. Methods: In this retrospective observational study, we analyzed 1227 patients aged ≥18 years in the TriNetX network who were diagnosed with PNH on or after 1 January 2007 and had ≥180 days of post-diagnosis follow-up data (97% were based in the United States). Patients were followed from 1 January 2007 to 6 May 2023. Disease management and outcomes were analyzed for all patients, including those with chronic anemia who were complement-inhibitor naïve. Chronic anemia was defined as hemoglobin <10 g/dL without any hemoglobin measure of ≥10 g/dL between 3 months prior to PNH diagnosis (index date) and 6 months after diagnosis. PNH-related hospitalization was defined by specific International Classification of Diseases codes. The baseline period was defined as 1 year prior to PNH diagnosis. Event rates were estimated for hospitalization (recurrent), transfusions (recurrent), BMF, and death. Rates are adjusted for exposure time (time between diagnosis and end of follow-up) and reported as per person-year with 95% confidence intervals (CIs). Results: In the overall cohort, 58% of patients were female, and the median (interquartile range) age was 56 (38-68) years. During a median 35 (19-62) months of follow-up, 322 (26%) patients received blood transfusions and 172 (14%) patients received C5i. Median time to C5i initiation since diagnosis was 1 (0-10) month with a median treatment duration of 14 (0-49) months. Out of 1227 patients, 50 (4%) had chronic anemia and were complement-inhibitor naïve. The median length of follow-up in this subgroup was 14 (7-43) months. Most of these patients (96%) had PNH with bone marrow disorder subtype. Median hemoglobin and lactate dehydrogenase levels at baseline were 8 (7-8) g/dL and 313 (218-489) U/L, respectively. Out of these 50 patients, first-line treatment was initiated a median of 1 (1-6) month after diagnosis, with anticoagulants and corticosteroids being the most frequently prescribed. During follow-up, 32 (64%) of these patients experienced ≥1 hospitalization (rate 0.78, 95% CI 0.62-0.95) with a median of 3 (2-9) days stay for the first hospitalization. Anemia (42%), abdominal pain (36%), and infections (9%) were the leading causes of admission. In addition, 26 (52%) patients were transfusion dependent (rate 1.52, 95% CI 1.30-1.77) and 30 (60%) experienced BMF (rate 0.71, 95% CI 0.48-0.99). Moreover, 21 (42%) of these patients died during follow-up (rate 0.19, 95% CI 0.12-0.28). Discussion: These findings indicate that complement-inhibitor naïve patients with chronic anemia have substantial disease burden, including frequent hospitalization, high transfusion dependency, and early mortality. In addition, the results show that only a minority of patients in this cohort received C5i. Study limitations include that mortality is likely to be underestimated, as only in-hospital deaths are captured in these data. The small sample size limits the drawing of robust conclusions. However, overall, these findings support the need to address PNH disease burden and improve disease management.

Longitudinal Systemic Bevacizumab Therapy Produces Cost Savings and Improves Quality-Adjusted Life Expectancy in the Care of Patients with Hereditary Hemorrhagic Telangiectasia with Moderate-to-Severe Bleeding

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is the second-most-common hereditary bleeding disorder worldwide, afflicting 1 in 5000 or 1.4 million persons. Unlike peer disorders hemophilia and von Willebrand disease, there are no FDA or EMA-approved therapies. The current standard-of-care (SOC) consists of red blood cell (RBC) transfusion, IV iron supplementation, and local hemostatic procedures (i.e., nasal, gastrointestinal). However, bleeding pathophysiology is amenable to vascular endothelial growth factor inhibition, and IV bevacizumab has shown great promise as a disease-modifying therapeutic. The multisite, international InHIBIT-Bleed study employed a pre- versus post-bevacizumab design and was the largest clinical study of HHT (n=238). InHIBIT-Bleed demonstrated that longitudinal systemic bevacizumab significantly improved clinical symptoms, raised hemoglobin levels, and nearly abrogated IV iron infusion and RBC transfusion need for patients with HHT. Although bevacizumab is an expensive biologic agent with a financial barrier to access, we hypothesized that reduction in health resource utilization and improvement in transfusion dependence will improve quality-of-life for patients with HHT at costs commensurate with added clinical value. Accordingly, we conducted the first cost-effectiveness analysis of bevacizumab therapy in HHT. Methods: For this independent analysis free of industry influence, we built a Markov simulation of adult patients with HHT to examine the cost-effectiveness of bevacizumab added to SOC versus SOC alone, over a lifetime time-horizon and across accepted willingness-to-pay (WTP) thresholds. Costs were assessed in 2023 US dollars. We employed study data for pre- and post-bevacizumab that included descriptive statistics for 1) hemostatic procedures, 2) hospitalizations, 3) emergency department visits, 4) RBC transfusions, and 5) iron infusions. Treatment-specific patient time and lost wages were also accounted for across IV infusions, emergency department visits, hospitalizations, and hemostatic procedures. Probabilities of RBC- and iron-related adverse events were sourced from hemovigilance reports, the 2015 National Blood Collection and Utilization Survey and 2008-2017 World Health Organization's VigiBase. Ferric carboxymaltose was used as the base-case iron supplement, and a scenario analysis examined ferumoxytol. Effectiveness was calculated in QALYs, and employed age-adjusted utilities derived using HHT-specific EQ-5D index values, with the 2019 Global Burden of Disease Study used to account for the degree of anemia improvement reported with bevacizumab. The primary outcome was the incremental cost-effectiveness ratio (ICER), or incremental net monetary benefit (iNMB) if intervention was found to be cost-saving. The secondary outcome was the aggregated patient time spent receiving HHT-specific care. We concluded by conducting deterministic and probabilistic sensitivity analyses, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations. Results: In the base-case, bevacizumab versus SOC cost $959,000 and $1,533,000 while accruing 24.1 and 21.8 QALYs, respectively. The iNMB with bevacizumab was $916,000 [95% credible interval $454,000-$1,994,000] and $1,004,000 [95% CI $473,000-$2,237,000] from the US health system and societal perspectives, respectively, at a WTP of $150,000/QALY. Bevacizumab also saves patients 125 hours per year lived. Deterministic sensitivity analysis revealed that no parameter variance changes the model result. In probabilistic sensitivity analysis bevacizumab was favored in 100.0% of 10,000 Monte Carlo iterations: saving cost with increased QALYs in 99.6% and cost-effective in the remaining 0.4% of iterations (Figure 1). Similar cost-savings were found in the scenario analysis with ferumoxytol. Conclusion: By reducing the need for hemostatic procedures, hospitalizations, emergency visits, RBC transfusions, and iron infusions, bevacizumab is, unusually, a cost-saving intervention that also improves the quality-adjusted life expectancy of patients with HHT. Bevacizumab also saves patient time spent on receiving HHT-specific care. Collecting long-term follow-up data to evaluate continued response to bevacizumab will help assess its value versus future advances in the care of patients with HHT.

Early Efficacy of IST in Combination with Hetrombopag and Rhtpo As First-Line Treatment for Naïve Severe Aplastic Anemia

BACKGROUND: Immunosuppressive therapy (IST) (anti-thymocyte immunoglobulin (ATG) and cyclosporine (CSA)) is the treatment of choice for patients with acquired severe aplastic anemia (SAA) who are ineligible for hematopoietic stem cell transplantation (HSCT), which results in a hematological response (HR) in about 60-70% of SAA patients. TPO is a hepatic-secreted hematopoietic growth factor that specifically regulates platelet production, induces hematopoietic stem cell differentiation to megakaryocytes by binding to the TPO receptor (MPL), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production and release. Several previous studies have shown that IST combined with rhTPO or hetrombopag can improve the early hematologic response of SAA patients, especially the proportion of good hematologic response (good HR) in the early stage. RhTPO and TPORA have different binding sites with thrombopoietin receptor (c-MPL) and do not have competitive binding, which may produce synergistic effect. A retrospective study showed that eltrombopag combined with rhTPO increased the IST HR and improved the quality of hematologic remission in SAA with mild adverse effects. Therefore the combination of TPORA and rhTPO in SAA patients undergoing IST treatment may result in faster and higher HR rates. Clinical studies have confirmed that hetrombopag, act similarly to eltrombopag in SAA, but there are no clinical studies of hetrombopag in combination with rhTPO in SAA. OBJECTIVE: To evaluate the early-efficacy and safety profile of IST in combination with hetrombopag, and rhTPO in patients with primary, severe aplastic anemia. METHODS: This study was designed for patients with primary aplastic anemia major aged 14-70 years after January 2023 from a single center. This group were planned to be get treat of IST combination with rhTPO 15000U/d for 8 weeks from the first day of ATG and hetrombopag 15mg/d for at least 6 months. The primary endpoint was to observe the good response rate, blood product transfusion and safety profile of the study regimen for the treatment of primary SAA for 3 months. Efficacy Criteria：Complete response (CR): HGB>100 g/L, PLT> 100×10 9/L and ANC>1.5×10 9/L; ② Good partial response (GPR): HGB>80g/L, PLT> 50×10 9/L and ANC>1.0×10 9/L; ③ Partial response (PR): withdrawal from blood product transfusion dependence (HGB>70g/L, PLT> 20×10 9/L), hematologic tests improved and no longer met the SAA criteria, but blood count did not meet the GPR criteria. ④No response to treatment (NR): Continuous transfusion dependency was classified as no response. and/or blood count still met SAA criteria. We defined CR+GPR+PR as HR and CR+GPR as good HR. RESULTS: The trial group proposes to enroll 39 patients and currently includes 8 patients who can be evaluated for 3-month efficacy of IST treatment. And the control group includes two groups of IST combined rhTPO group and IST combined HPAG group in our previous center, and the cohort study of the results of the three groups. In this study, the HR rate of 8 patients can be assessed at present as 75% (6/8), and the rate of good HR was 50% (4/8). The HR of 33 patients in the control IST+rhTPO group was 66.67% (22/33), and the rate of good HR was 36.4% (12/33); the HR rate of 32 patients in the control IST+HPAG group was 46.9% (15/32), and the rate of good HR was 21.9%. The HR rate and good HR rate of the trial group were higher than those of the IST+rhTPO group and the IST+HPAG group (75%v66.67%v46.9%; 50%v36.4%v21.9%). None of the 8 patients enrolled in the trial group had any transformation of myelofibrosis, myelodysplastic syndrome and acute myeloid leukemia during the follow-up period. CONCLUSION: HR was obtained at 3 months in 6 of the 8 patients with severe remodeling IST+rhTPO+ hetrombopag in this study, with a good HR rate of 50%, which is the highest good efficacy response we know of in a prospective study of Chinese SAA patients to date. This confirms that rhTPO combined with hetrombopag can synergize the recovery of bone marrow hematopoietic function in SAA patients treated with IST, and its clinical effect is superior to that of various TPO-Ras or rhTPO that have been widely used. It is expected that more cases will be included in the later stages and that better results will be obtained. 【Keywords】severe aplastic anemia; recombinant human thrombopoietin; hetrombopag ; immunosuppression treatment.

Association of Hemoglobin Levels with Healthcare Resource Utilization and Costs in Non-Transfusion-Dependent α- and β-Thalassemia: A Retrospective Observational Study Using Real-World Data

Introduction: Alpha (α)- and beta (β)-thalassemia result from reduced synthesis of α- or β-globin, respectively, leading to ineffective erythropoiesis, chronic hemolytic anemia (HA), and related complications. Thalassemia can also be characterized phenotypically as transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT). Decrease in hemoglobin (Hb) has been linked to increased risk of comorbidities and number of comorbidities in NTD β-thalassemia. Healthcare resource utilization (HCRU) has been analyzed in TDT in the US, but there is limited research on the association of Hb levels with HCRU and costs in α- and β-NTDT. Objective: To assess the association of average Hb levels with HCRU and costs in adult patients with α- and β-NTDT using retrospective claims data. Methods: This study analyzed data from the Merative ® MarketScan ® Commercial, Medicare, and Lab Results Databases for patients with thalassemia and no evidence of other HAs who were ≥18 years of age on the index date (date of the first observed diagnosis code for α- or β-thalassemia). Patients were stratified by type of thalassemia (α- or β-thalassemia) and by transfusion dependence (NTDT or TDT). NTDT was defined as <8 transfusions within 12 months of follow-up or with >42 days between any 2 adjacent transfusions. To evaluate if the results in NTDT were driven by patients with β-NTDT, patients with α-NTDT were also analyzed separately. Hb levels, HCRU (inpatient [IP] admissions, outpatient [OP] visits, and emergency room [ER] visits), and costs were assessed during a variable-length follow-up period (at least 12 months from the index date to end of plan enrollment, end of study, or IP death, whichever occurred first). Available Hb levels were averaged across the follow-up period for each patient. HCRU (number and type of service) and costs (US dollars) were converted to per-patient per-year values. All dollar estimates were inflated to 2020 (using Medical Care Component of Consumer Price Index). To assess the association of Hb levels with HCRU and cost outcomes, univariate regression analyses with negative binomial models were conducted. Percent changes in cost and incidence rate ratios of HCRU associated with 1 g/dL decrease in Hb level and corresponding 95% confidence intervals and p values (with significance level set to 0.05) were reported. Results: In the Commercial/Medicare database, 4077 adult patients with thalassemia and a variable length follow-up of at least 12 months were identified (median length of follow-up: 943 days). Of these, 909/4077 (22.3%) had at least 1 Hb value during the follow-up period in the Lab Results database, including 400 patients (44.0%) with α-thalassemia, 509 (56.6%) with β-thalassemia, 898 (98.8%) with NTDT (α or β), and 11 (1.2%) with TDT (α or β). The average Hb value per patient with NTDT (α and β; N=898) was 11.3 g/dL (11.5 g/dL for α-NTDT; N=400). In the NTDT group, 4.1% had at least 1 transfusion in first 12 months of follow up (3.6% had 1-3 transfusions and 0.5% had 4-7). For all patients with NTDT, with each 1 g/dL decrease in Hb, the number of IP admissions increased by 17%, OP visits by 8%, and ER visits by 11% (all p<0.001). For patients with α-NTDT, with each 1 g/dL decrease in Hb, the number of IP admissions increased by 15%, OP visits by 6%, and ER visits by 16% (all p<0.01; Table 1). Regarding costs for all patients with NTDT, with each 1 g/dL decrease in Hb, total healthcare costs increased by 15% (p<0.001), IP costs by 56% (p<0.001), OP costs by 12% (p<0.001), ER costs by 20% (p<0.003), and prescription costs by 12% (p=0.061). For patients with α-NTDT, with each 1 g/dL decrease in Hb, total healthcare costs increased by 14% (p<0.001), IP costs by 47% (p<0.001), OP costs by 10% (p<0.001), ER costs by 30% (p<0.003), and prescription costs by 9% (p=0.322). It is possible that because of incorrect/incomplete coding, some patients with thalassemia minor may have been included in the analyses, which may account for the higher-than-expected Hb levels in the NTDT cohorts. This may, in turn, underestimate the impact of Hb level on HCRU and costs. Conclusion: In this study, each 1 g/dL decrease in Hb was associated with significantly higher HCRU and costs. This association was seen in both the NTDT group and α-NTDT subgroup suggesting that both α-NTDT and β-NTDT experience this burden. This analysis indicates that raising Hb levels in patients with both α- and β-NTDT could result in reduced HCRU and costs.

Quality of Life Analysis in Patients with AA Using the QLQ-AA/PNH-54 at Initial Diagnosis of AA - a Registry Based Analysis

Objectives: Aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are ultra-rare, acquired bone marrow failure syndromes (BMFS) with need for long-term care and high morbidity despite recent therapeutic advances. There is a lack of disease-specific assessment tools of quality of life (QoL) in AA/PNH patients. So far, QoL has mostly been estimated according to surrogate parameters (e.g. blood counts, transfusion dependence or toxicity of treatment in AA patients) or has been assessed with tools specifically designed for cancer patients (e.g. EORTC Quality of Life Questionnaire QLQ-C30) or with tools focusing on fatigue (e.g. Functional Assessment of Chronic Illness Therapy, FACIT-Fatigue, PNH patients). Therefore, the QLQ-AA/PNH-54 has been developed to allow a patient tailored QoL assessment in patients with AA or PNH. Here, we present the first descriptive data of the QLQ-AA/PNH-54 of 74 AA patients at the timepoint of initial diagnosis collected between 2018 and 2020 (prior to the SARS-CoV-2 pandemic). Methods: The QLQ-AA/PNH-54 was designed, psychometrically validated, and is currently finally validated for PNH within the IPIG (international PNH interest group)-registry. Parallel to this process, the tool was implemented within the Aachen AA/BMF registry as an instrument for real-life QoL evaluation in AA patients. In total, 54 QoL items regarding physical functioning (21 items), psychological aspects (26 items) and health care related issues (7 items) are comprised. Patients rank the occurrence of each item within the last 14 days on a scale between 0 and 3 (0 = did not occur, 1 = low, 2 = moderate, 3 = severe). Results: 74 AA patients (37 female/ 37 male, mean/median/range age 38.42/ 35.47/ 11-73 years) were included. Patients were diagnosed with nsAA (n=11), sAA (n=23), vsAA (n=18), AA NOS (n=20) and AA/PNH-Overlap (n=2), respectively. Broken down into different functional scales, the most frequently and highest rated scales concerned psychosocial aspects (> 60 % of the patients scored 1-3; > 30% of the patients scored 3). Patients were especially burdened by worries and uncertainties with regards to their future, activity planning security and need for cautiousness in everyday life. Tiredness was the major symptom reported in relation to physical functioning. Patients often feared deterioration of their blood results as the most important health care-related issue. In comparison, low occurrence of pain, orthostatic dysregulation, susceptibility for infections, dyspnea, sleep disturbance and tendency to bleed was reported regarding physical functioning (scored 0 by over 40 to over 50 % of the patients). Similarly, low scores were reported for impairment of activities of daily life in terms of completion of household tasks and hobbies or loss of physical attraction. Conclusion: QoL of AA patients at initial diagnosis was mainly impaired by tiredness and a high psychological burden. Interestingly, complications frequently feared and highlighted by treating physicians had a minor impact on patients' QoL. These results emphasize the importance of further QoL analysis from patient view and recommend to especially focus on the psychological burden of AA patients in patient communication at initial diagnosis.