Red Blood Cell Transfusion Requirements Research Articles

Outcomes after lung transplantation performed using elective cardiopulmonary bypass: A single-center experience

PurposeThere remains significant variability in the use of intraoperative mechanical circulatory support in lung transplantation. This report details our outcomes using elective CPB in lung transplantation. MethodsWe performed a single institution analysis of consecutively enrolled patients who underwent isolated lung transplantation between August 2020 and April 2023. Primary outcomes included rates of grade 3 PGD and one-year survival. Results40 consecutive lung transplants were performed on CBP over the study period. The average PaO2/FiO2 at 72 hours was 369.7+121.4, with grade 3 PGD occurring in two patients (5%). The median intra-operative packed red blood cell transfusion requirement was 300 (93.75-727.5) mL. Freedom from non-elective re-operation was 82.5% (n=33). Mortality was 0% at 90-days, and one-year survival was 90.5%. ConclusionLung transplantation can be safely performed with elective CPB support.

Impact of anemia requiring transfusion or erythropoiesis-stimulating agents on new-onset cardiovascular events and mortality after continuous renal replacement therapy

Anemia is common in critically ill patients undergoing continuous renal replacement therapy (CRRT). We investigated the impact of anemia requiring red blood cell (RBC) transfusion or erythropoiesis-stimulating agents (ESAs) on patient outcomes after hospital discharge in critically ill patients with acute kidney injury (AKI) requiring CRRT. In this retrospective cohort study using the Health Insurance Review and Assessment database of South Korea, 10,923 adult patients who received CRRT for 3 days or more between 2010 and 2019 and discharged alive were included. Anemia was defined as the need for RBC transfusion or ESAs. Outcomes included cardiovascular events (CVEs) and all-cause mortality after discharge. The anemia group showed a tendency to be older with more females and had more comorbidities compared to the control group. Anemia was not associated with an increased risk of CVEs (adjusted hazard ratio [aHR]: 1.05; 95% confidence interval [CI]: 0.85–1.29), but was associated with an increased risk of all-cause mortality (aHR: 1.41; 95% CI 1.30–1.53). For critically ill patients with AKI requiring CRRT, anemia, defined as requirement for RBC transfusion or ESAs, may increase the long-term risk of all-cause mortality.

A155 METASTATIC EPITHELIOID ANGIOSARCOMA AND RECURRENT GASTROINTESTINAL BLEEDING: A CASE REPORT

Abstract Background Angiosarcomas are aggressive tumors of the vascular endothelium that represent less than 3% of all sarcomas. Epithelioid angiosarcomas are a distinct subtype, and in exceedingly rare circumstances can involve the gastrointestinal tract leading to significant bleeding. Aims Report a case of metastatic epithelioid angiosarcoma as a cause of recurrent gastrointestinal bleeding and the utility of endoscopy in obtaining a diagnosis. Methods A retrospective case report. Results A 71 year old female with a history of type two diabetes and coronary artery disease presented to a peripheral hospital with a two week history of fatigue, abdominal pain, and intermittent fevers for which she was diagnosed with pyelonephritis. Computed tomography (CT) scan of the abdomen/pelvis was unremarkable on admission. Her stay was complicated by cardiac ischemia prompting the initiation of dual antiplatelet therapy and anticoagulation. After a few days she developed melena and an acute hemoglobin drop requiring red blood cell (RBC) transfusion. Gastroscopy revealed a few superficial erosions in the stomach and duodenum. She went on to develop hypercalcemia prompting a repeat CT abdomen/pelvis which showed multiple lytic bone lesions, innumerable small lung nodules, and areas of hypoattenuation in the liver. Contrast enhanced MRI abdomen was performed to better assess the liver, showing a geographic area of signal abnormality without mass like features. The patient was transferred to a tertiary centre for ongoing work-up and management. Shortly after arrival, a bone biopsy from a lytic lesion of the iliac crest was taken. Initial histopathology was inconclusive for malignancy. During this time, she had ongoing melena and need for intermittent RBC transfusions. Enteroscopy revealed multiple centrally ulcerated, hemorrhagic, erythematous/purpuric lesions throughout the stomach and proximal small bowel (Figure 1a). A duodenal lesion with fresh clot was clipped and multiple biopsies were taken from the stomach and duodenum. Histopathology from a gastric biopsy confirmed the diagnosis of epithelioid angiosarcoma (Figure 1b). PET scan revealed uptake in bone, lungs, and liver. The patient received 1 cycle of palliative chemoradiation, however this was discontinued due to frailty. Overt bleeding and intermittent RBC transfusions continued. The patient was transferred to full comfort care and died within 4 months of initial presentation to hospital. Conclusions Epithelioid angiosarcoma involving the gastrointestinal tract should be considered as a cause for upper gastrointestinal bleeding. Our case highlights the endoscopic characteristics and the importance of endoscopic biopsy in obtaining a histopathologic diagnosis. Figure 1a. Enteroscopy showing metastatic angiosarcoma to the stomach and small bowel. A. Gastroesophageal junction; B. Cardia and fundus; C. Duodenal bulb; D. Second portion of duodenum. Figure 1b. Metastatic epithelioid angiosarcoma to the stomach. A-B. Low and medium power H&E; C. Cytokeratin AE1/3; D. Ber-EP4; E. CD31; F. ERG. Funding Agencies None

A Novel Scoring System Predicting Red Blood Cell Transfusion Requirements in Patients Undergoing Invasive Spine Surgery.

Background: Access to blood products is crucial for patient safety during the perioperative course. However, reduced donations and seasonally occurring blood shortages pose a significant challenge to the healthcare system, with surgeries being postponed. The German Blood Transfusion act requires that RBC packages become assigned to an individual patient, resulting in a significant reduction in the available blood products, further aggravating shortages. We aimed to develop a scoring system predicting transfusion probability in patients undergoing spine surgery to reduce assignment and, thus, increase the availability of blood products. Methods: The medical records of 252 patients who underwent spine surgery were evaluated and 18 potential predictors for RBC transfusion were tested to construct a logistic-regression-based predictive scoring system for blood transfusion in patients undergoing spine surgery. Results: The variables found to be the most important included the type of surgery, vertebral body replacement, number of stages, and pre-operative Hb concentration, indicating that surgical specification and the extent of the surgical procedure were more influential than the pre-existing patient condition and medication. Conclusions: Our model showed a good discrimination ability with an average AUC [min, max] of 0.87 [0.6, 0.97] and internal validation with a similar AUC of 0.84 [0.66, 0.97]. In summary, we developed a scoring system to forecast patients' perioperative transfusion needs when undergoing spine surgery using pre-operative predictors, potentially reducing the need for RBC allocation and, thus, resulting in an increased availability of this valuable resource.

Fewer severe infections with tranexamic acid in patients with hematologic malignancies

BackgroundTranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty. ObjectivesTo address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies. MethodsWe performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901). ResultsTXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease. ConclusionPatients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.

Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients.

Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo-HSCT) had inferior overall survival (OS). This single-center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long-term outcomes after allo-HSCT through multivariate analyses. A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011-2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1-18 units) or PLT (98.2% transfused, median 6, range 1-144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8-60.3%) and 86.1% (95% CI: 83.2-88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow-up among survivors (n = 307) was 7.1 years (range: 2.7-11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5-year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49-2.25), leukemia-free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43-2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45-2.89) (p < .001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p = .34) or PLT (p = .64) transfusion independence. Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non-relapse complications.

Early Treatment of Acetabular Fractures via an Anterior Approach Increases Blood Loss but not Packed Red Blood Cell Transfusion.

To determine if time from hospital admission to surgery for acetabular fractures using an anterior intrapelvic (AIP) approach affected blood loss. Multicenter retrospective study. Three level 1 trauma centers at 2 academic institutions. 195 adult (age >18) patients with adequate records to complete analysis and no pre-existing coagulopathy. AIP approach without other significant same day procedures (irrigation and debridement and external fixation were the only other allowed procedures). Multiple methods for evaluating blood loss were investigated, including estimated blood loss (EBL), calculated blood loss (CBL), and packed red blood cell (PRBC) transfusion requirement. On continuous linear analysis, increasing time from admission to surgery was significantly associated with decreasing CBL at 24 hours (-1.45 mL per hour by Gross, p=0.003; -0.440 g of Hgb per hour by Hgb balance, p=0.003) and 3 days (-1.69 mL per hour by Gross, p=0.013; -0.497 g of Hgb per hour by Hgb balance, p=0.010) postoperative, but not EBL or PRBC transfusion. Using 48-hours from admission to surgery to define early versus delayed, blood loss was significantly greater in the early group compared to delayed [453 (IQR 277-733) mL early versus 364 (IQR 160-661) delayed by Gross, p=0.017; 165 (IQR 99-249) g early versus 143 (IQR 55-238) g delayed by Hgb balance, p=0.035], but not EBL or PRBC transfusion. Additionally, in multivariate linear regression, neither giving tranexamic acid nor administering prophylactic anticoagulation for venous thromboembolism on the morning of surgery affected blood loss at 24 hours or 3 days postoperative. There is higher blood loss with early surgery using an AIP approach, but early surgery did not affect PRBC transfusion and may not be clinically relevant. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Development of a Risk Assessment Model for Predicting Red Blood Cell Transfusion in Neonatal Patients.

The goal was to develop a risk assessment model for predicting red blood cell (RBC) transfusion in neonatal patients to assist hospital blood supply departments in providing small portions of RBCs to those requiring RBC transfusion on time. Clinical information was collected from 1,201 children admitted to the neonatal unit. Clinical factors associated with predicting RBC transfusion were screened, and prediction models were developed using stepwise and multifactorial logistic regression analyses, followed by the evaluation of prediction models using receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). Overall, 81 neonatal patients were transfused with RBCs, and the variables of gestational age at birth, age < 1 month, receipt of mechanical ventilation, and infant anemia were included in the final prediction model. The area under the curve of the prediction model was 0.936 (0.921 - 0.949), which was significantly higher than that of the individual indicators of gestational age at birth, age at admission < 1 month, receipt of mechanical ventilation, and infant anemia (p < 0.001). DCA showed a standardized net benefit for the possible risk of infant RBC transfusion at 0.1 - 1.0. We developed a risk assessment model to predict the risk of RBC transfusion in neonatal patients that can effectively assess the risk of RBC transfusion in children.

Efficacy of Radiotherapy for Hemostasis in Tumor-Related Bleeding

Introduction: Hemorrhage is a common complication of malignancy. When undergoing invasion and angiogenesis, malignancies can produce highly vascular lesions with friable and disorganized vessels that are prone to bleeding (Hughes and Radhakrishna, Br J Hosp Med (Lond), 2019). Among patients with advanced cancer, around 10% have bleeding symptoms, which can impact both the quality and quantity of life (Katano and Yamashita, Cureus, 2021). Palliative radiotherapy (RT) has been associated with achieving hemostasis in a variety of bleeding malignancies, including gastric, bladder, lung, and gynecologic cancers. The goal of this study was to better determine the efficacy of radiotherapy in reducing transfusion requirements. Methods: A retrospective chart review of patients was performed after IRB approval. Patients who received radiation for controlling malignancy-associated hemorrhage were included in this study. The outcome measure was change in red blood cell (RBC) transfusion requirements from the month prior to the month following palliative RT. Data was obtained from the institution's electronic medical record. Change in transfusion requirements was analyzed using Welch's t-test and bleeding recurrence was analyzed using the exact test of goodness-of-fit. Results: A total of 6002 patients were screened and 30 cases (63.3% female, average age at radiation treatment 62 years) were included in the study with RT treatment dates 2019-2023. Sixteen malignancy types were represented, with pancreatic adenocarcinoma and endometrial adenocarcinoma being the most common (both 4, 13.3%). Median radiation dose was 13 Gy (range 3-30) delivered over a median of 3.5 fractions (range 1-10). Bleeding was not noted to recur in 73.3% of the cases ( P = 0.02). For those patients with recurrent bleeding, median time from RT to recurrent bleeding was 58 days (range 11-544). Transfusion requirements decreased from an average of 2.7 RBC units over one month prior to completion of RT to 1.1 units for the month following completion of RT ( P = 0.03). Median survival after completion of RT was 132 days (range 3-698). Conclusion: This study showed that radiation therapy resulted in apparent cessation of hemorrhage in over 70% of cases of hemorrhagic malignancies with a significant decrease in RBC transfusion requirements over one month. This suggests that RT is effective in stopping hemorrhage in a variety of malignancies as well as reducing transfusion requirements. More work is needed to test this hypothesis on larger populations, as well as investigation on the mechanism by which RT results in hemostasis.

Real-World Retrospective Study of Non-Transfusion Dependent Patients with Myelodysplastic Syndromes Treated with Luspatercept: A Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are common hematologic malignancies in older adults that are characterized by abnormal bone marrow function leading to reduced blood cell production, persistent cytopenias, with a risk that patients may progress to acute myeloid leukemia (AML). Due to the high rate of anemia, many patients with MDS require red blood cell transfusions (RBCT), which, in turn, are associated with a high clinical and economic burden. In the phase 3 randomized COMMANDS and MEDALIST clinical trials, luspatercept reduced the severity of anemia among transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)-refractory and ESA-naive patients with lower-risk (LR)-MDS (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736(23)00874-7, Fenaux P, et al. N Engl J Med 2020;382:140-151). However, there are limited real-world data on the use of luspatercept in patients who are non-transfusion dependent (NTD) or have a low transfusion burden. This study aims to describe the real-world clinical outcomes and treatment patterns before and after the initiation of luspatercept in patients with LR-MDS who were NTD before luspatercept initiation, in the USA. Methods:In this retrospective claims-based cohort study, data from the Symphony Health database (Jan 1, 2010 to June 30, 2022) were used to identify adults with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Patients were considered NTD if they had no unique dates with a claim for RBCT during the 8-week period before or on the index date. Patients were excluded if they received chemotherapy or had a diagnosis of refractory anemia with excess blasts or AML during the study period, as they were presumed to have higher-risk MDS. Patients were also excluded if they had a diagnosis of β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months pre-index (baseline period) or prior use of hypomethylating agents (HMAs). Patient demographics and clinical characteristics were assessed during the baseline period, and patients' RBCT status (NTD or TD) was measured for 6 months after the index date. A patient was considered 8-week NTD if they had no RBCT in ≥ 1 rolling 8-week period; 12-week, 16-week, and 24-week NTD patients were defined similarly, using increasing durations of NTD. Administration of other MDS therapies (ie, chemotherapy, ESA, granulocyte colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD ®] agent) was measured pre-index and post-index until the end of clinical activity or data availability (follow-up). Results: Of the 871 eligible patients who received luspatercept 589 (67.6%) were NTD before luspatercept initiation. Among this NTD population, the mean (standard deviation [SD]) age was 74.7 (6.3) years and 57.2% were male. Before luspatercept initiation, 15.3% of patients received 2 treatment classes and 0.8% received ≥ 3 treatment classes. Almost all patients (98.5%) maintained 8-week NTD status in the 6 months after luspatercept initiation. Similarly, 96.8%, 94.1%, and 88.6% of patients maintained NTD status for at least 12, 16, and 24 weeks in the 6 months after luspatercept initiation, respectively (Figure 1). Most patients (64.7%) did not require any additional MDS-related treatments during the study follow-up period, (median [SD] 15.7 [7.4] months). Overall, 77.1% of patients were treated with luspatercept for &amp;gt; 6 months and 68.4% for &amp;gt; 12 months. After luspatercept initiation, patients most commonly received treatment with ESAs or HMAs (14.9%; Figure 2). Conclusion:This is the first real-world evidence study to address luspatercept treatment in patients who were NTD prior to luspatercept treatment, which resulted in positive clinical outcomes and few RBCTs.Almost all patients with LR-MDS who were NTD at luspatercept initiation maintained 8-week NTD status during the 6 months after luspatercept initiation. The majority of patients did not receive a RBCT for a 24-week period after luspatercept initiation. Finally, over three-quarters of the patients remained on luspatercept and two-thirds of patients did not receive additional MDS-related treatments after a median follow-up of 15.7 months.

Clinical Effectiveness and Safety of Momelotinib Compared with Continued Ruxolitinib or Best Available Therapy in Patients with Myelofibrosis Who Required RBC Transfusions: Subgroup Analysis of the Phase 3 Simplify-2 Study

Introduction: Splenomegaly, constitutional symptoms, and anemia are key clinical features of myelofibrosis (MF); approximately one-third of patients (pts) are anemic at diagnosis, and most develop anemia over time. While Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) and fedratinib (FED) may address symptoms and splenomegaly, they do not manage and may exacerbate anemia. Treatments for anemia include erythropoiesis-stimulating agents (ESAs), often in combination with RUX or FED, and androgens such as danazol; however, these have shown limited efficacy. Red blood cell (RBC) transfusions are the mainstay of anemia management in MF, but transfusion dependency is associated with diminished quality of life and is a negative prognostic factor for survival. Treatments that address anemia as well as spleen volume and symptoms are needed. Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms in pts with MF across 3 phase 3 trials. To evaluate outcomes in pts who switched to MMB vs continuing RUX or best available therapy (BAT) despite transfusion requirement, we present a descriptive subgroup analysis of pts enrolled in SIMPLIFY-2 (NCT02101268) who were considered transfusion dependent (TD; ≥4 units of RBC transfusions in the previous 8 wk or hemoglobin [Hb] level &amp;lt;8 g/dL) or transfusion requiring (TR; receiving transfusions but not meeting TD criteria) at baseline (BL). Methods: SIMPLIFY-2 was an international, multicenter, open-label, phase 3 clinical trial investigating the efficacy and safety of MMB vs BAT in pts with MF who had suboptimal responses or hematologic toxicities while receiving RUX. Pts (N=156) were randomized 2:1 to receive open-label MMB or BAT, which was RUX in 88.5% of pts. Treatment washout from prior RUX was not permitted before study enrollment. The primary endpoint was spleen volume reduction ≥35% (SVR35). Total Symptom Score (TSS) response rate (≥50% reduction; TSS50) and transfusion independence response (TI-R; no RBC transfusions for ≥12 wk immediately before the end of wk 24, with all Hb levels ≥8 g/dL) were key secondary endpoints. This post hoc, descriptive analysis focused on pts treated with either MMB or BAT, who were considered non-transfusion-independent (non-TI), defined as either TD or TR, at BL. Results: In SIMPLIFY-2, 72 of 104 pts (69%) in the MMB arm and 33 of 52 pts (63%) in the BAT arm were non-TI at BL, and BL characteristics were balanced between both patient groups. Mean duration of prior treatment with RUX was 64.6 and 59.5 wk in non-TI pts in the MMB and RUX arms, respectively. Average BL TSS for this subpopulation was 18.6. All pts randomized to the MMB arm received a starting dose of 200 mg daily. In the BAT arm, 29 of 33 pts (88%) were treated with RUX, with 59% receiving a BL dose of ≤20 mg daily. ESAs were administered to 5 pts in the BAT arm. At wk 24, SVR35 was observed in 7 of 72 pts (10%) treated with MMB and 1 of 33 pts (3%) treated with BAT. TSS50 was achieved in 21 of 72 pts (29%) treated with MMB, but there were no responses in the BAT arm. Additionally, TI-R was achieved in 25 of 72 pts (35%) treated with MMB compared with only 1 of 33 (3%) treated in the BAT arm on RUX. Many responders with MMB achieved 2 or all 3 endpoints (16 of 36 responders [44%]) (Figure); there were no dual or triple responses in the BAT arm. Of the 5 pts in the BAT arm who received ESAs, only 1 pt each (different pts per response) achieved SVR35, TSS50, or TI. Safety outcomes were consistent with those previously reported for the intent-to-treat (ITT) population. Conclusions: In RUX/BAT-treated pts with MF who required RBC transfusions, continued treatment with RUX/BAT in most pts resulted in poor treatment outcomes compared with MMB. Specifically, treatment with MMB demonstrated an ability to deliver higher SVR, TI, and TSS response rates. The lower SVR35 rate in both arms, similar to the overall ITT population, was likely a result of lack of washout from prior JAK inhibitor treatment. While pt numbers were limited, similar findings were observed compared with pts who received ESAs. Overall, these data support MMB as a potential alternative treatment option for pts with MF who require RBC transfusions. Figure. Responses at Week 24 for Non-TI Patients at Baseline

Retrospective Analysis of the Relationship between Transfusion Independence and Bone Marrow Fibrosis Reduction in Patients with Myelofibrosis Treated with Pacritinib Versus Ruxolitinib

Background Pacritinib is a JAK1-sparing JAK2/IRAK1/ACVR1 inhibitor for treatment of myelofibrosis (MF). In addition to improving spleen volume and symptoms, pacritinib is associated with anemia benefit in MF patients. Recent in vivo studies have shown that dual JAK2/IRAK1 inhibition is associated with improvement in both cytopenias and bone marrow reticulin fibrosis (BMF) in an inflammation-driven murine MF model ( Cuenca Zamora E, et al. EHA 2023; P987 and P990). Here, we retrospectively analyzed the relationship between achieving transfusion independence and reduction in BMF in MF patients treated with pacritinib 200 mg twice daily (BID) vs ruxolitinib (RUX) on the phase 3 PERSIST-2 study. Methods: PERSIST-2 enrolled patients with platelet counts ≤100 x 10 9/L. This analysis focused on pacritinib 200 mg BID and on patients who received RUX as best available therapy (BAT) who enrolled ≥12 weeks prior to study termination and who required red blood cell (RBC) transfusions at baseline. The proportion of patients who achieved transfusion independence response (TI-R, any 12-week interval with no RBC transfusions) was ascertained for pacritinib vs RUX. The proportion of patients with BMF reduction (≥1 grade decrease in reticulin fibrosis from baseline at week 24) was reported among patients on pacritinib achieving TI-R vs. non-response (NR). Results: The analysis included 41 patients on pacritinib (median dose intensity 100% through week 24) and 18 on RUX (median daily dose 10mg at week 24). Baseline characteristics were similar between the groups, including median platelet count (41 vs 38 x 10 9/L) and median hemoglobin (8.7 vs 8.6 g/dL). All patients required RBC transfusion at baseline. A significantly greater proportion of patients treated with pacritinib vs RUX achieved TI through week 24: 37% (n=15/41) vs 6% (n=1/18), P=0.023. Nominally, this trend held for those with baseline platelets &amp;lt;50 x 10 9/L: 28% vs 8%, P=0.222. In addition, a greater percentage achieved a 50% reduction in RBC transfusions over any 12 weeks (49% vs 6%, P=0.001). Paired bone marrow assessments at baseline and week 24 were available for 18/41 of patients on pacritinib, of whom 44% (8/18) achieved TI-R on study. The proportion of patients who experienced BMF reduction (&amp;gt;=1 grade at any point) was significantly greater among TI-R (62.5%, n=5/8) compared to TI-NR (10%, n=1/10) on pacritinib ( P=0.043). Of the 5 patients who achieved TI-R and BMF reduction, all had grade 2-3 fibrosis at baseline, and 2 experienced a reduction from grade 3 to grade 1 ( Figure 1). By contrast, paired bone marrow biopsies were available for 5 patients on RUX, and there was no association between fibrosis reduction in TI-R (0%, n=0/1) and TI-NR (25%, n=1/4). Conclusions: In cytopenic MF patients from PERSIST-2, TI-R on pacritinib was associated with BMF improvement. Though these results are based on a small sample size, they contrast with recent data suggesting no correlation between BMF reduction and TI-R on the JAK1/2 inhibitors momelotinib and ruxolitinib ( Oh ST, et al. Blood 2022;140 (Supp 1):821-23). While differences in study design could have impacted these results, these findings suggest that distinct inhibitory profiles may further distinguish the clinical impact of these treatments. Further studies are warranted to confirm the relationship between BMF reduction and anemia benefit in patients treated with pacritinib. Study funded by CTI BioPharma Corp., a Sobi company

Clinical Parameters, Anemia, and Spleen Response in Patients with MF-Related Anemia Treated with Luspatercept: Efficacy Sub-Analysis from the ACE-536-MF-001 Study

Introduction: Approximately 24% of patients with myelofibrosis (MF) have anemia requiring red blood cell (RBC) transfusion at initial diagnosis. For patients with MF, chronic anemia and RBC transfusion dependence (TD) often increase throughout the disease course and are an indicator of poor prognosis. Luspatercept (LUSPA) is an erythroid maturation agent approved to treat anemia in adults with β-thalassemia and myelodysplastic syndrome requiring RBC transfusions. Primary results from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated reductions in MF-related anemia and transfusion dependence (Gerds et al. ASCO 2023 7016). Here we provide an extended analysis of the impact of LUSPA on clinical parameters and transfusion burden over time, and associated management of MF disease symptoms. Methods: Patients were enrolled into cohorts based on TD and ruxolitinib (RUX) treatment. Patients received LUSPA 1.0 mg/kg subcutaneously (with titration up to 1.75 mg/kg), administered on day 1 of each 21-day cycle (starting dose was 1.33 mg/kg for cohort 3B expansion). Patients were defined as TD if receiving an average of 4-12 RBC units/84 days immediately up to cycle 1 day 1 (C1D1). For non-transfusion dependent (NTD) patients, anemia was defined as 3 or more hemoglobin (Hgb) level measurements of ≤ 9.5 g/dL recorded on at least 3 different days in the 84-day period immediately preceding C1D1. The primary endpoint was anemia response, assessed at day 169 (week 24) and defined as 84 consecutive days without RBC transfusion for TD patients, and 84 consecutive days with Hgb increase of ≥ 1.5 g/dL from baseline without transfusion for NTD patients. Treatment was extended if clinical benefit was observed at day 169. Secondary and exploratory endpoints included anemia response for the entire treatment period, transfusion burden, and clinical and laboratory parameters. Results: A total of 95 patients were enrolled: cohort 1 (NTD, no RUX, n = 22), cohort 2 (TD, no RUX, n = 21), cohort 3A (NTD, RUX, n = 14), and cohort 3B (TD, RUX, n = 38). A total of 63 (66.3%) patients continued to the follow-up period. The mean (SD)/median (range) duration of treatment was 42.8 (47.6)/24.0 (2.0-232.0) weeks and mean/median (range) follow-up duration after first dose was 101.1/78.0 (2.1-232.1) weeks. Anemia response was seen across all cohorts. Among transfusion-dependent patients (cohorts 2 and 3B), transfusion independence ≥ 12 weeks was observed in 4 (19.0%, 95% CI 5.45-41.91) and 12 (31.6%, 95% CI 17.5-48.7) patients, respectively, in the entire treatment period. Additionally, approximately half of patients with TD achieved a 50% reduction in transfusion burden; 10 (47.6%) patients in cohort 2 and 20 (52.6%) patients in cohort 3B had ≥ 50% reduction in transfusion burden over any 84-day period in the entire treatment period, including 16 patients from cohorts 2 and 3B who achieved transfusion independence (100% reduction) (Figure). Changes in laboratory parameters of Hgb, serum erythropoietin, serum ferritin, and platelet count at day 169 are summarized in the Table; in addition, patients with clinical benefit continuing LUSPA treatment after day 169 showed ferritin decreases with longer follow-up from cycle 13 (n = 20) to cycle 33 (n = 6). Additionally, there was minimal (~1 cm) to no increase in median spleen size across patients in all cohorts. Of the 3 patients in cohort 3B who increased their RUX dose during LUSPA treatment, spleen size remained stable, with a -4.0 cm, 1.0 cm, and 3.0 cm change from baseline during the entire treatment period, respectively. Conclusions: In the phase 2 ACE-536-MF-001 study, LUSPA demonstrated improvements in anemia and transfusion burden in patients with MF. Further analysis of clinical and laboratory parameters may reveal differences between responders and non-responders. Spleen size stability was observed in all patients; this suggests that LUSPA does not worsen splenomegaly and may support continual use of RUX for MF disease and symptoms. Study support: Bristol Myers Squibb.

Impact of Symptom Benefit and Transfusion Response on Survival in Myelofibrosis Patients Treated with Pacritinib: PERSIST-2 Landmark Survival Analysis

Background: Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated symptom benefit measured by TSS (v2.0, excluding tiredness) vs best available therapy (BAT) in PERSIST-2, which enrolled cytopenic myelofibrosis patients with platelets ≤100×10 9/L. Recent datashowed that in patients with cytopenic MF, a ≥10% reduction in spleen volume at 12 weeks is associated with improved survival in patients treated with pacritinib ( Ajufo H, et al., J Clin Oncol;2023:14(16):Suppl). Surprisingly, this association was not confirmed in patients treated with BAT (82% of whom were on ruxolitinib). The association between other important measures of clinical benefit such as symptom burden reduction and anemia improvement on survival in patients treated with pacritinib has not previously been described. Methods: Patients randomized to pacritinib 200 mg BID and to BAT on PERSIST-2 were included if they were alive and on study at the start of the week 12 efficacy assessment period. Survival was assessed by Total Symptom Score (TSS; v2.0 excluding tiredness) reduction at various thresholds (≥50%, ≥20%, ≥10%, &amp;gt;0%) and transfusion independence (TI) response. TI was assessed among patients who required red blood cell (RBC) transfusion at baseline (within 90 days) and was defined, for the purposes of a landmark survival analysis, as the absence of RBC transfusions over any 12-week period from first dose through week 14 (allowing for a ±2-week window around week 12). Overall survival (OS) was estimated via the K-M method following the landmark approach; survival in responders vs non-responders was compared using the log-rank test. Results: Of the 59 patients treated with pacritinib who had a reduction of TSS≥10%, the median age was 67 years, 25% had a baseline high-risk DIPSS, median platelet count was 61 x10 9/L, median hemoglobin was 9.7 g/dL, and baseline TSS was 19.1. Reduction of TSS≥10% was associated with improved OS, with 1 death among 59 responders vs 4 deaths among 30 non-responders (hazard ratio [HR]=0.12, 95% confidence interval [CI]: 0.01, 0.79] P=0.021, Fig 1a). Similar to spleen volume reduction, the association between TSS response and OS weakened at more stringent TSS response thresholds (Fig 1c, e), with the BAT arm not showing an association between TSS response and OS at any threshold. (Fig 1b, d, f). In order to assess the relationship of specific TSS domains and survival , a landmark OS analysis was performed based on ≥20% reduction in physical function scores (sum of ‘tiredness’ and 'inactivity'), spleen-related symptom scores (sum of 'abdominal discomfort', ‘early satiety’, and 'left rib pain'), and cytokine-related symptom scores (sum of 'itching', ‘night sweats’, and ‘bone pain‘). For cytokine-related symptoms, the number of deaths in PAC responders was significantly different compared to non-responders, with 0 deaths among 35 responders vs 2 among 15 non-responders ( P=0.0325). Conversely the deaths among responders (2/22) vs non-responders (2/20) were not significantly different in the BAT arm. For the physical function and spleen-related symptom subscales, no significant differences between PAC responders and non-responders was observed (HR=0.60; 95% CI [0.05, 6.74] P=0.679) and (HR=0.26; 95% CI 0.02, 2.93, P=0.2435) respectively. Among 36 patients on PAC who received RBC transfusions at baseline, 7 achieved TI over at least a 12-week period up to the time of the landmark analysis. There were no deaths among TI responders compared to 2 (6.9%) among TI non-responders. There were too few TI responders on BAT (only 2 out of 38) to assess the impact on survival. Conclusion: In cytopenic myelofibrosis patients enrolled in PERSIST-2, having a reduction of TSS≥10% on full-dose PAC was associated with OS benefit - a finding that has not been noted with other JAK inhibitors to date. By contrast, this association was not found with BAT, (82% of these patients received ruxolitinib). Thus, reductions in TSS in patients treated with PAC were associated with an OS benefit. It is possible that pacritinib, with its distinctive mechanism of action, may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia, and further studies are required to understand the potential mechanisms of these distinct clinical observations. Study funded by CTI BioPharma Corp., a Sobi company.

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 &amp;lt; 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 &amp;lt; 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

RBC Exchange Transfusion As an Adjunct Therapy to Control Iron Overload in Patients with Transfusion-Dependent Thalassemia

Background Patients with transfusion-dependent thalassemia (TDT) require red blood cell (RBC) transfusions as frequently as every 2-4 weeks to maintain a pre-transfusion hemoglobin of 9.0-10.5 g/dL for patients without cardiac complications. Chronic RBC transfusions increase body iron stores leading to iron deposition in liver, pancreatic, and cardiac tissues. Deferoxamine, deferiprone, and deferasirox are the iron chelators currently licensed for clinical use to manage iron overload in TDT patients with side effects ranging from nausea to nephrotoxicity and hearing loss. RBC exchange transfusion (RBCX), particularly in conjunction with isovolumic hemodilution, has been utilized for patients with sickle cell disease as a means of stabilizing iron overload. The 2015 ASFA Red Blood Cell Exchange consensus supports RBCX to reduce or prevent iron overload in sickle cell disease. Review of literature shows that RBCX can be beneficial as an acute intervention for patients with TDT and pulmonary hypertension however there is a paucity of literature documenting chronic RBCX use in TDT patients with iron overload. Case series This series presents five patients with TDT who were transitioned from chronic simple RBC transfusions to chronic RBCX after developing treatment-refractory iron overload as evidenced by serum ferritin elevation. Patients were treated on a transfusion schedule with a pre-transfusion goal hemoglobin of 9.5g/dL or higher and interval 4-6 weeks. Patient A is a 14 year-old male who developed significant iron overload (peak ferritin of 7077) on deferasirox 20 mg/kg/day and MRI T2 imaging suggestive of iron deposition. After transition to RBCX, ferritin decreased significantly with a post-RBCX mean of 1382. Blood utilization was 4200 ml three months pre-RBCX and 5625 ml three months post-RBCX. Patient B is a 23 year-old male with a peak ferritin of 1310 prior to RBCX on 23 mg/kg/day of deferasirox complicated by mild hearing loss. Serum ferritin has shown stabilization, with a mean post-RBCX ferritin of 880. Blood utilization was 2400 ml three months pre-RBCX and 8100 ml three months post-RBCX. Patient C is a 17 year-old male with a peak ferritin of 1400 with deferasirox management complicated by acute renal injury. Mean serum ferritin of 633 post-RBCX. Blood utilization was 1200 ml three months pre-RBCX and 5200 ml three months post-RBCX. Patient D is a 17 year-old male managed on 23 mg/kg/day of deferasirox with a peak ferritin of 3060 on pre-RBCX. The patient transitioned to chronic RBCX with mean serum ferritin of 1073. Blood utilization was 1800 ml three months pre-RBCX and 7700 ml three months post-RBCX. Patient E is a 17 year-old male with peak ferritin of 3404 despite 20 mg/kg/day of deferasirox prior to chronic RBCX. Mean serum ferritin after transition to RBCX was found to be 1282. Blood utilization was 1500 ml three months pre-RBCX and 4900 ml three months post-RBCX. All 5 patients have tolerated RBC exchange procedures without complications. Serum ferritin levels pre- and post-RBC exchange were trended pre- and post- RBCX (Figure 1). Serum ferritins were averaged together for each patient to obtain an equal number of time points considered prior to and after starting RBCX therapy. Descriptive statistics (Table 1) were used to summarize average ferritin levels for the patient group. A Wilcoxon signed-rank test was performed to assess the median difference in ferritin level from pre-RBCX to post-RBCX. All analyses were conducted in SAS version 9.4. P &amp;lt;0.05 is considered statistically significant. Median pre-RBCX ferritin level for the study group is 2489.3 (Inter-quartile range (IQR): 1190.0, 2659.0). The median post-RBCX ferritin level for the series is 1329.3 (IQR: 941.0, 1711.0). After subtracting the post-RBCX ferritin level from the pre-RBCX ferritin level, the median change for the group is 457 (IQR: 249.0, 1160.0) (p=0.06). Conclusion This case series documents the successful clinical application of chronic RBCX in TDT patients as a means of stabilizing serum ferritin levels over time. Mean ferritin levels were significantly lower, clinically, after transitioning from chronic simple RBC transfusion to RBCX (Table 1), though analysis is limited due to cohort size. Blood utilization increased after transitioning to RBCX. Next steps in evaluating our practice for the patient group will be to evaluate iron deposition status with MRI T2* imaging.

Red Blood Cell Transfusion Independence Status Is an Independent Predictor of Survival: A Post Hoc Time-Dependent Analysis of the Phase 3 Simplify-1, Simplify-2, and Momentum Trials

Introduction: The management of anemia in myelofibrosis (MF), a chronic progressive myeloproliferative neoplasm, remains an ongoing medical need as it is present in approximately 30% of patients (pts) at diagnosis and &amp;gt;50% after 1 year, contributing to negative impacts such as fatigue, medical complications, and poor quality of life. Furthermore, anemia and resulting transfusion need are independent predictors of poor prognosis. Momelotinib (MMB) is a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 (ACVR1) inhibitor that has demonstrated spleen, symptom, and anemia benefits, including increases in hemoglobin (Hb) and reduction or elimination of red blood cell (RBC) transfusion requirements in pts with MF. Data from the phase 3 SIMPLIFY-1 (S1), SIMPLIFY-2 (S2), and MOMENTUM studies have shown an association between transfusion independence at wk 24 and prolonged overall survival (OS) with MMB (Mesa R, et al. Leukemia. 2022; Verstovsek S, et al. ASH 2022. Poster 3028). Because these analyses did not adjust for additional prognostic factors or effect modifiers nor potential longitudinal changes in transfusion status over time, the impact of transfusion status on OS has not been fully characterized. Here, we describe an analysis investigating the prognostic influence of RBC transfusion status over time and other covariates on OS from the S1 (NCT01969838), S2 (NCT02101268), and MOMENTUM (NCT04173494) studies irrespective of the treatment received. Methods: These treatment-agnostic OS analyses incorporated data from 3 multicenter, international, randomized trials investigating MMB vs an active comparator. Analyses were performed in the safety populations of S1 (N=430; MMB vs ruxolitinib [RUX], JAK inhibitor [JAKi] naive), S2 (N=156; MMB vs best available therapy [88.5% RUX], JAKi experienced), and MOMENTUM (N=195; MMB vs danazol, JAKi experienced). In the current analysis, which accounts for evaluations of transfusion status every 4 wk, time-dependent covariates (RBC transfusion status, categorized as either transfusion independent [TI; absence of RBC transfusion and no Hb level &amp;lt;8 g/dL in the prior 12 wk] or non-TI [not satisfying the criteria for TI]) and fixed baseline covariates (age, sex, MF subtype, Eastern Cooperative Oncology Group [ECOG] status, JAK2 mutational profile, Total Symptom Score, International Prognostic Scoring System [IPSS] score for S1, Dynamic IPSS [DIPSS] score for S2 and MOMENTUM, platelet count, baseline spleen volume as assessed by central reading of magnetic resonance imaging/computed tomography scan) were evaluated to determine their prognostic impact. An extended Cox model was used to generate an overall hazard ratio (HR) using all available follow-up time for each study, and independent variables were retained if a backward variable selection method determined that they were significantly associated with OS. Results: Significant covariates associated with survival across the 3 trials are presented in the table, with RBC transfusion status as a consistent prognostic variable. In S1, age, platelet count, and baseline spleen volume were also significantly associated with OS, and in S2, significant covariates included age, baseline spleen volume, and DIPSS. In MOMENTUM, only RBC transfusion status was significantly associated with survival. When accounting for differences in prognostic factors and effect modifiers as well as changes in transfusion status over time, results from MOMENTUM demonstrate a strong and significant relationship between transfusion status and OS (HR, 5.18; 95% CI, 1.86-14.47; P=.0017), suggesting that non-TI pts have a higher risk of all-cause mortality of more than 5 times that of TI pts. Similar results with respect to the survival benefits of TI status were observed in both S1 (HR, 3.32; 95% CI, 2.31-4.78; P&amp;lt;.0001) and S2 (HR, 1.87; 95% CI, 1.07-3.29; P=.0287). Conclusions: These data demonstrate that when accounting for differences in known prognostic factors and effect modifiers as well as changes in RBC transfusion status over time, a consistent and statistically significant relationship was observed between transfusion status and OS across all 3 phase 3 MMB trials. Consistent with inclusion of transfusion status in DIPSS-plus risk assessment, these data validate TI status as a clinically relevant and meaningful endpoint that is prognostic for survival in JAKi-naive and JAKi-experienced disease settings.

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period &amp;gt; 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

Longitudinal Assessment of Transfusion Intensity in Patients with JAK Inhibitor-Naive or -Experienced Myelofibrosis Treated with Momelotinib in the Phase 3 Simplify-1 and Momentum Trials

Introduction: Anemia is a cardinal feature of myelofibrosis (MF), along with splenomegaly and constitutional symptoms. Red blood cell (RBC) transfusions, often used to manage anemia in patients (pts) with MF, are a negative prognostic factor for overall survival and are associated with diminished quality of life and increased healthcare-related economic burden. Momelotinib (MMB), a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms. Prespecified anemia endpoints in MMB phase 3 studies prioritized achievement of a strict transfusion independence response, defined as no transfusions for ≥12 wk immediately before the end of wk 24, with all hemoglobin levels ≥8 g/dL. Longitudinal analysis of transfusion intensity (units per 28 days) in a phase 2 trial of MMB in pts with transfusion-dependent MF demonstrated a reduction in transfusion burden in most (85%) pts (Harrison C, et al. EHA 2023). Here, we further characterize the impact of MMB and comparators on transfusion burden in pts with JAK inhibitor-naive and -experienced MF from the phase 3 SIMPLIFY-1 and MOMENTUM trials. Methods: This analysis evaluated time-dependent transfusion burden in pts enrolled in the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials. SIMPLIFY-1 included pts with JAK inhibitor-naive MF randomized (1:1) to receive MMB or ruxolitinib (RUX). In MOMENTUM, pts with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score ≥10), anemic (hemoglobin &amp;lt;10 g/dL), JAK inhibitor-experienced MF were randomized (2:1) to receive MMB or danazol (DAN). All RBC units transfused were collected during the 24-wk randomized treatment period of each study and during the 84 days before receipt of randomized treatment on study for baseline assessment. Time-dependent transfusion burden was quantified by number of RBC units administered, in a tabular display of baseline- and treatment-period intensity. Pts were grouped jointly based on the baseline- and treatment-period intensity of RBC units per 28 days into ordinal bins: exactly zero units, &amp;gt;0 to 1 unit, &amp;gt;1 to 2 units, &amp;gt;2 to 3 units, &amp;gt;3 to 4 units, and &amp;gt;4 units. Results: In SIMPLIFY-1 (JAK inhibitor-naive pts), 150 of 213 evaluable pts (70%) in the MMB arm and 163 of 216 evaluable pts (76%) in the RUX arm required zero units of RBC transfusion per 28 days at baseline. Of pts who required zero units of transfusion at baseline, a higher proportion in the MMB arm (142 of 150 [95%]) maintained a requirement of zero RBC transfusions during randomized treatment of 24 wks vs the RUX arm (93 of 163 [57%]). Overall, the mean RBC transfusion burden per 28 days declined 0.10 units (SD, 0.701) from baseline to randomized treatment in the MMB arm and increased 0.39 units (SD, 1.016) in the RUX arm. Using ordinal bins, 87% of pts in the MMB arm maintained (144 [67.6%]) or improved (41 [19.2%]) RBC transfusion intensity during randomized treatment compared with baseline vs 54% in the RUX arm (maintained, 94 [43.5%]; improved, 23 [10.6%]) (Figure). In MOMENTUM (JAK inhibitor-experienced pts), most pts had some transfusion requirement at baseline, with 26 of 130 (20%) in the MMB arm and 11 of 65 (17%) in the DAN arm requiring zero units of RBC transfusion per 28 days. During randomized treatment, a higher proportion of pts in the MMB arm (46 of 130 [35%]) required zero units of RBC transfusion vs the DAN arm (11 of 65 [17%]), including a higher proportion of those who had zero RBC transfusion requirement at baseline who maintained zero RBC transfusion requirement during randomized treatment (MMB, 92%; DAN, 64%). The mean RBC transfusion burden per 28 days declined 0.86 units (SD, 1.748) from baseline to randomized treatment in the MMB arm and declined 0.28 units (SD, 1.584) in the DAN arm. Using ordinal bins, 85% of pts in the MMB arm maintained (25 [19.2%]) or improved (85 [65.4%]) RBC transfusion intensity compared with baseline vs 63% in the DAN arm (maintained, 7 [10.8%]; improved, 34 [52.3%]). Conclusions: These data demonstrate that MMB was associated with better maintenance of RBC transfusion intensity and zero RBC transfusion status vs RUX in pts with MF who were JAK inhibitor naive and showed greater reduction in RBC transfusion burden from baseline vs DAN in pts with MF who were JAK inhibitor experienced. Across both trials, ≥85% of pts treated with MMB maintained or improved transfusion intensity.

Interactions between Iron Overload, Oxidative Stress, and Somatic Mutations in Myelodysplastic Syndromes; Evidence from the Literature

Introduction: Somatic mutations (SM) are central to the pathophysiology of myelodyspastic syndromes (MDS). Iron overload (IOL) from transfusion of red blood cells (RBC) and the oxidative stress that results from the ability of iron to transfer electrons and undergo Fenton chemistry are common and are associated with adverse clinical endpoints (infections, cardiac events, exacerbation of bone marrow failure, event-free survival, progression-free survival, overall survival) in MDS. We reviewed the literature to elucidate what evidence is available indicating an interaction between iron, oxidative stress and specific SM in MDS. Methods: A series of PubMed searches were done including the key words of each specific mutation combined with iron, oxidative stress, and reactive oxygen species (ROS, a measure of oxidative stress), focusing on SM prevalent in MDS and/or included in the molecular International Prognostic Scoring System (IPSS-M; 31 mutations in all, including IPSS-M mutations and TET2). Citations relevant to hematopoietic stem and progenitor cells, cells of the hematopoietic microenvironment, and myeloid disorders were favoured for review. Mutations of familial predisposing conditions were also searched in combination with iron, oxidative stress and ROS. Results: Of 31 mutations found in the IPSS-M, an additional four mutations found in familial predisposing conditions (DDX41, GATA2, CHEK2, SAMD9) were searched as was TET2, for a total of 35 mutations. Fifty-four references were identified. Fifty-three references were preclinical/translational in nature, with one case report (WT1). The most frequent alterations in iron/ROS were with the SF3B1 mutation, with 11 citations. Thirteen of 31 (42%) of SM in combination with iron, oxidative stress/ROS had citations. Reports for combination with iron or oxidative stress/ROS, respectively, included early (TP53, IDH2, RUNX1, SF3B1, STAG2, TET2; and TP53, DNMT3A, IDH2, NPM1, U2AF1) and late (NRAS, CEBP3A; and CBL, NRAS) mutations. Both gain of function (TP53, IDH2, NRAS, SF3B1; and TP53, IDH2, NRAS, U2AF1) and loss of function (STAG2, TET2; and CBL) mutations had relevant citations identified. Cellular pathways affected included tumour suppressor (TP53 for both iron and oxidative stress/ROS), signal transduction (NRAS for both), splicing factors (SF3B1; U2AF1), DNA stability (STAG2) and (hypo) methylation (TET2; DNMT3A). There were reports of an impact at multiple levels on iron/ROS and cellular/systemic physiology in the context of SF3B1 mutation, for example: ERFE+12 (containing 12 additional nucleotides and translated to an ERFE protein containing 4 additional amino acids; 358 vs 354 in wild type) present in SF3B1 mutated MDS does like the usual ERFE suppress hepcidin, impacting iron at a systemic level; enzymes of iron, heme and iron sulfur cluster physiology are altered, impacting iron physiology at a cellular level; and mitochondrial ferritin sequesters iron, leading to cytoplasmic iron deficiency, lowering ROS and thus possibly protecting cells from oxidative damage. Table 1 shows examples of iron/ROS interactions with SF3B1, TET2, DNMT3A, U2AF1, STAG2, NRAS, TP53, IDH2, CBL, NPM, ETNK, PTPN11, WT1 and RUNX1. Figure 1 shows MDS pathophysiology and where interactions between SM and iron/oxidative stress/ROS may impact this pathophysiology. No investigations were identified relevant to the mutations of familial predisposing conditions, including DDX41, GATA2, CHEK2 and SAMD9 in combination with iron/oxidative stress/ROS. Discussion: Searching IOL, oxidative stress and ROS in combination with MDS somatic mutations uncovered information as to how iron/redox status may interact with SM to affect MDS pathophysiology. Of particular interest is the cytoplasmic iron deficiency induced in the presence of SF3B1 mutation, the only SM conferring favourable prognosis in MDS in the IPSS-M. Given the pleiotropic cellular, intracellular and subcellular mechanisms involved, investigation regarding when and how targeting iron overload by reducing RBC transfusion requirements, binding iron or attenuating ROS may alter cellular and clinical outcomes in the setting of specific somatic mutations is warranted.