Rates Of Transfusion Independence Research Articles

Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial

A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N=60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75mg/m2) or decitabine (20mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Efficacy and safety of roxadustat in the treatment of refractory non-severe aplastic anemia

Objective: To evaluate the efficacy and safety of roxadustat in patients with refractory non-severe aplastic anemia (NSAA) . Methods: The clinical data of patients with refractory NSAA who had been treated with roxadustat continuously for at least 3 months and followed up for more than 6 months at Peking Union Medical College Hospital from October 2020 to August 2022 were retrospectively collected. The demographic information, clinical data, treatment efficacy, adverse reactions, and outcomes were evaluated, and the factors influencing efficacy were analyzed. Results: A total of 41 patients were included. The male-to-female ratio was 16∶25, and the median age was 52 (18-84) years. The median duration of roxadustat treatment was 5 (3-20) months, and the median follow-up was 15 (6-26) months. Hematologic improvement-erythroid (HI-E) was 12.2%, 29.3%, 46.3%, 43.9%, and 30.3% at 1, 2, 3, 6, and 12 months, respectively. The rate of transfusion independence was 28.5%, 38.1%, and 33.3% at 3, 6, and 12 months, respectively. Hemoglobin returned to normal in some patients after treatment with roxadustat. The incidence of adverse events was 22%, all of which were grade Ⅰ-Ⅱ and recoverable. No factors that could affect HI-E were identified. By the end of follow-up, 45% of the patients relapsed, with a median time to relapse of 7 (3-12) months. No clonal evolution was observed, and one patient died. Conclusion: Roxadustat effectively improved anemia with good tolerance in patients with refractory NSAA.

Efficacy of Luspatercept in Low-Risk Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes (MDS) in whom erythropoiesis-stimulating agent therapy is not effective, inevitably become RBC-transfusion dependent, unless other lines of therapy are offered. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, has been FDA approved for use in MDS with ring sideroblasts (RS) and/or detection of an SF3B1 mutation. The efficacy of luspatercept in lower risk (LR) MDS (regardless of RS) patients has been evaluated in clinical and real-world (RWD) studies, suggesting conflicting data. OBJECTIVES This study aimed to conduct a systematic review and meta-analysis of clinical trials and RWD evidence to evaluate the efficacy of luspatercept among lower risk MDS patients. METHODS Prospective randomized controlled trials (RCTs) and phase II trials, retrospective cohort studies and case series of patients with MDS treated with single agent luspatercept were retrieved from PubMed, EMBASE and conference proceedings. References were screened until June 30 th 2023. Two reviewers appraised the quality of the studies and extracted data. Primary outcome was the rate of transfusion independence (for at least 8 weeks). Secondary outcomes included erythroid hematologic improvement (HI-e) rate and safety. Subgroup analysis was conducted for MDS-RS and SF3B1 mutation. Studies were critically appraised using Joanna-Briggs Institute checklists. All studies were included in the meta-analysis. RESULTS We screened 244 titles and eventually included 9 studies, conducted between 2013-2022, and including 839 MDS patients who were treated with luspatercept. Of them: 2 RCTs, one single arm phase 2, and 6 retrospective “real-world” (RWD) studies. Six were published in peer reviewed journals and three RWD studies published as abstracts. Median age of patients ranged between 68-75 years and 707/839 patients had MDS-RS. Three studies were of moderate-high quality (N= 389) and 6 were deemed moderate quality (N=450). Rates of transfusion independence for at least 8 weeks were highly variable ranged between 8-87% among all patients and between 42-87% among MDS-RS subgroup. The median duration of longest response ranged between 23.9-42 weeks. Rates of erythroid hematologic improvement (HI-e), ranged between 25-100%. Pooled estimate of achieving independence from red-cell transfusion for &amp;gt;= 8 weeks was 39.5% (95% CI 0.24, 0.55; I²=96.6%, p&amp;lt;0.001) by meta-analysis. Pooled estimate of HI-e was 54.4% (95% CI 0.44,0.65; I²=87.8%, p&amp;lt;0.001). The most common cause for drug discontinuation was lack or loss of response and disease progression. CONCLUSION The response rate to luspatercept is highly heterogenous among different studies. Overall, the response rate and duration in the RWD setting did not compare favorably with clinical trials. Of note, the vast majority of patients had MDS-RS and the role of luspatercept in the management of patients with MDS without RS is still unclear, even when data from several studies are pooled together. This study has many limitations arising from heterogeneity of patient characteristics and outcomes ascertainment. This highlights the need for standardized post-marketing studies of new drugs and the heterogeneity in RWD patient population.

A Phase 2 Study of Canakinumab in Patients with Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Background Myelodysplastic syndromes (MDS) lie on a continuum of myeloid neoplastic progression between clonal hematopoiesis (CH) and acute myeloid leukemia (AML). Interleukin 1 beta (IL-1β)-induced inflammasome activation is a mechanism of cancer initiation and progression. Given that IL-1β upregulation induces aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs), we hypothesize that IL-1β plays a critical role in MDS pathogenesis, and targeting IL-1β signaling will overcome aberrant MDS HSPCs' myeloid skewing. Here, we report final results of a phase 2 study evaluating the safety and efficacy of canakinumab, an IL-1β inhibitor, in patients with lower-risk MDS or chronic myelomonocytic leukemia (CMML). Methods We conducted a single center, open-label phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged ≥ 18 with IPSS-R ≤ 3.5 MDS/CMML who have previously been treated were included in the study. Patients received 300 mg of canakinumab on day 1 of a 4-week cycle. The primary objective was to determine the clinical activity of canakinumab in MDS/CMML patients. Response was assessed using the modified International Working Group 2006 criteria for MDS (Cheson et al. 2006). Secondary objectives were to evaluate the safety profile including rate of transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). All patients who received 1 dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov (NCT04239157). Findings Between August 2020 and May 2023, 27 patients were enrolled in the phase 2 portion of this study, and 2 patients failed screening. The median age was 74 years with 15 (60%) male patients; 20 patients (80%) were post-hypomethylating agent failure with a median number of prior lines of therapy of 2 (1-5). Transfusion dependency was observed in 24 patients (96%) prior to canakinumab initiation. Fourteen (56%) patients showed normal karyotype. IPSS-R stratification revealed an intermediate-2 risk in 12 (48%) patients and a high risk in one (4%). The most common mutations were SF3B1 (40%), TET2 (32%), DNMT3A (28%), and RUNX1 (24%). IPSS -M risk score was calculated for 24 cases showing one (4%) very low (VL), four (16%) low (L), 14 (16%) moderate low (ML), eight (32%) moderate high (MH), five (20%) high (H), and two (8%) very high (VH) risk categories. Canakinumab was well tolerated and no drug-related toxicities were observed. One death due to sepsis, which was deemed not treatment-related, occurred on the study drug. Out of 23 evaluable patients, the overall response rate was 17·4%, with erythroid and platelet hematological improvement (HI-E and HI-P, respectively) confirmed in 3 (13.0%) patients and 1 (4.3%) patient, respectively. Thirteen patients had stable disease (56·5%) and 6 (26·1%) progressed during therapy, 1 of which transformed to AML (Fig. 1). TI was achieved in 3 patients (median DoR 8·53 months (95% CI 0·41-16·1) and 2 of them maintained TI for over 12 months. With a median follow-up time of 22·6 months (95% CI 15·0-29·4), median OS was 17·3 months (95% CI 14·3-not estimable). We performed separate univariate analyses to evaluate any associations between the IPSS-M and OS/PFS. The median OS in patients with higher-risk MDS by IPSS-M (MH, H, VH) was 15·0 months vs 29·4 months in the lower-risk disease by IPSS-M (VL, L, ML) group (p=0·12). Interestingly, statistically significant findings were observed with 1-year PFS when stratifying patients into higher vs lower risk MDS by IPSS-M (64·3% vs 100·0%, respectively; p=0·022, Fig. 2). Conclusion In this cohort of MDS patients who had experienced multiple lines of prior therapy and exhibited high-molecular-complexity, canakinumab showed limited efficacy (HI 17.3%). Nevertheless, canakinumab showed a good safety profile and yielded sustained long-term responses in patients with single somatic driver mutation in TET2 or DNMT3A. This suggests that clonal complexity, and therefore disease burden, may be a determining factor in response to canakinumab. Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P &amp;lt;0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P&amp;lt;0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial

CONCLUSIONS Transfusion-dependent anemia and related fatigue are commonly associated with lower-risk myelodysplastic syndromes (LR-MDS) and frequently not improved with therapy. Patients with symptoms associated with anemia have an impaired quality of life and inferior overall survival. In IMerge (NCT02598661), the phase 3, randomized, global trial of patients with LR-MDS and a red blood cell transfusion burden of ≥4 U, imetelstat-treated patients had a significantly higher transfusion independence rate than those treated with placebo and showed sustained improvement in patient-reported fatigue via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Sekeres et al. EHA 2023. P732). Here, we assess the impact of imetelstat on several patient-reported outcomes (PROs) relevant to LR-MDS. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Analyses included symptom-specific derived scores for the following parameters: dyspnea, measured by 1 FACT-An and 1 QUALMS item; physical function and systemic symptoms, by 3 FACT-An items each; pain, by 2 FACT-An items; and bleeding, by 1 QUALMS item. Higher scores indicated improvement. QUALMS total score and physical burden score were also analyzed. Psychometric analyses were conducted using blinded interim data to document the measurement properties of these item sets and define the scores that would be used to specify PRO end points in IMerge; all analyses were exploratory and were conducted in the intention-to-treat (ITT) population. The overall effect of imetelstat on each score was evaluated from the repeated measurement mixed model (RMMM) comparing the least-squares means (LSMs) of change in score estimated in the 2 treatment groups using all available data while on treatment up to cycle 30. A positive mean change in the dyspnea score was observed throughout the treatment, up to cycle 24, in the imetelstat group but not in the placebo group (Figure). The RMMM analysis showed an overall change in dyspnea score from baseline of 0.53 (by LSM with 95% CI, 0.241-0.825) with imetelstat versus −0.40 (by LSM with 95% CI, −0.794 to 0.003) with placebo, with a significant difference between the treatment groups (LSM difference, 0.93; 95% CI, 0.446-1.411; P &amp;lt; .001; Table). The model-based mean change estimates for each score showed that, despite having high transfusion burden at baseline, patients in the imetelstat group did not experience more deterioration in any of the other outcomes than those in the placebo group (Table). In addition, the QUALMS composite scores suggested significantly improved health outcomes with imetelstat versus placebo based on RMMM. LSM difference was 4.66 (95%CI, 0.862-8.461; P = .016) and 6.34 (95% CI, 1.771-10.913; P = .007) for QUALMS total and QUALMS physical burden, respectively (Table). Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Estimating Transfusion-Related Medical Costs and Associated Time Burden in Patients with Myelofibrosis: A Comparison of Momelotinib Vs Ruxolitinib Based on Simplify-1

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by splenomegaly, debilitating symptoms, and bone marrow fibrosis. Transfusion-dependent (TD) anemia is present in one-quarter of patients (pts) with MF at diagnosis and becomes more common over time. Transfusion dependence imposes a high cost burden on healthcare systems, with annual total medical costs up to 9 times higher for TD pts than for non-TD pts (Gerds A, et al. ASH 2022. Abstract 1729). Momelotinib (MMB) is a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor that has demonstrated symptom, spleen, and anemia benefits in pts with MF across 3 phase 3 trials. Evidence in JAK inhibitor-naive pts comes from SIMPLIFY-1 (NCT01969838), a randomized, double-blind, phase 3 trial of MMB vs ruxolitinib (RUX). Eligible pts had International Prognostic Scoring System high-risk or intermediate-2-risk MF, or intermediate-1-risk MF associated with symptomatic splenomegaly, hepatomegaly, or anemia (hemoglobin &amp;lt;10 g/dL) and/or unresponsiveness to available non-JAK inhibitor therapy. MMB was associated with higher red blood cell (RBC) transfusion independence rates (66.5% vs 49.3%), lower transfusion dependence rates (30.2% vs 40.1%), and fewer RBC units transfused (median of zero units/month vs 0.4 units/month) compared with RUX by week 24. This study estimated the projected differences between MMB and RUX in total medical costs as well as cost and time burden associated with outpatient transfusion visits, based on results from SIMPLIFY-1, in all pts with MF and separately in those aged ≥65 years. Methods: Analyses were based on transfusion status (TD, transfusion independent [TI], or transfusion requiring [TR]) and mean rates of outpatient transfusion visits over 24 weeks in SIMPLIFY-1. TD was defined as ≥4 RBC units transfused or hemoglobin &amp;lt;8 g/dL in the prior 8 weeks, TI was defined as no RBC transfusions and all hemoglobin ≥8 g/dL in the prior 12 weeks, and TR was defined as being neither TD nor TI. Projected cost offsets for MMB relative to RUX were calculated based on observed transfusion status and rates over 24 weeks from SIMPLIFY-1 combined with cost estimates for TD vs TI/TR from the IBM MarketScan Database used to inform commercial health plans. Projected time savings were calculated similarly using transfusion rates from SIMPLIFY-1 and previously reported time burden estimates for transfusion visits in pts with TD β-thalassemia (Knoth RL, et al. EHA2022. Poster P1741). For pts aged ≥65 years, individual pt data from SIMPLIFY-1 and cost estimates from the Medicare fee-for-service database were used instead. Results: Based on the IBM MarketScan Commercial Database, projected average annual total medical cost savings based on week 24 transfusion status with MMB vs RUX were $20,215 per pt with baseline TD status and $23,991 per pt with baseline TI/TR status. Fewer outpatient transfusion visits with MMB vs RUX resulted in projected annual savings of $25,704 per pt with baseline TD status and $12,083 per pt with baseline TI/TR status. Among pts with baseline TD status, projected annual time savings in transfusion visits for MMB vs RUX (147 vs 253 hours) totaled 106 hours per pt (42 hours, preparation and waiting; 50 hours, transfusion and recovery; 15 hours, travel), a 42% reduction for MMB vs RUX. In the subgroup analysis that focused on pts aged ≥65 years, based on the Medicare fee-for-service database, projected average annual total medical cost savings with MMB vs RUX were $11,102 per pt with baseline TD status and $17,373 per pt with baseline TI/TR status. Fewer outpatient transfusion visits with MMB vs RUX resulted in projected annual savings of $28,826 per pt with baseline TD status and $18,255 per pt with baseline TI/TR status. Among pts aged ≥65 years with baseline TD status, projected annual time savings in transfusion visits accounted for MMB vs RUX (160 vs 279 hours) totaled 119 hours per pt (47 hours, preparation and waiting; 56 hours, transfusion and recovery; 16 hours, travel), a 43% reduction for MMB vs RUX. Conclusions: Reductions in transfusion dependence and transfusion visits for MMB vs RUX were associated with projected healthcare system savings in transfusion costs and transfusion-related time burden in JAK inhibitor-naive pts with MF, including in subgroup analyses of pts aged ≥65 years.

Patient-Reported Outcomes (PRO) of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naïve, Transfusion-Dependent (TD), Lower-Risk Myelodysplastic Syndromes (LR-MDS): Results from the Phase 3 COMMANDS Study

Background: For symptomatic anemia in patients with LR-MDS, supportive treatment with erythropoietin stimulating agents (ESAs), such as epoetin alfa, remains the current standard of care, which has limited and transient effect. The phase 3, open-label, randomized, controlled COMMANDS study demonstrated that luspatercept significantly improved the rate of transfusion independence and hemoglobin levels, when compared to epoetin alfa in ESA-naïve and transfusion-dependent (TD) patients with LR-MDS (Platzbecker U, et al. Lancet. 2023;S0140-6736(23)00874-7). Objective: The objective of this interim analysis was to assess the effect of luspatercept versus epoetin alfa on patient-reported outcome (PRO) using data from the first 24 weeks of the COMMANDS study. Methods: In COMMANDS, 356 patients were randomized 1:1 to luspatercept (Q3W) or epoetin alfa (QW). PROs, as one of the secondary objectives, were assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire.The EORTC QLQ-C30 was assessed on Day 1 prior to the first dose (baseline) and every 6 weeks thereafter; the FACT-An was administered at baseline, weekly for 3 weeks, and then every 3 weeks thereafter. Time to sustained improvement on domains of the EORTC QLQ-C30 and FACT-An was assessed between treatment arms using a stratified Cox proportional hazards regression model. Sustained improvement was defined as improvement from baseline ≥ pre-specified responder definition, sustained for at least 42 days through Week 25 Day 1 (W25D1). Overall treatment tolerability, assessed by the FACT-An item GP5 (“I am bothered by side effects of treatment”), was descriptively summarized at W25D1 by treatment arm. All analyses were conducted on the respective PRO-evaluable populations for each instrument, including patients who had completed the assessment at baseline and at least one post-baseline visit, unless otherwise specified. Results: The EORTC QLQ-C30 evaluable population consisted of 150 and 144 patients randomized to luspatercept and epoetin alfa, respectively (median age 74.5 years and 54% male). Population sizes were similar for other PRO measures. Demographics, disease characteristics, and PRO domain scores at baseline were generally comparable between treatment arms. Completion rates of PRO assessments were moderately high for both arms (approximately 70-90%) through the W25D1 visit. Luspatercept resulted in a higher probability of sustained improvement through W25D1 in almost all domains of the EORTC QLQ-C30 and FACT-An compared to epoetin alfa, with significant differences (nominal p-value &amp;lt;0.05) in dyspnea (hazard ratio [HR] [95% confidence interval]: 3.18 [1.03, 9.81]) and 7 other domains of the EORTC QLQ-C30 (role functioning, cognitive functioning, pain, insomnia, appetite loss, constipation, and financial difficulties). Patients in both arms experienced similar overall treatment tolerability, with &amp;gt;67% of all patients still on treatment reporting to be “not at all” bothered by treatment side effects through W25D1. Conclusions: The findings from these interim PRO analyses indicate that treatment with luspatercept increased sustained improvement across quality-of-life domains when compared to epoetin alfa. Luspatercept was also found to be well-tolerated by the majority of patients. All of these PRO findings further support the benefits of luspatercept in ESA-naïve and TD patients with LR-MDS.

Efficacy and Safety of Single Agent Proximal Complement Inhibitors in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients with Residual Anemia Despite of Adequate Terminal Complement Inhibitor Use

Background: Introduction of C5 inhibitors is a major advancement in the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) patients. First Eculizumab and then Ravulizumab significantly improved anemia by controlling intravascular hemolysis (IVH), reduced thrombosis risk, improved quality of life and prolonged survival. However, a significant proportion of PNH patients remain anemic with transfusion dependence despite maximal C5 inhibition due to C3 mediated residual extravascular hemolysis (EVH). Recently two randomized, open label, controlled trials with proximal complement inhibitors were studied in this patient population comparing against C5 inhibitors as single agents with excellent results. Here we compare efficacy and safety data of proximal complement inhibitors pegcetacoplan (C3 inhibitor), Iptacopan (factor b inhibitor) based on published or presented data. Methods: We compared the efficacy and safety data of randomized portion of PEGASUS and APPLY-PNH trials. PEGASUS trial is a phase 3, randomized, open label, active-comparator controlled trial with Pegcetacoplan (a pegylated pentadecapeptide that targets C3) compared efficacy and safety against eculizumab in PNH patients with Hb &amp;lt;10.5 despite of treatment with Eculizumab (Hillerman, et al NEJM 2021;384). Primary end point of the study was mean change in Hb level from baseline to week 16. APPLY-PNH is an open label randomized, multicenter phase 3 trial compared Iptacopan 200 mg BID (oral factor b inhibitor) monotherapy with standard of care C5 inhibition therapy. (Regis P. de Latour et al. Blood (2022) 140 (Suppl 2): LBA-2). Primary end points of the trial were Hematological response defined as an increase in Hb of ≥ 2 g/dL from baseline and Hb ≥ 12 g/dL in absence of transfusions. Secondary end points included number of clinical and hematological markers of hemolysis and safety. Results: Summarized in table 1. PEGASUS trial included 80 patients with 41 in pegcetacoplan arm and 39 in Eculizumab arm. APPLY-PNH included 97 patients with 62 in Iptacopan arm compared to 35 in standard of care anti C5 therapy. Majority of baseline characteristics were similar between two studies. Mean age in both studies was around 50 years and close to 2/3rd of patients in each study were females. Median duration of prior C5 therapy was between 3-4 years in both studies. More than half of patients in both studies required PRBC transfusions in preceding months prior to enrollment. Baseline mean Hb was between 8-9 g/dL, LDH between 250-300 U/L, mean absolute retic count (ARC) 190-200x109/L. Both studies showed superiority in change from baseline Hb with +2.69 g/dL in PEGASUS trial with all available data regardless of transfusion events and +3.63 in APPLY-PNH trial. Both studies showed either noninferiority or superiority in freedom from transfusions and change in ARC. Interestingly, LDH change was not significant in both studies. Change from baseline fatigue FACIT-score was numerically better but not tested in PEGASUS trial and was superior in APPLY-PNH. No major vascular events or serious infections by encapsulated bacteria were reported in either study. Breakthrough hemolysis was reported in 4 out of 40 patients in PEGASUS trial that led to treatment discontinuation in 3 patients and 2 out of 62 patients in APPLY-PNH trial, however none of them required treatment discontinuation. Conclusions: PEGASUS and APPLY-PNH trials showed that in patients with persistent anemia despite C5 inhibitor therapy, proximal complement inhibition with either pegcetacoplan (C3 inhibitor) or Iptacopan (factor b inhibitor) as a single agent showed significant improvement in Hemoglobin with higher rate of transfusion independence with control of extra vascular hemolysis while maintaining intravascular hemolysis control with no serious infections. These studies represent another major advancement in the management of PNH patients. Long term follow up is needed regarding safety and to identify better ways to manage breakthrough hemolysis in patients on proximal complement inhibitors.

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML

Abstract Purpose: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression. Patients and Methods: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN. Results: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment. Conclusions: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1–targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens.

Olutasidenib in post-venetoclax patients with mIDH1 AML.

e19041 Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574 .

Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies.

Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and early mortality in case of patient non-adherence to supportive treatment. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) used to be the only curative option, although the indispensable need for an HLA-matched donor markedly restricted its universal application. The evolution of gene therapy approaches made possible the ex vivo delivery of a therapeutic β- or γ- globin gene into patient-derived hematopoietic stem cells followed by the transplantation of corrected cells into myeloablated patients, having led to high rates of transfusion independence (thalassemia) or complete resolution of painful crises (sickle cell disease-SCD). Hereditary persistence of fetal hemoglobin (HPFH), a syndrome characterized by increased γ-globin levels, when co-inherited with β-thalassemia or SCD, converts hemoglobinopathies to a benign condition with mild clinical phenotype. The rapid development of precise genome editing tools (ZFN, TALENs, CRISPR/Cas9) over the last decade has allowed the targeted introduction of mutations, resulting in disease-modifying outcomes. In this context, genome editing tools have successfully been used for the introduction of HPFH-like mutations both in HBG1/HBG2 promoters or/and in the erythroid enhancer of BCL11A to increase HbF expression as an alternative curative approach for β-hemoglobinopathies. The current investigation of new HbF modulators, such as ZBTB7A, KLF-1, SOX6, and ZNF410, further expands the range of possible genome editing targets. Importantly, genome editing approaches have recently reached clinical translation in trials investigating HbF reactivation in both SCD and thalassemic patients. Showing promising outcomes, these approaches are yet to be confirmed in long-term follow-up studies.

Efficacy of Short-Duration Alemtuzumab in T-Cell Large Granular Lymphocytic Leukemia: Potential for a Response-Adapted Strategy

Introduction T-cell large granular lymphocytic leukemia (T-LGL) is a chronic incurable malignancy where once refractory to immunosuppressive therapy, few treatment options and no optimal treatment consensus exists. Alemtuzumab, 10 milligrams (mg) intravenously (IV) administered daily for a total of 10 doses, has been shown to be effective for relapsed or refractory (R/R) T-LGL (Dumitriu, et al. Lancet Haematol 2016); however, it can be associated with severe infusion reactions and infections. Given the palliative nature of T-LGL-directed treatments and the increasing potential for toxicity with cumulative alemtuzumab exposure, we conducted a retrospective analysis to describe the efficacy and safety of abbreviated alemtuzumab regimens in R/R T-LGL patients. Methods We identified patients ≥18 years with R/R T-LGL who were treated with short-duration (defined as ≤ 5 doses) alemtuzumab between 2012 and 2022 from the University of Washington lymphoma database. Patients who received prior alemtuzumab were excluded. The primary endpoint was overall hematologic response rate (ORR). Secondary efficacy endpoints included hematologic response rate at 3 and 6 months, rate of transfusion independence, progression-free and overall survival. Safety endpoints included rate of infusion reactions and infections, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation. Results Nine patients meeting criteria were identified (Table 1). Five patients received alemtuzumab 10 mg IV daily for 5 doses and 4 patients received alemtuzumab 10 mg IV weekly for 4 doses. Median age was 65 (range 34-81) years and the median number of prior regimens was 3 (range 1-5). All (100%) patients were refractory to immunosuppressive therapy. Seven (78%), 1 (11%) and 1 (11%) patients had unilineage, bilineage and trilineage cytopenias, respectively. Five patients (56%) had autoimmune comorbidities and five (56%) required periodic transfusions. No patients had myelodysplasia on bone marrow biopsy. Overall, 6 (67%) patients had a hematologic response with 2 patients achieving a partial response (PR) and 4 patients achieving a complete response (CR). ORR at 3 and 6 months was 56% and 44%, respectively. Two (40%) patients achieved transfusion independence. The 3 patients without a hematologic response were retreated with alemtuzumab 10 mg IV daily for 10 doses with 1 subsequently achieving a CR. At a median follow-up time of 7.2 (range 2.3-36.6) months, 3 out of 6 patients who achieved a response had disease relapse; 8 (89%) patients were alive and 1 had died from COVID-19 pneumonia. Among the 5 patients who received alemtuzumab at 10 mg daily for 5 doses, ORR was 40% with 1 patient achieving PR and 1 patient achieving CR. ORR at 3 and 6 months was 40% and 40%, respectively. One (20%) patient had an infusion reaction. Two patients (40%) had subclinical CMV viremia which resolved with valganciclovir. No cases of EBV viremia were noted. Four patients completed alemtuzumab at 10 mg weekly for 4 doses; ORR was 100% with 1 patient achieving PR and 3 achieving CR. Hematologic response rate at 3 and 6 months was 75% and 50%, respectively. Three (75%) patients relapsed at 3, 4 and 14.2 months, respectively; 2 were retreated 4-6 times with alemtuzumab 10 mg IV weekly for 2 to 6 doses each time, with both achieving hematologic responses with each course of treatment. One (25%) patient experienced an infusion reaction. No cases of CMV or EBV viremia were noted. Conclusions Short-duration alemtuzumab is effective and well tolerated in R/R T-LGL with responses observed in 67% overall and no cases of CMV viremia detected in the weekly dosing group. Alemtuzumab given at 10 mg IV weekly for 4 doses or until a response is noted followed by retreatment upon relapse was particularly effective; this abbreviated, response-adapted alemtuzumab strategy should be prospectively explored in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PB1921: A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAMIBAROTENE/AZACITIDINE VERSUS PLACEBO/AZACITIDINE IN NEWLY DIAGNOSED ADULT PATIENTS SELECTED FOR RARA-POSITIVE HR-MDS (SELECT-MDS-1)

Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). This RARA positivity enables biologically targeted therapy with tamibarotene (formerly SY-1425), an oral selective RARα agonist with potential to provide clinical benefit for HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial Phase 2 clinical data in RARA+ relapsed/refractory HR-MDS patients treated with single agent tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) demonstrated high complete response rates with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene plus aza was generally well tolerated with no increase in myelosuppression compared to single agent aza (de Botton 2020). HR-MDS and AML have common cytogenetic abnormalities and gene mutations present in the blast populations in each condition. The historical precedent demonstrating similar clinical outcomes among patients with HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of the combination of tamibarotene plus aza in the HR-MDS population, with the opportunity to improve upon the clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Aims: This is a global Phase 3, multi-center, randomized, double-blind, placebo-controlled study comparing the activity of tamibarotene plus aza, to placebo plus aza in RARA+ patients with ND HR-MDS. The primary objective is to compare the complete remission rate of tamibarotene plus aza vs. placebo plus aza, with secondary objectives to compare objective response rate, event-free survival, overall survival, transfusion independence rate, time to and duration of initial and complete responses, and safety. Methods: Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a bone marrow blast count > 5% at study entry. Patients suitable for allogeneic HSCT at the time of screening, or who received prior treatment for MDS with any HMA, chemotherapy or allogeneic HSCT are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or days 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per the modified IWG MDS criteria (Cheson 2006). Results: Approximately 190 patients will be randomized 2:1 and stratified by IPSS-R risk group and geographic region, providing 90% power to detect the difference in CR rates between the experimental and control arms, respectively, with one-sided alpha of 0.025. Summary/Conclusion: The SELECT-MDS-1 trial opened to enrollment in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe (NCT04797780).

A randomized, double-blind, placebo-controlled study of tamibarotene/azacitidine versus placebo/azacitidine in newly diagnosed adult patients selected for RARA+ HR-MDS (SELECT-MDS-1).

TPS7075 Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). Biologically targeted therapy with tamibarotene, an oral selective RARα agonist, has potential to provide clinical benefit for RARA+ HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA+ R/R HR-MDS patients treated with tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) showed high complete response rates (CR) with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/aza was generally well tolerated with no increase in myelosuppression compared to aza alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of tamibarotene/aza in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Methods: This Phase 3, multi-center, randomized, double-blind, placebo-controlled study will compare activity of tamibarotene/aza to placebo/aza in RARA+ patients with ND HR-MDS. The primary objective is to characterize and compare the CR rate of tamibarotene/aza vs placebo/aza, with secondary objectives to characterize ORR, EFS, OS, transfusion independence rate, time to and duration of initial and complete responses, and safety. Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms, with a one-sided alpha of 0.025. Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a blast count &gt; 5% at study entry. Patients suitable for transplant at screening, or with prior treatment for MDS with any HMA, chemotherapy or transplant are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per modified IWG MDS criteria (Cheson 2006). The SELECT-MDS-1 trial opened in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe. Clinical trial information: NCT04797780.

What's new in myeloproliferative neoplasia?

Treatment of myeloproliferative neoplasia (MPN) is based on patients' individual risk-stratification and includes cytoreductive agents for high-risk essential thrombocythemia (ET), polycythemia vera (PV) and Myelofibrosis (MF). Classical cytoreductive drugs largely fail to modify the basic clonal composition of the disease. In contrast, in PV for example treatment with Ropeg-Interferon not only results in higher hematological response rates compared to hydroxyurea but in addition significantly reduces JAK2 allele-burden in high-risk PV patients as well as it depletes concurrent cytogenetic and molecular abnormalities. Treatment with Ropeg-Interferon so far is only approved for high-risk PV. A very recent trial however also demonstrated this disease-modifying effect also in low-risk PV patients in addition to an increased rate of transfusion independence. Thus, Ropeg-Interferon is the current standard for first line treatment of high-risk PV and we assume that the data in low-risk PV will lead also to a broader clinical use of Ropeg-Interferon this particular patient group, as it may decrease transformation to MF or even MPN-blast crisis.Myelofibrosis management has been extended by novel JAKi. Fedratinib is the first second generation JAK-inhibitor approved for Ruxolitinib-intolerant or refractory patients. Fedratinib reduces both spleen volume as well as symptom burden. Two other second generation JAK-inhibitors are in clinical development for MPN treatment. Pacritinib has demonstrated efficacy in reducing both spleen volume and symptom score in MF including a cohort of Ruxolitinib-pretreated patients and Momelotinib is the only JAK-inhibitor which has been shown to alleviate anemia in addition to its effect on improving spleen volume and symptom. So far, neither Pacritinib nor Momelotinib are currently EMA-approved for MPN treatment.Finally, it has recently been acknowledged that inflammation is a key driver of MPN pathogenesis. Both, mutated as well as non-clonal inflammatory and other stromal cells produce significant amounts of local cytokines. Also the initiation of the neoplastic process itself seems to depend on inflammatory cytokines. Recent scRNASeq data revealed components of the alarmin complex (S100A8 und S100A9) drive this local sterile inflammation process, which also represents a potential therapeutic target, as the S100A8 and A9 inhibitor Tasquinimod reduced fibrosis in a pre-clinical animal model.

Pevonedistat (PEV) + Azacitidine (AZA) Versus AZA Alone As First-Line Treatment for Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) with 20-30% Marrow Blasts: The Randomized Phase 3 PANTHER Trial (NCT03268954)

Pevonedistat (PEV) + Azacitidine (AZA) Versus AZA Alone As First-Line Treatment for Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) with 20-30% Marrow Blasts: The Randomized Phase 3 PANTHER Trial (NCT03268954)

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352.