Lower-risk Myelodysplastic Syndromes Research Articles

A Randomized Double-Blind Placebo-Controlled Phase II Multi-Center Study of Inflammation Modification of Canakinumab to Prevent Leukemic Progression of Clonal Cytopenias of Unknown Significance (CCUS): Impact Study

Background and Significance: High-risk Clonal Cytopenia of Undetermined Significance (HR-CCUS) is defined by prolonged cytopenias (> 4 months) in 1 or more cell lineages plus myeloid-disorder-associated mutations. CCUS patients with spliceosome mutations, DNMT3A, TET2, or ASXL1 mutations in combination with at least 2 other somatic mutations appear to have an extremely high rate of progression to myeloid neoplasms (MN) with a 95% 5-year cumulative probability of developing a MNsuch asMDS, MPN, or AML (13-fold increased risk compared to patients with cytopenia classified). Several studies implicate the inflammasome in CH progression to MDS/AML. Interleukin (IL)-1β is a key upstream cytokine in the inflammasome that strongly induces IL-6. Mutations in another key protein in the inflammasome, cryopyrin, result in high systemic levels of IL-1β and are associated with auto-inflammatory diseases. We hypothesize that the preclinical and clinical data showing a benefit of IL-1β inhibition in patients with CH, is due to reduced downstream activations of inflammasome proteins. Canakinumab is a high-affinity human monoclonal anti-human IL-1β antibody- FDA approved for the treatment of IL-1β driven inflammatory and oncologic diseases. By binding specifically to human IL-1β, canakinumab blocks the interaction of IL-1β with the IL-1 receptor, leading to inhibition of its downstream targets, thereby preventing IL-1β-induced gene activation and the production of inflammatory mediators. A phase II clinical trial investigating the use of canakinumab in combination with azacitidine is currently studying the impact canakinumab may have on disease progression in relapsed/refractory low or intermediate risk MDS patients (NCT04239157). This has now been extended to newly diagnosed MDS as new emerging data looks promising [unpublished data]. No significant toxicities have been reported. Thus, we hypothesize that the treatment of HR-CCUS patients, for whom there is no current disease modifying therapy, with an inflammasome targeting antibody, would prevent or significantly delay development of a MN, improve cytopenias and decrease the clone size as well as prevent further clonal evolution. Study Design and Methods: This study (NCT05641831) is a Phase II multicenter, randomized, two-arm, double-blind placebo-controlled study in patients with HR-CCUS (Figure 1). Patients with HR-CCUS, no known hematological malignancy, and any mutational combination as deemed appropriate by the inclusion criteria - are randomized to the study Arm or control Arm. Patients assigned to the study arm will be eligible to receive canakinumab, 300 mg subcutaneously every 3 months for 2 years. Patients assigned to the control arm will receive placebo every 3 months for 2 years. Bone marrow biopsies will be done for both arms every 6 months to monitor for disease progression (WHO 2016). PB samples will be collected every 3 months to monitor for disease progression. Patient-reported outcomes will be collected at the time of disease assessment. Statistical plan: The null hypothesis assumes the time to overt MN (MDS/MPN/CMML/AML) is equal in the control and study arms (H 0: HR=1) versus the alternative hypothesis that the risk of an event is lower in the study arm (H 1: HR<1). Assuming exponential survival, 71 events (overt MN) are required for the final analysis to detect a hazard ratio of 0.55 (median 2 years for the control arm versus 3.636 years for the study arm) using a log-rank test with 80% power and one-sided significance level of 5%. This includes one interim futility analysis when 50% of the targeted number of events (36) have been observed. At the time of the interim analysis, futility will be declared if the hazard ratio is greater than 1 and in favor of the control arm. The futility boundary is statistically non-binding in that there is not a final significance level adjustment. If the futility boundary is crossed, then the study will terminate early; patients randomized to the control arm will continue standard of care off study and patients randomized to the study arm will discontinue treatment with Canakinumab. Accounting for 5% drop-out, this calculation assumes accrual of 89 patients over 3 years and a minimum follow-up of 5 years (or until withdrawal, death, or study closure; earliest event). To date, 5 patients have been randomized and enrolled on study (Table 1).

Net Clinical and Quality of Life Benefit of Luspatercept in Transfusion-Dependent MDS: A Win Ratio Analysis Using Data from the Phase 3 MEDALIST Study

Background: Patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) often experience various anemia-related symptoms and functional impairments. Treatments reducing red blood cell (RBC) transfusion burden could impact these symptoms and/or functions to varying degrees depending on patients' conditions at baseline and warrants the use of composite endpoints, including both clinical outcomes and patient-reported outcomes (PROs) to fully capture these benefits. However, conventional statistical approaches may not satisfactorily assess composite outcomes, especially when the components of the composite outcomes have different types of scales and/or degrees of importance to stakeholders. The win ratio (WR) approach, one of the generalized pairwise comparison methods commonly used for assessing treatments in cardiovascular diseases, offers hierarchical structure, statistical power, and flexibility to address these challenges. Objective: This exploratory analysis used the WR approach to assess the net benefit of luspatercept vs. placebo on composite clinical/PRO endpoints using data from the MEDALIST study. Methods: Four different WR scenarios were performed, in each of which every possible patient-to-patient pair between the luspatercept and placebo arms was compared on a set of relevant clinical/PRO endpoints in a pre-specified order of assumed priority from patients' perspectives, accompanied with a pre-determined rule to assign a win, loss, or tie for luspatercept in each pairwise comparison on each endpoint. If a win or loss could not be determined on a given endpoint, then the next endpoint in the hierarchy was evaluated until a win or loss occurred. Otherwise, if all pre-specified endpoints were evaluated, a tie was assigned. The scenarios considered two clinical endpoints: RBC-transfusion independence [TI] ≥8 weeks over Weeks 1-24 and RBC-TI over Weeks 1-24. PRO endpoints included changes from baseline to the end of Week 24 in five key domains of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), categorized as improvement (≥10-point improvement), stable (10 > change >-10), or worsening (≥10-point worsening). Improvement was considered a better outcome than stable and worsening, and stable was considered better than worsening when determining a win or loss for luspatercept on each of the PRO endpoints. The four different scenarios of composite clinical/PRO endpoints and their order of priority, shown in the Table were pre-specified for assessment . The WR (nominal 95% CI, p-value) for luspatercept on each scenario of the composite clinical/PRO endpoints was calculated as the total number of pairs with a win divided by the total number of pairs with a loss. A WR >1 indicates that luspatercept is more favorable than placebo. Results: 153 patients randomized to the luspatercept arm were compared to 76 patients randomized to the placebo arm, for a total of 11,628 pairwise comparisons within each WR analysis. In all four scenarios, WRs were nominally statistically significantly in favor of luspatercept ( Table). Most wins favoring luspatercept were attributed to wins on the clinical endpoint. Among those pairs who tied on the clinical endpoint, the luspatercept arm experienced more wins (or tied) in almost all of the five PRO endpoints. WRs were similar whether PRO endpoints were prioritized over others or not. Conclusions: The analysis findings indicate that, for two randomly selected patients with low-risk TD MDS, the odds that the patient treated with luspatercept would have a better outcome (if not tied) than the patient with placebo, is significantly higher than 1, ranging between 1.51 to 1.90. The analysis also shows that when multiple clinical and PRO endpoints, especially with different importance to stakeholders, are considered to provide a comprehensive treatment benefit, WR can be a useful and valuable approach for making this evaluation.

Performance of the Molecular International Prognostic Scoring System (IPSS-M) in Hypomethylating Agent-Treated Patients with Myelodysplastic Syndromes

Background: Patients with myelodysplastic syndromes (MDS) undergo risk stratification with various prognostication tools, such as the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). Recently, the Molecular IPSS (IPSS-M) was developed incorporating genomic data in addition to clinical and cytogenetic characteristics. Though IPSS-M has been shown to improve prognostication in all MDS patients at baseline, its utility in specifically patients undergoing hypomethylating agent (HMA) therapy remains unknown. Here, we assess the efficacy of IPSS-M in HMA-treated patients with MDS. Methods: We retrospectively evaluated all untreated patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who later received HMA therapy. Patient characteristics and bone marrow (BM) data, including morphology, cytogenetics, and mutations, were assessed at diagnosis. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in July 2023. Results: Out of 799 untreated MDS patients, 455 patients (57%) eventually underwent treatment with HMA. At diagnosis, the median age was 69 (range: 22-90) with 289 (64%) male patients. Patients were generally high risk, with therapy-related MDS in 160 (35%), complex cytogenetics in 167 (37%), and TP53 mutations in 168 (37%). By IPSS-R, 259 patients (58%) had high- or very high-risk disease, and 340 patients (75%) had higher-risk disease (moderate high-, high-, and very high-risk) by IPSS-M. A total of 291 patients (64%) were treated with HMA monotherapy, and lower-risk MDS patients received more cycles of HMA (p < 0.001). By IPSS-R, the median overall survival was 60.0 months (95% CI: 46.0, not estimable (NE)) in very low-, 87.4 months (95% CI: 59.9, NE) in low-, 36.2 months (95% CI: 30.0, 58.1) in intermediate-, 23.7 months (95% CI: 19.6, 34.8), in high-, and 12.8 months (95% CI: 11.0, 16.7) in very high-risk patients (p < 0.0001) with a concordance index of 0.669. Figure 1 depicts the reclassification of patients between IPSS-R and IPSS-M. Risk stratification by IPSS-M (Figure 2) provided similar results: not reached (95% CI: 56.8, NE) in very low-, 60.0 months (95% CI: 49.8, NE) in low-, 40.8 months (95% CI: 22.8, NE) in moderate low-, 44.2 months (95% CI: 27.8, NE) in moderate high-, 33.4 months (95% CI: 22.8, 44.5) in high-, and 16.6 months (95% CI: 13.8, 19.4) in very high-risk patients (p < 0.0001). The concordance index of IPSS-M in all HMA-treated MDS patients was 0.648. When analyzing patients with MDS who were more likely to undergo HMA as per standard-of-care treatment (those with IPSS-M moderate low-, moderate high-, high-, and very high-risk disease), the IPSS-M remained statistically significant (p < 0.0001) though less discerning in the patients with moderate-risk MDS, as seen by the concordance index of 0.620. Conclusions: In this group of MDS patients treated with HMA, the IPSS-M did not provide additional prognostic power over the IPSS-R though median overall survival remained inversely proportional to IPSS-M risk category. Concordance indices for survival remained below 0.7, likely due to the overlapping curves in moderate-risk patients by IPSS-M. Further development and validation of prognostic scoring systems in patients treated with HMA are warranted.

Clinical and economic effects of technology updates to the electronic health record for the management of erythopoetic stimulating agents and MDS-associated anemia.

509 Background: NCCN Guidelines recommend erythropoietic stimulating agents (ESAs) to manage symptomatic anemia in patients with lower-risk myelodysplastic syndrome (MDS) and serum EPO ≤500 mU/mL. Epoetin alfa and darbepoetin alfa have been used with a variety of dosing strategies in clinical practice, and patients often require dose adjustments to achieve an optimal clinical response, including transfusion independence. The objective of this study was to increase concordance with guidelines supported initial and subsequent doses of ESAs in The US Oncology Network (The Network). Methods: The Network developed a dosing guidance tool to standardize ESA dosing for anemia associated with MDS. These updates were made to the electronic health record (eHR) in October 2022 and included creation of an MDS-specific ESA regimen. The primary endpoint of initial dose concordance was evaluated in a retrospective chart review of patients with MDS, initiating treatment with an ESA, and randomly selected prior to and after implementation of the eHR changes. Secondary endpoints included subsequent ESA dose concordance at 4-weeks and 8-weeks post-implementation, percent of patients who reached hemoglobin (Hb) goal ≥10 g/dL by week 12, number of ESA orders using the MDS-specific regimen, and number of patients with transfusions after start of ESA. Fisher’s exact test was used to analyze the primary endpoint, and descriptive statistics were used for secondary endpoints. Darbepoetin claims data from five practices was also used to evaluate changes in payment denials during the intervention period. Results: The analysis included 50 patients (25 pre and 25 post). The primary outcome of overall initial dose concordance was 36% and 48% pre- and post-implementation periods respectively. The initial dose concordance was 73% vs. 29% (P=0.0472) in the group of patients who received an ESA using the new MDS-specific regimen (n=11) vs. non-MDS specific (n=14). Additionally, any ESA dose concordance (initial, 4-week post-, or 8-week post-ESA) using MDS-specific regimen vs. non-MDS specific occurred in 91% and 43% of patients post-implementation. The secondary outcome of Hb goal reached and percent transfused was 32% and 48% vs. 44% and 32% pre- and post-implementation respectively. During the study post-implementation period, first denial claims for darbepoetin decreased by 41%. Conclusions: Modification of ESA regimens to include MDS-specific dosing guidance resulted in a 12% increase in the initial dose concordance. A 48% increase in any dose concordance was noted when using MDS-specific ESA regimens vs. non-MDS specific ESA regimens. Based on these findings, additional eHR changes were implemented to increase the use of MDS-specific ESA regimens, and impact data are pending.

The Evolving Landscape: Exploring the Future of Myelodysplastic Syndrome Treatment with Dr. Rami Komrokji.

This perspective delves into the evolving landscape of Myelodysplastic Syndrome (MDS) treatment. MDS presents a significant clinical challenge, often progressing to acute myeloid leukemia. For low-risk MDS, the emphasis is on personalized care through comprehensive risk assessment, clinical monitoring, and tailored interventions, including promising agents like erythropoiesis-stimulating agents, lenalidomide, and luspatercept, with the anticipation of an expanding therapeutic arsenal and early intervention for improved outcomes. In contrast, high-risk MDS treatment is evolving towards upfront doublet or triplet therapies with a focus on minimal residual disease (MRD) monitoring. A holistic approach integrates various modalities, including stem cell transplant and post-transplant maintenance, all guided by individual patient circumstances. Risk-adapted strategies are crucial for enhancing patient outcomes. Precision medicine for MDS treatment is budding, largely driven by Next Generation Sequencing (NGS). NGS aids in early diagnosis, prognostication, and the targeting of specific mutations, with molecular data increasingly informing treatment responses and allowing for tailored interventions. Clinical trials within homogeneous patient groups with similar molecular profiles are becoming more common, enhancing treatment precision. In conclusion, the future of MDS treatment is moving towards personalized medicine, leveraging advanced technologies like NGS and molecular insights to improve outcomes in the realm of hematological malignancies.

Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms

BackgroundMyelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients.ResultsOf the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants – H1778R – was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC.ConclusionsIPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India.

Omicron related COVID-19 prevention and treatment measures for patients with hematological malignancy and strategies for modifying hematologic treatment regimes

The Omicron variant of SARS-CoV-2 has rapidly become the dominant strain worldwide due to its high transmissibility, although it appears to be less pathogenic than previous strains. However, individuals with hematological malignancy (HM) and COVID-19 remain susceptible to severe infection and mortality, especially those with chronic lymphocytic leukemia (CLL) and those undergoing chimeric antigen receptor T-cell (CAR-T) treatment. Hematologists should thoroughly assess the severity of the patient’s hematological disease and the potential risk of SARS-CoV-2 infection before initiating chemotherapy or immunosuppressive treatment. Vaccination and booster doses are strongly recommended and patients with a poor vaccine response may benefit from long-acting COVID-19 neutralizing monoclonal antibodies (such as Evusheld). Early use of small molecule antiviral drugs is recommended for managing mild COVID-19 in HM patients and those with severe immunodeficiency may benefit from SARS-CoV-2 neutralizing monoclonal antibody therapy and high-titer COVID-19 convalescent plasma (CCP). For moderate to severe cases, low-dose glucocorticoids in combination with early antiviral treatment can be administered, with cytokine receptor antagonists or JAK inhibitors added if the condition persists or worsens. In the treatment of hematological malignancies, delaying chemotherapy is preferable for CLL, acute leukemia (AL), and low-risk myelodysplastic syndrome (MDS), but if the disease progresses, appropriate adjustments in dosage and frequency of treatment are required, with the avoidance of anti-CD20 monoclonal antibody, CAR-T and hematopoietic stem cell transplantation (HSCT). Patients with chronic myelocytic leukemia (CML) and myeloproliferative neoplasms (MPNs) can continue current treatment. What’s more, non-drug protective measures, the development of new vaccines and antiviral drugs, and monitoring of mutations in immunocompromised populations are particularly important.

Full-Dose Azacitidine in 5 Days Versus 7 Days With a Weekend Break in Myelodysplastic Syndromes: A Retrospective Cohort Study

IntroductionApart from transplantation, only azacitidine demonstrated a survival benefit in a phase III study in higher-risk myelodysplastic syndromes (MDS). The approved regimen is 75 mg/m2/day for 7 consecutive days, imposing a logistic challenge for outpatient weekend administration. Schedules with 5 days and 7 days with a weekend break (5 + 2) have been used for convenience despite the lack of strong scientific support. Most studies of alternative schedules were performed in lower-risk MDS and with dose reduction in the 5-day schedules. MethodsWe performed a single-center, retrospective cohort study to compare full-dose azacitidine (7 × 75 mg/m2) administration in 5-day and 5 + 2-day schedules in a higher-risk MDS cohort. We evaluated 100 patients for overall survival and a subsample (49 patients) for acute myeloid leukemia-free survival (AMLFS), probability of infections and transfusion burden. Kaplan-Meier analysis and Cox models were used for survival analyses. Linear and logistic regressions were applied for univariate and multivariate assessment. ResultsAfter a median follow-up of 10.8 months, patients treated with a 5-day schedule had a median overall survival of 12.5 months versus 15.0 months in the 5+2 group: HR 0.95 (95% CI, 0.57-1.56); P= .83. AMLFS was also similar between groups: HR 1.70 (95% CI, 0.70-4.14); P = .24. Azacitidine schedules were not predictive of infections nor number of red blood cell or platelet transfusions in multivariate analyses. ConclusionsIn higher-risk MDS, full-dose azacitidine (7 × 75 mg/m2) can be administered both in 5 days and in 7 days with a weekend break with no significant difference in survival, infection or transfusional outcomes.

Long-term utilization and benefit of luspatercept in transfusion-dependent, erythropoiesis-stimulating agent-refractory or -intolerant patients with lower-risk myelodysplastic syndromes with ring sideroblasts

Long-term utilization and benefit of luspatercept in transfusion-dependent, erythropoiesis-stimulating agent-refractory or -intolerant patients with lower-risk myelodysplastic syndromes with ring sideroblasts

Deep immunophenotypic analysis of the bone marrow progenitor cells in myelodysplastic syndromes

BackgroundDiagnosis of myelodysplastic syndromes (MDS) is often challenging and requires integration of clinical, morphologic, cytogenetics and molecular information. Flow cytometry immunophenotyping (FCIP) can support the diagnosis by demonstration of numerical and immunophenotypic abnormalities of progenitor and maturing myelomonocytic and erythroid populations. We have previously shown that comprehensive immunophenotypic analysis of the progenitor population is valuable in the diagnosis of MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This study was designed to improve the analysis method and confirm its value in a larger cohort of patients. MethodsFCIP of bone marrow samples from 105 patients with cytopenia(s) (with or without leukocytosis) and clinical concern for MDS or MDS/MPN was performed using a single-tube/10-color/13-marker assay. A modified analysis approach was used to obtain 11 progenitor parameters and 2 myelomonocytic parameters. ResultsSignificantly higher number of abnormalities were identified in MDS and MDS/MPN cases when compared to cytopenic patients not meeting the diagnostic criteria for MDS (Non-MDS). A FCIP score that combined the 13 parameters showed a sensitivity of 89.8% and specificity of 93.5% for the diagnosis of MDS and MDS/MPN. The sensitivity was 100% for both MDS/MPN and higher-risk MDS, and 81.3% for lower-risk MDS. ConclusionThis study confirms that detailed immunophenotypic analysis of the progenitor population is powerful in the diagnosis of MDS and MDS/MPN. The combination of markers used in the panel allowed for evaluation of two relatively new parameters, namely myeloid progenitor heterogeneity and stem cell aberrancy, which improved the sensitivity of the assay for lower-risk MDS.

Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis

AbstractPreexisting autoimmune disease affects between 10% and 30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in patients with MDS with and without autoimmune disease show discordant results. Using the Surveillance, Epidemiology, and End Results Medicare database, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 and 2017 and claim algorithms used to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents, and hematopoietic stem cell transplantation. Cox regression models estimated the impact on survival, and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15 277 patients with MDS, including 2442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, were predominantly female, and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.94; P < .001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR, 1.87; 95% CI, 1.17-2.99; P = .008), whereas no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low-risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis, simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.

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

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

Use of steroids in the management of low-risk myelodysplastic syndromes with autoimmune features.

The boundaries between myelodysplastic syndromes (MDS) and immune-mediated cytopenias are often difficult to establish and both conditions may benefit from immunosuppressive therapy. The optimal timing and doses of immunosuppressants are largely unknown. We systematically evaluated a retrospective cohort of 79 patients with low-risk MDS tested for anti-erythrocyte or anti-platelet autoantibodies to assess their frequency and the efficacy of immunosuppression, particularly with steroids. We found autoantibody positivity in 43% of cases and overt autoimmune diseases in 18%, including autoimmune hemolytic anemia, immune thromboctyopenia, and Evans syndrome. Steroid treatment improved cytopenia in about half of patients, with 26% achieving a complete recovery lasting for a median of 12 months. Better responses were observed in anemic patients with anti-erythrocyte autoantibodies than in those with anti-platelet autoantibodies, and the combination with recombinant erythropoietin (7/10) had a possible synergistic effect. Steroid doses were heterogeneous depending on the clinical intent (i.e., anti-inflammatory, immunosuppressive, anabolizing). Patients treated with a dose of 1 mg/kg day of prednisone for overt autoimmune cytopenia showed high rates of complete responses (60%). This observation suggests a trial with a short course (2-3 weeks) of standard steroid doses to ascertain efficacy and properly silence the autoimmune pathogenic mechanism. Steroid-related adverse events (16% of cases) should be monitored carefully in this elderly, frail population. In conclusion, features of autoimmunity are present in more than two-thirds of low-risk MDS patients and a trial with prednisone 0.5-1 mg/kg day for 2-3 weeks, with proper monitoring of adverse events, may be useful to improve cytopenias in selected cases.

POSTER: MDS-008 Impact of Timing of Achievement of Red Blood Cell-Transfusion Independence (RBC-TI) on Clinical Outcomes and Resource Utilization in Lower-Risk Myelodysplastic Syndromes (LR-MDS)

POSTER: MDS-008 Impact of Timing of Achievement of Red Blood Cell-Transfusion Independence (RBC-TI) on Clinical Outcomes and Resource Utilization in Lower-Risk Myelodysplastic Syndromes (LR-MDS)

MDS-008 Impact of Timing of Achievement of Red Blood Cell-Transfusion Independence (RBC-TI) on Clinical Outcomes and Resource Utilization in Lower-Risk Myelodysplastic Syndromes (LR-MDS)

MDS-008 Impact of Timing of Achievement of Red Blood Cell-Transfusion Independence (RBC-TI) on Clinical Outcomes and Resource Utilization in Lower-Risk Myelodysplastic Syndromes (LR-MDS)

MDS-358 Activity of Luspatercept and ESAs Combination for Treatment of Anemia in Lower-Risk Myelodysplastic Syndromes

MDS-358 Activity of Luspatercept and ESAs Combination for Treatment of Anemia in Lower-Risk Myelodysplastic Syndromes

POSTER: MDS-065 Treatment Patterns and Transfusion Outcomes Among Erythropoietin-Stimulating Agent (ESA)-Naïve Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) Receiving Luspatercept in Routine Clinical Practice in the United States (US)

POSTER: MDS-065 Treatment Patterns and Transfusion Outcomes Among Erythropoietin-Stimulating Agent (ESA)-Naïve Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) Receiving Luspatercept in Routine Clinical Practice in the United States (US)

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

ProGraME: A novel flow cytometry algorithm for the diagnosis of low-risk myelodysplastic syndromes in patients with cytopenia.

Flow cytometry (FC) is, together with morphology, genetics, and cytogenetics, used in the diagnostic assessment of cytopenia, as its value in evaluating bone marrow dysplasia been highlighted by several studies. However, despite the development of algorithms and guidelines, there is still a lack of standardization of the FC assessment of bone marrow dysplasia. By combining FC, together with morphological analysis and cytogenetic/molecular assessment in a training cohort of 209 patients, we created a novel score, ProGraME, which includes four parameters, each from a different cell lineage (Progenitor cells, Granulocytes, Monocytes, Erythroid precursors), solely based on relevant population gating. Points for ProGraME were attained for: lymphoid precursors ≤5% of all CD34+ cells (1.5 point); a granulocyte-to-lymphocyte side-scatter ratio ≤6 (1 point); a monocyte CD33-CV% ≥ 63 (2 points), and an erythroid precursor CD36-CV% ≥ 65 (2 points). Using a cutoff of ≥2 as suggestive of dysplasia, ProGraME showed a sensitivity of 91% and a specificity of 81% in the training cohort and 95% and 75%, respectively, in an independent validation cohort of 159 patients. In addition, ProGraME had a very high negative predictive value of 97.1% and 97.8% in the training and validation cohorts, respectively, offering a useful tool for excluding bone marrow dysplasia. Finally, among the 23 CCUS patients that scored positive for dysplasia with ProGraME in the training cohort, 16 of them (69%) carried high-risk mutations, suggesting that FC might help identify early changes of dysplasia. ProGraME can potentially optimize the FC diagnosis of low-risk myelodysplasia without minimal requirements of flow analysis other than accurate population gating.