International Prognostic Scoring System Research Articles

Comparison of the Revised 4 Th (2016) and 5 Th (2022) Editions of the World Health Organization (WHO) Classification in a Cohort of Patients with Lower-Risk Myelodysplastic Syndromes/Neoplasms (MDS) - a Glam Registry (REGLAM) Analysis

Background: The5 th (2022) edition of the WHO Classification for MDS recognizes MDS patients into two groups: MDS with defining genetic abnormalities and MDS morphologically defined. Further, the revised International Prognostic Scoring system (IPSS-R) assigns MDS patients into one of prognostic groups with distinct survival probabilities. However, both the IPSS-R and the 2022 WHO classification were developed based on data largely generated from patients in the high-income countries. There are limited data of how these systems perform in patients from developing and middle-income countries (LMIC). The primary objective of this study was to compare the performance of the two WHO classification: the revised 4 th (2016) and 5 th (2022) editions in IPSS-R defined Lower-Risk MDS Cohort of patients from LMIC in the GLAM registry. Methods: TheGlam Registry enrolls patients from 16 Latin-American countries, For this analysis, we selected Lower risk MDS (defined as IPSS <3.5) patients from Argentina, Brazil, Chile, Colombia, Mexico, Paraguay, and Uruguay. Patients with CMML and higher-Risk MDS were excluded. The study was conducted in compliance with local regulations, and all subjects signed inform consents. Descriptive statistics, Sankey Diagram, Kaplan Meier methods and the Confidential Interval for the 5-year survival probability were used to report the results. Overall survival (OS) was measured from time of diagnosis to last contact or death, and progression-free survival (PFS) was measured from time of diagnosis to disease progression, progression to acute myeloid leukemia (AML), or death. Results: A total of 223 LR-MDS patients were included in this analysis. Baseline characteristics and demographics are described in Table 1. Median age was 69 years, 47% were males, and 71% were non-Hispanic whites. The median blast count was 1% (range, 0-8%), and only 7% had therapy-related MDS. According to WHO-2016 edition, patients were classified as MDS-RS-SLD (n = 15 [6.72 %]); MDS-RS-MLD (n = 23 [10.3 %]); MDS-RS-T (n = 6 [2.7 %]), MDS-del(5q) (n = 15 [6.7 %]), MDS-SLD (n = 34 [15.2 %]), MDS-MLD (n = 116 [52 %]), MDS-EB1 (n = 11 [4.9 %]), MDS-EB2 (n = 0 [0 %]), and MDS-U (n = 3 [0.66 %]). According to WHO-2022 classification, subjects were classified as: MDS-del(5q) (n = 15 [6.7 %]), MDS-LB-SF3B1-RS (n = 40 [17.9% %]), MDS-biTP53 (n = 0 [0 %]), MDS-LB (n = 131 [58.7 %]), MDS-h (n = 27 [12.1 %]), MDS-IB1 (n = 10 [4.4 %]), MDS-IB2 (n = 0 [0 %]) and MDS-f (n = 0). Figure 1 represents the shifts in classification of patients between the 2016 and 2022 version. The 5-year survival probabilities (%) of MDS-SLD vs MDS-MLD (WHO-2016) was 62.5% (95CI 37.8-79.7) vs. 54.6% (95CI 39.9-65.6), and the 5-year PFS probabilities (%) for MDS-SLD vs MDS-MLD were 62.5% (95CI 37.8-79.7) vs 53.6% (95CI 39.9-65.6) respectively. There were no cases of biTP53-mutation among the 12.1% of patients who had testing for TP53. Three patients were re-classified from MDS-RS-MLD (WHO-2016) to MDS-LB (WHO-2022) because SF3B1 mutation was associated with complex karyotype, del(5q), del(7q) and/or TP53 monoallelic. Four patients with MDS-U (WHO-2016) were re-classified to MDS-LB (WHO-2022). MDS-LB category (WHO-2022) was a large and a very heterogeneous group with an OS and LFS of 5.2 years. Conclusions: Our study, to our knowledge, provides one of the first, if not the first, datasets from LMIC to describe characteristics of IPSS-R lower-risk MDS pts and their re-classification and corresponding survival according to the WHO 2016 and 2022 classifications. Limited availability of molecular analysis in real-life settings (e.g., TP53 mutations) highlights some of the challenges of using the 2022 WHO classification (as well as IPSS-M) LMIC. Understanding the epidemiology of MDS pts in LMIC is important especially as some of the newly approved agents for lower risk MDS are starting to be used in these countries.

Risk Factors Associated to Severe Episodes of Infection in Myelodysplastic Syndromes

INTRODUCTION. Mortality differs according to the Revised International Prognostic Scoring System (IPSS-R) risk categories in patients afflicted with myelodysplastic syndromes (MDS). Historically, high-risk (HR)-MDS (IPSS-R >3.5 points) is related to death caused by progression to acute myeloid leukemia (AML), while low-risk (LR)-MDS is associated with mortality due to severe infections (Nachtkamp K, et al. 2016), probably caused by neutrophile dysfunction and hindered oxidative burst. Studies of causes of death (COD) in MDS are scarce. A MD Anderson study in LR-MDS patients identified infections as the leading COD, followed by progression (Dayyani F, et al, 2010), while the Düsseldorf registry recognized infections as the main COD across all MDS categories (Neukirchen, J. et al, 2011). Considering that information in low- and medium-income countries is especially limited, this study aims to describe the characteristics and identify the risk factors for severe infectious events in patients afflicted by MDS in a third-level center in Mexico. METHODS. In this single-center retrospective study, we analyzed severe infection episodes, associated risk factors, and the COD in MDS patients.We included patients diagnosed with MDS from January 2000 to December 2021, according to the 2016 WHO criteria. We registered baseline characteristics and described the episodes of severe infection, defined as hospitalization events due to infectious diseases complicated with septic shock and/or respiratory failure requiring orotracheal intubation. We conducted uni- and multivariate analyses based on the following variables: neutropenia (≤0.5x10 9/L), monocytopenia (≤0.2x10 9/L), lymphopenia (≤1.0x10 9/L), ferritin (≥1,000ng/mL), autoimmune disease, MDS comorbidity index, COPD, granulocyte dysplasia, and treatment with azacytidine or pharmacological immunosuppression. RESULTS. We included 156 patients with MDS treated at our institution. Median age at diagnosis was 65 years (IQR; 55-75 years), 53% of which were women. Multilineage dysplasia was the most prevalent MDS type (59%), followed by excess blasts type 2 (11.5%). LR-MDS represented 68% (n=106), while HR-MDS, 32% (n=50). Hypocellularity in bone marrow biopsy was found in 24.4%. Eighty-seven patients developed 156 infectious episodes, 64.7% of which were severe. A median of 1 serious event (IQR: 0.75-1 event) occurred in each patient, with a median time to diagnosis of 13 months (IQR: 3.5-34.5 months). Infection sites and etiologies are described in Figure 1. Of note, we identified 14 fungal infections, 8 of them by Aspergillus, with a 37.5% death rate. Risk factors associated with increased severe infection risk were neutropenia during follow-up (OR 3.2; 95% CI 1.5-6.4; p=0.001), neutrophil hypogranularity at diagnosis (OR 2.1; CI 95% 1.1-4.1; p=0.029), hyperferritinemia (OR 2.46; CI 95% 1.2-4.9; p=0.011), and azacitidine treatment (OR 3.1; CI 95% 1.01-9.6; p=0.047). Fifty patients (32%) died. In both HR-MDS and LR-MDS groups, the main COD was infection (13 in HR group, 48.1%, vs 10 in LR group, 43.5%; p=0.782), followed by progression to AML (3 in HR group, 11.1%, vs 4 in LR group, 21.7%; p=0.444). Median overall survival was lower in patients with severe neutropenia (62 vs. 210 months; p=0.009) and hyperferritinemia (62 months vs. non-reached, p<0.001) (Figure 2). CONCLUSIONS In our MDS population severe infections represent the leading COD, regardless of risk category. More than half developed at least one infectious episode, 64.7% of which were severe. Fungal infections were highly lethal, suggesting antifungal prophylactic interventions could prove helpful. We found neutropenia during follow-up and hypogranularity at diagnosis to be significant risk factors, the latter perhaps reflecting neutrophil disfunction which should be further evaluated. Hyperferritinemia's association with increased infection and mortality urges to further understand its role in MDS pathophysiology, and could potentially prove a therapeutic target in infections disease prevention. Additionally, there is currently no consensus on infectious disease for use of azacitidine, which might add to a worsening risk of infection.

Molecular Measurable Residual Disease (MRD) Clearance (≤1%) Is Associated with Improved Clinical Outcomes in Patients with Higher-Risk Myelodysplastic Neoplasms (HR-MDS): An Exploratory Analysis of Stimulus-MDS1 in Patients Receiving Sabatolimab or Placebo + Hypomethylating Agent (HMA)

Background: Sabatolimab (MBG453) is a novel immunotherapy targeting TIM-3, an immuno-myeloid regulator expressed on both immune and leukemic stem cells. In the randomized, double-blind, placebo-controlled, Phase (Ph) II STIMULUS-MDS1 study (NCT03946670) in patients (pts) with HR-MDS, although improvements in complete remission (CR) and progression-free survival (PFS) were not statistically significant, sabatolimab + HMA was associated with longer duration of response (DoR), and the data suggest a delayed-onset benefit in the sabatolimab arm, as well as a potential treatment effect in pts with lower disease burden (Zeidan AM, et al. ASH 2022). The clinical significance of MRD in HR-MDS is not well established. We report an exploratory analysis of mutational clearance and MRD by next-generation sequencing (NGS) to evaluate the association with clinical outcomes. Methods: Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. ASH 2022). Peripheral blood (PBMC) and/or BM mononuclear cell (BMMC) samples were collected and NGS performed on genomic DNA extracted from baseline (BL) and on-treatment samples using a 38-gene NGS-error-corrected panel with sensitivity of 2% and 0.2% variant allelic frequency (VAF), respectively. Concordance and correlation between PBMC and BMMC were assessed. The prognostic value of clonal clearance at different VAF cut-offs (0.2%, 0.5% or 1%) was assessed. MRD-x status was defined as any mutation call above VAF cut-off x, excluding mutations in DNMT3A, TET2 and ASXL1 ( DTA). Association between MRD status and clinical outcomes was analyzed regardless of treatment to increase sample and used best overall response, 6-month landmark analysis, and a time-dependent Cox model to rule out immortal bias. Results: NGS was run on 332 BMMC samples from 112 pts and 439 PBMC samples from 123 pts (127 pts randomized). 112 pts had ≥1 qualifying BL mutation (NGS cohort) and 106 pts (sabatolimab + HMA, N=56; placebo + HMA, N=50) had ≥1 at follow-up (MRD cohort). BL characteristics were balanced between NGS/MRD cohorts and between treatments in the MRD cohort. Overall agreement in mutation calling at variant level between BMMC and PBMC was >97% (8312/8566 total mutation calls), with >88% positive (817/926) and >98% negative agreement (7495/7640). Across reported mutated variants (N=817), there was good correlation (pearson cor=0.88) in VAF between BMMC and PBMC. When considering all paired samples, concordance of best MRD status using PBMC or BMMC results at the pt level (N=95) was: MRD-0.2, 97%; MRD-0.5, 89%; MRD-1, 90%. Given good PBMC and BMMC agreement, results were combined (higher VAF used if both) for outcomes analysis. In the MRD cohort, 11% (N=12), 18% (N=19) and 27% (N=29) of pts achieved MRD-0.2, MRD-0.5 and MRD-1 negativity, respectively. Most pts with MRD-0.2, -0.5 and -1 clearance had documented response of CR/marrow CR [mCR] (>80%) or CR/partial remission [PR]/hematologic improvement [HI] (>75%). Best overall response of MRD-1 negativity achieved anytime on treatment was associated with improved PFS and overall survival (OS) in the overall population and for responding pts (CR/mCR or CR/PR/HI). Similar results were obtained in a landmark analysis at 6 months ( Fig 1). This was supported by a time-dependent Cox-model indicating that MRD-x negativity was associated with a lower hazard ratio for PFS and OS vs MRD-x positivity ( Fig 2). A consistently higher proportion of pts in the sabatolimab (N=56) vs placebo (N=50) arms had on-treatment mutation clearance at different cut-offs: MRD-0.2, 16.1% vs 6.0%; MRD-0.5, 25.0% vs 10.0%; MRD-1, 35.7% vs 18.0%, respectively. Conclusions: We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA. These findings will be further explored in the ongoing Ph III STIMULUS-MDS2 study (NCT04266301).

Sabatolimab in Combination with Hypomethylating Agents (HMAs) Was Safe in Patients (Pts) with Intermediate-, High-, or Very-High-Risk Myelodysplastic Syndrome (MDS)

CONCLUSIONS Complete remission (CR) with standard-of-care HMAs in pts with intermediate-, high-, and very-high-risk MDS is usually infrequent and transient, and prognosis remains poor for these pts, who have limited second-line treatment options. Sabatolimab is a high-affinity, humanized anti-TIM3 IgG4 monoclonal antibody that blocks the TIM3 immune checkpoint receptor, which is preferentially expressed on leukemic stem cells and blasts and plays a key role in regulating adaptive and innate immune responses. In a phase Ib study, sabatolimab in combination with intravenous (IV) HMA was safe and well tolerated in pts with high-risk MDS with overall response rates of 61.1% and 57.9% with decitabine and azacitidine, respectively. We present an interim analysis of the STIMULUS-MDS US trial (NCT04878432) to assess the safety of sabatolimab in combination with not only parenteral but also oral HMAs in pts with intermediate-, high-, and very-high-risk MDS. This is a multicenter, phase II, open-label, single-arm study of sabatolimab in combination with HMAs. Adults aged ≥18 years with intermediate-, high-, or very-high-risk MDS per Revised International Prognostic Scoring System criteria who were not previously treated with HMAs were eligible. Pts received an HMA of investigator's choice (decitabine/cedazuridine 35 mg/100 mg oral days 1-5, decitabine 20 mg/m 2 IV days 1-5, or azacitidine 75 mg/m 2 IV or subcutaneous [SC] days 1-7 or days 1-5 plus days 8 and 9) with sabatolimab 800 mg IV every 4 weeks starting at day 8 or any day between days 5 to 8. The primary objective of this study was to assess the safety of sabatolimab in combination with oral, IV, and SC HMAs. Secondary objectives included assessing the efficacy of the combination. The study includes a core phase for up to 12 months, an extension phase for efficacy and survival status up to 12 months after the core phase, and a post-treatment safety follow-up for 30 days following the last dose of HMA or 150 days following the last dose of sabatolimab, whichever is later. This interim analysis included 33 pts with intermediate-, high-, and very-high-risk MDS at the data cutoff of 6 months after cycle 1 day 1 of treatment with sabatolimab and an HMA. The median age was 69 years (range, 39-86). At data cutoff, 8 pts were in ongoing treatment, and 25 pts had discontinued the core phase. Reasons for discontinuation included new therapy for study indication (n=6), physician decision (n=6), pt decision (n=5), progressive disease (n=4), unsatisfactory therapeutic effect (n=2), adverse event (AE) (n=1), and death (n=1). Of those who discontinued study treatment, 6 pts were in ongoing evaluation in the extension phase and 3 pts were in ongoing evaluation in the post-treatment follow-up phase. The median duration (range) of exposure was 3.9 (0.92-5.91) months for sabatolimab and 4.2 (1.05-6.08) months for HMAs. Among 33 pts evaluable for safety, most experienced all-grade and grade ≥3 AEs, AEs requiring additional therapy, and serious AEs (Figure). However, the most frequent (≥10%) grade ≥3 AEs were expected hematologic AEs, including febrile neutropenia (42.4%), anemia (39.4%), neutrophil count decrease (39.4%), and platelet count decrease (36.4%). Nonhematologic grades ≥3 AEs occurring in >1 pt included hypertension (18.2%), pneumonia (9.1%), hypoxia (6.1%), and fall (6.1%). Only 1 pt was reported with encephalopathy leading to treatment discontinuation, which was not attributed to study treatment. One pt had a fatal AE for which the cause was not identified but not thought to be related to study treatment by the investigator. The best overall response results in up to 6 months of treatment were available for 22 pts. Marrow CR (mCR) with and without hematologic improvement (HI) was reported in 18.2% and 9.1%, respectively. Partial remission (PR) and stable disease (SD) with HI was reported in 4.5%, each. CR + mCR + PR was 31.8% (95% CI, 13.9%-54.9%), CR + PR + HI was 27.3% (95% CI, 10.7%-50.2%), and CR + mCR + PR + HI was 36.4% (95% CI, 17.2%-59.3%). This interim analysis of the STIMULUS-MDS US study demonstrated that sabatolimab in combination with an oral, IV, or SC HMA was safe and well tolerated, with AEs consistent with previous reports for pts with MDS treated with HMAs. Response rates for the combination are preliminary, and more information will be provided with longer follow-ups.

Clinical, Cytogenetic and Molecular Characterization of a 96 MDS and AML Cohort with TP53 Mutation

Introduction The last European LeukamiaNet (ELN) recommendations (Döhner H. et al. Blood. 2022) and the International Consensus Classification (ICC, Hasserjian R.P. et al. Virchows Arch. 2023) described a new entity, called myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) with TP53 mutation ( TP53mut), comprising high-risk MDS with an excess of bone marrow blasts cells (more than 10%) and a TP53 mutation (variant allele frequency VAF ≥ 10%). They suggested that MDS and AML represent a biologic continuum rather than two distinct diseases separated by a blast cutoff. Among teams who worked on that topic, T. Grob et al. ( Blood. 2022) studied the molecular characterization of high-risk AML and MDS with TP53mut and suggested that these two types of pathologies should be considered as a single entity, with no difference in molecular characteristics or survival. In this study, we describe the clinical, cytogenetic, and molecular characteristics of a cohort of 96 MDS and AMLs with TP53mut. Patients and methods We included all the patients with AML, MDS/AML, MDS with increased blasts (MDS-IB1) and MDS-low blast (MDS-LB) with at least one TP53mut (VAF ≥ 1%) received between Aug. 2020 and Dec. 2022 at the Institut Paoli-Calmettes (IPC, Marseille, France). Clinical and biological data were extracted retrospectively from the AML IPC database. Morphologic and cytogenetic data were analyzed by standard techniques. NGS was performed using a custom targeted panel of 60 genes (Custom Myeloid Lymphoid Solution, SOPHIA GENETICS). Results We registered 96 patients with a TP53 mutation (VAF ≥ 1%), divided into AML (n=60), MDS/AML (n=14), MDS-IB1 (n=12) and MDS-LB (n=10). Median age was 71 (range, 28-88). Thirty-eight patients had been treated for a prior solid malignancy and 26 patients had a history of myeloid malignancy. TP53mut was detected at diagnosis for 85 patients and at relapse or during follow-up for 12 patients (no NGS data available at diagnosis). We detected 142 mutations in the TP53 gene, mostly missense (73%) between exon 4 and exon 11 with a median VAF of 39% (Figure 1). We found 3 hotspots mutations in positions 273, 248 and 220 with respectively 9, 9 and 8 mutations. Biallelic status (presence of ≥ 2 mutations or a mutation + a deletion) was found in 66 patients (69%). Karyotypes were available for 95 patients. The karyotype was abnormal in 88% of cases, complex in 71% and unfavorable in 80% of cases according to ELN classification or Revised International Prognostic Scoring System (R-IPSS). Complete NGS analysis revealed at least one mutation in 59 of the other genes of the panel in 67 patients (70%), the most frequent being DNMT3A (22%), TET2 (17%), ASXL1 (13%) and PPM1D (11%) (Figure 2). In our cohort of TP53mut LB-MDS (n=10), we found that 9/10 patients had co-mutations in DNMT3A (n=4) , TET2 (n=6) and PPM1D (n=2) genes, 7/10 with biallelic status and 3/10 with complex karyotype. AML and MDS/AML patients with TP53mut detected at diagnosis (n=65) were treated with intensive chemotherapy (n=13), VEN-AZA (n=26), non-intensive therapy (n=14) or best supportive care (BSC, n=12). Seventeen patients were treated with allogeneic stem-cell transplantation (ASCT). With a median follow-up (FU) of 13 months, median overall survival (OS) of the whole cohort was 7 months (ranges, 1-41). Median OS in the AML and MDS/AML group was 6 months (ranges, 1-41). Patients treated with non-intensive approach had the longest median OS (15 months) compared to patients treated with intensive chemotherapy and VEN-based approaches (8 and 6 months, respectively) and patients treated with BSC (1 month, p=0.02). Patients with MDS-IB1 and MDS-LB had 11-months median OS (ranges, 1-28). The four patients treated with upfront ASCT were still alive at the last FU date and have an estimated median OS of 18.5 months (ranges, 6-26). Conclusion Our data confirm that MDS and AML with TP53 mutation are frequently associated with complex karyotypes and have a poor prognosis. nterestingly we identified mutations in PPM1D gene, involved in TP53 pathway, in 11% of cases. Patients with AML or MDS/AML treated with non-intensive approach seem to have the longest OS (15 months). Patients with MDS-IB1 or MDS-LB treated with upfront ASCT seem to have a prolonged OS (18.5 months). Clinical, functional and mechanistic studies are required to complete these findings.

Perspectives on Myelodysplastic Neoplasm Diagnosis: A Comparative Analysis of the Latest World Health Organization Classifications and the International Concensus Classification

Introduction : Myelodysplastic neoplasm (MDS) is a category of clonal hematopoietic stem cell neoplasms, defined by cytopenias and morphologic dysplasia, characterized by progressively ineffective hematopoiesis and increased risk of acute myeloid leukemia (AML). The 5th edition of the World Health Organization (WHO 2022) classification grouped MDS entities into two families: those having defining genetic abnormalities and those that are morphologically defined. The former newly included biallelic TP53 inactivation (MDS-biTP53) and SF3B1 mutation, meanwhile the latter newly included hypoplastic MDS (h-MDS) and MDS with fibrosis (MDS-F). An independent proposal, the International Consensus Classification (ICC), was also published during the same period. This study aims to compare and analyze these two classifications, focusing on MDS's diagnostic criteria and entity definition. Herein, we describe the redistribution of the MDS according to the WHO 2022 classification and ICC and evaluated their significance in predicting patient's outcomes. Methods : This study included a total of 639 patients who were diagnosed with MDS based on the 4th edition of WHO classification in Seoul St. Mary's hospital from 2016 to 2022. As part of the study, all patients were reclassified using the updated WHO 2022 classification and ICC through a comprehensive review of bone marrow aspiration and biopsy, as well as the results of whole genetic studies, including cytogenetic analysis, fluorescence in situ hybridization, and targeted panel next-generation sequencing. Risk stratification was determined by using the International Prognostic Scoring System for MDS (IPSS-R, WPSS and IPSS-M). Results : Among the 639 patients, six were classified as ‘clonal cytopenia of undetermined significance’ by WHO 2022 and ICC. In the WHO 2022 classification, 22 patients were categorized as AML, whereas ICC only identified nine of them due to low blast count (<10%). Out of the newly defined MDS patients (n=611), 12.6% (n=77) were genetically defined MDS, and 87.4% (n=534) were morphologically defined MDS. Regarding the WHO 2022 categories, MDS-biTP53 and MDS-SF3B1 accounted for 5.4% (n=33) and 6.3% (n=39) of cases, respectively, whereas h-MDS and MDS-F accounted for 11.9% (n=73) and 1.8% (n=11), respectively. As for the ICC, MDS, not otherwise specified (NOS) accounted for 327 patients with 77 having single lineage dysplasia and 250 having multilineage dysplasia. The h-MDS was also included in these criteria. Of 33 MDS-biTP53 cased identified by the WHO 2022 classification, 25 were categorized as MDS-TP53 and 8 as MDS/AML-TP53 in the ICC, which included an additional four patients. Moreover, 72 patients were classified as MDS/AML by ICC, with 35 of them presenting genetic mutations and 9 exhibiting cytogenetic abnormalities. The median survival of the 611 patients were 86 months (95% confidence interval (CI): 65-111). The WHO 2022 classification demonstrated significant prognostic discrimination based on diagnosis subtype (P <0.001). MDS-biTP53 exhibited the worst outcome [hazard ratio (HR): 7.24, 95% CI: 2.87 to 18.22], followed by MDS-F (HR: 5.64, 95% CI: 1.44 to 22.08) and MDS-IB2 (HR: 2.76, 95% CI: 1.72 to 4.42), in comparison to MDS-LB. On the other hand, the ICC did not reveal significant prognostic significance. The distribution of IPSS-R, WPSS and IPSS-M was similar and also showed meaningful prognostic discrimination (P <0.001). Conclusions : The results validated the clinical relevance of updated WHO 2022 classification for MDS and indicated that the newly defined categories such as MDS-biTP53 and MDS-F are unique disease types evidenced by their particular prognostic significance.

Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)

CONCLUSIONS Imetelstat, an oligonucleotide and a first-in-class telomerase inhibitor, selectively targets malignant hematopoietic stem and progenitor cells with high telomerase activity by direct binding to the RNA template. In patients with MDS the on-target effects of imetelstat are associated with the development of hematologic treatment-emergent adverse events (TEAEs). In the IMerge phase 3 trial, among patients treated with imetelstat, 68% experienced grade 3-4 neutropenia, and 62% had grade 3-4 thrombocytopenia; however, clinical consequences of grade 3-4 infection or bleeding were similar in patients treated with imetelstat and placebo (Platzbecker et al. EHA 2023. Abstr S165). Here, we report additional data on the occurrence and management of cytopenias after treatment with imetelstat. IMerge phase 3 trial (NCT02598661) is a multicenter study involving 178 patients with a median age of 72 years with red blood cell (RBC) transfusion dependency and LR-MDS relapsed/refractory to or ineligible for erythropoiesis-stimulating agents. Patients were randomized 2:1 to receive either imetelstat or placebo and stratified by prior RBC transfusion burden (4-6 or >6 U) and by International Prognostic Scoring System risk group. The safety population included all patients who received ≥1 dose of study drug and comprised 118 patients treated with imetelstat and 59 with placebo. TEAEs of neutropenia and thrombocytopenia with imetelstat treatment were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time: 42.7% and 48.5% in cycles 4-6, 36.8% and 44.7% in cycles 7-12, and 31.3% and 37.5% in cycle 13 and beyond. Based on laboratory assessment, neutrophil and platelet counts decreased from baseline levels in patients treated with imetelstat versus those treated with placebo (91.5% and 95.8% vs 47.5% and 33.9%, respectively). Neutropenia decreased to a maximum of grade 4 and 3 in 55 and 29 of imetelstat-treated patients, respectively, and >80% of cytopenia events stabilized to grade ≤2 within 4 weeks (Figure). The median time to grade 4 neutropenia was 5.0 weeks (range,1.1-90.3 weeks) for the imetelstat group vs 23.0 weeks (range, 23.0-23.0 weeks) for the placebo group. Similarly, median time to grade 4 thrombocytopenia was 5.2 weeks (range, 2.0-29.9 weeks) with imetelstat vs 35.5 weeks (range, 28.0-43.0 weeks) with placebo. It is noteworthy that among 47 patients who achieved the primary end point of 8-week RBC transfusion independence with imetelstat, 34 (72.3%) and 28 patients (59.6%) had grade 3-4 neutropenia and grade 3-4 thrombocytopenia, respectively. In the imetelstat group, 3 patients had grade 3-4 neutropenia concurrent with grade 3-4 infections, and no patients experienced grade 3-4 thrombocytopenia associated with grade 3-4 bleeding events. There were no grade 5 cytopenias for either imetelstat or placebo groups. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 39 patients (33.1%) and 27 patients (22.9%), respectively. Of imetelstat-treated patients, 6 (5.1%) discontinued treatment due to neutropenia (1 case, grade 4; all others, grade 3), and 4 (3.4%) discontinued due to thrombocytopenia (1 case, grade 2; 3 cases, grade 3). In addition to dose reductions and discontinuation of imetelstat, thrombocytopenia and neutropenia were managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Similar patterns of imetelstat dose modifications were seen in a pooled phase 2 and phase 3 safety analysis of IMerge. In the IMerge phase 3 trial, thrombocytopenia and neutropenia were the most common and most frequently reported grade 3-4 AEs during treatment cycles 1-3. However, these AEs were generally transient, reversible, and manageable through treatment delays and dose adjustments, allowing for patients to remain on treatment and continue to experience clinical benefit. Moreover, occurrence of grade 3-4 cytopenias in responders suggests that these TEAEs do not affect the efficacy of imetelstat.

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.

Ethnic Diversity in Presentation of Waldenström Macroglobulinaemia and IgM Mgcs in the United Kingdom- a Real-World Data Analysis

Introduction: Waldenström Macroglobulinaemia (WM) is a low-grade B-cell lymphoma characterised by lymphoplasmacytic marrow infiltration with a circulating IgM protein with an incidence of approximately 0.55 cases per 100,000 in the United Kingdom (UK). WM may be asymptomatic, symptomatic and/or associated with IgM-related entities (monoclonal gammopathies) of clinical significance (MGCS). A central aim of the WMUK Charity and Clinical Forum is to systematically upload demographic, clinical data and treatment outcomes from a significant proportion of the UK's WM population. Such data provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Clinical correlates with ethnicity are important but sparsely characterised. This analysis focusses on baseline demographics and outcomes across different ethnic groups in the UK. Methods: We retrospectively reviewed data from the Rory Morrison WMUK Registry, collating descriptive data of WM, non-IgM lymphoplasmacytic lymphoma and IgM MGCS from 24 centres across the UK, diagnosed between June 1978 and June 2023. Research ethics approval was obtained. Baseline characteristics were compared using χ 2 or Fisher's exact tests (categorical variables) or Wilcoxon Mann-Whitney/Kruskal-Wallis tests (continuous variables). Differences were considered significant at p-values <0.05. Statistical analyses were performed using STATA v17.0 (StataCorp, Texas, USA). Results: 1073 patients with documented self-reported ethnicity and a diagnosis of WM (n=985), non-IgM LPL (n=32) or IgM MGCS (n=88) were included. Those with asymptomatic IgM MGUS were excluded. Of 982 with a diagnosis of WM, 12% (114/985) had concurrent MGCS. Across the entire cohort, IgM MGCS comprised peripheral neuropathy including anti-MAG neuropathy (n=114), cold agglutinin disease/syndrome (n=43), AL amyloidosis (n=20), mixed autoimmune haemolytic anaemia (n=13), cryoglobulinaemia (n=8), Schnitzler syndrome (n=8) and C1 esterase deficiency (n=2). Non-IgM LPL had similar baseline characteristics to WM although a trend towards a lower presenting M-protein (7g/l vs 18g/l, p=0.07). Ethnicity was categorised in accordance with the UK National Census (ethnicity-facts-figures.service.gov.uk). The majority was white (90%; 968/1073: English/Welsh/Scottish/Irish) including 35 patients identified as ‘other’ white. The remaining 105 (10%) were from the following ethnic groups (collectively ‘ethnic minorities’, EM): 54 Asian (22 Indian, 4 Pakistani, 1 Bangladeshi, 7 Chinese, 20 other), 19 Black (5 African, 11 Caribbean, 3 other), 6 Mixed/multiple, 26 Other ethnic group. EM presented at a younger age compared to the white cohort (60 vs 65 years, p<0.001) with a lower presenting M-protein at WM diagnosis (11g/l vs 18g/l, p=0.028). A similar proportion of patients had IgM MGCS in white vs EM cohorts (11% vs 8%, p=0.69). In those with IgM MGCS alone, presenting M-protein was similar across both ethnic categories (5g/l vs 3g/l, p=0.36). MYD88 L265P mutation was assessed in 387 WM patients (36%), of which MYD88 L265P was identified in 88% (322/364) and CXCR4 mutation tested in 91 patients and mutated in 29% (26/91). MYD88-mutated WM was observed less frequently in the EM versus white cohorts (79% vs 90%, p=0.05). A similar proportion presented with symptomatic WM across ethnic groups (56% vs 53%, p=0.56). In those with WM diagnosed since 2010 (n=956), median follow up was 8 years (95% CI 7-8), median overall survival was not reached. International Prognostic Scoring System for WM (IPSSWM) was predictive of overall survival. Overall survival estimates did not differ when comparing ethnic groups. Conclusions: Analysis of the national registry for WM shows that ethnic minorities comprise 10% of WM/IgM MGCS, present with WM at a younger age, a lower M-protein and with a higher proportion of MYD88-wild type cases which may suggest different disease biology. There was no difference in overall survival in our cohort. Limitations include the retrospective analysis of real-world data and incomplete documentation of baseline data. Further analysis of molecular signatures across ethnicities, treatment and outcome is warranted and ongoing.

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction MDS are genetically heterogenous neoplasms with diverse prognoses. While hypomethylating agents (HMA) can improve outcomes, HSCT remains the only potentially curative therapy. The IPSS-M incorporates clinical and molecular features to improve outcome prediction beyond traditional risk stratification tools. The IPSS-M has been validated in studies that either variably included pts who underwent HSCT, were limited by sample size, or were single-institution analyses. We aimed to validate the performance of the IPSS-M in predicting outcomes among pts with MDS who were treated with HMAs and subsequently underwent HSCT. Methods The VALIDATE database includes MDS pts treated with frontline HMA from 14 specialized centers. Only pts with available molecular data pre-HMA therapy and subsequently underwent HSCT were included. Time-to-event analyses used Kaplan-Meier estimator and the log-rank test. Overall survival (OS) was measured from time of HSCT. Multivariate-adjusted survival analysis used Cox proportional hazards. We compared the different scoring scores by Harrell's c-index. This study was supported by an independent research grant from AbbVie. Results A total of 350 pts met eligibility ( Panel A). Median age was 63 years (IQR: 58-68). MDS with excess blasts 1/2 (66%) was the most common type. Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. The most prevalent mutations were TP53 (29%), ASXL1 (21%), RUNX1 (13%), STAG2 (12%), SRSF2 (12%), and DNMT3A (11%); 53% of pts had disease harboring >1 gene mutation. Only 44% had TP53 CN-LOH and 40% had MLL-PTD testing. The most common donor types were matched unrelated donors (MUD, 46%), haploidentical donors (21%), and matched related donors (MRD, 17%). Myeloablative, non-myeloablative, and reduced-intensity conditioning were used in 38%, 27%, and 27% of the pts, respectively. Only 14% of pts received post-HSCT maintenance therapy. Our cohort was enriched with very high risk (41%) and high risk (30%) IPSS-R groups at time of diagnosis, while very low (1%), low (9%), and intermediate (20%) IPSS-R risk groups accounted for remaining 29% of pts. According to the IPSS-M, pts were classified into very low (2%), low (10%), moderate low (13%), moderate high (14%), high (27%) and very high (34%) risk groups. The IPSS-M re-stratified 198 (57%) pts, of whom 77 (39%) pts were up-staged and 121 (61%) pts were down-staged. More specifically, 35% and 26% of pts with intermediate risk IPSS-R MDS, and 32% and 35% of pts with high risk IPSS-R MDS were up-staged and down-staged, respectively. Importantly, 45% of pts with very high risk IPSS-R MDS were down-staged. Median follow-up time was 20 (IQR:8-36) months (mo). The median OS for the entire cohort was 32 mo (IQR:10-Not reached [NR]). The IPSS-M groups showed significantly different OS (p-value= 0.001, Panel B)withmedian OS (mo, 95%CI) of: very low (NR, 11.5-NR), low (55, 22-NR), moderate low (48, 25-NR), moderate high (35, 22-NR), high (29, 23-NR), and very high (20, 13-28). The 5-year OS (%) were as following: very low (56%), low (47%), moderate low (37%), moderate high (40), high (43%), and very high (17%). IPSS-M risk (HR: 1.3, 95% CI:1.1-1.5) was significantly associated with OS in a multivariable model (HR, 95%CI) adjusted for age (1.01, 1.00-1.03), sex (1.2, 0.9-1.7), type of HMA used before HSCT (1.0, 0.9-1.1), number of HMA cycles (1.0, 0.9-1.05), donor type (1.0, 0.9-1.1), and conditioning regimen used (1.3, 1.1-1.5). For OS, the IPSS-M significantly stratified pts assigned to the very high risk IPSS-R subgroup (p=0.009). However, the IPSS-M showed comparable performance to IPSS-R with c-index (95%CI): 0.597 (0.555-0.640) vs. 0.599 (0.554-0.643), respectively, for OS. When IPSS-M/IPSS-R were analyzed as continuous scores, the c-index (95%CI) for OS were: 0.606 (0.561-0.651) vs. 0.611 (0.559-0.662). When focusing on the higher risk group defined as IPSS ≥.1.5, the IPSS-M (c-index: 0.584) still had performance comparable to the IPSS-R (c-index: 0.606). Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

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.

IPSS-M - Use for Predicting Survival and Progression in Patients with Ccus - a Retrospective Multi-Institutional Study

Background: Clonal cytopenia of undetermined significance (CCUS) is characterized by the presence of a clone with somatic mutations in genes associated with myeloid neoplasms (MN) or abnormal cytogenetics, along with unexplained and persistent cytopenias in the absence of significant marrow dysplasia. CCUS is considered a premalignant state with a risk of progression to MN. The clinical outcomes of patients (pts) with high risk CCUS (Weeks et al, NEJM Evidence 2023) may be similar that of some patients with myelodysplastic syndromes (MDS). This study aims to predict the outcomes of CCUS patients using the molecular international prognostic scoring system (IPSS-M) developed for MDS. Methods: A retrospective analysis was conducted in patients diagnosed with CCUS between 2015 and 2023, we included patients harboring pathogenic mutations (MUT) identified through next-generation sequencing (NGS) testing at two institutions: Mayo Clinic and the University of Texas Southwestern Medical Center, Dallas, TX, USA were included. Progression was considered present if patients with CCUS progressed into myeloid neoplasm at follow up. Statistical analysis was performed using JMP® 17.1.0 Software. IPSS-M risk scores were calculated via the IPSS-M Risk Calculator (mds-risk-model.com). Results: A total of 103 patients were included in the study. The median age was 72 years, the majority were male patients (73%), and the median bone marrow blast % at the time of NGS was 1%. Forty-five % had an isolated mutation in a single gene, and 55% had co-mutations in ≥1 gene. The median number of mutations was 2 (range 1 - 5), occurring across 43 different genes. The most common mutations were in TET2 (N=28; 27%), ASXL1 (N=21; 20%), SRSF2 (N=21; 20%), U2AF1 (N=18; 17%), DNMT3A (N=16; 16%), and TP53 (N=12; 12%). Additionally, 25% of patients had an abnormal karyotype. Hematologic and genetic characteristics are summarized in (Table 1A). The median IPSS-M score was -0.9 (-3 to +2.34) and the median IPSS- Revised (R) score was 2 (0 - 6). The majority of patients had low (L) IPSS-M risk category (53%), followed by moderate low (ML) (19%) and very low (VL) (17%). Per IPSS-R, the majority had low-risk category (47%), followed by VL (38%) and intermediate (14%). Overall, 26 (25%) pt died after a median follow-up of 34 months and 21% progressed to MN (MDS 14 & CMML 8), and 1 patient with MDS and 1 with CMML progressed to secondary AML (2%). The median overall survival (mOS) was not reached, with a 2-year estimated (YE) OS and leukemia-free survival (LFS) of 80%. Predictive Power: When utilizing the IPSS-M risk category ( L, M, H) * by combining the risk categories into L *(L+VL), M * (ML+MH), and H *(H+VH) to overcome the low sample size limitation, it significantly predicted OS (p < .0001) ( Figure 1A) and median MN-free survival (FS) (p < .0001) ( Figure 1B). The 2YE-OS rates by IPSS-M risk category were as follows: VL - 93%, L - 87%, ML - 75%, high (H) - 25%, very high (VH) - 0% and the 2YE-OS rates by IPSS-M ( L, M, H) are summarized in Table 1B. IPSS-M hazard ratio (HR) for OS was 1.6 for ( M*) compared to 25 for ( H *) risk category (p < .0001). The ( L *) category, being the largest, was used as the reference level. Conclusion: This study provides the first real-world experience of using the IPSS-M and a modified version of the IPSS-M ( L, M, H) * risk category model to predict survival and progression into MN in CCUS (MUT) pt. The IPSS-M risk category was found to be a significant predictor of OS and MN-free survival. We propose that larger cohorts are needed to validate our findings.

Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) across Different Risk Subgroups in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis-Stimulating Agents (ESAs) in IMerge Phase 3 Study

CONCLUSIONS IMerge (NCT02598661) is a phase 2/3 global study of imetelstat, a first-in-class telomerase inhibitor, for patients with RBC transfusion-dependent non-del(5q) LR-MDS R/R to or ineligible for ESAs, a population with unmet needs. Phase 3 results showed that the rate of ≥8-week, ≥24-week and 1-year RBC-TI was higher with imetelstat than placebo (Zeidan et al. ASCO 2023. Abstr 7004; Platzbecker et al. EHA 2023. Abstr S165). Toevaluate clinical efficacy of imetelstat across different International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), IPSS-R cytogenetic, or IPSS-molecular (IPSS-M) risk categories,cytogenetic analysis was performed centrally on bone marrow aspirates by karyotyping, and mutation profile was analyzed using peripheral blood samples by next-generation sequencing on a panel of 36 genes commonly mutated in MDS. Baseline IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk categories were derived for patients in the phase 3 portion of IMerge based on specific classification criteria, and rates of RBC-TI ≥8-week, ≥24-week, ≥1-year were assessed for each risk subgroup. In 105 IPSS-low patients, 95 (90.5%) remained IPSS-M very low/low/moderate low, and 10 patients (9.5%) upstaged to IPSS-M moderate high and high. In 50 IPSS-intermediate-1 patients, 39 (78%) remained IPSS-M very low/low/moderate low, and 11 patients (22%) upstaged to IPSS-M moderate high/high. Among 129 IPSS-R low/very low patients, 118 (91.5%) remained IPSS-M very low/low/moderate low, and 11 (8.5%) patients upstaged to IPSS-moderate high/high. In 25 IPSS-R-intermediate patients, 16 (64%) remained IPSS-M low/moderate low, and 9 patients (36%) upstaged to IPSS-M moderate high/high/very high. One IPSS-R high-risk patient remained IPSS-M high. Overall, significantly higher rates of ≥8-week, ≥24-week, and ≥1-year RBC-TI were achieved in patients receiving imetelstat (39.8%, 28%, and 13.6%) vs those receiving placebo (15%, 3.3%, and 1.7%). Further subgroup analysis demonstrated that imetelstat consistently had higher TI response rates than placebo across different risk subgroups, irrespective of classification system. For IPSS risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 40.0% vs 20.5% ( P = 0.034), 28.8% vs 5.1% ( P = 0.003), and 12.5% vs 2.6% ( P = 0.082), respectively, in patients with low risk and 39.5% vs 4.8% ( P = 0.004), 26.3% vs 0% ( P = 0.009), and 15.8% vs 0% ( P = 0.048), respectively, in patients with intermediate-1 risk. For IPSS-R risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 42.5% vs 19.6%, 29.9% vs 4.3%, and 11.5% vs 2.2%, respectively, in the low-risk subgroup. The TI rates of ≥8-week, ≥24-week, ≥1-year TI with imetelstat were 35%, 25%, and 20%, respectively, in the intermediate-risk subgroup, whereas placebo treatment had no response. The number of patients was too low in both arms of the very low or high IPSS-R subgroups to assess difference in TI response. For IPSS-R cytogenetic risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 37.1% vs 17.0%, 24.7% vs 4.3%, and 10.1% vs 2.1%, respectively, in very good/good risk groups and 54.5% vs 11.1%, 40.9% vs 0%, and 22.7% vs 0%, respectively, in the intermediate-risk group. For IPSS-M risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 47.8% vs 21.2%, 34.8% vs 3%, and 14.5% vs 0%, respectively, in patients with very low/low risk and 20.7% vs 6.3%, 10.3% vs 0%, and 6.9% vs 0%, respectively, in patients with moderate low/moderate high risk. In patients with high/very high risk, ≥8-week TI rates were 40% vs 0% with imetelstat vs placebo, with no ≥24-week or ≥1-year TI observed in either arm. All results are summarized in the Table. Improvement in RBC-TI rates was observed in patients treated with imetelstat vs placebo across different risk subgroups as defined by IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk profiles. Notably, placebo had not achieved durable (≥24-week and ≥1-year) TI response in the higher-risk groups irrespective of the risk classification assessment model used, while TI response rates with imetelstat in higher-risk subgroups with poor prognosis were similar to TI response rates in lower-risk subgroups of heavily transfused R/R ESA LR-MDS, indicating that clinical efficacy of imetelstat is independent of risk categories.

Favorable Outcomes for High-Risk MDS and Oligoblastic AML with MDS-Related Changes with Reduced Intensity Allogeneic Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide

Introduction: Newer classification systems label myelodysplastic syndrome (MDS) with 10-20% blasts and acute myeloid leukemia (AML) with MDS-related changes (AML-MR) on a continuum as they share common biologic features. The prognostic implication of blast percentage is less clinically relevant particularly in diseases with high-risk molecular features such as MDS/AML with TP53 mutations. The recently introduced Molecular International Prognostic Scoring System (IPSS-M) allows for a more personalized prognosis for MDS patients (pts) than the prior revised IPSS (IPSS-R), but it is less clear if this translates to better therapeutic choices or outcomes for pts. Allogeneic bone marrow transplantation (BMT) remains the only potentially curative approach. Increasingly clinical trials of novel compounds combined with hypomethylating agents (HMAs) have not shown improved efficacy over single agent HMAs, necessitating further study of BMT approaches for durable disease control across the spectrum of disease biology. No uniform approach to the conditioning regimen and GVHD prophylaxis for this pt population has proven superior. In the current study, we describe the outcomes of BMT with post-transplant cyclophosphamide (PTCy) for patients with high-risk MDS and oligoblastic AML-MR, and analyze the prognostic implication of their chromosomal and molecular profiles within the international scoring systems. Patients and methods: This is a retrospective analysis of patients with 5-30% blasts and IPSS-R ≥3 who underwent BMT with PTCy at Johns Hopkins Hospital between 1/2013 and 12/2020. Next generation sequencing (NGS) was performed within 12 months of diagnosis. Kaplan-Meier analysis was performed to evaluate overall survival (OS) and relapse-free survival (RFS). Competing risks analysis was performed to evaluate the incidence of relapse and non-relapse mortality (NRM). Cox-regression models were performed in univariate analyses with false discovery rate adjustment and then subsequently conducted for multivariable analyses to identify statistically significant and independent prognostic factors. Results: Ninety-four consecutive patients (65% male) were identified with a median age of 61 (range 22 - 75) years at diagnosis. Median follow-up was 4.8 years (range 5 days-9.6 years) post BMT. Two-thirds (63%) underwent haploidentical transplantation, and 91% received reduced intensity conditioning with Fludarabine, Cyclophosphamide, and TBI. Median age at BMT was 65 years (range 22 - 76). The median time from diagnosis to BMT was 7.9 months. 52 (57%) received HMA based treatment and 36 (39%) intensive chemotherapy prior to BMT. Graft failure occurred in 6 patients (6.4%) The 5-year OS rate was 53% (95% CI: 43%-65%), the 5-year RFS rate was 47% (95% CI: 38%-59%) ( Figure 1A). The incidence of relapse was 21% (95% CI: 13% - 30%) at 1 year and 31% (95% CI: 21% - 40%) at 2 years after BMT ( Figure 1B). NRM rate in the first-year was 7% (95% CI: 2%-13%) and 11% (95% CI: 4%-17%) in the first two years ( Figure 1B). The incidence of acute GVHD (aGVHD) grades 3 to 4 was 3.2%, whereas chronic GVHD (cGVHD) presented in 12 patients (12.7%) with only 2 patients (2.1%) having moderate to severe disease based on the NIH grading criteria. Univariate analysis showed that higher IPSS-R (HR 1.68, 95% CI 1.39 - 2.04), poor or very poor karyotype risk (HR 7.48, 95% CI 3.49 - 16.02), complex karyotype (HR 3.72, 95% CI 2.01 - 6.88), higher IPSS-M (HR 1.72, 95% CI 1.38 - 2.14), TP53 mutations (HR 6.53, 95% CI 3.36 - 12.7) and RAS mutations (HR 4.96, 95% CI 1.7 - 14.5) were associated with worse OS. IPSS-R was significantly correlated with the patients' response to bridge therapy (OR 1.34, P=0.036). IPSS-R, IPSS-M, poor or very poor karyotype risk, complex karyotype, TP53 and any RAS mutations and response to bridge therapy were independently associated with worse OS and RFS ( Table 1, Figure 1C). Conclusion: This retrospective analysis supports that BMT with PTCy is a durable approach for patients with high-risk MDS and oligoblastic AML-MR leading to high OS and RFS associated with a promising safety profile with low NRM and severe GVHD incidence. IPSS-R, IPSS-M, karyotype and response to bridge therapy are independent predictors of OS and RFS post-BMT. The presence of TP53 and/or RAS mutations defines a sub-group of patients with dismal outcomes representing an unmet need within this patient population.

HMR Mutations Drive Poor Prognosis in Myelofibrosis Patients with Lower JAK2V617F Allele Burden but Not in Those with Higher Allele Burden: Results of a Multicenter Study

JAK2V617F is the most common driver mutation in myelofibrosis (MF), followed by CALR and MPL alterations. Clinical variables included in the International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS), and DIPSS plus, as well as JAK2V617F allele burden are all well-established prognostic factors influencing the survival of MF patients. In addition, ASXL1, EZH2, SRSF2, IDH and U2AF1 mutations are classified as high-molecular risk (HMR) mutations in this context because of their close association with disease progression and leukemic transformation. However, the relationship between JAK2V617F allele burden and HMR mutations remains unclear. To address this, we recruited 122 MF patients (discovery cohort) diagnosed at the National Taiwan University Hospital (Taipei, Taiwan) who had available mutation profile determined by next-generation sequencing. For external validation, 82 MF patients from the Christie Hospital (Manchester, U.K.) and 51 MF patients from the Cleveland Clinic (Ohio, U.S.A.) and Vilnius University Hospital Santaros Klinikos (Vilnius, Lithuania) were enrolled. The median age of the discovery cohort was 61 years. JAK2V617F was the most common driver mutation (64.8%), followed by CALR (18%) and MPL mutations (9%). ASXL1 mutation was the most common (37%) genetic alteration other than driver mutations, followed by TET2 (16%) and EZH2 mutations (12%). Overall, 55 patients (45%) had at least one HMR mutation ( ASXL1, EZH2, SRSF2, IDH and U2AF1). With a median follow-up of 28.2 months, the median overall survival (OS) of the discovery cohort was not reached (NR) and was well risk-stratified by current prognostication systems, including IPSS, DIPSS plus, MIPSS70, and GIPSS. Notably, patients with at least one HMR mutation had significantly shorter leukemia-free survival (LFS) and OS than those without (both p<0.001). Next, we divided the 79 JAK2-mutated patients into lower- and higher-allele burden groups ( JAK2low and JAK2high) using the median (75%), as the cutoff. Concurring with previous reports ( Tefferi et al, Leukemia 2008; and Guglielmelli et al, Blood 2009), JAK2low patients had significantly inferior OS than JAK2high patients (median, 53 months vs NR, p=0.037). Among all JAK2-mutated patients, those with HMR mutations had a significantly shorter OS than those without (50 months vs NR, p<0.001). When considering HMR mutations and JAK2V617F allele burden together, the presence of HMR alterations conferred worse LFS and OS in JAK2low but not in JAK2high patients (HMR vs without HMR among JAK2low patients, p<0.001 and p<0.001; and JAK2high, p=0.822 and p=0.699, respectively). By and large, patients with concurrent HMR mutations and lower JAK2V617F allele burden had a distinctively inferior OS than those with other constellations of genomic lesions ( p<0.001, Figure 1A). This group of patients also had the shortest survival among the total cohort including both JAK2-mutated and wild patients ( p<0.001). The discriminating power of integrating HMR/ JAK2 allele burden for LFS and OS remained valid in the UK cohort (HMR vs without HMR: JAK2low, p=0.013 and p=0.012; and JAK2high, p=0.337 and p=0.600, respectively) and the US/Lithuania cohort (HMR vs without HMR: JAK2low, p=0.016 and p=0.013; and JAK2high, p=0.643 and p=0.446, respectively). Co-occurrence tests in the discovery and validation cohorts revealed that there was no shared mutational co-occurrence pattern among the 3 cohorts, excluding the potential confounding influence of specific concurrent mutations. More strikingly, time-dependent ROC curve analyses suggested that integrating JAK2 allele burden with HMR mutations could be complementary to current risk stratification systems in predicting LFS and OS of MF patients (Figure 1B) across 3 cohorts. Finally, HMR/ JAK2low was identified as an independent adverse prognostic factor by multivariable analysis, irrespective of age, risk stratification systems, and other mutations. In summary, we observe that HMR mutations accompanied by a lower mutant JAK2V617F allele burden identified a distinct MF population with significantly reduced survival and high risk of leukemic transformation, with independent prognostic relevance extrapolated to and validated in two independent cohorts. Experimental studies are ongoing to ascertain the underlying mechanistic basis and resolve the clonal architecture of this distinct MF genomic grouping.

Clinico-Genetic and Prognostic Analyses of 635 Patients with Myelodysplastic Neoplasms Based on the 2022 World Health Organization Classification

Myelodysplastic neoplasms (MDS) are a heterogeneous group of clonal myeloid neoplasms characterized by dysregulated hematopoiesis. In the past several years, major advances in molecular technologies and the development of next generation sequencing have deepened our understanding of MDS pathobiology. Revisions of the existing classification were warranted. Under the aegis of the International Agency for Research on Cancer, the 2022 World Health Organization (WHO) classification was released. The 2022 WHO proposed new categories including MDS with biallelic TP53 inactivation (MDS-bi TP53), MDS, hypoplastic (MDS-h) and MDS with fibrosis (MDS-f). In addition, the novel risk scoring system-Molecular International Prognostic Scoring System (IPSS-M) has been established. There are limited data that explore the application of the 2022 WHO classification of MDS in light of the IPSS-M. In this study, a cohort of 635 patients diagnosed as having primary MDS based on the 2022 WHO criteria was retrospectively reviewed. We aimed to elucidate the differences in genetic features and clinical outcomes among patients with different MDS subtypes, based on the 2022 WHO classification. The survival impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) was also evaluated. TruSight myeloid sequencing panel and the HiSeq platform were used to analyze the alterations of 54 myeloid neoplasm-relevant genes. Comparison of the genetic profiles of patients with different subtypes of MDS showed that patients with MDS-low blasts (LB) and those with MDS with LB and ring sideroblasts (RS) exhibited comparable mutation profiles, while patients with MDS- SF3B1 had different mutation pattern from that of these two subtypes. Among patients with MDS-increased blasts-1 (IB1), MDS-IB2 and MDS-f, patients with MDS-IB2 had higher frequencies of NRAS (9% vs. 2%, P=0.019) and mono-allelic TP53 (7% vs. 1%, P=0.031) mutations, and a trend of more TET2 (19% vs. 10%, P=0.059) mutations than those with MDS-IB1. In addition, patients with MDS-f exhibited lower incidence of TET2 (0% vs. 19%, P=0.020), and STAG2 mutations (8% vs. 27%, P=0.050) as compared to those with MDS-IB. Furthermore, patients with MDS-bi TP53 had specific concurrent genetic alterations with few co-occurring mutations which differed from those found in patients with MDS-IB or MDS-f. We performed pairwise survival comparisons among each subtypes of MDS (Figure 1). In low-risk MDS, patients with MDS-h had significantly longer median leukemia-free survival (LFS) and overall survival (OS) (185.5 months for median LFS and OS) compared with those with MDS-LB and RS [38.3 months for median LFS ( P=0.013) and OS ( P=0.010)], while had a similar outcome compared to those with MDS-LB [170.2 months for median LFS ( P=0.152) and OS ( P=0.146)], and MDS- SF3B1 [114.6 months for median LFS ( P=0.549) and OS ( P=0.528)]. For patients with increased blasts or bi TP53 mutations, those with bi TP53 inactivation had the worst outcomes (median LFS: 3.9 months and OS: 4.5 months, all P<0.001) compared to those with MDS-f (median LFS: 16.6 months and OS: 17.7 months), MDS-IB2 (median LFS: 10.0 months and OS: 17.7 months), and MDS-IB1 (median LFS: 25.6 months and OS: 31.4 months). Patients with MDS-f had similar survival to those with MDS-IB2 and IB-1 in terms of LFS (16.6 vs. 25.6 months, P=0.271) and OS (17.7 vs. 31.4 months, P=0.194) . Multivariable analysis showed that IPSS-M ( P<0.001), old age (HR for LFS: 1.023; for OS: 1.032, P<0.001), and the 2022 WHO categorization ( P<0.001) could predict LFS and OS independently and that HSCT could improve LFS (HR, 0.492, P=0.001) (Table 1). Subgroup analysis of the impact of transplantation using time-dependent Cox regression revealed that allo-HSCT could prolong both LFS and OS in patients with MDS-IB1 (HR for LFS: 0.293, for OS: 0.350, P<0.001), LFS alone (HR: 0.534, P=0.049) in patients with MDS-IB2, and a trend of LFS (HR: 0.305, P=0.078) in patients with MDS-f. However, allo-HSCT failed to remedy the dismal outcomes for patients with MDS-bi TP53. In conclusion, based on the evidence gathered from this cohort analysis, the 2022 WHO classification promote efficient segregation of this heterogeneous disease, with focus on the differences in molecular features and prognoses across different disease subtypes, leading to accurate MDS diagnosis and effective risk-adapted treatment.

A Patient-Centered Programmatic Approach for Higher-Risk Myelodysplastic Syndromes (HR-MDS) in the US Community Oncology Setting

Introduction: Prompt diagnosis and treatment are critical for patients with higher-risk myelodysplastic syndromes (HR-MDS) given the high likelihood of progression to leukemia and adverse clinical outcomes. However, pre-diagnosis dynamics can contribute to delays in diagnosis, genetic testing, and treatment initiation, especially among patients receiving care in the community oncology setting. A patient-centered program has been designed and is proposed to be executed in 4 phases: understanding adherence to guideline-concordant care for HR-MDS patients; gaining perspectives to contextualize the patient experience; and implementing a program that can monitor the process for improving patient outcomes (Figure 1). The objectives of this study are to evaluate and address the gaps and disparities of care in the diagnostic and treatment journey of patients with HR-MDS treated in a community oncology setting in order to provide an evidence-based understanding of the patient characteristics and journey to testing, diagnosis, and treatment (Phase 1 of the program). Methods: This is a retrospective chart review including patients treated in the community oncology network and identified in the Integra PrecisionQ deidentified database. Patients were identified as diagnosed with HR-MDS between January 1, 2014 and June 30, 2022, using a combination of ICD codes and receipt of hypomethylating agents in line with National Comprehensive Cancer Network guidelines as their first treatment. Eligible patients had at least 3 months of follow-up and at least 6 months of look-back prior to HR-MDS diagnosis. Signs and symptoms such as fatigue, weight loss, bruise, chills, night sweats, anemia, thrombocytopenia, and neutropenia that initiated the HR-MDS diagnosis journey were collected by manual curation. Results: A total of 350 patients aged 18 years or older diagnosed with HR-MDS over the study period were selected. The majority of patients included in this sample were White (82.6%) and male (59.4%) (Table 1). More than 50% of the 350 patients were ≥75 years old at diagnosis and most of them (91%) were diagnosed by a hematologist/oncologist in an outpatient setting. The median time from first sign/symptom to bone marrow biopsy and treatment initiation were 19.3 months (interquartile range [IQR] 8.9, 44.3) and 22 months (IQR 11.4, 45.8), respectively. Of the 350 patients included in the study, 342 (97.7%) had at least 1 sign or symptom leading to HR-MDS diagnosis, with the majority of patients presenting with anemia (77.2%), followed by thrombocytopenia (66.4%), fatigue (64.3%), and neutropenia (43.3%). International Prognostic Scoring System (IPSS) scores were not documented for nearly half (43.7%) of the patients included in this chart review. Conclusions: This initial analysis highlights several challenges in the HR-MDS patient care journey, including long time intervals elapsed between first sign/symptom and bone marrow biopsy, leading to further treatment, accompanied by a relatively high absence of IPSS score documentation. These findings suggest several potential opportunities to optimize patient care, such as shortening the time from symptoms to diagnosis and time from diagnosis to treatment, utilization and documentation of IPSS score, and prompt treatment initiation. Ultimately, this program aims to utilize this Phase 1 data to identify the gaps in care and to formulate quality measures to optimize care and facilitate timely diagnosis and appropriate treatment initiation among HR-MDS patients.

Phase 3b Study Design for a Comparison of Treatment Preference between Oral Decitabine/Cedazuridine and Azacitidine in Adult Patients with IPSS-R Intermediate Myelodysplastic Syndrome, IPSS Intermediate-2 or High-Risk Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukaemia, or Chronic Myelomonocytic Leukaemia

Myelodysplastic syndromes (MDS) are heterogeneous clonal bone marrow neoplasms characterised by marrow dysplasia, low blood counts and risk of progression to acute myeloid leukaemia (AML). Hypomethylating agents (HMAs) decitabine and azacitidine (AZA) are effective treatments for hematologic cancers including MDS. AZA is indicated to treat International Prognostic Scoring System (IPPS) defined Intermediate-2 (Int-2) and high-risk (HR) MDS, low blast AML (LB-AML; 20-30% blasts) with multi-lineage dysplasia, and chronic myelomonocytic leukaemia (CMML) with 10-29% blasts without myeloproliferative disorder. Oral decitabine/cedazuridine is currently the only oral hypomethylating agent indicated to treat IPSS Int-1, Int-2 or HR MDS and CMML, in the United States, Canada and Australia. AZA administration requires daily visits to a hospital or clinic for 7 days every 28 days, for either intravenous infusions, or large-volume subcutaneous (SC) injections for a minimum of 6 cycles.This places a burden on this patient population, resulting in low treatment adherence, early discontinuation, and subsequently low treatment uptake. Oral decitabine/cedazuridine is administered as one tablet daily for the first 5 days of a 28-day cycle for a minimum of 4 cycles. This allows patients to take their medication at a location of their choice. Alongside previously reported preference for oral therapy, patients may favour oral decitabine/cedazuridine over SC AZA due to improved treatment convenience and reduced discomfort. However, this is untested in a controlled setting. This study aims to evaluate preference between oral decitabine/cedazuridine and SC AZA treatment for adult patients with Revised International Prognostic Scoring System (IPSS-R) intermediate, IPSS Int-2 or HR MDS, LB-AML or CMML. This phase 3b, open-label, multi-centre study (NCT05883956) has sites planned in Australia (4 sites) and New Zealand (5 sites), to compare preference for oral decitabine/cedazuridine (Treatment A) and SC AZA (Treatment B). The study design includes 28 days of screening, four continuous 28-day cycles of study treatment, and a follow-up period with two 28-day cycles of continued therapy. Patients will be randomised to two balanced treatment sequences: ABBA or BAAB (Figure 1). Patients will express a preference twice in the study; after completing Cycle 1 and 2, and after completing Cycle 3 and 4. This cross-over design is twice the length of a typical 2-period AB vs BA design and allows patients to act as their own controls. The study design allows estimation of the treatment effect while mitigating factors that may influence preference. These include the order of treatments, and fluctuations in the patient's physical and disease state over the course of the trial. All available preferences expressed throughout the trial will be used for primary analysis. A total of 42 patients are planned for this study. The primary objective of this study is to compare patients' treatment preference for oral decitabine/cedazuridine and SC AZA for the treatment of MDS, LB-AML or CMML. Secondary objectives include evaluation of carers' and clinicians' treatment preference between oral decitabine/cedazuridine and SC AZA for the treatment and continued treatment of adult patients with MDS, LB-AML or CMML. The primary objective will be assessed by a treatment preference in myelodysplasia questionnaire (pTPMQ), which instructs patients to indicate a preference for injection, oral/tablets or no preference. The secondary objectives will be evaluated by a carer treatment preference in myelodysplasia questionnaire (cTPMQ) and a medical clinician treatment preference in myelodysplasia questionnaire (mTPMQ). Treatment discontinuation rates, quality of life and safety of SC AZA and oral decitabine/cedazuridine will also be compared. The primary analysis will be conducted with a multilevel logistic regression model analysing all available preferences. Descriptive statistics including frequencies, proportions, mean, standard deviation, median, and interquartile range will be used to summarize the study data. When complete, this study will address an evidence gap in the comparison of patient preference for oral decitabine/cedazuridine and SC AZA, and subsequently inform the value of oral decitabine/cedazuridine for the treatment of MDS, LB-AML and CMML.

Modification of the ELN Classification 2022 Refines Risk Assessment in MDS/AML Patients

Background: The International Consensus Classification (ICC) introduced MDS/AML as a novel myeloid disease entity defined by 10-19% blasts in the absence of AML-defining recurrent genetic abnormalities. MDS/AML patients should be eligible for AML-like treatment approaches in clinical trials. It has recently been shown that the AML-based risk classification according to European Leukemia Net (ELN) 2022 criteria fails in MDS/AML while an MDS-based risk classification according to Molecular International Prognostic Scoring System (IPSS-M) was applicable (Huber S et al. EHA 2023). Our aim was to refine the ELN 2022 criteria based on genome sequencing data to better reflect the outcome in this overlap category of MDS and AML. Methods: Non-therapy-related cases of 403 MDS/AML and 686 AML patients classified according to ICC were included. Bone marrow samples were analyzed by cytomorphology, cytogenetics and targeted NGS panel sequencing (median coverage 1500x). Overall survival (OS) was assessed in all AML patients and in a subcohort of 137 MDS/AML patients (median follow-ups: 5.6 and 10.2 years, respectively) in whom also whole genome sequencing (median coverage 100x) was performed. Results: MDS/AML patients had a median age of 74 years (female/male: 153/250). They were subclassified according to ICC as MDS/AML with mutated TP53 (14%), with myelodysplasia-related (MR) gene mutations (67%) or MR cytogenetic abnormalities (5%), or not otherwise specified (14%). Cytogenetic aberrations were detected in 173/403 (43%) cases including del(5q) (18%), -7/del(7q) (13%), and complex karyotypes (16%). Molecular aberrations were detected in 376/403 (93%) cases with a median number of 3 mutations. Most frequent gene mutations were ASXL1 (40%), TET2 (32%), SRSF2 (32%), and RUNX1 (29%); TP53 was mutated in (14%) (details in Figure 1A). Grouping of the MDS/AML cohort according to the ELN 2022 guidelines showed: no MDS/AML patient fulfilled criteria for the favorable ELN risk group, only 14% were classified as intermediate risk, and the vast majority (86%) as adverse risk. The survival of MDS/AML patients substantially differed from a bona fide AML cohort, in particular for adverse risk (Figure 1B left). To more adequately risk stratify MDS/AML patients, we aimed to modify current ELN criteria. Notably, in multivariate Cox regression analysis in addition to -7/del(7q) (hazard ratio/HR: 5.5) and mutated RUNX1 (HR: 2.2), also mutations in EZH2 (HR: 2.2) and in SF3B1 (HR: 0.3) remained significant prognostic markers for OS (all p<0.05). Following this, we defined three hierarchically defined risk groups for MDS/AML patients i) adverse (criteria: complex karyotype, -7/del(7q), mutation in TP53, RUNX1, EZH2), ii) intermediate (criteria: del(5q), mutation in ASXL1, SRSF2, U2AF1, ZRSR2, BCOR or STAG2) and iii) favorable (criteria: sole SF3B1 mutation or none of the abnormalities defined above). Overall, 149 MDS/AML patients (37%) were re-grouped compared to ELN 2022 categories resulting in 49% adverse, 35% intermediate and 16% favorable cases. Survival analysis revealed strong prognostic separations of the three new MDS/AML risk categories with median OS of 1.3 years for adverse, 3.1 years for intermediate and 8.1 years for favorable (overall p<0.001; Figure 1B right). The general survival prediction within MDS/AML was improved in the modified version compared to the original ELN 2022 (corrected Akaike information criterion using Cox models: 876 for modified vs. 902 for ELN 2022). Of note, the outcome of adverse risk MDS/AML according to the modified ELN was comparable to the OS of adverse risk AML according to the original ELN (median OS: 1.3 vs 0.7 years; p=0.304). Conclusion: ForMDS/AML patients, AML-based risk classification according to ELN 2022 guidelines is not applicable as the vast majority of cases are categorized into the adverse risk group based on mutations in splicing factor genes and other secondary-type mutations. Modification of the ELN risk categories reflects the partly MDS-based biology of the disease and substantially improves the prognostic stratification. Most importantly, patients with adverse outcome potentially benefitting from inclusion into clinical trials for novel substances are identified. The validity of the modified risk classification for MDS/AML patients undergoing specific treatment regimens remains to be confirmed in forthcoming studies.

Comparison of Two Reduced Intensity Conditioning Regimens (Baltimore with Clofarabine vs Thiotepa-Busulfan-Fludarabine) in Adults Receiving Peripheral Blood Stem Cell Haploidentical Transplantation for Myeloid Malignancies: A Retrospective Study of the SFGM-TC

Background: Haploidentical transplantation (haploT) has become a routine practice in many centers but the optimal conditioning regimen has yet to be determined. Indeed, the historic Baltimore reduced intensity conditioning (RIC) regimen has been associated with poor outcomes in myeloid malignancies. Two alternative RIC regimens have recently demonstrated promising results in this setting. One of them replaces fludarabine with second-generation nucleoside analogue clofarabine (Clo-Baltimore regimen [CloB], Chevallier et al., Oncotarget 2018) and the other combines thiotepa-busulfan-fludarabine (TBF, Duléry et al., BBMT 2019). Here we compared outcomes in order to determine if one of these two regimens was superior for the treatment of myeloid malignancies. Methods: This was a multicenter retrospective study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). All consecutive adults having received a haploT after a CloB or a TBF RIC regimen for a myeloid malignancy between September 2013 and May 2023 were eligible. Patients data were extracted from the PROMISE database. CloB consisted of clofarabine 30 mg/m²/day (d) 5 d, cyclophosphamide (Cy) 14.5mg/kg/d 2 d, and 2-Gy TBI on d-2. TBF consisted of thiotepa 5mg/kg 1 d, busulfan 3.2 mg/kg 2 d, a fludarabine total dose of 120 to 150 mg/m². Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cy (2 doses of 50mg/kg), followed by cyclosporine A and mycophenolate mofetil starting on d+5. Some patients received antithymocyte globulin (ATG) 2.5mg/kg/d on d-2. Graft source was exclusively peripheral blood stem cells (PBSC). To minimize bias between the CloB and the TBF groups, a propensity score matching (PSM) was constructed using a logistic regression model that included age, donor and recipient sex, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), disease, cytogenetic risk (European LeukemiaNet [ELN] 2022), previous transplant, use of ATG, and cytomegalovirus (CMV) status, with the nearest-neighbor algorithm, and strict matching of key factors. Matched groups were then compared for time to engraftment (absolute neutrophil count > 0.5 x 10 9/L) and platelet (PLT) recuperation (>50 x 10 9/L), overall survival (OS), progression-free survival (PFS), GVHD-free, progression-free survival (GRFS), non-relapse mortality (NRM), and incidences of relapse as well as acute and chronic GVHD. Results: A total of 329 patients from 25 centers were included, 267 (81%) receiving TBF and 62 (19%) CloB. After PSM, 51 patients remained in each group, with comparable baseline characteristics except for the proportion of previous allotransplants ( Table). Median age was 60 years, and median HCT-CI score was 2. Main diagnoses comprised acute myeloblastic leukemia (AML, n=72 [71%]), including 42% with adverse genetic risk, and myelodysplastic syndrome (MDS, n=22 [22%]), including 25% with high or very high Revised International Prognostic Scoring System (R-IPSS). Thirty-eight (37%) patients received ATG. Time to engraftment was equivalent after both TBF and CloB (19 d vs 19.5 d, respectively, p=0.70), but TBF patients achieved PLT recuperation faster (27 d vs 31 d, p=0.03). Median follow-up was 24 months. Two-year OS, PFS and GRFS were 55% vs 60% (p=0.19), 52% vs 60% (p=0.25), and 37% vs 50% (p=0.15) for TBF and CloB patients, respectively. No differences were observed in terms of grade 3-4 acute GVHD at 3 months (18 vs 20%, p=0.86) nor two-year extensive chronic GVHD (16% vs 8.3%, p=0.25). However, two-year NRM was significantly higher after TBF (41% vs 16%, p=0.003), while relapse incidence was lower (7.1% vs 24%, p=0.02, Figure). In multivariate analysis, CloB was associated with a lower risk of NRM (hazard ratio [HR] 0.31, 95%CI: 0.1-0.7, p=0.008) and a higher risk of relapse (HR 4.03, 95%CI: 1.2-13.9, p=0.03). Finally, in patients aged >60y, two-year OS was significantly lower for those receiving TBF conditioning (39% vs 61%, p=0.02, Figure) due to higher NRM (56% vs 23%, p=0.005). Conclusions: In this retrospective study, a TBF RIC regimen used for PBSC haploT in adults with myeloid malignancies appeared substantially more toxic than a CloB RIC regimen. However, its enhanced anti-leukemic effect suggests that it should be offered to younger patients with no comorbidities or to those with high-risk disease. Conversely, CloB should be proposed for older or frail patients.