Revised International Prognostic Scoring System Research Articles

Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

The AST/ALT (De Ritis) ratio as a significant prognostic factor in myelodysplastic syndrome

Background: The aspartate transaminase (AST)/alanine transaminase (ALT) ratio, also termed the De Ritis ratio, has been demonstrated to have an association with poor prognosis in several cancer types. However, its prognostic value in patients with myelodysplastic syndrome (MDS) remains unclear. Methods: A total of 265 MDS patients were divided into two groups by R. The clinical, laboratory, and follow-up data of patients with MDS were collected, while the relationship between AST/ALT ratio and overall survival (OS) and leukemia-free survival (LFS) were also analyzed. Results: The results showed that higher AST/ALT ratio was associated with higher age, β2-microglobulin level, and number of co-mutations (>4). Moreover, the high AST/ALT group had a significantly shorter OS and LFS than the low AST/ALT group. Multivariate analysis involving the Revised International Prognostic Scoring System (IPSS-R) showed that a higher AST/ALT ratio was an independent adverse factor for OS or LFS; however, the same was not noted in the multivariate analysis involving the new Molecular International Prognostic Scoring System (IPSS-M). Conclusions: Our study suggests that the AST/ALT ratio could be a simple and economic prognostic indicator for MDS and be used as a supplement to IPSS-R, especially when lacking of karyotype or mutation data.

Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes

AbstractThe human kinome, which comprises >500 kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndrome (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified 7 kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the kinase stratification score (KISS) by combining the weighted expressions of the 7 kinases and validated its prognostic significance in 2 external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for genesets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

Prognostic Value of Pretreatment Fetal Hemoglobin Levels in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia Treated with Azacitidine: A Single-center Retrospective Study.

Objective Azacitidine (AZA) has been the standard of care for elderly patients with high-risk myelodysplastic syndromes (MDS). However, reliable clinical predictors of outcome have yet to be identified. The prognostic value of fetal hemoglobin (HbF) levels has been reported for decitabine therapy. We evaluated pretreatment HbF levels in AZA monotherapy as a prognostic marker in MDS/acute myeloid leukemia (AML). Methods This study included chemotherapy-naïve patients who had received seven-day treatment schedules of AZA and whose HbF levels were measured at the onset of treatment between March 2011 and July 2020. Patients were grouped into HbF-normal (<1.0%) or HbF-elevated (≥1.0%) groups. Responses were classified according to the International Working Group 2006 criteria. Patients Twenty-nine patients were included and classified as having either MDS (n=21), chronic myelomonocytic leukemia (n=5), myelodysplastic/myeloproliferative neoplasm unclassifiable (n=1), or AML with <30% marrow blasts (n=2) based on the World Health Organization 2016 diagnostic criteria. According to the revised International Prognostic Scoring System classification, 20/29 patients were at intermediate, high, or very high risk. Pretreatment HbF levels were elevated in 13/29 patients. Results The median follow-up duration was 13.0 (range 1.5-93.5) months. The HbF-elevated group was associated with a significantly higher hematologic improvement rate (76.9% vs. 25%, p=0.009) and better overall survival (median, 21.0 vs. 13.0 months, p=0.048) than the HbF-normal group. Conclusion These results suggest that elevated pretreatment HbF levels can predict better outcomes in patients with MDS/AML treated with AZA.

Diagnosis and Treatment of Myelodysplastic Syndrome in the Era of Genetic Testing

Myelodysplastic syndrome (MDS) is a heterogeneous disorder with diverse prognoses influenced by cytopenias, genetic variants, and myeloblast proportions in the bone marrow. Accurate prognosis prediction and tailored treatment plans are essential. The International Prognostic Scoring System-Molecular (IPSS-M), which additionally reflects the impact of MDS-related genetic mutations to the clinical and laboratory information, is anticipated to offer superior prognostic accuracy compared to existing systems like the Revised International Prognostic Scoring System (IPSS-R). Despite its statistical complexity, its web-based calculation and ease of discussing results with patients using intuitive data sets provide notable advantages. Progress in MDS treatment, exemplified by effective anemia correction with an erythropoiesis-maturation agent in &lt;i&gt;SF3B1&lt;/i&gt;-mutated cases and efforts to refine poor prognoses in &lt;i&gt;TP53&lt;/i&gt;-mutated cases, reflects the evolving landscape of genetic-based interventions in MDS. Advancements in genetic diagnostic technology, combined with enhanced knowledge of the bone marrow niche, are anticipated to lead to significant improvement in MDS treatment outcomes in the future.

Myelodysplastic Syndromes and Myelodysplastic Syndromes/Myeloproliferative Neoplasms: A Real-World Experience From a Developing Country.

Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis. They manifest as dysplasia in bone marrow hemopoietic elements associated with peripheral cytopenias with variable risk of AML transformation. We analyzed retrospectively registry data collected prospectively from patients with primary MDS and patients with MDS/myeloproliferative neoplasm (MPN) in the Jordan University Hospital between January 2007 and September 2021. The registry captured epidemiologic information such as date of diagnosis, age, gender, date of AML transformation, cytogenetics, MDS subtype, risk group according to Revised International Prognostic Scoring System, and survival. The registry also captured baseline ferritin, B12, and lactate dehydrogenase levels. A total of 112 patients with MDS and MDS/MPN were included in the registry. Median age at diagnosis was 59 years. The male-to-female ratio was about 1.2. In a multivariate cox regression model, baseline serum ferritin significantly affected survival as patients with levels exceeding 1,000 μg/L had a risk of death three times higher compared with those with <1,000 μg/L levels (P < .05). To our knowledge, our study is the first comprehensive study examining the epidemiology and prognostic factors in patients with MDS and patients with MDS/MPN in Jordan. Our results show that MDS and MDS/MPN epidemiology in Jordan is different compared with Western countries. Our results also show that baseline serum ferritin levels can be used as a prognostic marker for patients with MDS.

Comparison of the Molecular International Prognostic Scoring System (IPSS-M) and Revised International Prognostic Scoring System (IPSS-R) in predicting the prognosis of patients with myelodysplastic neoplasms treated with decitabine

Abstract Background Molecular International Prognostic Scoring System (IPSS-M) is a newly developed prognostic model for myelodysplastic neoplasms (MDS), but has not yet been used widely. In this study, we aimed to compare the IPSS-M with the traditional Revised International Prognostic Scoring System (IPSS-R) in predicting the prognosis of decitabine treated-MDS patients. Patients and methods This retrospective cohort study was conducted on 19 newly diagnosed MDS patients who were examined for 51 gene mutations and received decitabine treatment. The survival analysis, including overall survival (OS), progression-free survival (PFS), and leukemia-free survival (LFS), was performed using the Kaplan–Meier method. Comparisons between the risk groups were carried out according to the IPSS-R and IPSS-M models. Results Among the 19 MDS patients, 12 (63.2 %) showed myeloid gene mutations, with the highest frequency of mutations in ASXL1, RUNX1, SRSF2, TET2, and TP53 (15.8 %). Survival analysis found that the OS was significantly different between the risk groups of both IPSS-R and IPSS-M models, but the PFS and LFS showed significant differences between the risk groups in only the IPSS-M model. The PFS of the moderate, high, and very high-risk groups were 34.66, 25.00, and 15.33 months (p=0.031); respectively. The LFS of the moderate, high, and very high-risk groups were 39.20, 25.00, and 18.37 months, (p=0.039); respectively. Conclusions Our results found that IPSS-M was better than IPSS-R in predicting the PFS and LFS of decitabine-treated MDS patients, IPSS-M may be superior to IPSS-R in predicting the prognosis of MDS patients.

Association between Leukemic Evolution and Uncommon Chromosomal Alterations in Pediatric Myelodysplastic Syndrome.

Pediatric myelodysplastic syndrome (pMDS) is a group of rare clonal neoplasms with a difficult diagnosis and risk of progression to acute myeloid leukemia (AML). The early stratification in risk groups is essential to choose the treatment and indication for allogeneic hematopoietic stem cell transplantation (HSCT). According to the Revised International Prognostic Scoring System, cytogenetic analysis has demonstrated an essential role in diagnosis and prognosis. In pMDS, abnormal karyotypes are present in 30-50% of the cases. Monosomy 7 is the most common chromosomal alteration associated with poor prognosis. However, the rarity of specific cytogenetic alterations makes its prognosis uncertain. Thus, this study aimed to describe uncommon cytogenetic alterations in a cohort of 200 pMDS patients and their association with evolution to AML. The cytogenetic analysis was performed in 200 pMDS patients by G-banding and fluorescence in situ hybridization between 2000 to 2022. Rare chromosome alterations were observed in 7.5% (15/200) of the cases. These chromosome alterations were divided into four cytogenetic groups: hyperdiploidy, biclonal chromosomal alterations, translocations, and uncommon deletions representing 33.3%, 33.3%, 20%, and 13.3%, respectively. Most of these patients (10/15) were classified with advanced MDS (MDS-EB and MDS/AML) and the initial subtype was present in five patients (RCC). The leukemic evolution was observed in 66.66% (10/15) of the patients. Most patients had poor clinical outcomes and they were indicated for HSCT. The study of uncommon cytogenetic alterations in pMDS is important to improve the prognosis and guide early indication of HSCT.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.

VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.

Platelet-to-lymphocyte ratio and absolute monocyte count have prognostic potential in primary myelodysplastic neoplasms.

The platelet-to-lymphocyte ratio (PLR), peripheral blood absolute monocyte count (AMC), and monocyte-to-lymphocyte ratio (MLR) are considered biomarkers of systemic immune and inflammation response. However, their prognostic potential in patients with myelodysplastic neoplasms (MDS) remains unclear. This study aimed to explore the predictive impact of PLR, MLR, and AMC on MDS outcomes. In total, 334 patients with primary MDS were included between January 2016 and December 2021 and were retrospectively followed up until December 31, 2022. The prognostic significance of PLR, MLR, and AMC was assessed using univariate and multivariate analyses, and predictive models were generated to estimate MDS outcomes. The area under their receiver operating curves was computed to compare the predictive power of these models. Fifty-one patients had disease progression, and 103 patients died during follow-up. In multivariate analyses, a higher PLR was an adverse independent factor for overall survival (OS) (p = 0.011), whereas a higher AMC indicated shorter progression-free survival (p = 0.003). The prognostic model incorporating PLR, MLR, and AMC with the Revised International Prognostic Scoring System (IPSS-R) risk categorization showed higher performance in predicting OS than the model that only utilized the IPSS-R category. Elevated PLR and increased AMC had independent prognostic value for adverse outcomes in patients with MDS. PLR, MLR, and AMC enhanced the IPSS-R risk categorization for OS prediction in MDS.

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 &amp;gt; 0.5 x 10 9/L) and platelet (PLT) recuperation (&amp;gt;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 &amp;gt;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.

Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes

Introduction: Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290). Methods: Adult patients were enrolled with de novo treatment-naive HR MDS defined by the Revised International Prognostic Scoring System (IPSS-R) score of &amp;gt;3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow (BM) blasts &amp;lt;20% at baseline. Patients received Ven 400 mg orally daily on Days 1-14 and Aza 75 mg/m 2 intravenously or subcutaneously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle (RP2D). The primary objective was to assess the complete remission (CR) rate. Key secondary objectives included determining marrow CR (mCR), overall response rate (ORR), hematologic improvement (HI), postbaseline red blood cell (RBC) and platelet transfusion independence (TI), overall survival (OS), duration of CR, time to next treatment (TTNT), transformation to acute myeloid leukemia (AML), and time to AML transformation. Responses were assessed by International Working Group 2006 criteria. Prophylactic antibiotics were mandated in Cycle 1 and recommended for Grade ≥3 neutropenia thereafter. Safety was analyzed in patients who received ≥1 dose of study treatment. Results: At thedata cutoff of May 31, 2023, 107 patients had received Ven+Aza at the RP2D. Key baseline characteristics for all treated patients are shown in Table 1A. Median age was 68 years (range, 26-87), 64% of patients had intermediate or poor cytogenetic risk, and &amp;gt;89% had ≥5% BM blasts. Median number of treatment cycles before transplantation was 3.0 (range, 1.0-11.0). At the median follow-up of 31.9 months (95% CI, 30.4-42.5), CR rate was 29.9% (95% CI, 21.4-39.5), with a median CR duration of 16.6 months (95% CI, 10.0-not reached [NR], Table 1B). Median OS was 26 months (95% CI, 18.1-51.5), with an estimated 12-month OS of 71.2% (95% CI, 61.4-78.9)and 24-month OS of 51.3% (95% CI, 41.2-60.5). Median OS for CR was NR. Median TTNT including transplantation was 6.8 months (95% CI, 5.6-8.3). Sixty-two (57.9%) patients received subsequent treatment, including transplantation in 42 (39.3%) patients; the median time to transplantation was 4.8 months (range, 1.4-16.8). Among patients who received transplantation post-study, 17 were transplant ineligible at study entry. Postbaseline TI rate was 61.7% for RBC and 72.0% for platelets. Median maximal duration of TI achieved was 5.4 months (range, 1.8-50.8) and 5.4 months (range, 1.9-56.0) for RBC and platelets, respectively. Postbaseline overall hematologic improvement (HI) was achieved in 51 (49.0%) of 104 evaluable patients, and specific responses included erythroid (40/93; 43.0%), platelet (32/74; 43.2%) and neutrophil (10/57; 17.5%) indices. All patients experienced ≥1 treatment-emergent adverse event (TEAE), with 94.4% of patients reporting grade ≥3 TEAEs. Serious adverse events (SAEs) occurred in 68.2% of patients. Common TEAEs of any grade were constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), diarrhea (41.1%), anemia (39.3%), vomiting (36.4%), and hypokalemia (26.2%). Grade ≥3 TEAEs reported in ≥20% of patients were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Infections were reported in 57% of patients, including SAEs in 40.2% of patients. Of the 59 deaths (55.1%) reported, 23 (21.5%) were due to disease progression and 7 (6.5%) to adverse events. Within 60 days after study start, 7 deaths (6.5%) were reported. Conclusion: Ven 400 mg for 14 days plus Aza combination was well tolerated with favorable responses of CR+PR+mCR in &amp;gt;80% and HI in nearly 50% of patients with treatment-naïve HR MDS. A separate Phase 3 study of this combination is ongoing to confirm survival benefit.

IPSS-M Predicts Survival Outcomes Significantly Better Than IPSS-R in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Neoplasms

Background The newly published molecular International Prognostic Scoring System (IPSS-M) represents a powerful risk stratification tool for treatment decision-making in myelodysplastic neoplasms (MDS); however, its utility in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains to be fully explored. Methods We retrospectively analyzed a large multicenter cohort of 347 MDS patients who underwent allo-HSCT between January 2017 and October 2022. The prediction accuracy of IPSS-M at diagnosis for 3-year survival outcomes was assessed and compared to that of the conventional revised International Prognostic Scoring System (IPSS-R). Results Among the 347 patients, median age at transplant was 48.3 years and 41.2% of patients were female. According to IPSS-M, patients were clustered as very low risk (1.2%), low risk (11.2%), moderately low risk (11.5%), moderately high risk (18.2%), high risk (33.4%), and very high risk (24.5%), resulting in a restratification of 49.3% of the entire cohort when compared with IPSS-R. Of these reclassified patients, 52.6% patients were upstaged and 47.4% were downstaged. Median follow-up time among the survivors was 28.6 (range, 4.7 to 76.6) months. With the IPSS-M model, overall survival (OS) and leukemia-free survival (LFS) discrimination was refined relative to the IPSS-R as evidenced by a 7.0 percentage- and 5.7 percentage-point increase in the concordance index (C-index), which was further supported by the lower Akaike Information Criterion and higher C-indexes in multivariate analyses. Among patients undergoing haploidentical HSCT, IPSS-M model also demonstrated significantly improved prognostic performance for LFS versus IPSS-R (C-index, 0.707 vs 0.604) which was validated by multivariate analyses. When restricting our analyses to younger patients (&amp;lt;49 years) and patients carrying detectable mutations, IPSS-M retained greater prognostic value with respect to OS and LFS; while it failed to stratify individual probability of OS and LFS in their counterparts. Conclusions IPSS-M was confirmed to increase prognostic discrimination at the individual level and is applicable to transplant-specific settings, which also had an advantage for subjects carrying mutations and younger patients.

Comparison of the 2022 ICC and Who Classification Systems of Myelodysplastic Neoplasms

Introduction: Recently, the World Health Organization (WHO) updated the 5th edition classification of myelodysplastic neoplasms (MDS) and the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemia was published. In this study, we aimed to compare several differences between WHO 2022 and ICC classifications. Methods: Our study consisted of 989 newly-diagnosed primary MDS subjects classified using the WHO 2016 criteria from 08/2016 to 07/2022. CD34 and CD117 immunostaining were used in 30 of 38 subjects with low blasts and BM fibrosis to evaluate a proportion of immature myeloid precursors. All subjects were negative for CD117+ cells. CD34+ BM cells ranged from 0% to 5%. Results: According to WHO 2022 classification, 36 MDS subjects with NPM1 mutation were reclassified as AML and 10 MDS-U subjects were reclassified as clonal cytopenia of undetermined significance (CCUS). Applying to the ICC criteria, 20 MDS subjects with NPM1 mutation were reclassified as AML and 8 MDS-U subjects were reclassified as CCUS. We analyzed the remaining patients. Among the 81 subjects classified as MDS-biTP53 according to WHO 2022, 10 subjects did not meet ICC criteria for MDS or MDS/AML with mutated TP53 because the VAF of TP53 mutation(s) was less than 10%. Subjects not qualifying for MDS or MDS/AML with mutated TP53 had lower Revised International Prognostic Scoring System (IPSS-R) scores, better IPSS-R-defined cytogenetics, a higher frequency of SF3B1 mutations and longer survival compared with subjects with MDS or MDS/AML with mutated TP53 according to ICC (All P-values＜ 0.005, Figure 1 Left). Our data suggested that TP53 mutational burden should also be considered in the diagnostic classification and the cut-off value of 10% seems reasonable. An additional difference between these two classifications is that ≥15% ring sideroblasts may be a surrogate for SF3B1 mutation in WHO 2022. But only those with SF3B1 mutation (VAF≥10%), without 5q-, -7 or complex karyotype and RUNX1 mutation can be diagnosed as MDS with mutated SF3B1(MDS- SF3B1) according to ICC. 23 of 76 subjects (30.3%) with MDS- SF3B1 according to the WHO 2022 classification did not meet the ICC criteria for MDS- SF3B1. Subjects not meeting the ICC for MDS- SF3B1 had lower WBCs ( P = 0.003) ,platelet concentrations ( P = 0.001), higher IPSS-M categories ( P = 0.024) and shorter survival compared with those with MDS- SF3B1 according to ICC( P = 0.003, Figure 1 middle). Therefore, our study shown that SF3B1-unmutated MDS-RS cases have different clinical features and outcome in comparison with SF3B1-mutated subjects and ICC criteria defined a more homogeneous disease entity of MDS- SF3B1. Apart from MDS with defining genetic abnormalities, substantial differences in morphologically defined MDS subtypes between WHO 2022 and ICC also need to be addressed. According to the WHO 2022 classification, only MDS-EB patients were furtherly categorized into MDS-EB with or without BM fibrosis. Here, we explore the impact of BM fibrosis in patients with MDS-LB. Among MDS patients without excess blasts and specific genetic abnormalities, 38 patients had fibrosis. Subjects with low blasts and fibrosis (MDS-LBf) had lower platelet concentrations ( P = 0.002), worse IPSS-R-defined cytogenetics and IPSS-R categories ( P ＜0.05) compared with those without excess blasts and myelofibrosis. MDS-LBf had worse survival compared with those with low blasts and without fibrosis (Figure 1 right, P = 0.007). Conclusion: Both the WHO 2022 and ICC criteria allow more accurate diagnoses and risk stratification. However, the presence of two separate classifications leads to the dilemma in clinical application. When it comes to MDS with defining genetic abnormalities, our analyses suggest ICC defines more homogeneous disease entities of MDS-SF3B1, MDS or MDS/AML with mutated TP53 subjects compared with WHO 2022. Although WHO 2022 places an emphasis on morphologically defined MDS and listed hypoplastic MDS (MDS-h) and MDS with fibrosis (MDS-f) as new entities. Our data shown that fibrosis is a poor prognostic factor in MDS subjects without excess blasts. These subjects tend to have more aggressive clinical manifestations than other MDS subjects with low blasts. Collectively, we propose to integrate these two classifications into one pipeline for diagnosis of MDS (Figure 2), avoiding disadvantages for each one. Bing Liand Zhijian Xiao were co-corresponding authors

Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia

Background: Waldenström Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous outcomes. The recently developed, Revised International Prognostic Scoring System for WM (rIPSS-WM) did not examine the prognostic impact of MYD88L265P, a somatic alteration present in most patients with WM. Moreover, rIPSS-WM could only be partially validated in an external cohort. Here, we report the performance of rIPSS-WM and propose a refined prognostic model with external validation. Methods: We reviewed medical records of treatment-naïve patients with active WM consecutively seen at Mayo Clinic, Rochester (MCR) between 01/01/1996 and 12/31/2017. We applied the rIPSS-WM model in patients with data available for all required parameters, including age, serum beta-2 microglobulin (β2M), serum lactate dehydrogenase (LDH) and serum albumin at diagnosis to assess the prognostic utility of this model. We then identified the dichotomized clinical and laboratory parameters prognostic for overall survival (OS) by univariate analyses (UVA) in our cohort. The significant parameters were analyzed to independently predict OS in a multivariable analysis (MVA) and to create a prognostic model, which was subsequently validated in an independent multi-institutional cohort. Results: We identified 889 patients with active WM at MCR, with a median follow-up of 8.2 [95% confidence interval (CI): 7.5-9] years. The estimated median OS for this cohort was 10.6 (95%CI: 9.7-11.4) years. Patients with available data in this cohort for the validation of rIPSS-WM (n=241) were risk stratified into very low (n=46), low (n=64), intermediate (n=58), high (n=46) and very-high risk groups (n=27) per rIPSS-WM, with the respective 5-year OS rates of 96%, 76%, 72%, 77% and 32%, demonstrating overlapping survival curves for the low, intermediate and the high-risk groups. Because rIPSS-WM could not be validated, we used the data from the MCR cohort and identified age at diagnosis of active WM, LDH &amp;gt;upper limit of normal (ULN), β2M &amp;gt;3µg/mL and albumin &amp;lt;3.5g/dL as statistically significant prognostic markers for OS on UVA. Notably, the presence of MYD88 L265P did not impact OS [median 11.4 years (95%CI: 10.1-not reached (NR) for MYD88 L265P genotype (n=231) versus 10 years (95% CI: 8.1-NR) for MYD88 WT genotype (n=65); p=0.33]. On MVA, LDH &amp;gt;ULN (HR 2.34), serum albumin &amp;lt;3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and &amp;gt;75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin &amp;lt;3.5 g/dL and age group 66-75 years and similarly, 2 points each for age &amp;gt;75 years and serum LDH &amp;gt;ULN per their impact on OS. Patients with the composite scores of 0, 1 and 2 were categorized as low risk, low- intermediate risk and intermediate risk, respectively. Due to similar OS for the scores of 3 to 5, these were combined to form the high-risk group of our proposed model: Modified Staging System for WM (MSS-WM). The median OS was 14.6 years [95%CI: 9.1 years-NR] for low-risk (score 0, n=71, 21%), 11.2 years (95% CI: 9.1-15.2 years) for low-intermediate risk (score 1, n=110, 32%), 8.1 years (95% CI: 6.4-12.2) for intermediate risk (score 2, n=81, 24%) and 5.5 years (95 % CI: 3.9-11 years) for the high-risk group (score ≥3, n=79, 23%); p&amp;lt;0.0001. In this derivation cohort, the 5-year OS rate was 93%, 82%, 69% and 55% and 10-year OS rate was 60%, 53%, 45% and 30% for the low, low-intermediate, intermediate, and high-risk cohort, respectively ( Figure 1A). We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p&amp;lt;0.0001). We then used data from an independent series of 335 treatment-naïve symptomatic patients from academic institutions (n=5) across the US and Europe for external validation of the MSS-WM model. The median follow-up for the validation cohort was 6.3 years (95% CI: 5.5-7.2 years). The 5-year OS was 93%, 90%, 75% and 57% and the estimated 10-year OS was 91%, 80%, 64% and 35% for the low risk (n= 86, 26%), low-intermediate (n=107, 32%), intermediate (n=86, 26%) and high-risk (n=59, 18%) cohorts, respectively (p&amp;lt;0.0001, Figure 1B). Conclusions: Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.

Methylation Biology of a Blood-Based MDS Risk Stratification Test

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies associated with a myriad of deleterious outcomes and a 5-year relative survival of 37%. MDS risk stratification is key for optimal treatment decisions. We previously demonstrated that methylation-based markers may help stratify MDS risk and achieved comparable performance relative to IPSS-R (the Revised International Prognostic Scoring System) by assessing the risk prediction ability of a classifier trained with features from either Bone Marrow (BM) whole-genome bisulfite sequencing (WGBS) or serum targeted methylation (TM) sequencing. Here, we elucidate the biological underpinnings of the methylation-based classifier and explore the survival stratification performance of our previously reported classifier. Methods: Utilizing datasets from BM WGBS and matched Serum TM sequencing of 127 patients with MDS (N=104) and secondary AML (N=23), we delineated the features used by the classifier by identifying differentially methylated regions (DMRs) that distinguished patients with overall survival of &amp;gt;3 years from those with &amp;lt;3 years. Our approach also included a functional enrichment and driver gene analysis associated with these DMRs, as well as cluster analysis across patients. We performed further evaluations of the survival outcomes of our BM WGBS and matched Serum TM prognostic classifier using concordance indices and log-rank tests. Results: Our analysis revealed 7,742 DMRs in BM WGBS and 14,093 DMRs in the Serum TM that significantly separated the long and short-term survival groups. Unsupervised hierarchical clustering of differential methylation patterns in both BM WGBS and Serum TM highlighted three distinctive subgroups of samples: short-term survivors, long-term survivors, and a group with intermediate survival outcomes. Notably, the short-term survivor group exhibited extensive hypermethylation across a majority of DMRs, which were linked to key biological pathways including calcium signaling, cAMP, MAPK, Rap1, and PI3K-Akt. Enrichment analysis of the BM WGBS DMRs between individuals with &amp;lt;3 and &amp;gt;3 years of survival underscored the differential hypermethylation of promoters, CpG islands, and CpG shores in association with worse survival outcomes. Our analysis of BM WGBS DMR driver genes via Hypergeometric Optimization of Motif EnRichment (HOMER) revealed potential contributors to differential survival outcomes, including known genes associated with MDS/AML, such as EWS/FLI-1, ERG, Pu.1, and RUNX1. Both pathway and driver gene analysis recapitulated previously known drivers of MDS to AML progression. The methylation classifier achieved comparable risk stratification performance for both BM WGBS comparing with IPSS-R (C-index: 0.69 [95% CI: 0.61-0.77] for methylation vs 0.71 [95% CI: 0.64-0.77] for IPSS-R) and Serum TM (C-index: 0.68 [95% CI: 0.60-0.75] for methylation vs. 0.70 [95% CI: 0.63-0.78] for IPSS-R). At a specificity threshold of 0.8, both BM WGBS and Serum TM prognostic classifiers were able to stratify between predicted short and predicted long survivors (BM WGBS HR: 2.83, p&amp;lt;0.0001; Serum TM HR: 3.01, p=0.0008). Conclusions: Our findings generated biological insights into the methylation-based risk stratification of MDS, shedding light on the specific genomic features and biological pathways that underlie these methylation patterns. We also demonstrated that methylation-based MDS risk stratification performs comparably with IPSS-R. These insights not only expand our understanding of the complexity of MDS, but also reinforce the potential of methylation-based sequencing as a viable, possibly less-invasive, alternative for MDS risk stratification compared to traditional IPSS-R methods.

Efficacy and Safety of Roxadustat for Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndrome (LR-MDS) with Low Red Blood Cell (RBC) Transfusion Burden: Results of Phase III Matterhorn Study

Presented on behalf of all MATTERHORN (FGCL-4592-082) study investigators Introduction: For patients (pts) with LR-MDS, anemia poses a major clinical challenge, with limited response to first-line erythropoietin (EPO)-stimulating agents (ESAs) and a median duration of response ≤2 years. Further, pts with RBC transfusion dependence (≥2 packed RBC [pRBC] units every 8 weeks [Q8W]) are less likely to respond to ESAs. Anemia treatments with novel mechanisms of action enabling transfusion independence (TI) are needed to reduce frequent RBC transfusion burden. Roxadustat is a first-in-class, hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia with chronic kidney disease. In the MATTERHORN (NCT03263091) dose-selection stage, roxadustat was well-tolerated, and 37.5% of pts (9/24) with LR-MDS and low RBC transfusion burden ([LTB] 1 pRBC unit Q8W for two consecutive 8-week periods or 2-4 pRBC units Q8W) achieved TI. In the MATTERHORN double-blind stage, TI response rate and safety of roxadustat were further assessed. Methods: MATTERHORN is an ongoing, double-blind, Phase III, randomized, placebo (PBO)-controlled trial. Eligible adult pts (≥18 years of age) had very low-, low-, or intermediate-risk primary MDS per Revised International Prognostic Scoring System (IPSS-R) classification (&amp;lt;5% bone marrow blasts); hemoglobin (Hb) ≤10.0 g/dL at baseline (BL); and LTB. Prior ESA use (&amp;gt;8 weeks before randomization) was permitted. Pts were randomized 3:2 to roxadustat or PBO, then stratified by serum EPO concentration (≤200 or 200-400 mIU/mL), IPSS-R risk, and transfusion burden. Pts received oral roxadustat (starting dosage: 2.5 mg/kg three times weekly based on the dose-selection stage) or PBO with best supportive care (BSC; per institutional criteria, including RBC transfusion) for a 52-week treatment period, followed by a 4-week follow-up period. Primary efficacy endpoint was percentage of pts with TI (the absence of RBC transfusion) for ≥56 consecutive days during the first 28 treatment weeks (TI responder). The percentage of pts with TI and mean Hb increase of ≥1.0 and ≥1.5 g/dL (averaged over 8 weeks) compared with BL pretransfusion Hb was also assessed (to be reported separately). Safety (including treatment-emergent adverse events [TEAEs] and serious TEAEs) was evaluated throughout the study. Results: As of the final 28-week interim analysis of the double-blind stage (data cutoff: April 24, 2023), 140 pts (82 roxadustat, 58 PBO) were randomized and treated. Across arms, median age was 71.5 years (range, 26-96), 59.3% (83/140) were male, and 80.0% (112/140) were white. Most pts (72.1% [101/140]) had IPSS-R low-risk disease and a transfusion burden of 2-4 pRBC units Q8W (92.1% [129/140]). Median (range) BL transfusion burden was 2.5 (1-10) pRBC units. Seventy pts (50.0%) received prior ESAs (98.6% [69/70] were ESA-refractory). Eighty-four pts (41/82 [50.0%] roxadustat, 43/58 [74.1%] PBO) completed 28 weeks of treatment, and 15 pts (6/82 [7.3%] roxadustat, 9/58 [15.5%] PBO) were continuing treatment. Median (range) treatment duration was 24.1 (1.1-28.0) weeks for the roxadustat arm and 28.0 (0.1-28.0) weeks for the PBO arm. A greater percentage of pts in the roxadustat arm compared with the PBO arm were TI responders (47.5% vs. 33.3%). However, this difference did not reach statistical significance ( p=0.22; figure). Percentages of pts with TEAEs of any grade, serious TEAEs, and TEAEs leading to treatment discontinuation were similar across arms (table). Six deaths occurred on study (roxadustat: pneumonia [n=2], acute myocardial infarction and ischemic stroke [n=1], multiorgan failure [n=1]; PBO: urosepsis [n=1], disease progression [n=1]). Three pts (all in roxadustat arm) progressed to acute myeloid leukemia. The study was terminated by the sponsor and is currently being completed. Conclusions: Despite not meeting the primary endpoint, roxadustat plus BSC was well-tolerated, and a high percentage of pts with LR-MDS and LTB were TI responders. The high TI response rate in the PBO arm, historically poor outcomes in pts with ESA-refractory disease, and the inclusion of pts who were not transfusion-dependent (1 pRBC unit Q8W) may have contributed to the lack of a statistically significant difference in TI response rates between arms. MATTERHORN outcomes highlight the continued unmet need for effective and safe therapies that reduce RBC transfusion burden in LR-MDS.

Daprodustat, a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, Improves Hematological Insufficiency without Progression of Myelodysplastic Syndrome with Chronic Kidney Disease

Introduction Hematological insufficiency is a critical issue in the treatment of myelodysplastic syndrome (MDS). The current standard treatment for cytopenia in MDS involves blood transfusion and the administration of erythropoiesis stimulating agents (ESAs). However, ESAs are only effective in certain patients with low erythropoietin levels; patients who are not suitable candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) require lifelong blood transfusions. As a result, there is a growing demand for new treatments for cytopenia in MDS, and researchers have been exploring various molecular-targeted drugs in recent years. One promising option is the hypoxia-inducible factor -prolyl hydroxylase inhibitor (HIF-PHi). This inhibitor stabilizes HIF1α, which in turn normalizes endogenous erythropoietin production and iron metabolism, leading to improved renal anemia. It is believed that HIF-PHi could potentially enhance MDS-related anemia by increasing erythropoietin levels. However, despite some case reports, there have been no comprehensive clinical studies evaluating the effectiveness and safety of HIF-PH inhibitors for MDS. Moreover, it is essential to address concerns related to HIF1α overexpression, which has been associated with exacerbating various malignant tumors, including MDS. To assess the safety and effectiveness of HIF-PHi for MDS, we conducted a prospective clinical trial evaluating an oral HIF-PHi called daprodustat. Methods The study included MDS patients with chronic kidney disease (CKD) stage ≥ 3, considering daprodustat's approval in Japan, at Ebina General Hospital. Patients with MDS who were treated with deoxyribonucleic acid methylation inhibitors and/or who underwent allo-HSCT were excluded. Participants were administered daprodustat at the approved dose for renal anemia and underwent regular blood sampling and bone marrow examination. The primary and secondary endpoints were the leukemia rate within 1 year after HIF-PHi administration and hematological improvement (HI), respectively. The study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the Institutional Review Board of the Ebina General Hospital (approval number: JMA-388). Written informed consent was obtained from all participants. Results Seventeen patients with MDS, with a median age of 81years, were included in the analysis. Revised International Prognostic Scoring System scores (IPSS-R) were very low, low, intermediate, high, and very high in 1, 11, 3, 1, and 1 patients, respectively. Five cases were changed from ESA treatment. Within 1 year after HIF-PHi administration, no patients developed leukemia, and both peripheral blood Wilms tumor 1 protein concentrations and bone marrow myeloblast counts remained unchanged from pre-treatment levels. HI was observed in 8 patients within 6 months, and the median dose was 6 (range, 2-12) mg for HI achievement. On univariate analysis, pretreatment transferrin saturation (TSAT, P = 0.002, Figure 1) and ferritin concentration ( P = 0.016) were inversely associated with HI achievement. However, pretreatment hepcidin concentration, erythropoietin concentration, previous ESA use, and IPSS-R were not associated with HI achievement. Notably, when a TSAT cutoff of &amp;lt; 45% was used, achieving HI showed a sensitivity and specificity of 87.5% and 100.0%. Moreover, patients with TSAT &amp;lt; 45% showed significant improvement in anemia after 3 months and beyond (Figure 2). No significant differences were observed in neutrophil and platelet counts between the two groups. Throughout the study, eleven adverse events occurred, including 6 infections, and 1 case each of myocardial infarction, eosinophilia, erythema multiforme, organizing pneumonia, and spinal fracture. Conclusion HIF-PHi administration did not lead to MDS progression. Notably, in MDS patients with CKD, low TSAT was a predictor for achieving HI by HIF-PHi.

Improved Quality of Life upon Shifting from Darbepoetin to Luspatercept in Patients with Low-Risk Myelodysplastic Syndrome (MDS)

Introduction: Low-risk MDS is characterized by refractory anemia due to Dyserythropoiesis 1. Standard of care treatment is mainly Erythropoiesis stimulating agents (ESA) or blood transfusion or both 1. Response to ESA is achieved in some patients whose erythropoietin (EPO) level is less than 500 mu/ml 2. Luspatercept is a red cell maturing agent that may lead to an increase in Hb of up to 3 g/dL 3 in responders. Response to ESA can be enhanced with the addition of Luspatercept 4. Hereby we are reporting successful shifting of two patients from Darbepoietin to Luspatercept with significant increase in Hb level and improvement in quality of life. Case 1: A 62-year-old man without previous illness presented in April 2018 with progressive symptomatic anemia. His body weight was 107 kg, and his physical examination was unremarkable other than pallor and tachycardia. The laboratory investigation revealed WBC, 5.62 x 10 3/uL, RBC 2.2 x 10 3/uL, Hb 7.8 g/dL, MCV 110.4 fl, platelets 706 x 10 3/uL, and reticulocytes 1%. Blood film showed reduced RBC count with numerous macrocytes and no other abnormalities. Bone marrow revealed 80% cellularity with Dyserythropoiesis, 16% ring sideroblasts, and 2% blasts. The Ferritin level, B12 levels were elevated (table). EPO level was elevated but less than 500 mlU/ml and the cytogenetic analysis showed normal karyotype. However his molecular profiling demonstrated SF3B1 and TET2 mutations. At the time of diagnosis, the Revised International Prognostic Scoring System (IPSS-R) was 2.0, indicating low risk MDS. He was given darbepoetin 300 mcg SC weekly for four weeks without any improvement, then darbepoetin dose was escalated to 500 mcg weekly with a good response. Hb level remained at 8.5 - 9.5 g/dl for three years. The patient's physical performance improved moderately, with an increase in walking distance on flat surfaces from 20 to 35 minutes. In August 2022, he was switched to Luspatercept 100 mcg SC on a three-weekly schedule. Within three months, his hemoglobin level increased to 10.8 g/dl and he experienced significant improvement in physical performance and mental well-being, along with a significant reduction in fatigue, enabling him to increase his walking distance to 76 minutes. Case 2: A 77-year-old man with type 2 diabetes mellitus and mild renal impairment who developed an unexplained progressive anemia. His body weight was 79 kg, and his physical examination was unremarkable other than pallor. His laboratory investigations showed WBC 4.5 x 10 3/uL, RBC 1.5 x 10 6/uL, Hb 5.2 g/dL, MCV 96 fl, platelets 706 x 10 3/uL, and reticulocytes 0.8 %. Blood film showed reduced RBC count, normocytic anemia, and no other abnormalities. Bone marrow revealed 60% cellularity with Dyserythropoiesis, 17% ring sideroblasts, and 1% blasts. His baseline serum creatinine was 1.8 mg/dl, and HbA1C 10.0. Two units of packed red blood cells were transfused every 2- 4 week to keep his Hb level around 8 g/dL. Darbepoetin 80 mcg SC weekly for four weeks,150 mcg weekly for 4 weeks and 300 mcg weekly for further 4 weeks without any response. Eventually, he responded to 500 mcg of Darbepoetin per week. As a result, his Hb increased to the range of 8.6-9.4 g/dl for one year, with moderate improvements in performance status. Darbepoetin was switched to Luspatercept 75 mcg three-weekly in January 2023, resulting in an increase in his hemoglobin level to 10.3 g/dl, with significant improvement in his energy level and overall well-being. Discussion: Blood transfusion and ESA have traditionally been used as standard treatments for low-risk MDS. Recently, Luspatercept in combination with ESA has shown enhanced effectiveness in elevating Hb levels. Both of our patients had significant increases in Hb levels along with a noticeable improvement in quality of life because of Luspatercept alone. Conclusion: Following the switch from Darbepoetin to Luspatercept, there was a significant improvement in Hb level and in quality of life in our 2 patients. This finding needs to be confirmed with larger studies.