IPSS Risk Research Articles

The impact of starting dose on overall survival in myelofibrosis patients treated with ruxolitinib: A prospective real-world study on AIFA monitoring registries.

Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF)-related splenomegaly or symptoms. The recommended starting dose depends on platelet count, regardless of haemoglobin level at baseline. In the recent years, an overall survival (OS) advantage was reported in patients treated with ruxolitinib compared with best available therapy. We analysed a large Italian cohort of 3494 patients identified by Agenzia Italiana del Farmaco (AIFA) monitoring registries. Of them, 2337 (66.9%) started at reduced dose: these patients were older (median age 70 vs. 67), with increased incidence of large splenomegaly (longitudinal diameter 20 vs. 19.1 cm, median volume 1064 cm3 vs. 1016 cm3), with higher IPSS risk (30.9% vs. 26.1%), and worse ECOG score (more than 1 in 14.3% vs. 9.8%). After balancing for baseline characteristics, Kaplan-Meier analysis showed a median OS of 78.2 months (95% CI 65.9-89) for patients who started at full dose and 52.6 (95% CI 49-56.6) months for patients who started with reduced dose (p < 0.001). Group analysis also showed a substantial difference in patients with intermediate-2 and high IPSS risk. The majority of MF patients in real-world analysis started with a reduced dose of ruxolitinib, which is associated with less favourable outcomes.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial

Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

INTRODUCTION: Hypomethylating agents (HMAs) are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). HMA failure (HMA-F) is associated with poor outcomes and median survival of 4 to 6 months. CPX-351 is a drug liposomal encapsulation of cytarabine (araC) and daunorubicin (dauno) at a synergistic 5:1 molar ratio approved for the treatment of pts with therapy-related acute myeloid leukemia (AML) or AML with MDS-related changes. Here we present the results of a phase I-II study of lower dose CPX-351 for HR-MDS and CMML after HMA-F. METHODS: We conducted a phase I/II clinical trial of CPX-351 for pts with MDS or CMML after HMA-F with Int-2 or High risk by IPSS, or Int-1 with &amp;gt;10% bone marrow (BM) blasts. The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 4 dose levels of CPX-351: 10 units/m 2 (dauno 4.4mg/m 2 and araC 10mg/m 2), 25 units/m 2 (dauno 11mg/m 2 and araC 25mg/m 2), 50 units/m 2 (dauno 22mg/m 2 and araC 50mg/m 2) and 75 units/m 2 (dauni 33mg/m 2 and araC 75mg/m 2). Therapy was administered intravenously on days 1, 3 and 5 of 28-day cycles during induction and on days 1 and 3 of re-induction or consolidation. Re-induction was allowed in pts not achieving response after induction. The primary end point was to evaluate safety and determine the maximum tolerated dose of CPX-351. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between June 2019 and September 2022, 23 pts have been treated: 15 in the phase I portion, and 8 in the phase II. A total of 17 pts had MDS, and 6 had CMML. Four (17%) pts had intermediate-1 risk IPSS and &amp;gt;10% blasts, 15 (65%) had intermediate-2 and 4 (17%) had high-risk IPSS. Median number of prior therapies was 1 (range 1-4) including 4 (17%) pts with failure to prior venetoclax therapy and 2 (9%) with prior HSCT. In the phase I portion, 3 pts received CPX-351 at dose level 1, 3 at dose level 2, 3 at dose level 3 and six at dose level 4. One pt treated at dose level 4 developed grade 2 congestive heart failure with grade 2 reduction in left-ventricular ejection fraction (LVEF). No additional DLTs were detected during the 28-day DLT evaluation window. The initial two pts treated at the P2RD of 75units/m 2 during phase II experienced cardiac complications: grade 3 congestive heart failure without reduction in LVEF and grade 3 right-sided heart failure, respectively. Study was amended to continue further treatment in phase II at dose level 3 (50units/m 2). Most common adverse events (AEs) were lower extremity edema (n=12, 52%), febrile neutropenia (n=11, 48%), dyspnea (n=10, 44%), mucositis (n=10, 44%), constipation (n=9, 39%), diarrhea (n=9, 39%), and generalized muscle weakness (n=9, 39%). Most common grade 3-4 AEs were febrile neutropenia (n=11, 48%), neutropenia (n=5, 22%), lung infection (n=4, 17%), diarrhea (n=4, 17%) and thrombocytopenia (n=3, 13%). The 4-week and 8-week cumulative incidences of mortality were 0% and 4%, respectively. Median number of days to cycle 2 was 47 days (range 30-83). Dose reductions of CPX-351 occurred in 4 (17%) pts. Median number of cycles was 3 (range 1-9). Median cycles to best response was 1 (range 1-3). Among pts with HR-MDS, the ORR was 71% (n=12): CR in 1 (6%), mCR with HI in 1 (6%) and mCR in 11 (59%) pts (Fig 1A). Among pts with BM blast reduction to &amp;lt;5% by the end of cycle 1, 11 (65%) and 9 (53%) had ANC recovery to &amp;gt;0.5x10 9/L and &amp;gt;1x10 9/L, respectively, and 8 (47%) and 6 (35%) had platelet recovery to &amp;gt;50x10 9/L and &amp;gt;100x10 9/L, respectively. Based on 2023 IWG response criteria, the ORR was 59% (n=10) including CR in 1 (6%), CR bilineage (CRbi) in 4 (24%) and CR unilineage in 5 (29%). Of 11 (65%) pts with baseline cytogenetic abnormalities, 2 (18%) and 2 (18%) achieved complete and partial cytogenetic responses, respectively. Three (13%) pts underwent HSCT at time of best response. Among pts with CMML (n=6), only one (17%) achieved response. Median response duration was 4.5 months (95% CI 0.7-8.2 months) and the median OS was 12.6 months (95% CI 3.6-21.7 months) (Fig 1B). CONCLUSIONS: Lower doses of CPX-351 in HR-MDS after HMA-F can induce clinically meaningful responses and be used as a bridge to allogeneic stem-cell transplant. Therapy is associated with median OS of 12.6 months in this population with expected survival of 4-6 months.

Red Cells Distribution Width and Prognosis in Myelofibrosis Patients Treated with Ruxolitinib

Introduction Myelofibrosis (MF) is a BCR::ABL1-negative myeloproliferative neoplasm characterized primarily by genetic abnormalities and an aberrant production of pro-inflammatory cytokines (including IL-2, IL-6, TNF-α, and TGF-β among others) released from pathological hematopoietic stem cells leading to the deposition of reactive fibrosis in the bone marrow (BM), at the same time the development of extramedullary hematopoiesis, mainly in the spleen and liver, and finally the production of red blood cells (RBC) of often bizarre shape, i.e. dacryocytes. Consequently, increased variability in RBC volume, so-called anisocytosis, is a hallmark of MF. A small number of studies have already demonstrated that quantitative measurement of anisocytosis in terms of red cells distribution width (RDW) may have a negative prognostic role in newly diagnosed MF patients. Aim In this study we further evaluate the prognostic impact of RDW in a series of patients with primary (PMF) and secondary myelofibrosis (SMF) at diagnosis and during treatment with ruxolitinib (RUX). Methods Between October 2014 and May 2023, the RDW of 49 consecutive patients with PMF or SMF (32 males and 17 females; median age at RUX initiation, 70.5 years) were retrospectively assessed at MF diagnosis, at RUX start and after 3, 6, 12, 24 and 36 months from therapy initiation. All patients were treated with RUX according to current indications, requiring an IPSS risk of at least intermediate-1. Red cells distribution width was routinely reported by automated cell counters as part of RBC count, with an upper limit of normal of 14.5% used as a cut-off in our laboratory. At the time of RDW evaluation, complete blood cells count and spleen size [expressed as the distance from the left costal margin (BCM) in cm] were available for all patients. Results Among 49 patients, 24 had PMF (10 prefibrotic and 14 overt fibrotic) and 25 SMF [15 had post-polycythemia vera (PPV)- and 10 post-essential thrombocythemia (PET)-MF]. The JAK2V617F mutation was detected in 38 (77.6%) cases, CALR mutations in 8 (16.3%), and MPL in 1 (2%), while 2 patients (4.1%) were “triple-negative”. Elevated RDW values were present in all but 3 patients at MF diagnosis with a median RDW of 18.7% (range, 13.3% - 25.7%). RDW was higher in patients with splenomegaly ( p=0.04) and with JAK2V617F mutation ( p=0.09). Furthermore, looking specifically at JAK2V617F-mutated cases, the greater the RDW values, the higher the JAK2V617F allele burden. Interestingly, a higher RDW value at diagnosis also correlated with a shorter time from MF diagnosis to RUX start (-3.5 months per one RDW unit, 95%CI: -7.5 to +0.4; p=0.08). We observed a modest (&amp;lt;1%) increase in RDW during the first 6 months of RUX treatment. In a multivariable random-intercept model that considers all time points and contains the covariates time, RUX dose, and hemoglobin (Hb), we also observed a clear decrease in RDW with increasing Hb (slope: -0.35% per g/dL of Hb, 95%CI: -0.56 to -0.14; p=0.001). Median overall survival (OS) from MF diagnosis was 6.5 years with a median duration of RUX treatment of 33.3 months. The median RDW at diagnosis of 18.7% was used as a cut-off to identify two subgroups of patients [Group 1 (N=22): RDW 18.7% to 25.7%; Group 2 (N=23): RDW 13.3% to 18.6%] showing a difference in OS [Group 1 vs. 2: Hazard Ratio (HR) 2.74, 95%CI: 1.13 to 6.65; p=0.03] ( Figure 1); the median OS was 8.5 (14 deaths) and 11.8 (9 deaths) years for the Group 1 and 2, respectively. Using continuous RDW at diagnosis, the crude HR was 1.21 per one RDW unit (95%CI: 1.06 to 1.37; p=0.004). In a Cox model adjusted for gender, age, and Hb, the HR was 1.13 (95%CI: 0.99 to 1.29; p=0.06). Notably, RDW at diagnosis was associated with a 35% increase in infectious disease mortality in a crude analysis (HR 1.35, 95%CI: 1.07 to 1.71, 8 deaths; p=0.01) and a 27% increase (HR 1.27, 95%CI: 0.99 to 1.63; p=0.07) in the adjusted analysis. Conclusions Red cells distribution width may represent a good integrative measure of several disease processes and also has prognostic significance at the time of MF diagnosis and during RUX treatment. Even though our preliminary observations are limited by the small number of patients and need to be further confirmed by larger studies, we can speculate that RDW may help in the rapid detection of MF patients with a poor prognosis, which can only partially be improved from currently available targeted therapies with JAK inhibitors.

IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA).

7004 Background: Unmet needs remain for red blood cell (RBC) TD pts with LR-MDS R/R or ineligible for ESA. In P2 of the IMerge study (NCT02598661), heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to lenalidomide and hypomethylating agents (len/HMA) treated with imetelstat, a telomerase inhibitor, achieved durable and continuous transfusion independence (TI). We report primary data from the P3 study of imetelstat in such pts. Methods: Heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to len/HMAs were randomized 2:1 to receive imetelstat 7.5 mg/kg or placebo every 4 wks. Primary endpoint was 8-wk TI; subgroup analyses included IPSS risk, prior transfusion burden and ring sideroblast (RS) status. Secondary endpoints included 24-wk TI, TI duration and hematologic improvement-erythroid (HI-E). Variant allele frequency (VAF) changes were explored. Results: As of Oct 2022, 178 pts were randomized. The primary endpoint was met (Table); 39.8% vs 15.0% of pts receiving imetelstat vs placebo, respectively, achieved 8-wk TI. The rate of 8-wk TI was significantly higher with imetelstat vs placebo across subgroups, including RS negative pts. Median TI duration was significantly longer for imetelstat vs placebo, 51.6 vs 13.3 wks, P &lt; 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P &lt; 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. In 3 of 4 genes frequently mutated in MDS, VAF reduction was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P &lt; 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration, P &lt; 0.001. No new safety signals were identified. The most common Grade 3/4 AEs were thrombocytopenia and neutropenia, with similar rates of Grade ≥3 bleeding and infections on imetelstat and placebo. In pts treated with imetelstat, cytopenias were manageable, of short duration, and &gt;80% were reversible to Grade ≤2 within 4 wks. Conclusions: For this LR-MDS pt population, imetelstat demonstrated statistically significant and clinically meaningful efficacy with high 8- and 24-wk TI rates, prolonged TI duration and increased hemoglobin. VAF reduction and its correlation to clinical endpoints support imetelstat’s disease-modifying potential. Safety results were consistent with prior reported experience. Clinical trial information: NCT02598661 . [Table: see text]

Distinct Clinical and Prognostic Features of Myelodysplastic Syndrome in Patients from the Middle East, North Africa, and Beyond: A Systemic Review.

Myelodysplastic syndrome (MDS) describes a group of bone marrow malignancies with variable morphologies and heterogeneous clinical features. The aim of this study was to systematically appraise the published clinical, laboratory, and pathologic characteristics and identify distinct clinical features of MDS in the Middle East and North Africa (MENA) region. We conducted a comprehensive search of the PubMed, Web of Science, EMBASE, and Cochrane Library databases from 2000 to 2021 to identify population-based studies of MDS epidemiology in MENA countries. Of 1935 studies, 13 independent studies published between 2000 and 2021 representing 1306 patients with MDS in the MENA region were included. There was a median of 85 (range 20 to 243) patients per study. Seven studies were performed in Asian MENA countries (732 patients, 56%) and six in North African MENA countries (574 patients, 44%). The pooled mean age was 58.4 years (SD 13.14; 12 studies), and the male-to-female ratio was 1.4. The distribution of WHO MDS subtypes was significantly different between MENA, Western, and Far East populations (n = 978 patients, p < 0.001). More patients from MENA countries were at high/very high IPSS risk than in Western and Far East populations (730 patients, p < 0.001). There were 562 patients (62.2%) with normal karyotypes and 341 (37.8%) with abnormal karyotypes. Our findings establish that MDS is prevalent within the MENA region and is more severe than in Western populations. MDS appears to be more severe with an unfavorable prognosis in the Asian MENA population than the North African MENA population.

PD-1 Inhibitors Can be the First-Line Therapy for Myelodysplastic Syndrome (MDS) --Study on the Bone Marrow Immune Microenvironment of MDS By Multispectral Imaging of Multiplex Immunofluorescence

Objective: Myelodysplastic Syndrome (MDS) is a special myeloid neoplasm with still limited treatment choices and poor survival. Although current therapies including HMAs have been shown to prolong survival, only 40-50% of patients respond to therapy, and responses are universally transient, with loss of response within 2 years. With the increasing understanding of the pathogenesis of MDS in recent years, MDS was found closely associated with the bone marrow microenvironment, including immune microenvironment (IME). More and more evidences show that the immune microenvironment of MDS is related with its disease characteristics and prognosis. Knowing more of the IME of MDS may facilitate the diagnose and treatment on MDS. However, till now little was known about the bone marrow immune microenvironment of MDS. Previous studies mostly applied multiparameter flow cytometry and based on the PB samples or frozen bone marrow fluid samples, less was known about the immune landscape of MDS bone marrow biopsies. Methods: We use multispectral imaging of multiplex immunofluorescence (mIF) to analyze the bone marrow biopsy slides and explore the bone marrow immune microenvironment of MDS patients. A total of 20 de novo MDS patients, 20 post-treatment MDS patients and 20 normal controls were included in this study. In HMAs treated group, 10 patients were response to HMA and another 10 patients were not response. HMAs were either decitabine with a dose at 20mg/m2 d1-5 or 5-Azacytidine with a dose at 75mg/m2 d1-7. The multiplex staining panel could differentiate the distinct cell subpopulations into CD34+CD117+ cells, CD8+ cells, PD1+ cells, CTLA4+ cells, CD8+PD1+ cells and CD8+CTLA4+ cells, CD8-PD1+ cells and CD8-CTLA4+ cells, respectively. We analyzed the proportion of these cells in MDS patients and normal controls, and analyzed the proportion of these cells in MDS patients with different IPSS risk stratifications, and we also assessed the degree of myelofibrosis in MDS patients and analyzed the relationship between myelofibrosis and immune cells. Results: We found that compared with the normal control, the proportion of CD8+ cells in de novo MDS patients increased, and CD8+PD1+ T cells increased too, but the CD8+CTLA4+ T cells decreased. Compared with the lower-risk groups, CD8+ T cells as well as CD8+PD1+ T cells increased in higher-risk groups, while CD8+CTLA4+ T cells decreased. We also found a higher CD8+ T cells as well as CD8+/PD1+ T cells in MDS-F patients, especially in MDS-F patients with higher IPSS risk levels. We also found that compared with the normal control, the proportion of CD8+ T cells per CD34+CD117+ cell reduced, and was lower in IPSS int-2 risk/high-risk group than that in low-risk/int-1 risk group. But the proportion of CD8+PD1+/CD34+CD117+ increased compared with normal control. To analyze the bone marrow immune microenvironment after HMAs treatment, CD8+PD1+ T cells decreased in patients who are effective to HMAs, but still remain high in patients who had no response to HMAs, so did the proportion of CD8+PD1+/CD8+ and CD8+PD1+/CD34+CD117+. However, such findings were not found on CD8+/CTLA4+ T cells. Conclusions: Our research findings provide a new insight on the bone marrow IME of MDS. The results confirmed that the immune checkpoint molecule PD-1 positive CD8+ T cells are abundant in MDS IME and associated with the risk. However, CTLA4 may not be a major molecule interfere with the IME of MDS. Our result also suggest that PD-1 inhibitor combines with HMAs might be used as a first-line therapy for de novo MDS patients to cover those patients who may not have response to HMAs. Also, PD-1 inhibitor may cover higher risk MDS and MDS-F, the latter is a high-risk subtype of MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis

Purpose Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its significant morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision making. Patient and Methods Registry data were retrieved from patients diagnosed with MF between January 2000 and October 2021 in 59 Spanish institutions. A total of 1,386 patients were randomly divided into a training set (80% of the cohort) and a test set (20% of the cohort). A machine learning (ML) technique (random forests) was used to model overall survival in the training set and validate the results in the test set. Results The ML model, based on eight clinical variables determined at diagnosis, achieved high accuracy in predicting overall survival (training set c-index, 0.750; test set c-index, 0.744) and leukemia-free survival (training set c-index, 0.697; test set c-index, 0.703). We confirmed the superiority of the model compared with the IPSS in the prediction of survival at all time points evaluated (Figure 1A). Importantly, the model was superior to the IPSS regardless of age range (<60 or >60 years). We derived 4 equally distributed groups of patients from the model predictions, comprising 25% of patients each. By comparing this distribution with the IPSS risk groups, we observed that circa 50% of patients were reassigned to a different risk group by the ML algorithm (Figure 1B). Additionally, we did not observe any benefit from including MPN driver mutations or high-risk somatic mutations in the model. Furthermore, the ML model outperformed the prognostic accuracy of the MIPSS70 in primary MF and the MYSEC-PM in secondary MF. Conclusion The AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) is based exclusively on clinical variables that are readily available in any healthcare facility. This simple model has demonstrated high prognostic accuracy for predicting survival in patients with primary and secondary MF, outperforming other well-established risk scoring systems. An interactive web calculator of this model can be accessed in the following link: https://geneticsoncohematology.com/MF/ Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MPN-355 Patients With Prefibrotic Myelofibrosis and Inferior Outcome, a Single-Center Analysis.

The 2016 WHO classification distinguishes prefibrotic primary myelofibrosis (pre-PMF) as a separate entity from overt MF, with less marrow fibrosis (only grade 0-1) and more favorable survival. To characterize pre-PMF patients referred to our institution between 2000 and 2020 and identify patients with the worst outcomes. A retrospective study of 130 newly diagnosed pre-PMF patients with available marrow fibrosis grading. IPSS scores and individual factors used in IPSS scoring were annotated (Cervantes et al. Blood. 2009), Main Outcomes: Overall survival (OS) of patients according to IPSS risks and the presence of individual IPSS risk factors: i) hemoglobin < 10 g/dL; ii) WBC >25×109/L; and iii) peripheral blasts ≥1%, in the context of age >65 years and ± systemic symptoms (Kaplan-Meier analysis with log-rank test). The majority of patients had grade 1 fibrosis (88%). A total of 58 patients (45%) had intermediate, 2, or high-risk IPSS. No, one, and two individual IPSS risk factors (i-ii) were identified in 27%, 24%, and 11% of patients, respectively, but 38% had symptoms. Median OS (95% CI) for the entire cohort was 68 months (42-94 months); for IPSS low-ntermediate was not reached; for IPSS 1 was 179 months (65-not expressed); for IPSS 2 was 65 months (32-98 months), and for IPSS high was 27 months (5-49 months). Median OS (95% CI) for patients without risk factors ± symptoms was not reached. Median OS for patients with one risk factor ± symptoms was 48 months (33-63 months), whereas median OS for patients with two risk factors was 16 months (8-24 months). Forty-one percent of patients required disease=directed therapy (JAK inhibitors in 37, stem cell transplantation in 8). Patients without the need for therapy or those who received JAK inhibitors had superior median OS (range 81-100 months) over treated patients without exposure to JAK inhibitors (median OS of 45 months). About 20% of patients with pre-PMF have poor outcomes, with median OS < 3 years. The use of JAK inhibitor improves outcomes among symptomatic patients in need of therapy.

Dynamics of PD-1 expression are associated with treatment efficacy and prognosis in patients with intermediate/high-risk myelodysplastic syndromes under hypomethylating treatment

Hypomethylating agents (HMAs) are widely used in patients with higher-risk MDS not eligible for stem cell transplantation. However, the general response rate by HMAs is lesser than 50% in MDS patients, while the relapse rate is high. Emerging evidence indicates that demethylating effects committed by HMAs may facilitate the up-regulation of a range of immune checkpoints or cancer suppressor genes in patients with MDS, among which the programmed death protein 1 (PD-1) and its ligands are demonstrated to be prominent and may contribute to treatment failure and early relapse. Although results from preliminary studies with a limited number of enrolled patients indicate that combined administration of PD-1 inhibitor may yield extra therapeutic benefit in some MDS patients, identifications of this subgroup of patients and optimal timing for the anti-PD-1 intervention remain significant challenges. Dynamics of immune checkpoints and associated predictive values during HMA-treatment cycles remained poorly investigated. In this present study, expression levels of immune checkpoints PD-1 and its ligands PD-L1 and PD-L2 were retrospectively analyzed by quantitative PCR (Q-PCR) in a total of 135 myelodysplastic syndromes (MDS) cohort with higher-risk stratification. The prognostic value of dynamics of these immune checkpoints during HMA cycles was validated in two independent prospective cohorts in our center (NCT01599325 and NCT01751867). Our data revealed that PD-1 expression was significantly higher than that in younger MDS patients (age ≤ 60) and MDS with lower IPSS risk stratification (intermediate risk-1). A significantly up-regulated expression of PD-1 was seen during the first four HMA treatment cycles in MDS patients, while similar observation was not seen concerning the expression of PD-L1 or PD-L2. By utilizing binary logistic regression and receiver operating characteristic (ROC) models, we further identified that higher or equal to 75.9 PD-1 expressions after 2 cycles of HMA treatment is an independent negative prognostic factor in predicting acute myeloid leukemia (AML) transformation and survival. Collectively, our data provide rationales for monitoring the expression of PD-1 during HMA treatment cycles, a higher than 75.9 PD-1 expression may identify patients who will potentially benefit from the combined therapy of HMA and PD-1 inhibitors.

Survival and risk of vascular complications in myelofibrosis-A population-based study from the Swedish MPN group.

To gain knowledge of underlying risk factors for vascular complications and their impact on life expectancy in myelofibrosis. From a cohort of 392 myelofibrosis patients registered in the Swedish MPN registry 58 patients with vascular complications during follow-up were identified. Patients with vascular complications were compared with both 1:1 matched controls and the entire myelofibrosis cohort to explore potential risk factors for vascular complications and their impact on survival. Incidence of vascular complications was 2.8 events per 100 patient-years and the majority of complications were thrombotic. Patients with complications were significantly older and had lower hemoglobin when compared to the entire cohort. In the case-control analysis, no significant risk factor differences were observed. The major cause of death was vascular complications and median survival was significantly impaired in patients with vascular complications (48 months) compared to controls (92 months). Inferior survival in patients with vascular complications was found to be dependent on IPSS risk category in a Cox regression model. Vascular complications have a considerable impact on survival in MF. At diagnosis, risk assessment by IPSS does not only predict survival but is also associated with the risk of vascular complications.

PB2057: REAL -WORLD OVERALL SURVIVAL OF MYELOFIBROSIS PATIENTS ON RUXOLITINIB – A 6 YEAR ANALYSIS IN ALBANIAN POPULATION

Background: The survival and the outcome of the patients with Myelofibrosis has been prolonged with the use of Janus kinase inhibitors. The long term follow -up of the patients with primary /secondary Myelofibrosis treated with ruxolitinib demonstrated through several clinical trials an improvement in overall survival and in the quality of life of those patients. The use of IPSS risk classification in Myelofibrosis has played an important role in the prognostic stratification of the patients predictioning also the survival. Aims: Our study aims to evaluate the Overall Survival (OS) of all the patients diagnosed with Myelofibrosis and treated with Ruxolitinib from 2015 until january 2022. We also aimed to evaluate the role of IPSS risk group classification in the outcome and survival of MF patients in the Albanian population. Methods: We selected retrospectively all the patients diagnosed in our University Hospital Center “Mother Teresa” in Tirana, Albania with primary and secondary Mielofibrosis who started the treatment with ruxolitinib from 2015 until January 2022. We collected the data from the registries and database of Hematology Clinic based on the first availability of ruxolitinib in Albania since 2015. The data were analysed with SPSS Statistics 25.01. Results: From 2015 until January 2022 we have treated with Ruxolitinib 103 patients diagnosed with Myelofibrosis, 87 (84.5%) were primary MF and 16 (15.5%) were secondary MF. The median age resulted of 64 (range 31 – 88) years old. According to the IPSS risk group classification 1(!%) resulted IPSS Low risk, 21 (20.4%) were IPSS Int-1 risk, 49 (47.6%) resulted IPSS Int-2 risk, and 32(31.1%) were IPSS High risk. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of IPSS, we delineated 4 risk groups with no overlapping in their survival curves and the respective median survivals were 75, 40, 33, and 24 months We classified as IPSS Low risk all the patient with IPSS low and Int-1 risk, and as High risk all the patients with IPSS Int-2 and High risk. We identified 22 (21.4%) low risk patients and 81(78.7%) high risk patients. We compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01. Image:Summary/Conclusion: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm who can develop de novo (primary MF) or secondary in patients with antecedent polycythemia vera (PV) or essential thrombocythemia (ET). The mean age at the moment of diagnosis is 65 year old. In our study me median age at the moment of the diagnosis resulted 64 years old. In our study we compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01Despite the established fact on efficacy of Ruxolitinib in MF patients, real -world data still are limited. Our objective was to analyse the overall survival of our patients with Mielofibrosis under treatment with ruxolitinib, however additional data are needed.

Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy.

7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text]

Response Assessment to Erythropoietin-Zeta (Epo-Alpha Biosimilar) Therapy in Low-Risk Myelodysplastic Syndromes.

Background. This prospective observational study aimed to verify the efficacy of erythropoietin zeta in the treatment of patients with low-risk myelodysplastic syndrome. Methods. Patients with low/int-1 IPSS risk and serum erythropoietin level below 500 U/L were enrolled. Treatment consisted of erythropoietin zeta 40,000 U subcutaneously once a week. The primary endpoint was the erythroid response. According to Simon’s two-stage statistical design, 36 patients were recruited. The median age was 75 years (range 56–83 years), male/female ratio was 1.1/1, median baseline serum erythropoietin was 57.9 U/L (range 9.4–475 U/L). 53% of patients had low-risk disease, while the remaining had Int-1 risk. Results. After 8 weeks, a significant response (rise in Hb levels of at least 1.5 g/dL) was achieved in 18 patients (50%) out of 36. However, 17 patients did not improve; 8/17 patients pursued the 40,000 U weekly schedule of erythropoietin zeta, and 4/8 (50%) of them reached the erythroid response after 16 weeks. Nine patients underwent dosage doubling (40,000 U twice per week), and 5/9 (55%) of them achieved the erythroid response. Conclusion. Compared with data from the literature, this prospective study revealed that EPO-zeta is a safe and effective therapeutic option in low-risk MDS patients.

Treatment of higher-risk myelodysplastic syndrome

Introduction. The myelodysplastic syndromes are a group of clonal haematopoietic stem cell disorders characterized by cytopenia, dysplasia, ineffective hematopiesis, recurrent genetic abnormalities, and increased risk of developing acute myeloid leukemia. In this paper, we present the review and recommendations for treatment of high risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations treatment of high risk myelodysplastic syndromes are based on expert opinion based on review of literature and contemporary recommendations for treatment of high risk for myelodysplastic syndromes. Recommendations. Higher-risk myelodysplastic syndromes should be defined in patients risk group with &gt; 3.5 IPSS-R score. Allo- HSCT is recommended in fit higher-risk patients with IPSS-R &gt; 3.5 as well as in fit lower-risk patients with poor risk features according to EBMT/ELN International expert panel and myelodysplastic syndromes right group. Acute myeloid leukemia like or hypomethylation treatment before Allo-HSCT is indicated in patients with myelodysplastic syndromes with ? 10% of blasts. Azacitidine is recommended in intermediate-2 and high risk IPSS patients who are not eligible for transplantation with minimal number of six cycles to define response. Acute myeloid leukemia like treatment is recommended in fit higher-risk for patients with myelodysplastic syndromes with excess of blasts, good performance status, without substantial comorbidities, and with no poor/very poor cytogenetics/genetics. Conclusion. The treatment of fit higher-risk patients should be based on allo-SCT. In patients who are not candidates for transplant hypomethylation treatment is indicated as well as acute myeloid leukemia like treatment in selected patients.

The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

Updated Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

Updated Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

A Pooled Overall Survival Analysis of The COMFORT Studies: 2 Randomized Phase 3 Trials of Ruxolitinib For The Treatment of Myelofibrosis

A Pooled Overall Survival Analysis of The COMFORT Studies: 2 Randomized Phase 3 Trials of Ruxolitinib For The Treatment of Myelofibrosis

Which Patients with Myelofibrosis Should Receive Allogeneic Stem Cell Transplantation? A Decision Analysis Based on the Systematic Review of 4,341 Patients

▪Allogeneic transplantation (ASCT) offers a chance of cure for younger patients with myelofibrosis (MF) and non-relapse mortality (NRM) has progressively declined thus making transplant feasible also in older patients. Since JAK2 inhibitors recently showed to ameliorate survival of intermediate-2 and high-risk patients, the selection of candidates for ASCT has become particularly complex. The large number of predictive variables influencing the decision to transplant MF patients makes exhaustive multivariate analyses unfeasible. Moreover, no case-control study could yet include a large portion of patients assigned to ruxolitinib. Therefore, we implemented a decision model simulating a cohort of 10,000 55 year-old patients newly diagnosed intermediate 2 MF: patients were assigned either to ASCT or to ruxolitinib. Patients assigned to ASCT were allowed to move monthly among 4 Markov health states (pre-transplant, post-transplant, relapse and death) according to pooled data from a systematic review of transplant reports published (EMBASE) from January 2010 to May 2017 and reporting at least 30 patients. We retrieved 50 publications (4 prospective studies) reporting 4,341 MF patients receiving ASCT mostly (62%) from matched donors, mostly after the year 2000. Median age at transplant was 55 years and median time elapsed from diagnosis was 21 months. IPSS at transplant was mainly intermediate-2 (40%) or high (21%), however, 216 ASCT were performed after blast transformation. At a median follow-up of 38 months, 2-year non-relapse mortality (NRM) was 25% (95%CI: 21.4-28.6%) and cumulative incidence of relapse 22% (95%CI: 17.5-26.5%). On the other arm of the decision model, patients assigned to ruxolitinib had a 0.0105 monthly chance of moving from the alive to the dead state, according to the survival rates reported by COMFORT trials (Vannucchi'15, Verstovsek '17). The same probability of death was assigned to patients waiting for ASCT. Based on the above input data, the model outputs confirmed an appropriate calibration: 5-year cumulative NRM was 25% and 5-year survival in ruxolitinib-treated patients was 59%. The above model forecast 101 versus 99 mean survival from diagnosis if ASCT is included into the treatment pathway. However, very large confidence intervals surrounded the above estimates, therefore, sensitivity analysis explored the impact of different age, IPSS risk and molecular profile, based on the hazard ratios reported by multivariate analyses (Gangat'11, Guglielmelli'17, Palandri'17, Kroger'17, Panagiota'14, Bregante'16, Ditchowasky'12). Despite the long survival yield of ruxolitinib, ASCT provided a survival gain higher than 6 months in intermediate-2 patients younger than 50 years and in high risk patients younger than 65 years. On converse, patients with intermediate-1 risk (- 39 months) or carrying CALR mut 1 (-41 months) were expected to achieve a shorter survival with ASCT. The model allowed to explore complex combinations of clinical and genetic profiles: results are reported in the Figure. ASCT advantage over ruxolitinib was questioned in high-risk older patients harboring CALR mut1, while ASCT was expected to provide a longer survival in intermediate-1 patients lacking any of the three funding mutations. Despite its simplicity, the present decision model has the potential to test several clinical scenarios, depending on the clinical response to ruxolitinib, the presence of multiple detrimental mutations or the availability of alternative donors. Still the model has some limitations mainly related to the assumed multiplicative interactions among predictive variables and to the assumed exponential shape of survival curves. Secondly, the model was calibrated as to project the same five-year survival as ruxolitinib-treated patients of COMFORT studies, but longer follow-up survival data are still missing. Moreover, survival gains of a few months should be carefully balanced against quality of life detriments imposed by ASCT. Nevertheless, results are consistent with recent consensus recommendations and, as a larger portion of patient is tested for funding and non-funding mutations, integration and validation of the model will be possible by retrospective databases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

An MDS Specific Frailty Index Based on Cumulative Deficits Adds Independent Prognostic Value to Established Clinical Prognostic Scoring Systems

An MDS Specific Frailty Index Based on Cumulative Deficits Adds Independent Prognostic Value to Established Clinical Prognostic Scoring Systems