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Introduction: Membranopathies encompass haemolytic disorders arising from genetic variants in erythrocyte membrane proteins, including hereditary spherocytosis and stomatocytosis. Congenital dyserythropoietic anaemia type II (CDA II) is associated with the SEC23B gene and can exhibit phenotypic similarities to membranopathies. Current treatment options for these conditions, apart from splenectomy, are primarily supportive. Mitapivat, a novel pyruvate kinase (PK) activator, has demonstrated efficacy in increasing haemoglobin levels and reducing haemolysis in patients with PK deficiency, thalassemia, sickle cell disease and a mouse model of hereditary spherocytosis., Methods and Analyses: Sa fe t y and eff i cacy of mitapivat s ul f ate in adult patients with er y throcyte membranopathies (SATISFY) is a prospective, multicentre, single-arm phase two trial involving approximately 25 adult patients (≥18 years) diagnosed with a membranopathy or CDA II. During the 8-week dose escalation period, subjects will receive an initial dose of 50 mg mitapivat two times per day and may increase to 100 mg two times per day at week 4 based on the safety and changes in haemoglobin levels. Patients tolerating mitapivat well may be eligible to continue in two consecutive 24-week fixed dose periods.The primary objective of this study is to evaluate the safety of mitapivat, assessed through the occurrence of treatment-emergent adverse events. Secondary objectives include assessing the effects of mitapivat on haemoglobin levels, haemolysis, erythropoiesis, patient-reported outcome measures and spleen size.SATISFY aims to assess the safety and efficacy of mitapivat in adult patients with red blood cell membranopathies and CDA II, with the aim of establishing proof-of-concept in patients living with these rare conditions., Ethics and Dissemination: NCT05935202/CTIS:2023-503271-24-01. Findings will be published in peer-reviewed journals., Trial Registration Number: Clinicaltrials.gov, NCT05935202. CTIS:2023-503271-24-01. Registered 07-July-2023. Protocol number: 2.1. https://clinicaltrials.gov/study/NCT05935202., Competing Interests: Competing interests: AG: consultant for Agios Pharmaceuticals, Bristol Myers Squibb, Novartis Pharmaceuticals, Novo Nordisk A/S, Pharmacosmos UK Ltd and Vertex Pharmaceuticals; received research support from Agios Pharmaceuticals, Novo Nordisk A/S, Saniona and Sanofi. EJvB: advisory committee member for Agios Pharmaceuticals.; received research funding from Agios Pharmaceuticals, Novartis Pharmaceuticals, Pfizer and RR Mechatronics International B.V. KHMK: consultant for Agios Pharmaceuticals, Alexion Pharmaceuticals, Inc., Bristol Myers Squibb, Forma Therapeutics, Pfizer, Novo Nordisk A/S and Vertex Pharmaceuticals; received honoraria from Bristol Myers Squibb and Novo Nordisk A/S; member of the data safety monitoring board of Bioverativ; received research funding from Agios Pharmaceuticals and Pfizer. RvW: consultant for Agios Pharmaceuticals; research funding from Agios Pharmaceuticals and Pfizer. MAER: research funding from Agios Pharmaceuticals and Axcella Health., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are clonal myeloid malignancies, characterized by bone marrow failure leading to cytopenias (and possible myeloproliferation for CMML) and a high propensity to evolve to Acute Myeloid Leukemia (AML)., Objective and Methods: The aim of our retrospective study was to evaluate the clinical and hematological features; the prevalence of MDS subtypes, R-IPSS, and the outcome of 106 Armenian MDS/CMML patients diagnosed over the 2008-2020 period in a single Armenian Hematology center and compare them to French MDS patients included in the GFM registry., Results: Median age in the Armenian cohort was 64 years (range 19-84) and 55% were males. The main MDS subtypes were MDS-MLD (29.2%) and MDS-SLD (27.3%), the least frequent was del 5q (0.9%). By comparison, a higher prevalence of MDS-MLD, MDS-EB2, and MDS-RS was found in the French cohort. Armenian patients' cohort generally had poor access to standard MDS treatment and 42.3% of the patients were transfusion dependent. Overall survival, however, did not significantly differ between Armenian and French cohorts., Conclusion: Our study stresses issues regarding epidemiology, access to diagnosis, difficulties of risk stratification, and access to treatment., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context., Methods: This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m 2 cytarabine and 44 mg/m 2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802., Findings: Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death., Interpretation: CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients., Funding: Jazz Pharmaceuticals., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML)., Patients and Methods: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m 2 /d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression., Results: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 10 9 /L and 31.2 × 10 9 /L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04)., Conclusion: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407)., Competing Interests: Raphael ItzyksonHonoraria: AbbVie, Astellas Pharma, Celgene/Bristol Myers Squibb, Novartis, ServierConsulting or Advisory Role: Amgen, Celgene/Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, Novartis, ServierResearch Funding: Janssen (Inst), Novartis (Inst) Valeria SantiniHonoraria: Celgene/Bristol Myers Squibb, NovartisConsulting or Advisory Role: Celgene/Bristol Myers Squibb, Novartis, Menarini, Takeda, Gilead Sciences, AbbVie, Syros Pharmaceuticals, ServierResearch Funding: Celgene (Inst)Travel, Accommodations, Expenses: Janssen-Cilag, Celgene Sylvain ThepotHonoraria: Astellas Pharma, Novartis, AbbVie, BMSiTravel, Accommodations, Expenses: Amgen, AbbVie Lionel AdesHonoraria: Celgene, AbbVie, Jazz Pharmaceuticals, BerGenBio, Silence Therapeutics, NovartisResearch Funding: Celgene (Inst) Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Amgen, Novartis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Bristol Myers Squibb/Celgene Michael LübbertConsulting or Advisory Role: Syros Pharmaceuticals, AbbVieResearch Funding: Johnson & Johnson (Inst) Ulrich GermingHonoraria: Celgene, Novartis, Jazz PharmaceuticalsConsulting or Advisory Role: CelgeneResearch Funding: Celgene (Inst), Novartis (Inst) Anna Maria PelizzariTravel, Accommodations, Expenses: Janssen-Ortho Sophie ParkHonoraria: Novartis/Ipsen, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Novartis, Pfizer, Bristol Myers Squibb/CelgeneResearch Funding: Pfizer, TakedaTravel, Accommodations, Expenses: Pfizer, Novartis Nadja JaekelHonoraria: Novartis Georgia MetzgerothHonoraria: Roche Pharma AG, Novartis, GlaxoSmithKlineConsulting or Advisory Role: GlaxoSmithKline Francesco OnidaTravel, Accommodations, Expenses: Takeda, Kyowa Kirin International, Medac Andrea PatriarcaConsulting or Advisory Role: Sanofi, SOBISpeakers' Bureau: Novartis Italy, Incyte Aspasia StamatoullasConsulting or Advisory Role: Pfizer, JanssenTravel, Accommodations, Expenses: Pfizer Katharina GötzeHonoraria: BMSConsulting or Advisory Role: BMS, AbbVie, Servier/PfizerResearch Funding: BMS Eric SolaryResearch Funding: Servier (Inst)Travel, Accommodations, Expenses: Novartis Uwe PlatzbeckerHonoraria: Celgene/Jazz, AbbVie, Curis, Geron, JanssenConsulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co. KGResearch Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Chris (Inst)Patents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene (Inst)No other potential conflicts of interest were reported.

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the 'European Myelodysplastic Neoplasms Cooperative Group' (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response., (© 2022. The Author(s).)

In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: MDS-RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD)., Study Design and Methods: We performed a retrospective "real-life" observational study of 6 months in 100 MDS-RS TD patients, recruited in 12 French centers, to describe transfusion characteristics, and evaluate the frequency and causes of hospitalizations, health costs, and morbidity, associated with transfusion dependency, in a French population of RBC transfusion-dependent MDS-RS patients., Results: 79% of the patients had high transfusion burden (HTB) and 21% low transfusion burden (LTB). HTB patients had a longer disease duration (6 vs. 3.7 years, p = 0.0078), more frequent iron chelation (82% vs. 50%, p = 0.0052) and higher serum ferritin (p = 0.03). During the 6-month study period, 22% of the patients required inpatient hospitalization, 36% of them for symptomatic anemia requiring emergency RBC transfusion. The 6-month median transfusion costs, including the cost of the day care facility, transportation to and from the hospital, iron chelation, and lab tests, was 16,188€/patient., Discussion: MDS-RS represents the archetypal type of chronically transfused lower-risk MDS. Most of those patients have a high transfusion burden and thus frequently need visits to the hospital's day care facility, and frequent hospitalizations, with an overall high median treatment cost. Those costs should be compared with costs of new treatments potentially able to avoid RBC transfusion dependence and to reduce the complications of chronic anemia in MDS-RS patients., (© 2022 AABB.)

Patient-reported outcomes (PROs) are relevant and valuable end points in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. According to international guidelines, candidate PROs were identified from a comprehensive literature search of MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first round and 38 patients and 32 hematologists in the second round. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected "general quality of life" as a core PRO. Hematologists also selected "transfusion-dependency burden" and "ability to work/activities of daily living" as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; P < .05) in the first round and for 19 PROs in the second round, with "disease knowledge" and "confidence in health care services" rated notably higher by patients. The overall mean PRO ratings correlation between the 2 groups was moderate (Spearman's rank correlation coefficient = 0.5; P < .05). This first consensus on a core set of PROs jointly developed by patients and hematologists forms the basis for patient-centered care in daily practice and clinical research., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Purpose: TP53 -mutated ( TP53m ) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions., Patients and Methods: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients., Results: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively., Conclusion: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone., Competing Interests: Thomas CluzeauConsulting or Advisory Role: Abbvie, Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche, Takeda, Syros PharmaceuticalsSpeakers' Bureau: Novartis, Amgen, Sanofi, Astellas PharmaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Pfizer, Sanofi Jacqueline Lehmann-CheConsulting or Advisory Role: AstraZeneca, Roche Pierre PeterlinConsulting or Advisory Role: Jazz Pharmaceuticals, Abbvie, Astellas Pharma, Daiichi Sankyo/Lilly Odile Beyne RauzyTravel, Accommodations, Expenses: Novartis Christian RecherConsulting or Advisory Role: Roche, Pfizer, Incyte, Novartis, Otsuka, Astellas Pharma, Daiichi Sankyo, Macrogenics, Janssen, Abbvie, Jazz Pharmaceuticals, Amgen, CelgeneResearch Funding: Abbvie, Roche, MaaT Pharma, Daiichi Sankyo, Agios, Chugai Pharma, Astellas Pharma, Jazz Pharmaceuticals, Novartis, Amgen, CelgeneTravel, Accommodations, Expenses: Gilead Sciences, Daiichi Sankyo, Novartis, Amgen, Celgene, Sanofi, Incyte Aspasia StamatoullasHonoraria: CelgeneConsulting or Advisory Role: TakedaTravel, Accommodations, Expenses: Pfizer Lise WillemsHonoraria: Abbvie, Janssen, Novartis Emmanuel RaffouxTravel, Accommodations, Expenses: Abbvie, Roche Bruno QuesnelResearch Funding: Daiichi Sankyo Europe GmbH Michael LoschiConsulting or Advisory Role: Astellas Pharma, Iqone, NovartisTravel, Accommodations, Expenses: Novartis/Pfizer, MSD Antoine F. CarpentierStock and Other Ownership Interests: AltevaxHonoraria: Gilead SciencesConsulting or Advisory Role: Bristol-Myers Squibb David A. SallmanConsulting or Advisory Role: Syndax, Novartis, Magenta Therapeutics, Kite Pharma, Intellia Therapeutics, Gilead Sciences, Bristol-Myers Squibb, Aprea AB, Abbvie, Celyad, AgiosSpeakers' Bureau: Bristol-Myers Squibb, Incyte, AgiosResearch Funding: Jazz Pharmaceuticals, CelgenePatents, Royalties, Other Intellectual Property: Intellectual Property Patent for LB-100 in MDS Rami KomrokjiStock and Other Ownership Interests: AbbvieConsulting or Advisory Role: Acceleron Pharma, Abbvie, Geron, Jazz Pharmaceuticals, Bristol-Myers Squibb, Incyte, NovartisSpeakers' Bureau: Bristol-Myers Squibb, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Incyte Lionel AdesResearch Funding: CelgeneHonoraria: Novartis, Silence Therapeutics, BerGenBio, Jazz Pharmaceuticals, Abbvie, Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: CelgeneNo other potential conflicts of interest were reported.

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza ® ), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra ® ), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra ® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response ( P =0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high ( P =0.03) primary versus secondary azacitidine failure ( P =0.01) and a high rate of demethylation in blood during the first cycle of treatment ( P =0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered a t clinicaltrials.gov identifier: 02197676 )., (Copyright© 2019 Ferrata Storti Foundation.)

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352)., (Copyright© Ferrata Storti Foundation.)

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML., (Copyright © 2014 Elsevier Ltd. All rights reserved.)