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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/m2/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 × 109/L and 31.2 × 109/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 ).

Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).

Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.

Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.

Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.

Flow chart of the study displaying the three cohorts.

TP53 mutations characteristics among t-MN PARPi national cohort.

Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.

Purpose:To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).Experimental Design:In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.Results:From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.Conclusions:In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

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).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.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.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.

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

International audience; 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.

International audience; Acute and chronic renal failures are very common after allogeneic HSCT. These complications have a real impact on mortality and morbidity of transplant recipients. Within the framework of the ninth workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, various causes and mechanisms of renal failure, diagnostic work-up, treatment and recommendations to limit renal failure after transplantation are reviewed. Recommendations to adjust medications to avoid renal failure are also proposed in this article.

Resume Les complications stomatologiques de l’allogreffe de cellules souches hematopoietiques (CSH) sont frequentes et tres inconfortables pour les patients. La reaction du greffon contre l’hote represente la principale complication. Les infections, les troubles du gout et les risques carcinologiques constituent les autres effets secondaires de la procedure. Differents traitements locaux sont utilises mais restent imparfaits. Dans le cadre de la dixieme edition des ateliers d’harmonisation des pratiques en allogreffe, organises par la Societe francophone de greffe de moelle et de therapie cellulaire (SFGM-TC) a Lille, en septembre 2019, la demarche diagnostique et les traitements des complications orales apres allogreffe de CSH ont ete revus apres analyse des resultats des etudes publiees.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.

5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine.

International audience; Background: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo-HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo-HSCT.Methods: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically.Results: Average gamma globulin levels between D-7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P = .65). Gamma globulin level

International audience; Objectives: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE.Methods: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders.Results: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83).Conclusions: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Background Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.

International audience; Nucleoside and nucleotide analogs are essential tools in our limited arsenal in the fight against cancer. However, these structures face severe drawbacks such as rapid plasma degradation or hydrophilicity, limiting their clinical application. Here, different aspects of nucleoside and nucleotide analogs have been exposed, while providing their shortcomings. Aiming to improve their fate in the body and combating their drawbacks, two different approaches have been discussed, the prodrug and nanocarrier technologies. Finally, a novel approach called "PUFAylation" based on both the prodrug and nanocarrier technologies has been introduced, promising to be the supreme method to create a novel nucleoside or nucleotide analog based formulation, with enhanced efficacy and highly reduced toxicity.

The benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (

Next-generation sequencing (NGS) is used to investigate the presence of somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains unclear. We report the findings of an observational, multicenter study that aimed to assess the impact of somatic mutation testing by NGS in a reallife setting of chronic myeloid malignancies. A total of 177 patients were enrolled, partitioned into two overlapping groups. In group A (n=94), the indication was to search for clonal hematopoiesis, in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (n=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was used on DNA extracted from blood or bone marrow samples. Within group A, the detection of clonal hematopoiesis supported the diagnosis of chronic myeloid malignancies for 31 patients while the absence of clonal hematopoiesis ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostically relevant somatic mutations in 32 patients, which had a therapeutic impact in 18 cases. By determining the presence or absence of somatic mutations, the application of NGS in daily practice was found to be useful for an integrated final diagnosis in 83% of the patients. Moreover, the search for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate implementation of new investigations may have a significant positive medico-economic impact by enabling appropriate management of patients.

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.

Introduction Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) Patients and Methods Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features. Results Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21–90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behcet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1–162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11–3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21–9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank Conclusion This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.

International audience; Background: The R-DHAP regimen (rituximab, cisplatin, dexamethasone, and high-dose cytarabine) is standardly used to treat relapsed Non-Hodgkin lymphoma (NHL). Despite scarce data, cisplatin is frequently substituted with oxaliplatin (R-DHAOx) to avoid nephrotoxicity. We compared nephrotoxicity of cisplatin and oxaliplatin based on creatinine-based trajectory modeling.Methods: All patients with NHL treated by R-DHAP or R-DHAOx in Angers hospital between January 01, 2007, and December 31, 2014, were included. Patients received cisplatin 100 mg/m2 or oxaliplatin 130 mg/m2 (d1) with cytarabine (2000 mg/m2 , two doses, d2), dexamethasone (40 mg, d1-4), and rituximab (375 mg/m2 , d1). Creatinine levels were recorded before each cycle. Individual profiles of trajectories were clustered to detect homogeneous patterns of evolution.Results: Twenty-two patients received R-DHAP, 35 R-DHAOx, 6 switched from R-DHAP to R-DHAOx due to nephrotoxicity. Characteristics of patients were similar between two groups. Patients receiving R-DHAP experienced more severe renal injury than patients receiving R-DHAOx (68% vs. 7.7%, P < .001). Two homogeneous clusters appeared: cluster A, with a majority of R-DHAOx (32, 91.4%), was less nephrotoxic than B, with a majority of R-DHAP (19, 86.4%), with a decreased average serum creatinine level (P < .0001). There were no other differences between clusters.Conclusions: Our study confirms that R-DHAOx regimen causes less nephrotoxicity than R-DHAP regimen.

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient’s DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

Background: Allo HSCT is a potentially curative treatment in MDS which, in higher risk (IPSS high and int 2) MDS demonstrated an overall survival (OS) advantage over conventional treatment (especially HMAs) in retrospective (Koreth et al., JCO 2013) and prospective (Robin et al. leukemia 2015) studies. Retrospective studies, on the other hand, suggested no OS advantage for allo HSCT in lower risk MDS (IPSS low and int 1), except possibly in the "poorest" lower risk MDS subsets, as classified by the WPSS (Alessandrino et al. AMJH 2013) However, about 25% of lower risk MDS patients are reclassified as higher risk by the R-IPSS and a proportion of other lower risk MDS can also harbor some higher risk features that compromise their outcome. MDS-ALLO-RISK trial (clinicaltrial.gov NCT02757989), was designed to assess outcome of lower risk MDS patients with some high-risk features after HLA-matched donor HSCT. Method: The primary objective of this study was to demonstrate an OS improvement in lower risk MDS patients with some high risk features with a donor compared with those without a donor (with a 3 year OS of 70% versus 40%, respectively) . Inclusion criteria were: IPSS low or int1 MDS with at least one of the following characteristics: 1) R-IPSS intermediate or higher 2) RBC transfusion dependent anemia and failure to two or more treatments (including EPO, Lenalidomide or HMA ); 3) platelets < 20 G/L requiring transfusions 4) ANC < 0.5 G/L with severe infection 5) no contra indication to allo HSCT 6) age Results: 79 patients were included, 64 in group A and 15 in group B. Median age was 62.4 (IQR: 58-65) years in group A and 66 (IQR: 60.5-68) years in group B. Patients in group A were more frequently males (73 vs 40%, p=0.029), WHO was CMML in 8 (10%), MDS-SLD in 5 (8%), MDS-MLD in 9 (11%), MDS-EB1 in 41 (52%), MDS-RS in 12 (15%), unclassified in 4 (6%) without significant differences between the two groups. IPSS /IPSS-R was similar in both groups: IPSS low in 10% (11% in group A and 7% in group B) and Int-1 in 90%. IPSS-R: very low risk (6% vs 0%); low risk (25% vs 27%); intermediate (50% vs 47%); high (19% vs 27%); no very high risk. Among the 64 patients with a donor, 58 (92%) received HSCT, 2 died before HSCT; 2 had progressive disease and 2 are planned for HSCT. Transplanted patients received reduced intensity conditioning regimen with busulfan 6.4mg/kg, fludarabine 150mg/m2 and ATG (rabbit antithymocyte globulin therapy, grafalon®) 30mg/kg and cyclosporine-mycophenolate mofetil as GVHD prophylaxis. In group A, 21/64 had died, including 13 died from a non-relapse cause. In group B, 4/15 patients had died, 3 from MDS progression and one from CNS bleeding. Three-year OS was 60% (95%CI: 46.9-76.8) in group A and 64.2% (41.3-99.6) in group B (p=NS). At the time of analysis, 20 and 5 patients had progressed/relapsed in group A and B respectively. with a cumulative incidence of relapse/progression (from inclusion) of 27.4% (IC95%: 15;39.8) in group A and 41.7% (IC95%:9.2;74.2) in group B (p=0.71). Among the 58 transplanted patients, 11 (19%) died without disease progression, including one death from a solid tumor. 3 years non-relapse mortality in transplanted patients was 23.4% (IC95%:9.7;37). 3 years Incidence of grade 2 to 4 acute GVHD was 40.8% and 3 years chronic GVHD was 24.9%. Conclusion: In this, to our knowledge, first prospective study in IPSS lower risk patients with some unfavorable clinical or biological features, HLA identical donor (sibling or 10/10 unrelated) HSCT yielded a 3-year OS of 60%. Non relapse mortality was however 23%, and OS somewhat lower than expected (70% at 3 years) and similar to that observed in patients without a donor. Long-term follow-up is needed to better define subgroups of IPSS lower risk MDS that may benefit from allo HSCT. Disclosures Sebert: Abbvie: Consultancy; BMS: Consultancy. Cluzeau: Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Amgen: Speakers Bureau; Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Ades: ABBVIE: Honoraria; NOVARTIS: Honoraria; CELGENE/BMS: Honoraria; CELGENE: Research Funding; JAZZ: Honoraria, Research Funding; TAKEDA: Honoraria. Fenaux: JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Robin: NEOVII MEDAC NOVARTIS: Research Funding.

Background and aims: intensive chemotherapy (IC) has been used since the early 90's in the treatment of higher risk MDS, yielding 40 to 50% complete response (CR) but prolonged myelosuppression and 10 to 30% early deaths. IC is also recommended before allogeneic (allo) SCT when marrow blasts are increased (De Witte et al, Blood, 2017). CPX-351, a liposomal combination of cytarabine and daunorubicin, proved greater efficacy than classical IC with 3+7 in secondary-AML, including in patients with 20-30% marrow blasts and those who subsequently received allo SCT (Lancet et al, Lancet Haematol, 2021). We evaluated response to CPX-351 in a group of untreated higher risk MDS patients, most of whom were candidates for allo SCT. Methods: This prospective study, involving 12 GFM centers, included int-2 or high IPSS MDS, previously untreated with HMA or chemotherapy, and aged Results: 31 patients were included between July 2020 and January 2021. Median age was 62 years (range 31-69); WHO classification: 26 MDS-EB2, 5 CMML-2; IPSS: int-2: 84%, high: 16%; R-IPSS: intermediate: 29%, high: 55%, very high: 16%; karyotype: 2 very good, 22 good, 3 intermediate, 2 poor, 2 very poor. 27 patients received one induction cycle and 4 (in stable disease (SD) after the first cycle), a second induction cycle. Response rates, eventually evaluated a median of 53 days (range 28-112) from onset of induction, were with ELN 2017 criteria: CR: 52%, CRi: 13%, MLFS: 23%, SD: 13% and with IWG 2006 criteria : CR: 23%, mCR: 45%, mCR + HI-P: 6%, mCR + HI-P + HI-N: 6%, mCR + HI-N: 3%, PR: 3%, SD: 13%. Minimal residual disease assessment by NGS and flow cytometry will be presented at the meeting. 24/27 patients with baseline marrow blasts >10%, reached 20G/L and >50G/L were: 16 (range 0-55) days and 28 (range 8-51), respectively and to ANC >1G/L: 26 (range 2-60) days. Only one patient had grade ≥ 3 mucositis and 4 had grade ≥ 2 alopecia during induction treatment. No patient died during induction treatment or required management in the intensive care unit. With a median follow-up of 201 days (range 102-350), 22 of the 30 patients initially considered for allo SCT received transplant after no (10 pts), 1 (9 pts), 2 or 3 (3 pts) consolidation cycles and 5 are planned for allo SCT. Reasons for not being transplanted were, investigators' choice (n=1), relapse (1), no donor (1) and invasive fungal infection (n=1). None of the 4 non transplanted patients received consolidation cycles. Reasons for not receiving consolidation cycles were persistent cytopenia (n=5), cardiac toxicity (n=2), failure to achieve CR or PR (n=2). At the time of analysis (June 2021), 4 patients had relapsed, after 3 to 6 months of response. Conclusions : CPX-351 is effective in higher risk MDS/CMML, especially to achieve blast clearance, and as a bridge to allo SCT. Figure 1: waterfall plot according to IWG 2006 and ELN 2017 criteria Figure 1 Figure 1. Disclosures Fenaux: Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria; Takeda: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. OffLabel Disclosure: CPX-351 use off-label for myelodysplastic syndroms in a prospective trial

Background : ENA is a selective inhibitor of IDH2 approved in the US for the treatment of patients with relapsed/refractory IDH2 mutated AML. Little is known on its efficacy in patients with IDH2m myelodysplastic syndromes. Here we report the preliminary results of a Phase 2 study evaluating the safety and efficacy of ENA in three different cohorts of MDS : Higher risk MDS having failed HMA (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom, cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed ESA (cohort C, n=10). (ClinicalTrials.gov NCT03744390). Methods : Subjects enrolled in cohort A, B or C received continuous 28-day cycles of ENA - 100 mg PO QD. In cohort B, Azacitidine (75 mg/m2/d x 7 days, SC) was added to Enasidenib after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was Overall hematological response (including CR, PR,stable disease with HI according to IWG 2006). All patients who achieved CR, PR or HI were considered as responders and could continue treatment until loss of response. Secondary endpoints of the trial included safety,duration of response, EFS, Overall survival and translational project evaluating the role of biomarkers on response.We report interim results in the first 26 pts enrolled. Resul t s : At data cut off (6/15/2021), 45 pts were enrolled, including 26 who were evaluable for the primary endpoint. 11, 9 and 6 were enrolled in cohort A, B and C respectively. Median age was 75.5 years and 34.6% were female. WHO was MDS-MLD, MDS-RS-SLD, MDS-RS-MLD, MDS-EB1, MDS-EB2, CMML and AML (with 20-30% blast) in 1, 2, 3,4, 10, 2 and 4 pts, respectively. IPSS was low, intermediate 1, int 2 and high in 1, 7, 13, 5 resp. IPSS-R was low,intermediate, high and very high in 4, 8, 11, 3 resp. At data cut off, 10 pts were still on treatment. Most common reasons for discontinuing ENA were Treatment failure (7.7%), disease progression (23.1%), adverse events (7.7%) and death (3.8%). Three patients experienced a differentiation syndrome (1 in cohort A and 2 in cohort B) that resolved without sequelae. Other most common grade 3-4 AEs were nausea/diarrhea (n=4) and thrombocytopenia (n=5). Overall best response rate (ORR including CR, PR, and HI) was achieved in 11 pts (42 %), including 6 CR (55%), 2 PR (18%), 2 mCR with HI (18%), 1 Stable disease with HI (9%). ORR was achieved in 3 (27 %), 5 (56 %) and 3 (50%)in cohort A, B and C respectively. In cohort B, AZA wad added to ENA in 3 patients who were primarily resistant to ENA. Among them, 2/3 patients subsequently achieved a response. Moreover, CR was seen in 2, 1 and 3 in cohort A, B and C respectively. The 6 months response rate was 29.5 % [6 ;59], 53.1 % [11.7 ;83] and 50 % [7.7 ;82.9] in cohort A, B and C respectively. At the time of analysis, all responses but 2 were sustained. Responses were lower (p=0.27) among the 23 pts with IDH2 R140 (30.4%) as compared to the 3 with IDH2 R172 mutation (66.7%). With a median follow up of 8.6 months, the median OS was 17.3 months (figure 1). Six patients died during follow-up, including 4/11 in cohort A, 1/9 in cohort B and 1/6 in cohort C. The 6 months death rate observed was 8.2 % [0 ;18.4] and the 1-year OS was 55.4%, 100% and 80% in cohorts A, B and C, respectively. Four patients evolved to AML (2 and 2 in cohort A and B) with a 1y risk of AML of 19.3%. Conclusion : Results from the first 26 patients included in this study show that ENA has no limiting toxicity in patients with MDS and that it can provide responses in 42% of patients. These responses appear to be encouraging, especially in first-line (low and high risk) patients. An update of this study will be presented. Figure 1 Figure 1. Disclosures Ades: JAZZ: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding. Sebert: BMS: Consultancy; Abbvie: Consultancy. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Laribi: Novartis: Other: Personal Fees, Research Funding; AstraZeneca: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Jansen: Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Platzbecker: AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Geron: Honoraria; Novartis: Honoraria. Fenaux: Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. OffLabel Disclosure: enasidenib is not approved for MDS

Background: Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation. Little is known on its efficacy in patients with IDH1 mutated MDS. Here we report interim results of a Phase 2 study evaluating safety and efficacy of IVO in three different cohorts of MDS patients: Higher risk MDS having failed azacytidine (AZA) (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom,) as a first line treatment (cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed EPO (cohort C, n=10). (ClinicalTrials.gov NCT03503409). Methods: Subjects enrolled in cohort A, B or C received continuous 28-day cycles of IVO - 500 mg orally QD. In cohort B, AZA (75 mg/m2/d x 7 days, SC) was added to IVO after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was overall hematological response rate (ORR) at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006). All responders allowed to continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival and translational project evaluating the role of biomarkers on response. We report the preliminary results on the first 26 pts enrolled. Results: At data cut off (6/15/2021), 32 patients had been enrolled, including 26 who were evaluable for the primary endpoint. 13, 11 and 2 were enrolled in cohort A, B and C respectively. Median age was 76 years and 50% were female. WHO was MDS-MLD, MDS-EB1, MDS-EB2, CMML and low blast count AML in 2, 2, 12, 1 and 9 patients respectively. IPSS-R was low, intermediate, high and very high in 2, 6, 5 and 13 resp. IDH1 mutation was p.R132C in 15 patients, p.R132H in 7, p.R132G/S in 3 and not specified in 1. The ORR was 69% (18 patients) including 12 CR (46%), 1 PR and 5 HI. Most patients achieved response after 3 cycles (17/18). Response was achieved in 7 (54%), 10 (91%) and 1 (50%) in cohort A, B and C respectively. Moreover, CR was achieved in 3, 8 and 1 in cohort A, B and C respectively. In cohort B, AZA was added to IVO in one patient after 3 cycles, without additional response. With a median follow up of 9.1 months, the median duration of response of the 18 responders was 7.4 months, 9 of them lost their response, and two had died without loss of response (from bleeding and after HSCT, respectively). IPSS-R was the only prognostic factor of response after 6 cycles. At data cut off, 12 patients had progressed (9 in cohort A, 2 in cohort B and 1 in cohort C) and 11 (42%, 10 in cohort A and 1 in cohort C) patients had died, mostly of relapse/progression (n=5/11), infection in 1, suicide in 1, hemorrhage in 1 and other unrelated causes in 3. Median overall survival was 14 months in the whole cohort, 7.7 and not reached in cohort A and B resp. The most common treatment-related serious adverse event (SAE) was differentiation syndrome (4/5), one died and three resolved without sequelae. One patient had febrile neutropenia related to IVO, resolved without sequelae. Conclusion: IVO was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, IVO was particularly effective in treatment naïve higher risk MDS patients with IDH1 mutations (cohort B). These encouraging preliminary results have to be confirm in more patients. The IDIOME study is still ongoing, and molecular monitoring results of IDH1 mutations will be presented. Disclosures Sebert: BMS: Consultancy; Abbvie: Consultancy. Cluzeau: Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

Because of the persistently high rates of relapse of patients with high-risk acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), post-transplantation maintenance therapy has been proposed. We previously initiated a Phase II trial in which epigenetic therapy was combined with immunotherapy in an attempt to reduce disease relapse. In that study, low-dose azacitidine (AZA) and escalating doses of donor lymphocyte infusion (DLI) were given as post-allo-HSCT maintenance treatment. In the present study, we retrospectively analyze a larger cohort of patients receiving post-transplantation maintenance therapy and provide updates on some patients of the earlier study. The objectives of the present study were to analyze the cumulative incidence of relapse (CIR), overall survival (OS), and progression-free survival (PFS) and the incidence of acute and chronic graft-versus-host disease (GVHD) of patients with high-risk AML or MDS receiving post-transplantation maintenance treatment with AZA with or without DLI. We retrospectively analyzed 77 patients (54 with AML, 23 with MDS) considered at high risk based on either their genomic or clinical status at transplantation. Following allogeneic transplantation, they received at least 1 cycle of prophylactic or preemptive low-dose AZA with or without escalating doses of DLI to prevent disease relapse. Almost one-half of the patients (47%) were able to receive the full 12 cycles of scheduled AZA, and a majority (79%) received at least 1 DLI. With a median follow-up of 24 months, 19 patients (25%; 16 with AML, 3 with MDS) relapsed, at a median of 9.8 months (range, 4 to 58.6 months), giving a 22% CIR at 24 months. OS and PFS at 24 months were 70.8% and 68.3%, respectively. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 27.4% and 45%, respectively. Only a minority of patients (11%) required delayed administration of AZA. These findings confirm that AZA-DLI maintenance is both tolerable and effective in reducing the risk of post-transplantation relapse.

Context: Thrombocytopenia ( Methods: In this a phase I/II, open-label, single arm, multicenter study, key inclusion criteria were: WHO 2008 defined HMA-naive CMML, PLT < 50 x109/L, marrow blasts ≤ 5%, IPSS low/int-1 in MD-CMML, and in MP-CMML no or only 1 severity criteria (Hb < 10 g/dL, ANC > 16 x109/L, abnormal karyotype, extramedullary disease), spleen size < 16 cm. ELT was started at 100mg/d (amended to 50 mg/d) with escalating dose up to 300mg/d for at least 12 weeks. Primary endpoint was Platelet Response (HI-P) at 12 weeks, according to IWG 2006 criteria. Responders could continue ELT until protocol-defined progression, loss of response or toxicity. Results: Between August 2014 and September 2018, 30 pts (median age 77.5 years; M/F 22/8) including 21 MD-CMML and 9 MP-CMML were enrolled. 19 pts had CMML-0 and 11 pts CMML-1 with median PLT count of 32 x109/L (IQR 21-43 x109/L). 12 pts were PLT transfusion dependent (PLT-TD). In the 28 pts sequenced, TET2 mutation (mut) was found in 26 pts, RUNX1mut in 16 pts, SRSF2mut in 11 pts, ASXL1mut in 9 pts, signaling mut in 10 pts and PHF6mut in 5 pts. Median ELT dose at 12 weeks was 150 mg/d (IQR 100-262.5 mg/d). At 12 weeks, 14 pts (46.7%) achieved HI-P (95%CI 28 ; 66%) including 10 MD-CMML and 4 MP-CMML irrespective of PLT-TD status (p=0.46). Responders and non-responders mutational profile was comparable except that none of the 5 PHF6mut pts responded (p=0.06). Responders received ELT for a median of 33 weeks (IQR 17.3-49.5 weeks) with one responder still on therapy at 24 months. Median duration of response was 3.4 months (95%CI: 1.7-11.6 months). Loss of response were due to PLT decrease (11 pts) or transfusion (5 pts) and disease progression (3 pts). At 12 weeks, bleeding symptoms (all grades) were present in 3 (38%) non-responders and 4 (29%) responders. Clinical and biological grade≥ 3 adverse events (AE) were reported in 15 pts each. Before 12 weeks, 24 clinical and 16 biological AE occurred in 7 and 10 pts resp. Toxicity was cardiovascular, pulmonary or gastro intestinal in 2 pts each resp., hepatic and musculo-skeletal in 1 pt each and others in 3 pts. Biological toxicity was hepatic in 4 pts, electrolytic in 4 pts and others in 3 pts. Five pts discontinued ELT due to persistent drug related toxicity. No therapy-related deaths were reported. With a median follow-up of 17 months, 14 pts progressed (including 4 AML transformations) and 17 died. The12-month cumulative incidence of AML was 7% (95%CI: 1-21%). No factors were associated with risk of transformation in univariate analysis (neither WBC nor molecular mutational profile). Two-years OS and PFS were 47% (95%CI: 31-71%) and 28% (95%CI: 15-52%) respectively. Splice mutations were associated with better PFS in univariate analysis (HR=0.29, (95%CI: 0.11-0.76%); p=0.012). In the 21 CMML pts with PLT < 50 x109/L and ≤5% BM blasts from our previous CMML cohort (Itzykson JCO 2013) who were not exposed to ELT, the 12-month estimates cumulative incidence of AML was 10% (95%CI: 0-23%). Comparison with a larger historical cohort not exposed to ELT is ongoing. Conclusion: In CMML patients with severe thrombocytopenia and no marrow blast excess, treatment with ELT is safe and induces frequent but mostly transient responses without increasing the risk of CMML progression. ELT could thus help manage a situation at risk of bleeding such as a scheduled surgical procedure. Phase III studies may be useful to confirm the role of ELT in CMML patients with thrombocytopenia. Disclosures Rabian: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Braun:Daiichi Sankyo: Honoraria; Servier: Research Funding. Ades:jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Celgene/BMS: Research Funding. Solary:Janssen: Research Funding. Itzykson:Oncoethix (now Merck): Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Abbvie: Honoraria; Stemline: Membership on an entity's Board of Directors or advisory committees.