Publications by authors named "Lionel Adès"

145 Publications

Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML, an ALFA study.

Blood 2021 Feb 24. Epub 2021 Feb 24.

Institut Gustave Roussy, Villejuif, France.

IDH inhibitors are effective in AML, and trials evaluating frontline combinations with intensive chemotherapy (IC) are ongoing. Data on the prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are conflicting in each IDH-mutated subgroup treated by IC, while this information is important for trial design and results interpretation. We retrospectively analyzed 127 IDH1, 135 IDH2R140 and 57 IDH2R172 newly diagnosed AML patients treated with IC in three Acute Leukemia French Association (ALFA) prospective trials. We addressed in each IDH subgroup the prognostic impact of clinical and genetic covariates, and the role of HSCT in eligible patients. In IDH1 patients, presence of NPM1 mutations was the only variable predicting improved OS in multivariate analysis (p < 0.0001). In IDH2R140, normal karyotype (p= 0.008) and NPM1 mutations (p = 0.01) predicted better OS. NPM1 mutations were associated with better DFS (p = 0.0009) whereas presence of DNMT3A mutations was associated with shorter DFS (p = 0.0006). In IDH2R172, platelet count was the only variable retained in the multivariate model for OS (p = 0.002). Among non-favorable ELN-2010 eligible patients, 71 (36%) achieved an HSCT in first complete remission (CR1) and had longer OS (p = 0.03) and DFS (p = 0.02) than not-transplanted patients. Future clinical trial testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the main prognostic factor in IDH1 and IDH2R140 mutated AML. HSCT improve OS of non-favorable IDH1/2-mutated AML and should be fully integrated in the treatment strategy.
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http://dx.doi.org/10.1182/blood.2020010165DOI Listing
February 2021

Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Haematologica 2021 May 1;106(5):1414-1422. Epub 2021 May 1.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), F-75012, Paris.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.
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http://dx.doi.org/10.3324/haematol.2020.272559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094121PMC
May 2021

Eprenetapopt Plus Azacitidine in -Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

J Clin Oncol 2021 May 18;39(14):1575-1583. Epub 2021 Feb 18.

GFM.

Purpose: -mutated () 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 MDS and AML patients.

Results: Fifty-two 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 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 ( < .01) and higher age ( = .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 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.
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http://dx.doi.org/10.1200/JCO.20.02342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099409PMC
May 2021

Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort.

Blood Adv 2021 01;5(1):176-184

Cote d'Azur University, Hematology Department, Centre Hospitalier Universitaire de Nice, Nice, France.

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD <10-3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P < .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients <60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years.
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http://dx.doi.org/10.1182/bloodadvances.2020003159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805314PMC
January 2021

Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study.

Semin Arthritis Rheum 2020 10 11;50(5):879-884. Epub 2020 Jul 11.

Department of Internal Medicine, Assistance Publique-Hôpitaux de Marseille, Hôpital La Timone, Marseille, France.

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%), Behçet'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 <0.05).

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.
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http://dx.doi.org/10.1016/j.semarthrit.2020.07.002DOI Listing
October 2020

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
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http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
October 2020

Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy.

Leukemia 2021 03 24;35(3):712-723. Epub 2020 Jun 24.

Service Hématologie Adultes, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-0932-8DOI Listing
March 2021

Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results.

Blood Adv 2020 05;4(9):1942-1949

Department of Hematology, Saint-Louis Institute for Research, Université de Paris, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.

In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.
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http://dx.doi.org/10.1182/bloodadvances.2019001349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218423PMC
May 2020

Should Transplantation Still Be Considered for Ph1-Negative Myeloproliferative Neoplasms in Transformation?

Biol Blood Marrow Transplant 2020 06 28;26(6):1160-1170. Epub 2020 Feb 28.

Hematology and Transplantation, Saint Louis Hospital, Paris, France; University of Paris, INSERM U976, Paris, France. Electronic address:

BCR-ABL-negative myeloproliferative neoplasms (MPNs) in transformation have a dismal prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the sole curative therapeutic option. We retrospectively analyzed 53 molecularly annotated patients treated at Saint Louis Hospital, Paris, diagnosed with MPN in transformation between 2008 and 2018. The median patient age was 65 years, and the median interval between MPN diagnosis and MPN transformation was 46 months. The median overall survival (OS) of the entire cohort after transformation was 7.1 months. OS was better for patients treated with hypomethylating agents (HMAs) or with chemotherapy compared than for those treated by best supportive care or single-agent targeted therapy (median, 9.1 months versus 1.5 months; P < .001). Patients treated with chemotherapy more often achieved complete remission compared with those treated with HMAs (68% versus 29%; P = .02), and were more often candidates for transplantation (59% versus 14%; P = .02), but the median OS was similar in the 2 groups. We then compared the outcomes in transplant recipients and nonrecipients using the Mantel-Byar methodology and found that allo-HSCT did not improve survival. In multivariate analysis, independent factors in prognosis were performance status at transformation (P < .01), initial treatment with HMAs or chemotherapy (P = .02), and the ability to achieve complete remission during follow-up (P < .01). Our data demonstrate that the indication for allo-HSCT for high-risk MPN should be discussed before transformation, because transplantation rescues few patients after transformation.
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http://dx.doi.org/10.1016/j.bbmt.2020.02.019DOI Listing
June 2020

Next-Generation Sequencing in Myeloid Neoplasm-Associated Sweet's Syndrome Demonstrates Clonal Relation between Malignant Cells and Skin-Infiltrating Neutrophils.

J Invest Dermatol 2020 09 17;140(9):1873-1876.e5. Epub 2020 Feb 17.

Université de Paris, Paris, France; INSERM UMR976, Centre de Recherche sur la Peau, Paris, France; Dermatology Department, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.12.040DOI Listing
September 2020

Outcome of older (≥70 years) APL patients frontline treated with or without arsenic trioxide-an International Collaborative Study.

Leukemia 2020 09 19;34(9):2333-2341. Epub 2020 Feb 19.

Hematology Department, Hospital Universitari i Politècnic, La Fe, Avinguda Fernando Abril Martorell, 106, 46026, València, Spain.

Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P < 0.001). The same held true when restricting the analysis according to the treatment period after the year 2000. OS of patients in CR1 was not different between ATO/ATRA ± CTX compared with CTX/ATRA (P = 0.20). High (>10 × 10/l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P < 0.001) compared with lower WBC in the CTX/ATRA group, but not in the ATO/ATRA ± CTX group (P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis.
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http://dx.doi.org/10.1038/s41375-020-0758-4DOI Listing
September 2020

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.

N Engl J Med 2020 01;382(2):140-151

From Service d'Hématologie Séniors, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris and Université Paris 7, Paris (P.F., L.A.), Service des Maladies du Sang, Hôpital Huriez, Centre Hospitalier Universitaire (CHU) de Lille, Lille (B.Q.), the Department of Internal Medicine, CHU Toulouse, Institut Universitaire du Cancer de Toulouse, Toulouse (O.B.-R.), and Université Cote d'Azur, Département d'Hématologie Clinique, CHU Nice, Nice (T.C.) - all in France; Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig (U.P.), Klinik für Hämatologie, Onkologie, and Klinische Immunologie, Universitätsklinik Düsseldorf, Düsseldorf (U.G.), and Klinik und Poliklinik für Innere Medizin III, Technische Universität München, Munich (K.S.G.) - all in Germany; the Department of Haemato-Oncology, King's College London, London (G.J.M.), Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford (P.V.), and the Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds (D.B.) - all in the United Kingdom; the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (G.G.-M.); Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto (R.B.); MDS Unit, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence (V.S.), the Department of Oncology and Hematology, S. Orsola-Malpighi University Hospital, Bologna (C.F.), the University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia (M.C.), the Hematology Unit, Santi Antonio e Biagio e Cesare Arrigo Hospital, Alessandria (F.S., V.G.), and Dipartimento Biomedicina e Prevenzione, University of Rome Tor Vergata, Rome (M.-T.V.) - all in Italy; the Hematology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Salamanca (M.D.-C.), Unidad de Hematología, Hospital Universitario Virgen del Rocío, Seville (J.F.F.), and the Department of Hematology, Hospital Universitario Cruces, Vizcaya (B.A.) - all in Spain; the Department of Hematology Science, School of Medicine, Ankara University, Ankara, Turkey (O.I.); the Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland (M.A.S.); the Department of Hematology, Algemeen Ziekenhuis Sint-Jan, Bruges (D.S.), and Universitair Ziekenhuis Gent, Ghent (D.M.) - both in Belgium; the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (A.E.D.); the Division of Hematology-Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center (J.G.J.), and Albert Einstein College of Medicine (A.V.) - both in New York; the Department of Hematology, University Medical Center of Groningen, University of Groningen, Groningen, the Netherlands (E.V.); Stanford University Cancer Center, Stanford, CA (P.L.G.); the Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm (E.H.-L.); the Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT (A.M.Z.); Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville (M.R.S.); Celgene, Summit, NJ (A.L., J.Z., A.R., D.R.D.); Celgene International, Boudry, Switzerland (A.B.); Acceleron Pharma, Cambridge, MA (P.G.L., M.L.S.); and Moffitt Cancer Center, Tampa, FL (R.S.K., A.F.L.).

Background: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study.

Methods: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.

Results: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.

Conclusions: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).
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http://dx.doi.org/10.1056/NEJMoa1908892DOI Listing
January 2020

Giant-cell arteritis associated with myelodysplastic syndrome: French multicenter case control study and literature review.

Autoimmun Rev 2020 Feb 13;19(2):102446. Epub 2019 Dec 13.

Department of Internal Medicine, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France Sorbonne Université, France; Sorbonne Universités, INSERM U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France. Electronic address:

Introduction: Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MDS/MPN) can be associated with giant cell arteritis (GCA). In this nationwide study by the "French Network of dysimmune disorders associated with hemopathies" (MINHEMON) the objective was to evaluate characteristics, treatment and outcome of GCA MDS-MDS/MPN.

Patients And Methods: Retrospective analysis of patients that presented a MDS or MDS/MPN associated with GCA. Treatment efficiency, relapse-free and overall survival of GCA MDS-MDS/MPN were compared to GCA alone.

Results: Twenty-one patients with GCA MDS-MDS/MPN were included with median age 76 [42-92], M/F ratio 2.5, 8 MDS with multilineage dysplasia (38%), 4 chronic myelomonocytic leukemia (19%), at low or intermediate risk according to IPPS and IPSS-R. The prevalence of headaches, jaw claudication and anterior ischemic optic neuropathy was significantly lower in patients with GCA MDS-MDS/MPN compared to idiopathic GCA (14.3%, 0% and 0% versus 30%, 25%, and 25%, respectively; p < .05). Other clinical and histology findings were similar. All GCA patients received steroid therapy as first-line treatment. Complete or partial response was observed in 14 GCA MDS-MDS/MPN patients (66.7%), of whom 6 (28.6%) received combined immunosuppressive therapies (versus 10% of idiopathic GCA; p = .07). Relapse incidence was similar in the two groups. Steroid dependence was more frequent among GCA MDS-MDS/MPN patients (12 (57%) versus 18 (22.5%); p < .05). Relapse-free and steroid-free survivals were significantly decreased in GCA MDS-MDS/MPN patients (log rank 0.002 and 0.049 respectively), but not overall survival.

Conclusion: Characteristics of GCA MDS-MDS/MPN seem different than idiopathic GCA, with a distinct clinical phenotype and poorer outcome with a higher risk of steroid dependence and relapse.
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http://dx.doi.org/10.1016/j.autrev.2019.102446DOI Listing
February 2020

BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias.

Leuk Res 2019 12 7;87:106269. Epub 2019 Nov 7.

INSERM/CNRS UMR 944/7212, Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris Cancer Research Institute (PACRI), Paris, France; Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hopitaux de Paris, France. Electronic address:

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.
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http://dx.doi.org/10.1016/j.leukres.2019.106269DOI Listing
December 2019

Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.

Blood Adv 2019 11;3(22):3579-3589

Department of Malignant Hematology and.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.
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http://dx.doi.org/10.1182/bloodadvances.2019000922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880887PMC
November 2019

How we manage adults with myelodysplastic syndrome.

Br J Haematol 2020 06 30;189(6):1016-1027. Epub 2019 Sep 30.

service d'hématologie séniors, hôpital St Louis, assistance publique - hôpitaux de Paris (APHP) and Université de Paris, Paris, France.

The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into "lower risk" MDS (LR-MDS) and "higher risk" MDS (HR-MDS). In LR-MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR-MDS it aims at delaying disease progression and prolonging survival. In LR-MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR-MDS with deletion 5q. Allogeneic stem cell transplantation (allo-SCT) is sometimes considered in LR-MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo-SCT is the only potentially curative treatment for HR-MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo-SCT, in the absence of unfavourable karyotype.
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http://dx.doi.org/10.1111/bjh.16206DOI Listing
June 2020

Synergistic effects of PRIMA-1 (APR-246) and 5-azacitidine in -mutated myelodysplastic syndromes and acute myeloid leukemia.

Haematologica 2020 06 5;105(6):1539-1551. Epub 2019 Sep 5.

Faculté de Médecine Université Paris Diderot Paris 7, Paris

Myelodysplastic syndromes and acute myeloid leukemia with mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1(APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in -mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in -mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that -mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments.
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http://dx.doi.org/10.3324/haematol.2019.218453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271596PMC
June 2020

Germline DDX41 mutations define a significant entity within adult MDS/AML patients.

Blood 2019 10;134(17):1441-1444

Institut de Recherche Saint-Louis, INSERM U944/CNRS Unité Mixte de Recherche (UMR) 7212, Paris, France.

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.
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http://dx.doi.org/10.1182/blood.2019000909DOI Listing
October 2019

Non-allogeneic immunotherapy in acute myeloid leukaemia.

Lancet Haematol 2019 09 7;6(9):e443-e444. Epub 2019 Aug 7.

Hôpital Saint Louis, Assistance publique Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France; INSERM U944, Paris, France.

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http://dx.doi.org/10.1016/S2352-3026(19)30159-0DOI Listing
September 2019

A variant erythroferrone disrupts iron homeostasis in -mutated myelodysplastic syndrome.

Sci Transl Med 2019 07;11(500)

Université de Paris, Paris 75006, France.

Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the splicing factor gene. Patients with MDS with mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative transcript in patients with MDS with the mutation. Induction of this transcript in primary -mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an gene mutation than in patients with wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with -mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant transcript that was restricted to -mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
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http://dx.doi.org/10.1126/scitranslmed.aav5467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005358PMC
July 2019

Guadecitabine in myelodysplastic syndromes: promising but there is still progress to be made.

Lancet Haematol 2019 06 3;6(6):e290-e291. Epub 2019 May 3.

Hopital Saint Louis and INSERM U944, 75010 Paris, France.

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http://dx.doi.org/10.1016/S2352-3026(19)30079-1DOI Listing
June 2019

Autoantibodies in myelodysplastic syndromes and chronic myelomonocytic leukemia.

Leuk Lymphoma 2019 10 8;60(10):2594-2596. Epub 2019 Apr 8.

Sorbonne University, Internal Medicine Department, Saint Antoine Hospital , Paris , France.

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http://dx.doi.org/10.1080/10428194.2019.1599114DOI Listing
October 2019