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1. Imatinib with intensive chemotherapy in AML with t(9;22)(q34.1;q11.2)/BCR::ABL1. A DATAML registry study

Author

Camille Gondran, Pierre-Yves Dumas, Emilie Bérard, Audrey Bidet, Eric Delabesse, Suzanne Tavitian, Thibaut Leguay, Françoise Huguet, Cécile Borel, Edouard Forcade, François Vergez, Jean-Philippe Vial, Jean Baptiste Rieu, Nicolas Lechevalier, Isabelle Luquet, Alban Canali, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Arnaud Pigneux, Christian Récher, Laetitia Largeaud, and Sarah Bertoli

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1 +AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1 +AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50–91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1 +AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1 +AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1 +AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.

Published
2024
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2. Dismal outcome of refractory or relapsing patients with myelodysplasia‐related acute myeloid leukemia partially alleviated by intensive chemotherapy

Author

Harmony Leroy, Noémie Gadaud, Emilie Bérard, Emilie Klein, Isabelle Luquet, Jean‐Philippe Vial, Jean‐Baptiste Rieu, Nicolas Lechevalier, Suzanne Tavitian, Thibaut Leguay, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Audrey Sarry, Anne‐Charlotte deGrande, Christian Récher, Arnaud Pigneux, Sarah Bertoli, and Pierre‐Yves Dumas

Subjects
acute myeloid leukemia, azacitidine, intensive chemotherapy, myelodysplasia‐related changes, primary induction failure, refractoriness, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Acute myeloid leukemia (AML) with myelodysplasia‐related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate‐ or adverse‐risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. Methods A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63‐year‐old) with what was called at the time AML‐MRC has been explored, and data are reported here. Results Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1–5.6) with a mean 1‐year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. Conclusions These data, reporting about an ill‐explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.

Published
2024
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4. Retrospective, real‐life study of venetoclax plus azacitidine or low‐dose cytarabine in French patients with acute myeloid leukemia ineligible for intensive chemotherapy

Author

Louise Laloi, Natacha Chaumard Billotey, Pierre‐Yves Dumas, Franciane Paul, Alban Villate, Célestine Simand, Luc Fornecker, Florent Puisset, Sarah Bertoli, Marion Boissard Simonet, Kamel Laribi, Dyhia Houyou, Alberto Santagostino, Claire Michel, Gabrielle Roth Guepin, Elodie Guerineau, Reza Tabrizi, Mathilde Hunault, Aurélien Giltat, Eléonore Kaphan, Claude Bulabois, Elodie Cartet, Clément Rocher, Florence Lachenal, Stéphane Morisset, Christian Récher, Arnaud Pigneux, Amine Belhabri, Mauricette Michallet, and Anne‐Sophie Michallet

Subjects
acute myeloid leukemia, azacitidine, low‐dose cytarabine, venetoclax, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low‐dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real‐life conditions. Method This retrospective, real‐life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Result Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03‐16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second‐line/beyond, median progression‐free survival was 4.0 months (95% confidence interval [CI] 2.7‐12.8) with venetoclax‐HMA and 3.4 months (1.3‐8.9) with venetoclax‐LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax‐based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed.

Published
2023
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5. Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia

Author

François Vergez, Laetitia Largeaud, Sarah Bertoli, Marie-Laure Nicolau, Jean-Baptiste Rieu, Inès Vergnolle, Estelle Saland, Audrey Sarry, Suzanne Tavitian, Françoise Huguet, Muriel Picard, Jean-Philippe Vial, Nicolas Lechevalier, Audrey Bidet, Pierre-Yves Dumas, Arnaud Pigneux, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Martin Carroll, Gwenn Danet-Desnoyers, Jean-Emmanuel Sarry, and Christian Récher

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.

Published
2022
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6. A scoring system for AML patients aged 70 years or older, eligible for intensive chemotherapy: a study based on a large European data set using the DATAML, SAL, and PETHEMA registries

Author

Emilie Bérard, Christoph Röllig, Sarah Bertoli, Arnaud Pigneux, Suzanne Tavitian, Michael Kramer, Hubert Serve, Martin Bornhäuser, Uwe Platzbecker, Carsten Müller-Tidow, Claudia D. Baldus, David Martínez-Cuadrón, Josefina Serrano, Pilar Martínez-Sánchez, Eduardo Rodríguez Arbolí, Cristina Gil, Juan Bergua, Teresa Bernal, Adolfo de la Fuente Burguera, Eric Delabesse, Audrey Bidet, Pierre-Yves Dumas, Pau Montesinos, and Christian Récher

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as NPM1 mutations (without FLT3-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (n = 283, 51%; median OS = 18 months), 3–12% (n = 226, 41%; median OS = 9 months) and

Published
2022
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7. Impact of Mutational Status and Prognostic Factors on Survival in Chronic Myelomonocytic Leukemia With Systemic Inflammation and Autoimmune Disorders

Author

Charles Dussiau, Henry Dupuy, Audrey Bidet, Mathieu Sauvezie, Anne-Charlotte De-Grande, Lisa Boureau, Etienne Riviere, Edouard Forcade, Fabrice Bonnet, Pierre-Yves Dumas, Pierre Duffau, Arnaud Pigneux, Jean-François Viallard, Sophie Dimicoli-Salazar, and Estibaliz Lazaro

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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8. Intermediate-dose cytarabine or standard-dose cytarabine plus single-dose anthracycline as post-remission therapy in older patients with acute myeloid leukemia: impact on health care resource consumption and outcomes

Author

Jean Galtier, Camille Alric, Emilie Bérard, Thibaut Leguay, Suzanne Tavitian, Audrey Bidet, Eric Delabesse, Jean Baptiste Rieu, Jean-Philippe Vial, François Vergez, Nicolas Lechevalier, Isabelle Luquet, Emilie Klein, Anne-Charlotte de Grande, Audrey Sarry, Arnaud Pigneux, Christian Récher, Sarah Bertoli, and Pierre-Yves Dumas

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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9. Killer immunoglobulin‐like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment‐free remission

Author

Pierre‐Yves Dumas, Emilie Bérard, Claire Bréal, Stéphanie Dulucq, Delphine Réa, Franck Nicolini, Edouard Forcade, Melody Dufossée, Jean‐Max Pasquet, Béatrice Turcq, Audrey Bidet, Noel Milpied, Julie Déchanet‐Merville, Xavier Lafarge, Gabriel Etienne, François‐Xavier Mahon, and French Intergroup in Chronic Myeloid Leukemia

Subjects
chronic myeloid leukemia, imatinib, killer immunoglobulin‐like receptors, natural killer, treatment‐free remission, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin‐like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B‐positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32‐0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment‐free remission rates. Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte‐mediated control of leukemic residual disease control in patient with CML relapse.

Published
2019
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10. MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms

Author

Pierre-Yves Dumas, Olivier Mansier, Valerie Prouzet-Mauleon, Junji Koya, Arnaud Villacreces, Philippe Brunet de la Grange, Damien Luque Paz, Audrey Bidet, Jean-Max Pasquet, Vincent Praloran, Franck Salin, Mineo Kurokawa, François-Xavier Mahon, Bruno Cardinaud, and Eric Lippert

Subjects
Atypical myeloproliferative neoplasms, HOXB4, miR-10a, DNMT3A, Epigenetic, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients. Methods MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2’deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34+ cells with lentiviral vectors encoding the pri-miR-10a precursor. Results MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. Conclusions MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.

Published
2018
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11. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

Author

Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, and Jean-Max Pasquet

Subjects
acute myeloid leukemia, FLT3-ITD, tyrosine kinase inhibitors, persistence, leukemic initiating cells, autophagy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

Published
2022
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12. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL

Author

Pierre-Yves Dumas, Cécile Naudin, Séverine Martin-Lannerée, Brigitte Izac, Luana Casetti, Olivier Mansier, Benoît Rousseau, Alexandre Artus, Mélody Dufossée, Alban Giese, Pierre Dubus, Arnaud Pigneux, Vincent Praloran, Audrey Bidet, Arnaud Villacreces, Amélie Guitart, Noël Milpied, Olivier Kosmider, Isabelle Vigon, Vanessa Desplat, Isabelle Dusanter-Fourt, and Jean-Max Pasquet

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

Published
2019
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13. Unsupervised Flow Cytometry Analysis Allows for an Accurate Identification of Minimal Residual Disease Assessment in Acute Myeloid Leukemia

Author

Jean Philippe Vial, Nicolas Lechevalier, Francis Lacombe, Pierre-Yves Dumas, Audrey Bidet, Thibaut Leguay, François Vergez, Arnaud Pigneux, and Marie C. Béné

Subjects
acute myeloid leukemia, molecular markers, multiparameter flow cytometry, minimal/measurable residual disease, unsupervised analysis, FlowSOM, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The assessment of minimal residual disease (MRD) is increasingly considered to monitor response to therapy in hematological malignancies. In acute myeloblastic leukemia (AML), molecular MRD (mMRD) is possible for about half the patients while multiparameter flow cytometry (MFC) is more broadly available. However, MFC analysis strategies are highly operator-dependent. Recently, new tools have been designed for unsupervised MFC analysis, segregating cell-clusters with the same immunophenotypic characteristics. Here, the Flow-Self-Organizing-Maps (FlowSOM) tool was applied to assess MFC-MRD in 96 bone marrow (BM) follow-up (FU) time-points from 40 AML patients with available mMRD. A reference FlowSOM display was built from 19 healthy/normal BM samples (NBM), then simultaneously compared to the patient’s diagnosis and FU samples at each time-point. MRD clusters were characterized individually in terms of cell numbers and immunophenotype. This strategy disclosed subclones with varying immunophenotype within single diagnosis and FU samples including populations absent from NBM. Detectable MRD was as low as 0.09% in MFC and 0.051% for mMRD. The concordance between mMRD and MFC-MRD was 80.2%. MFC yielded 85% specificity and 69% sensitivity compared to mMRD. Unsupervised MFC is shown here to allow for an easy and robust assessment of MRD, applicable also to AML patients without molecular markers.

Published
2021
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14. Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study

Author

Pierre-Yves Dumas, Sarah Bertoli, Emilie Bérard, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Thibaut Leguay, Harmony Leroy, Noémie Gadaud, Jean Baptiste Rieu, Jean-Philippe Vial, François Vergez, Nicolas Lechevalier, Isabelle Luquet, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Arnaud Pigneux, and Christian Récher

Subjects
acute myeloid leukemia, FLT3-ITD mutation, primary induction failure, relapse, tyrosine kinase inhibitors, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.

Published
2020
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15. Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia Before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study

Author

Sarah Bertoli, Pierre-Yves Dumas, Emilie Bérard, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Suzanne Tavitian, Noémie Gadaud, Thibaut Leguay, Harmony Leroy, Jean-Baptiste Rieu, Jean-Philippe Vial, François Vergez, Nicolas Lechevalier, Isabelle Luquet, Emilie Klein, Audrey Sarry, Anne-Charlotte De Grande, Christian Récher, and Arnaud Pigneux

Subjects
acute myeloid leukemia, flt3-itd mutation, flt3-tkd mutation, primary induction failure, refractory, relapse, tyrosine kinase inhibitors, gilteritinib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse−Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0−32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27−45), 24.7% (95%CI: 1−33) and 19.7% (95%CI: 1−28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

Published
2020
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16. Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Author

Solène Fernandez, Vanessa Desplat, Arnaud Villacreces, Amélie V. Guitart, Noël Milpied, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, and Pierre-Yves Dumas

Subjects
acute myeloid leukemia, tyrosine kinase, inhibitors, targeted therapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

Published
2019
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18. Retrospective, real‐life study of venetoclax plus azacitidine or low‐dose cytarabine in French patients with acute myeloid leukemia ineligible for intensive chemotherapy

Author

Louise Laloi, Natacha Chaumard Billotey, Pierre‐Yves Dumas, Franciane Paul, Alban Villate, Célestine Simand, Luc Fornecker, Florent Puisset, Sarah Bertoli, Marion Boissard Simonet, Kamel Laribi, Dyhia Houyou, Alberto Santagostino, Claire Michel, Gabrielle Roth Guepin, Elodie Guerineau, Reza Tabrizi, Mathilde Hunault, Aurélien Giltat, Eléonore Kaphan, Claude Bulabois, Elodie Cartet, Clément Rocher, Florence Lachenal, Stéphane Morisset, Christian Récher, Arnaud Pigneux, Amine Belhabri, Mauricette Michallet, and Anne‐Sophie Michallet

Subjects
Cancer Research, Oncology, Radiology, Nuclear Medicine and imaging
Abstract

Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low-dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real-life conditions.This retrospective, real-life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy.Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03-16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second-line/beyond, median progression-free survival was 4.0 months (95% confidence interval [CI] 2.7-12.8) with venetoclax-HMA and 3.4 months (1.3-8.9) with venetoclax-LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax-based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed.

Published
2022

19. First clinical description of a pedigree with complete NAF1 deletion

Author

Jean Galtier, Sophie Dimicoli-Salazar, Aurélien Trimouille, Elodie Lainey, Patrick Revy, Audrey Bidet, Yoann Vial, Edouard Forcade, Marie-Laure Negrier-Leibreich, Etienne Rivière, Julie Tinat, Nathalie Le Meur, Christelle Ménard, Arnaud Pigneux, Thibaut Leguay, Pierre-Yves Dumas, Ba Ibrahima, and Caroline Kannengiesser

Subjects
Cancer Research, Oncology, Hematology
Published
2022

20. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study

Author

Loic Vasseur, Laurène Fenwarth, Jérôme Lambert, Stéphane de Botton, Martin Figeac, Céline Villenet, Maël Heiblig, Pierre-yves Dumas, Christian Récher, Celine Berthon, Emilie Lemasle, Delphine Lebon, Juliette Lambert, Christine Terré, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Meyling H Cheok, Raphaël A. Itzykson, Nicolas Duployez, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Claude Huriez [Lille], CHU Lille, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Département de Génétique [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), and Service de pathologie [CHU Lille]

Subjects
[SDV]Life Sciences [q-bio], Hematology
Abstract

International audience; Whether the LSC17 gene expression can improve risk stratification in the context of NGS-based risk stratification and measurable residual disease (MRD) in AML patients treated intensively has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. Multiple (cyto)genetic alterations were associated with changes in LSC17, such as higher LSC17 in patients with RUNX1 or TP53 mutations, and lower scores in those with CEBPA and NPM1 mutations. LSC17-high patients had a lower rate of complete response (CR) or CR with incomplete platelet recovery (CRp) after one induction course in a multivariable analysis (OR=0.41, p=0.0007) accounting for European LeukemiaNet 2022 (ELN22) risk groups, age, and white blood cell (WBC) count. The LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% versus 52.7% in LSC17-low patients, p

Published
2023

21. CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study

Author

Pierre Peterlin, Yannick Le Bris, Pascal Turlure, Patrice Chevallier, Audrey Ménard, Marie-Pierre Gourin, Pierre-Yves Dumas, Sylvain Thepot, Ana Berceanu, Sophie Park, Marie-Anne Hospital, Thomas Cluzeau, Simon Bouzy, Jose-Miguel Torregrosa-Diaz, Louis Drevon, Rosa Sapena, Fatiha Chermat, Lionel Ades, Sophie Dimicoli-Salazar, Sylvie Chevret, Marie-Christine Béné, and Pierre Fenaux

Subjects
Hematology
Published
2023

22. Prognostic value of post-induction medullary myeloid recovery by flow cytometry in acute myeloid leukemia

Author

Céline ROW, Nicolas Lechevalier, Jean-Philippe VIAL, Aguirre Mimoun, Jean-Noël Bastie, denis caillot, Emmanuel Sleiman, Arnaud Pigneux, Thibault Leguay, Mary Callanan, Marc Maynadie, Marie-Christine Béné, Pierre-Yves Dumas, and Julien Guy

Abstract

Risk stratification and treatment response evaluation are key features in acute myeloid leukemia (AML) management. Immunophenotypic and molecular approaches all rely on the detection of persisting leukemic cells by measurable residual disease techniques. A new approach is proposed here by assessing medullary myeloid maturation by flow cytometry through a myeloid progenitor ratio (MPR). The normal MPR range was defined using reference normal bone marrows (n= 48). MPR was considered balanced if between 1 and 4 and unbalanced if 4. MPR was retrospectively assessed at baseline and post-induction for 206 newly diagnosed AML patients eligible for intensive treatment from two different French centers. All AML baseline MPR were unbalanced and thus significantly different from normal MPR (pvs80.2%, HR, 2.96; 95%CI, 1.81-4.84, pvs 64.4%, HR, 2.11; 95%CI, 1.39-3.18, pNPM1/FLT3-ITD status. A balanced post-induction MPR conversely conferred favorable outcomes and reflects medullary myeloid recovery.

Published
2023

23. Supplementary Figure 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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”).

Published
2023

24. Supplementary Figure 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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

Published
2023

25. Supplementary Figure 4 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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

Published
2023

26. Supplementary Table 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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

Published
2023

27. Supplementary Figure 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Flow chart of the study displaying the three cohorts.

Published
2023

28. Supplementary Table 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

TP53 mutations characteristics among t-MN PARPi national cohort.

Published
2023

29. Supplementary Table 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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

Published
2023

30. Data from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

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.

Published
2023

31. Molecular Response Analysis By High Throughput Sequencing in Higher Risk Myelodysplastic Syndrome (HR-MDS) Treated Intensively with CPX-351

Author

Yannick Le Bris, Simon Bouzy, Audrey Ménard, Pascal Turlure, Patrice Chevallier, Marie-Pierre Gourin, Pierre-Yves Dumas, Sylvain Thepot, Anna Berceanu, Sophie Park, Marie-Anne Hospital, Thomas Cluzeau, Jose-Miguel Torregrosa Diaz, Louis Devron, Rosa Sapena, Fatiha Chermat, Sophie Dimicoli Salazar, Marie C Béné, Pierre Fenaux, and Pierre Peterlin

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

32. Epag 2015 : A Phase II Randomized Placebo-Controlled Study to Assess the Impact on Outcome of Eltrombopag Administered to Elderly Patients with Acute Myeloid Leukemia Receiving Induction Chemotherapy. a French Innovative Leukemia Organization (FILO) Study

Author

Arnaud Pigneux, Pierre-Yves Dumas, Marc Bernard, Norbert Vey, Audrey Bidet, Ariane Mineur, Mathilde Hunault, Martin Carre, Mario Ojeda, Anne Banos, Pierre Peterlin, Romain Guieze, Yohan Desbrosses, Gabrielle Roth Guepin, Celestine Simand, Thibaut Leguay, Emmanuel Gyan, Eric Jourdan, Jean-Philippe Vial, Tony Marchand, Yosr Hicheri, Marie C Bene, Jean Francois Hamel, and Christian Recher

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

33. Data from Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3-ITD Acute Myeloid Leukemia

Author

Vanessa Desplat, Jean-Max Pasquet, Isabelle Vigon, Arnaud Pigneux, Thibaut Leguay, Solene Fernandez, Delphine Martineau, Audrey Bidet, Olivier Mansier, Layal Massara, Ali El-habhab, Amélie V. Guitart, Arnaud Villacreces, and Pierre-Yves Dumas

Abstract

Purpose:AXL has been shown to play a pivotal role in the selective response of FLT3-ITD acute myeloid leukemia (AML) cells to FLT3 tyrosine kinase inhibitors (TKI), particularly within the bone marrow microenvironment.Experimental Design:Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through in vitro models mimicking hematopoietic niche conditions, ex vivo in primary AML blasts, and in vivo with dosing regimens allowing plasma concentration close to those used in clinical trials.Results:We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation. In vivo, use of the MV4–11 cell line with hematopoietic engraftment demonstrated that gilteritinib was more effective than quizartinib at targeting leukemic cells in bone marrow. Finally, FLT3-ITD AML patient-derived xenografts revealed that this effect was particularly reproducible in FLT3-ITD AML with high allelic ratio in primary and secondary xenograft. Moreover, gilteritinib and quizartinib displayed close toxicity profile on normal murine hematopoiesis, particularly at steady state.Conclusions:Overall, these findings suggest that gilteritinib as a single agent, compared with quizartinib, is more likely to reach leukemic cells in their protective microenvironment, particularly AML clones highly dependent on FLT3-ITD signaling.

Published
2023

35. Azacitidine, intensive chemotherapy or best supportive care in relapsed or refractory acute myeloid leukemia, a DATAML registry study

Author

Noémie Gadaud, Harmony Leroy, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Sophie Dimicoli-Salazar, Jean-Baptiste Rieu, Isabelle Luquet, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Pierre Bories, Arnaud Pigneux, Christian Récher, Pierre-Yves Dumas, and Sarah Bertoli

Subjects
Antimetabolites, Antineoplastic, Leukemia, Myeloid, Acute, Cancer Research, Treatment Outcome, Oncology, Chronic Disease, Azacitidine, Humans, Registries, Hematology
Abstract

We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (

Published
2022

36. LSC17 Score Is Complementary with Minimal Residual Disease to Stratify NPM1 -Mutated Acute Myeloid Leukemia:An ALFA Study

Author

Loïc Vasseur, Laurène Fenwarth, Xavier Thomas, Jérôme Lambert, Stéphane de Botton, Martin Figeac, Céline Villenet, Pierre-Yves Dumas, Christian Recher, Céline Berthon, Emilie Lemasle, Delphine Lebon, Juliette Lambert, Christine Terré, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Meyling Cheok, Raphael Itzykson, Nicolas Duployez, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Centre Hospitalier Lyon Sud [CHU - HCL] [CHLS], Hopital Saint-Louis [AP-HP] [AP-HP], Institut Gustave Roussy [IGR], Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS], BoRdeaux Institute in onCology [Inserm U1312 - BRIC], Institut National de la Santé et de la Recherche Médicale [INSERM], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen [CLCC Henri Becquerel], CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 [HEMATIM], Centre Hospitalier de Versailles André Mignot [CHV], Service d'Hémato-oncologie [CHU Saint-Louis], Institut pour la recherche sur le cancer de Lille [Lille] [IRCL], Génomes, biologie cellulaire et thérapeutiques [GenCellDi (U944 / UMR7212)], Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Université de Lille, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Versailles André Mignot (CHV), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Immunology, Cell Biology, Hematology, Biochemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2022

39. Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO

Author

Pierre-Yves Dumas, Emmanuel Raffoux, Emilie Bérard, Sarah Bertoli, Marie-Anne Hospital, Maël Heiblig, Yohann Desbrosses, Caroline Bonmati, Cécile Pautas, Juliette Lambert, Corentin Orvain, Anne Banos, Florence Pasquier, Pierre Peterlin, Tony Marchand, Madalina Uzunov, Jamilé Frayfer, Pascal Turlure, Thomas Cluzeau, Eric Jourdan, Chantal Himberlin, Emmanuelle Tavernier, Alban Villate, Stephanie Haiat, Marie-Lorraine Chretien, Martin Carre, Sylvain Chantepie, Ioana Vaida, Mathieu Wemeau, Safia Chebrek, Gaelle Guillerm, Romain Guièze, Houria Debarri, Eve Gehlkopf, Kamel Laribi, Ambroise Marcais, Alberto Santagostino, Marie-Christine Béné, Ariane Mineur, Arnaud Pigneux, Hervé Dombret, and Christian Récher

Subjects
Cancer Research, Oncology, Hematology
Abstract

The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

Published
2022

40. Long-Term Survival of Acute Myeloid Leukemia Responding Patients Who Stopped Azacytidine and/or Venetoclax Because of Poor Tolerance or Physician Choice: A Retrospective Multicenter Study from the French Innovative Leukemia Organization (FILO)

Author

Sylvain Garciaz, Justine Decroocq, Sarah Bertoli, Amine Belhabri, Pierre-Yves Dumas, Celestine Simand, Kamel Laribi, Alberto Santagostino, Martin Carre, Aline Schmidt, Gaspard Aspas Requena, Chantal Himberlin, Marie-Anne Hospital, Christian Recher, and Norbert Vey

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

41. Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Vincent Marmouset, Justine Decroocq, Sylvain Garciaz, Gabriel Etienne, Amine Belhabri, Sarah Bertoli, Lauris Gastaud, Celestine Simand, Sylvain Chantepie, Madalina Uzunov, Alexis Genthon, Celine Berthon, Edmond Chiche, Pierre-Yves Dumas, Jacques Vargaftig, Géraldine Salmeron, Emilie Lemasle, Emmanuelle Tavernier, Jeremy Delage, Marion Loirat, Nadine Morineau, Felix Blanc-Durand, Patricia Pautier, Veronique Vergé, Nathalie Auger, Myrtille Thomas, Laetitia Stefani, Marion Lepelley, Thomas Boyer, Sylvain Thepot, Marie-Pierre Gourin, Pascal Bourquard, Matthieu Duchmann, Pierre Morice, Mauricette Michallet, Lionel Ades, Pierre Fenaux, Christian Recher, Hervé Dombret, Arnaud Pages, Christophe Marzac, Alexandra Leary, Jean-Baptiste Micol, Université de Picardie Jules Verne (UPJV), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], CHU Lille, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CH de Saint-Nazaire, CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ovarian Neoplasms, Cancer Research, Immunology, Neoplasms, Second Primary, Cell Biology, Hematology, Poly(ADP-ribose) Polymerase Inhibitors, Carcinoma, Ovarian Epithelial, Biochemistry, Oncology, Mutation, Humans, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Germ-Line Mutation
Abstract

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.

Published
2022

42. VANDA regimen followed by blinatumomab leads to favourable outcome in patients with Philadelphia chromosome-negative B-precursor acute lymphoblastic leukaemia in first relapse

Author

Luc Heraudet, Jean Galtier, Simon Favre, Florent Peyraud, Titouan Cazaubiel, Harmony Leroy, Nathan Mottal, François‐Xavier Gros, Edouard Forcade, Laurence Clément, Pierre‐Yves Dumas, Arnaud Pigneux, and Thibaut Leguay

Subjects
Adult, Recurrence, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Acute Disease, Antibodies, Bispecific, Humans, Antineoplastic Agents, Philadelphia Chromosome, Hematology, Neoplasm Recurrence, Local, Precursor Cell Lymphoblastic Leukemia-Lymphoma
Abstract

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia (R/R BCP-ALL) have very poor outcome. Blinatumomab as single agent has shown activity in R/R BCP-ALL. We aimed to assess the activity of blinatumomab in concomitant association with intensive chemotherapy. Seventeen patients with R/R BCP-ALL were treated with combination of blinatumomab and VANDA (etoposide, cytarabine, mitoxantrone, dexamethasone and asparaginase) regimen. Complete remission (CR) was achieved in 14/17 patient (82%) and 11/17 (65%) were transplanted. One-year leukaemia-free survival was 58.8% for the whole cohort and 90.9% for transplanted patients. These preliminary data suggest that the VANDA-blinatumomab salvage regimen leads to a very high rate of CR and HSCT in suitable patients.

Published
2022

44. Correction: Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia

Author

Pierre Milpied, Arnaud Villacreces, Christelle Piperoglou, Eric Vivier, Frédéric Vély, Laurine Gil, Adeline Crinier, Pierre-Yves Dumas, Zoran Ivanovic, Emilie Narni-Mancinelli, Bertrand Escalière, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux., Université de Bordeaux Ségalen [Bordeaux 2], Inserm U1035, Biotherapies des Maladies Genetiques et Cancers, Universite' de Bordeaux,CHU de Bordeaux,Pole de Biologie et Pathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM) Hôpital Timone Enfants, Service d'Immunologie - Marseille Immunopôle, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM), Etablissement Français du Sang Nouvelle Aquitaine [Bordeaux] (EFS Bordeaux Nouvelle Aquitaine), Innate Pharma, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Hôpital de la Timone [CHU - APHM] (TIMONE), Université de Bordeaux (UB), MSDAvenir, Innate Pharma, Fondation de France, Centre de Ressources Biologiques Cancer, Bordeaux Biotheques Sante at Bordeaux University Hospital, BB-0033-00036, ANR-17-RHUS-0007,PIONEER,Precision Immuno-Oncology for advanced Non small cell lung cancer patients with PD-1 ICI Resistance(2017), European Project: 694502,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,TILC(2017), DUMENIL, Anita, Caugant, Julien, Precision Immuno-Oncology for advanced Non small cell lung cancer patients with PD-1 ICI Resistance - - PIONEER2017 - ANR-17-RHUS-0007 - RHUS - VALID, and Targeting Innate Lymphoid Cells - TILC - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2017-01-01 - 2021-12-31 - 694502 - VALID

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Cell, Immunology, Bone Marrow Cells, Spleen, NK cells, Biology, scRNASeq, Article, Natural killer cell differentiation, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, AML, Antigens, CD, Stress, Physiological, medicine, Humans, Cytotoxic T cell, Immunology and Allergy, RNA-Seq, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Innate immunity, 0303 health sciences, Gene Expression Regulation, Leukemic, Correction, RNA, Myeloid leukemia, Cell Differentiation, Tissue Donors, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Gene Ontology, medicine.anatomical_structure, Infectious Diseases, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Single-Cell Analysis, 030215 immunology
Abstract

SummaryNatural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56bright NK cells, NK0 cells, as the precursor of both circulating CD56dim NK1-like NK cells and CD56bright NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160high group had a significantly higher survival rate.

Published
2021

45. Looking for somatic mutations in UBA1 in patients with chronic myelomonocytic leukemia associated with systemic inflammation and autoimmune diseases

Author

Joël Decombe, Audrey Bidet, Anne-Charlotte De-Grande, Pierre-Yves Dumas, Estibaliz Lazaro, Pierre Duffau, Jean-François Viallard, Charles Dussiau, Etienne Rivière, Mathieu Sauvezie, Henry Dupuy, Arnaud Pigneux, Sophie Dimicoli-Salazar, Edouard Forcade, Fabrice Bonnet, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0303 health sciences, Cancer Research, Somatic cell, business.industry, Chronic myelomonocytic leukemia, Hematology, UBA1, Systemic inflammation, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Immunology, medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, In patient, medicine.symptom, business, 030304 developmental biology
Published
2021

46. Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries

Author

Audrey Bidet, Hubert Serve, Pierre-Yves Dumas, Carsten Müller-Tidow, Josefina Serrano, Teresa Bernal, Sarah Bertoli, Juan Bergua, Eduardo Rodriguez Arbolí, Uwe Platzbecker, Pilar Martínez-Sánchez, Martin Bornhäuser, Eric Delabesse, Adolfo de la Fuente Burguera, Christian Recher, Arnaud Pigneux, Michael Kramer, Claudia D. Baldus, David Martínez-Cuadrón, Pau Montesinos, Emilie Bérard, Cristina Gil, Christoph Röllig, and Suzanne Tavitian

Subjects
Cancer Research, medicine.medical_specialty, medicine.medical_treatment, EARLY DEATH, NEWLY-DIAGNOSED AML, Intensive chemotherapy, ACUTE MYELOID-LEUKEMIA, REGIMENS, Lower risk, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Long term survival, MANAGEMENT, Humans, Medicine, In patient, VENETOCLAX, Registries, ELDERLY-PATIENTS, AZACITIDINE, Aged, Aged, 80 and over, Chemotherapy, EPIGENETIC THERAPY, business.industry, Significant difference, Myeloid leukemia, Hematology, Patient data, CARE, Leukemia, Myeloid, Acute, Treatment Outcome, Oncology, Azacitidine, business
Abstract

The outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P

Published
2022

47. Overlapping features of therapy-related and de novoNPM1-mutated AML

Author

Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Récher, Christoph Röllig, Martin Bornhäuser, Hubert Serve, Carsten Müller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, and Brunangelo Falini

Subjects
Immunology, Cell Biology, Hematology, Settore MED/15, Biochemistry
Abstract

NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of “therapy-related” NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.

Published
2022
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48. Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome

Author

Isabelle Luquet, Emilie Klein, Jean Galtier, François Vergez, Arnaud Pigneux, Audrey Bidet, Pierre-Yves Dumas, Anne-Charlotte de Grande, Audrey Sarry, Héloïse Rey, Fabien Despas, Jean Baptiste Rieu, Suzanne Tavitian, Nicolas Lechevalier, Emilie Bérard, Thibaut Leguay, Christian Recher, Camille Alric, Jean-Philippe Vial, Sarah Bertoli, and Eric Delabesse

Subjects
Adult, medicine.medical_specialty, Myeloid, Disease-Free Survival, Interquartile range, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Cumulative incidence, Retrospective Studies, Myeloid Neoplasia, business.industry, Retrospective cohort study, Hematology, Middle Aged, medicine.disease, Minimal residual disease, Leukemia, Myeloid, Acute, Leukemia, Regimen, medicine.anatomical_structure, Cytarabine, business, Delivery of Health Care, medicine.drug
Abstract

Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.

Published
2020

49. Reduce Mortality and Morbidity in Acute Myeloid Leukemia With Hyperleukocytosis With Early Admission in Intensive Care Unit: A Retrospective Analysis

Author

Pierre-Yves Dumas, Harmony Leroy, Titouan Cazaubiel, Nathan Mottal, Olivier Guisset, Mathieu Sauvezie, Fabrice Camou, Francois-Xavier Gros, Nahema Issa, Arnaud Pigneux, Gaelle Mourissoux, and Thibaut Leguay

Subjects
Hematology department, medicine.medical_specialty, health care facilities, manpower, and services, medicine.medical_treatment, Early admission, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Retrospective analysis, Clinical endpoint, Medicine, Intensive care unit, Mortality, Chemotherapy, Acute myeloid leukemia, business.industry, Myeloid leukemia, Retrospective cohort study, 030220 oncology & carcinogenesis, Emergency medicine, Original Article, Hyperleukocytosis, business, 030215 immunology
Abstract

Background: Patients presenting with acute myeloid leukemia (AML) at diagnosis are at high risk of severe complications and death, particularly with high white blood cell (WBC) count. In this retrospective study, we evaluate interest of early and systematic support in the intensive care unit (ICU) for AML with hyperleukocytosis (AML-HL) at diagnosis. Methods: Patients with AML-HL, defined by WBC > 50 × 10 9 /L, primary referred in ICU (“Early ICU”) without organ failure and before initiating chemotherapy induction were compared to patients first admitted in the Hematology Department who required a secondary transfer in ICU ( “Late ICU” ) or not ( “No ICU” ). Primary end point was mortality during the first month, and secondary end points were the use of life-sustaining therapies in ICU and risk factors for ICU transfer and mortality. Results: One hundred fifty-four patients were included: 77 (50%) to the group “No ICU” , 18 (12%) to “Late ICU” and 59 (38%) to “Early ICU” . Mortality at day 30 was higher in “Late ICU” than in "Early ICU" and "No ICU", with 27.8%; 16.9% and 2.6% respectively (P < 0.001). "Late ICU" patients had an increased use of life-sustaining therapy comparing to "Early ICU" patients (56% vs. 29%, P = 0.04). Conclusions: Early referral to ICU reduces morbidity and seems an effective strategy to reduce short-term mortality in AML-HL at diagnosis. J Hematol. 2020;9(4):109-115 doi: https://doi.org/10.14740/jh691

Published
2020

50. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

Author

Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, Jean-Max Pasquet, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Etablissement Français du Sang Nouvelle Aquitaine [Bordeaux] (EFS Bordeaux Nouvelle Aquitaine), and Vigon, Isabelle

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, autophagy, FLT3-ITD, leukemic initiating cells, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, persistence, acute myeloid leukemia, Article, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, hemic and lymphatic diseases, tyrosine kinase inhibitors, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, RC254-282
Abstract

Simple Summary One of the most frequent molecular anomalies in acute myeloid leukemia (AML) is the mutation of the fms-like receptor tyrosine kinase 3 through internal tandem duplications, giving rise to a constitutive proliferative signaling. Even though clinical trials have shown that targeting this mutated kinase is of interest and well tolerated, there is still a high frequency of relapse. The emergence of AML cells upon treatment is linked to their maintenance through resistance and persistence mechanisms. Because FLT3-ITD AML cells require autophagy, we explored the consequence of autophagy inhibition by blocking the PI3-kinase class III, Vps34, when AML cells were committed. Results in vitro, ex vivo and in vivo suggest that remission with low minimal residual disease in FLT3-ITD AML offers a promising therapeutic window to target persistent leukemic cells. Abstract Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

Published
2021

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