Publications by authors named "Arnaud Pigneux"

103 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

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Am J Hematol 2021 Apr 17. Epub 2021 Apr 17.

Department of Hematology, Inserm U1163, IMAGINE Institute, Paris University, Necker Hospital, Paris, France.

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.
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http://dx.doi.org/10.1002/ajh.26200DOI Listing
April 2021

Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial.

Eur J Haematol 2021 Mar 25. Epub 2021 Mar 25.

Hématologie Clinique, Hôpital Cochin, AP-HP, Paris, France.

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
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http://dx.doi.org/10.1111/ejh.13626DOI Listing
March 2021

Conventional chemotherapy for acute myeloid leukemia in older adults: Impact on nutritional, cognitive, and functional status.

Eur J Haematol 2021 Jun 27;106(6):859-867. Epub 2021 Mar 27.

Clinical Hematology, Grenoble University Hospital, Grenoble, France.

Objectives: The impact of conventional treatment for acute myeloid leukemia (AML) on the nutritional, cognitive, and functional status of elderly patients is seldom studied. This assessment was performed in the context of the LAMSA 2007 trial.

Methods: The trial enrolled 424 patients with de novo AML. Among them, 316 benefited from geriatric assessment (GA) including nutritional, cognitive, and functional status and were scored according to Eastern Cooperative Oncology Group (ECOG) and sorror for the prediction of treatment toxicity, morbidity, and mortality. Patients were investigated at diagnosis for three times during follow-up.

Results: This study showed that AML and its treatment have no impact on cognitive (P = .554) nor functional status (P = .842 for Activity of Daily Living and P = .087 for Instrumental Activities of Daily Living). The nutritional status improved over time (P = .041). None of these three parameters at baseline, associated or not with ECOG and sorror scores, impacted survivals or toxicities.

Conclusions: The cognitive, functional, and nutritional status had no impact in this cohort of fit elderly AML patients without unfavorable cytogenetics. The GA tools used provided no additional information compared with ECOG and sorror scores, to predict toxicity, morbidity, or mortality due to intensive chemotherapy.
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http://dx.doi.org/10.1111/ejh.13624DOI Listing
June 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

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

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Hematology Biology, Nantes University Hospital, 44000 Nantes, France.

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.
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http://dx.doi.org/10.3390/cancers13040629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914957PMC
February 2021

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.

Leukemia 2021 Feb 4. Epub 2021 Feb 4.

EBMT Paris Study Office, Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Paris, France.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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http://dx.doi.org/10.1038/s41375-021-01135-2DOI Listing
February 2021

Minimal residual disease monitoring in acute myeloid leukemia with non-A/B/D-NPM1 mutations by digital polymerase chain reaction: feasibility and clinical use.

Haematologica 2020 12 10;Online ahead of print. Epub 2020 Dec 10.

CHU Lille, Laboratory of Hematology, F-59000 Lille, FRANCE; Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche contre le Cancer de Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille.

Not available.
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http://dx.doi.org/10.3324/haematol.2020.260133DOI Listing
December 2020

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

J Hematol 2020 Dec 1;9(4):109-115. Epub 2020 Oct 1.

CHU de Bordeaux, Hopital Haut Leveque, Service d'Hematologie Clinique et Therapie Cellulaire, 1 Avenue de Magellan, 33600 Pessac, France.

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/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.
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http://dx.doi.org/10.14740/jh691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665861PMC
December 2020

Outcomes of Antifungal Prophylaxis in High-Risk Haematological Patients (AML under Intensive Chemotherapy): The SAPHIR Prospective Multicentre Study.

J Fungi (Basel) 2020 Nov 12;6(4). Epub 2020 Nov 12.

Blood Diseases Department, Hospital Group Haut Leveque, Avenue de Magellan, 33604 Pessac, France.

Antifungal prophylaxis (AFP) is recommended by international guidelines for patients with acute myeloid leukaemia (AML) undergoing induction chemotherapy and allogeneic hematopoietic cell transplantation. Nonetheless, treatment of breakthrough fungal infections remains challenging. This observational, prospective, multicentre, non-comparative study of patients undergoing myelosuppressive and intensive chemotherapy for AML who are at high-risk of invasive fungal diseases (IFDs), describes AFP management and outcomes for 404 patients (65.6% newly diagnosed and 73.3% chemotherapy naïve). Ongoing chemotherapy started 1.0 ± 4.5 days before inclusion and represented induction therapy for 79% of participants. In 92.3% of patients, posaconazole was initially prescribed, and 8.2% of all patients underwent at least one treatment change after 17 ± 24 days, mainly due to medical conditions influencing AFP absorption (65%). The mean AFP period was 24 ± 32 days, 66.8% stopped their prophylaxis after the high-risk period and 31.2% switched to a non-prophylactic treatment (2/3 empirical, 1/3 pre-emptive/curative). Overall, 9/404 patients (2.2%) were diagnosed with probable or proven IFDs. During the follow-up, 94.3% showed no signs of infection. Altogether, 20 patients (5%) died, and three deaths (0.7%) were IFD-related. In conclusion, AFP was frequently prescribed and well tolerated by these AML patients, breakthrough infections incidence and IFD mortality were low and very few treatment changes were required.
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http://dx.doi.org/10.3390/jof6040281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712136PMC
November 2020

Horizontal meta-analysis identifies common deregulated genes across AML subgroups providing a robust prognostic signature.

Blood Adv 2020 10;4(20):5322-5335

Centre National de la Recherche Scientifique (CNRS) Equipe Recherche Labellisée (ERL) 7001-Leukemic Niche and Redox Metabolism (LNOx), Groupe Innovation et Ciblage Cellulaire (GICC) EA 7501, Université de Tours, Tours, France.

Advances in transcriptomics have improved our understanding of leukemic development and helped to enhance the stratification of patients. The tendency of transcriptomic studies to combine AML samples, regardless of cytogenetic abnormalities, could lead to bias in differential gene expression analysis because of the differential representation of AML subgroups. Hence, we performed a horizontal meta-analysis that integrated transcriptomic data on AML from multiple studies, to enrich the less frequent cytogenetic subgroups and to uncover common genes involved in the development of AML and response to therapy. A total of 28 Affymetrix microarray data sets containing 3940 AML samples were downloaded from the Gene Expression Omnibus database. After stringent quality control, transcriptomic data on 1534 samples from 11 data sets, covering 10 AML cytogenetically defined subgroups, were retained and merged with the data on 198 healthy bone marrow samples. Differentially expressed genes between each cytogenetic subgroup and normal samples were extracted, enabling the unbiased identification of 330 commonly deregulated genes (CODEGs), which showed enriched profiles of myeloid differentiation, leukemic stem cell status, and relapse. Most of these genes were downregulated, in accordance with DNA hypermethylation. CODEGs were then used to create a prognostic score based on the weighted sum of expression of 22 core genes (CODEG22). The score was validated with microarray data of 5 independent cohorts and by quantitative real time-polymerase chain reaction in a cohort of 142 samples. CODEG22-based stratification of patients, globally and into subpopulations of cytologically healthy and elderly individuals, may complement the European LeukemiaNet classification, for a more accurate prediction of AML outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020002042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594391PMC
October 2020

First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia.

J Clin Oncol 2020 12 14;38(36):4260-4273. Epub 2020 Oct 14.

The Christie NHS Foundation Trust, Manchester, United Kingdom.

Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor.

Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm.

Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).
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http://dx.doi.org/10.1200/JCO.19.03250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768337PMC
December 2020

Antifungal Stewardship in Hematology: Reflection of a Multidisciplinary Group of Experts.

Clin Lymphoma Myeloma Leuk 2021 Jan 18;21(1):35-45. Epub 2020 Aug 18.

Department of Oncology and Hematology, Strasbourg University Hospitals and Strasbourg University, Strasbourg, France.

We have presented a practical guide developed by a working group of experts in infectious diseases and hematology to summarize the different recommendations issued by the different international groups on antifungal agents used for hematology patients. In addition, a working group of experts in the domains of nephrology, hepatology, and drug interactions have reported their different recommendations when administering antifungal agents, including dose adjustments, monitoring, and management of their side effects. This guide will enable prescribers to have a document available that will allow for better and optimal use of antifungal agents for hematology patients with consideration of the toxicity and interactions adjusted to each indication.
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http://dx.doi.org/10.1016/j.clml.2020.08.010DOI Listing
January 2021

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study.

Leukemia 2021 May 18;35(5):1291-1300. Epub 2020 Sep 18.

Clinical Hematology, Bordeaux University Hospital, Bordeaux University, Inserm 1035, Bordeaux, France.

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITD/NPM1 mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
May 2021

A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.

Blood 2021 01;137(4):524-532

Service d'Hématologie Clinique, Hôpital Henri Mondor, AP-HP, Créteil, France.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.
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http://dx.doi.org/10.1182/blood.2020005524DOI Listing
January 2021

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

Blood Adv 2020 08;4(16):3840-3849

Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

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.
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http://dx.doi.org/10.1182/bloodadvances.2020002511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448603PMC
August 2020

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

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) -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 -internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with -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 ( = 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 -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.
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http://dx.doi.org/10.3390/cancers12082044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465142PMC
July 2020

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

Cancers (Basel) 2020 Mar 25;12(4). Epub 2020 Mar 25.

CHU Bordeaux, Service d'Hématologie Clinique et de Thérapie Cellulaire, F-33000, Bordeaux, France.

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) -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 -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 ( = 48, 27.6%) or relapsed ( = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy ( = 99, 56.9%), azacitidine or low-dose cytarabine ( = 9, 5.1%), other low-intensity treatments ( = 17, 9.8%), immediate allogeneic stem cell transplantation ( = 4, 2.3%) or best supportive care only ( = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, = 32, 28.1%; relapsed, = 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% ( = 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 -mutated AML remains very poor with standard salvage therapy.
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http://dx.doi.org/10.3390/cancers12040773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226007PMC
March 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

Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase.

Br J Clin Pharmacol 2020 05 3;86(5):991-998. Epub 2020 Feb 3.

CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure.

Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period.

Results: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2).

Conclusion: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.
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http://dx.doi.org/10.1111/bcp.14211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163380PMC
May 2020

Clofarabine Improves Relapse-Free Survival of Acute Myeloid Leukemia in Younger Adults with Micro-Complex Karyotype.

Cancers (Basel) 2019 Dec 30;12(1). Epub 2019 Dec 30.

ALFA Group, 75010 Paris, France.

Acute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: = 92 patients, HDAC arm: = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; = 0.004). From our study cohort, 8% of patients displayed mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337-4.041), = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens.
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http://dx.doi.org/10.3390/cancers12010088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017244PMC
December 2019

Chromosomal Abnormalities and Prognosis in -Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

J Clin Oncol 2019 10 20;37(29):2632-2642. Epub 2019 Aug 20.

St Vincent's Hospital, Melbourne, Australia.

Purpose: Nucleophosmin 1 () mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene () is absent (-ITD) or present with a low allelic ratio (-ITD). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

Methods: We analyzed associations between karyotype and outcome in intensively treated patients with /-ITD AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

Results: Among 2,426 patients with /-ITD AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with /-ITD AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the mutational status on outcome.

Conclusion: Karyotype abnormalities are significantly associated with outcome in /-ITD AML. When adverse-risk cytogenetics are present, patients with share the same unfavorable prognosis as patients with wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in /-ITD AML.
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http://dx.doi.org/10.1200/JCO.19.00416DOI Listing
October 2019

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Int J Mol Sci 2019 Jul 12;20(14). Epub 2019 Jul 12.

Institut National de la Santé et de la Recherche Médicale, U1035 Bordeaux, France.

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.
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http://dx.doi.org/10.3390/ijms20143429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679203PMC
July 2019

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

Haematologica 2019 10 28;104(10):2017-2027. Epub 2019 Mar 28.

Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux

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.
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http://dx.doi.org/10.3324/haematol.2018.205385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886433PMC
October 2019

Chronic myelomonocytic leukaemia followed by blastic plasmacytoid dendritic cell neoplasm.

Br J Haematol 2019 05 19;185(3):398. Epub 2019 Feb 19.

Laboratoire d'Hématologie Universitaire de Bordeaux, Pessac, France.

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http://dx.doi.org/10.1111/bjh.15794DOI Listing
May 2019

Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey.

BMC Cancer 2018 Nov 12;18(1):1100. Epub 2018 Nov 12.

Sektion für Hämatologische Spezialdiagnostik, Klinik für Innere Medizin II, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Langer Segen 8-10, D-24105, Kiel, Germany.

Background: In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries.

Methods: A web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years' experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice.

Results: MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries.

Conclusions: This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + .
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http://dx.doi.org/10.1186/s12885-018-5002-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233570PMC
November 2018

Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial.

J Clin Oncol 2018 Nov 27;36(32):3203-3210. Epub 2018 Sep 27.

Arnaud Pigneux and Pierre-Yves Dumas, Bordeaux University Hospital, Bordeaux University, INSERM 1035; Louis-Rachid Salmi, Ariane Mineur, and Julien Asselineau, Bordeaux University Hospital, Bordeaux; Marie C. Béné, and Jacques Delaunay, Nantes University Hospital, Nantes; Caroline Bonmati, Nancy University Hospital, Nancy; Romain Guièze, Clermont-Ferrand University Hospital, Clermont Ferrand; Isabelle Luquet, Eric Delabesse, and Christian Récher, Toulouse University Hospital, Toulouse; Pascale Cornillet-Lefebvre, Reims University Hospital, Reims; Jean-Christophe Ianotto, Brest University Hospital, Brest; Mario Ojeda-Uribe, Mulhouse Regional Hospital, Mulhouse; Mathilde Hunault and Norbert Ifrah, Angers University Hospital and INSERM U 892/CNRS 6299, Angers; Anne Banos, Cote Basque General Hospital, Bayonne; Luc Matthieu Fornecker, Strasbourg University Hospital, Strasbourg; Marc Bernard, Rennes University Hospital, Rennes; Eric Jourdan, Nîmes University Hospital, Nîmes; Norbert Vey, Institut Paoli Calmettes, Marseilles; Hacene Zerazhi, Avignon General Hospital, Avignon; Yosr Hishri, Montpellier University Hospital, Montpellier; Roselyne Delepine, Tours University Hospital, Tours; and Jean-Yves Cahn, Grenoble University Hospital, Grenoble, France.

Purpose: Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin.

Patients And Methods: Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety.

Results: From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( = .01). The proportional hazards assumption was rejected for OS ( = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( = .04), and fewer patients required a second treatment after ICL.

Conclusion: Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.
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http://dx.doi.org/10.1200/JCO.2018.78.7366DOI Listing
November 2018

Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group.

Haematologica 2018 12 19;103(12):2033-2039. Epub 2018 Jul 19.

Hopital Saint Louis, Université Paris Diderot, France

In standard-risk acute promyelocytic leukemia, recent results have shown that all- retinoic acid plus arsenic trioxide combinations are at least as effective as classical all- retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all- retinoic acid and the "classical" cytarabine for consolidation treatment (after all- retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x10/L, after an induction treatment consisting of all- retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all- retinoic acid. Patients with a white blood cell count >10x10/L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all- retinoic acid consolidation groups, respectively (=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (=0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (=0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (=0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. ().
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http://dx.doi.org/10.3324/haematol.2018.198614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269295PMC
December 2018

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis.

Oncotarget 2018 Jun 1;9(42):26724-26736. Epub 2018 Jun 1.

Department of Hematology and Cell Therapy, University Hospital, F-33000 Bordeaux, France.

Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment. We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed. A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%. In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.
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http://dx.doi.org/10.18632/oncotarget.25477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003556PMC
June 2018