Publications by authors named "Jean-Michel Cayuela"

91 Publications

Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL.

J Hematol Oncol 2021 May 3;14(1):74. Epub 2021 May 3.

Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France.

IDH1 and IDH2 mutations (IDH1/2) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2. Mutational patterns of IDH1/2 in T-ALL present some specific features compared to AML. Whereas IDH2 mutation was frequent in T-ALL (25 of 51 mutations), the IDH2 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2 were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.
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http://dx.doi.org/10.1186/s13045-021-01068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091755PMC
May 2021

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 Jan 22. Epub 2021 Jan 22.

Inserm CIC 1427, Université de Paris, Paris, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
January 2021

Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

Am J Hematol 2020 11 19;95(11):1314-1323. Epub 2020 Sep 19.

Department of Hematology, INSERM U 1052, CRCL, Centre Léon Bérard, Lyon, France.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.
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http://dx.doi.org/10.1002/ajh.25945DOI Listing
November 2020

Influence of major transcript subtype on outcome in patients with chronic myeloid leukemia in chronic phase treated frontline with nilotinib.

Oncotarget 2020 Jun 30;11(26):2560-2570. Epub 2020 Jun 30.

French Group of CML, Bordeaux, France.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of transcript as a result of reciprocal translocation between chromosome 9 and 22. The most common transcripts subtypes are e13a2 (b2a2) and e14a2 (b3a2). The prognostic impact of the type of transcript has been the subject of controversies over time. In the imatinib era, several studies have suggested a deeper and faster response in patients expressing e14a2. However, the impact on response after first line therapy with a second-generation tyrosine kinase inhibitor, nilotinib, is unknown. We retrospectively evaluated 118 patients newly diagnosed with chronic phase CML and treated frontline with nilotinib inside or outside clinical trial in five French centers. Only patients expressing e14a2 or e13a2 transcripts alone were analyzed. At baseline, 55.3% expressed e14a2, 44.7% expressed e13a2. The median age was 51 years and median follow-up was 49 months. Relative risks of CML at diagnosis were similar according to the ELTS score ( = .87). Complete hematological response and complete cytogenetic response rates were similar among groups. Patients expressing e14a2 transcripts compared to e13a2 transcripts had deeper and faster molecular responses, when considering MMR (100% vs 84.1%, = .007) with a median time of 6.7 and 17.1 months or MR (100% vs 59.9%, = .005) with a median time of 39.7 and 70.9 months, respectively. A sustained treatment free remission was observed in 10/10 patients with e14a2 versus 1/3 with e13a2 transcript ( = .04). In conclusion, even treated with nilotinib first line, patients with chronic phase CML expressing e13a2 transcript have a lower rate of deep molecular responses.
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http://dx.doi.org/10.18632/oncotarget.27652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335668PMC
June 2020

Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission.

Blood Adv 2020 07;4(13):3034-3040

Department of Molecular Biology, Centre Hospitalier de Versailles, Le Chesnay, France.

Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.
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http://dx.doi.org/10.1182/bloodadvances.2020001772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362352PMC
July 2020

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants.

Cancer Cell 2019 10 19;36(4):431-443.e5. Epub 2019 Sep 19.

Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4280, Salt Lake City, UT 84112, USA; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.
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http://dx.doi.org/10.1016/j.ccell.2019.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893878PMC
October 2019

Nilotinib efficacy, safety, adherence and impact on quality of life in newly diagnosed patients with chronic myeloid leukaemia in chronic phase: a prospective observational study in daily clinical practice.

Br J Haematol 2019 12 8;187(5):615-626. Epub 2019 Aug 8.

Department of Medical Oncology, Institut Bergonié, Bordeaux, France.

This observational, prospective study assessed, in a daily clinical practice, the molecular response, safety, quality of life (QoL) and treatment adherence in 183 patients with chronic myeloid leukaemia in chronic phase (CML-CP), receiving nilotinib as first-line treatment. Premature study termination before 24 months of follow-up occurred in 61 patients (33·3%), and was essentially due to nilotinib treatment discontinuation (n = 53; 29%), motivated by treatment intolerance (n = 29; 15·8%) and inefficacy (n = 19; 10·4%). After 24 months of treatment, 112/122 patients (91·8%) had a molecular assessment, 95·5% of whom achieved a major molecular response (MMR), 32·1% achieved uMR , defined as an undetectable molecular disease with 4-log molecular response sensitivity (≥10 000 ABL1 transcripts). The Morisky Green Levine Medication Adherence Scale was completed by 94/122 patients (77·0%), and 89·4% of these patients obtained a satisfactory level of treatment adherence, defined as a score ≥3. Patients' QoL was good at baseline and stable during the follow-up period. The two most common nilotinib-related adverse events (AEs) were pruritus (14·8%) and asthenia (13·7%). Seven patients (3·8%) experienced at least one cardiovascular ischaemic AE. This French nationwide cohort study provides relevant information in daily clinical practice indicating that nilotinib is a valuable first-line treatment option for CML-CP patients.
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http://dx.doi.org/10.1111/bjh.16145DOI Listing
December 2019

[Recommendations from the French CML Study Group (Fi-LMC) for BCR-ABL1 kinase domain mutation analysis in chronic myeloid leukemia].

Bull Cancer 2020 Jan 26;107(1):113-128. Epub 2019 Jul 26.

Siège social, institut Bergonié, Groupe d'étude français pour la leucémie myéloïde chronique Fi-LMC, 229, cours de l'Argonne, 33000 Bordeaux, France.

In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.
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http://dx.doi.org/10.1016/j.bulcan.2019.05.011DOI Listing
January 2020

Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia.

Blood Adv 2019 07;3(13):1981-1988

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% ( = .177).
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http://dx.doi.org/10.1182/bloodadvances.2018028993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616254PMC
July 2019

The rising prevalence of chronic myeloid leukemia in France.

Leuk Res 2018 06 17;69:94-99. Epub 2018 Apr 17.

Institut Gustave Roussy, Service de Biostatistique et d'Epidémiologie, Villejuif, F-94805, France; CESP, Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Sud Univ., Villejuif, France.

Outcomes in chronic myeloid leukemia (CML) have been dramatically improved since the emergence of imatinib and the subsequent generation of tyrosine kinase inhibitors (TKI) in the early 2000s. Indeed, CML is now associated with near-normal life expectancy for the majority of patients, provided they adhere to lifelong TKI-based treatment. This paradigm, in which CML can be regarded as a chronic disease, has inherent consequences on the prevalence of the disease. Our objective was to study CML prevalence trend in the French population from 1960 to 2060. We used a cohort component-based model to forecast the prevalence of CML using projections of the French population, the estimated incidence rates by age and sex, and various hypotheses on the year-specific relative survival. CML prevalence in France is estimated at 2.5 per 100,000 inhabitants before the 1980s, with a progression up to 6 by 2002. Since 2002 this trend has increased further, with current and predicted prevalence reaching levels around 18 and 24 per 100,000 in 2018 and 2030 respectively. CML prevalence reaches 30 per 100,000 by 2050 when progression slows. Our simulations show that prevalence of CML is driven by both population aging and relative survival improvement. The grey area corresponds to the expected prevalence of CML.
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http://dx.doi.org/10.1016/j.leukres.2018.04.008DOI Listing
June 2018

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group.

Cancer 2018 07 3;124(14):2956-2963. Epub 2018 May 3.

French Chronic Myeloid Leukemia Study Group, Bergonié Institute, Bordeaux, France.

Background: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice.

Methods: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice.

Results: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction.

Conclusions: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31411DOI Listing
July 2018

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

Blood 2018 01 19;131(3):289-300. Epub 2017 Oct 19.

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, INSERM U1151, Paris, France.

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for and alterations. Patients with () mutations and () germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with GL and GL mutations or and mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 10/L, gHiR classifier, and MRD ≥10 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 10/L, gLoR classifier, and MRD <10 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 10/L, it identifies a significant subgroup of patients with a low risk of relapse.
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http://dx.doi.org/10.1182/blood-2017-04-778829DOI Listing
January 2018

Treatment-free remission in patients with chronic myeloid leukemia.

Int J Hematol 2018 Oct 8;108(4):355-364. Epub 2017 Jul 8.

Laboratoire Central d'Hématologie, EA3518 Université Paris 7 and France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC), Hôpital Saint-Louis, Paris, France.

Clinical trials have formally demonstrated that in chronic myeloid leukemia (CML), patients treated with tyrosine kinase inhibitors (TKI) who achieved and maintained deep molecular responses could discontinue their treatment after several years without facing overt signs of disease relapse in approximately 50% of the cases. In patients with a molecular relapse, prompt re-introduction of TKI therapy was able to rapidly restore deep molecular responses. The concept of a lifelong therapy with TKI has thus been challenged and treatment-free remission (TFR) strategies will soon integrate clinical practice, providing that safe recommendations will be established. In this article, we give an update on TKI discontinuation studies in CML and we also provide an overview of upcoming TFR clinical and biological challenges.
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http://dx.doi.org/10.1007/s12185-017-2295-0DOI Listing
October 2018

Persistent risk of adult T-cell leukemia/lymphoma after neonatal HTLV-1 infection through exchange transfusion.

Int J Hematol 2017 Jun 30;105(6):859-862. Epub 2017 Jan 30.

Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, 75015, Paris, France.

A 36-year-old Caucasian male presented with adult T-cell leukemia/lymphoma (ATL). HTLV-1 contamination was attributed to a neonatal exchange transfusion. Remission was achieved but 11 years later he presented with symptoms suggesting ATL relapse. Molecular studies of T-cell clonality and virus integration sites revealed a clonal disease, distinct from the first tumor.
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http://dx.doi.org/10.1007/s12185-016-2174-0DOI Listing
June 2017

Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group.

J Clin Oncol 2017 Jan 14;35(2):185-193. Epub 2016 Nov 14.

Marie Balsat, Xavier Thomas, and Sandrine Hayette, Centre Hospitalier Lyon Sud, Pierre Benite; Aline Renneville, Alice Marceau, Olivier Nibourel, Céline Rodriguez, and Claude Preudhomme, CHRU of Lille; Aline Renneville, Alice Marceau, Olivier Nibourel, and Claude Preudhomme, Cancer Research Institute of Lille and Université Lille; and Céline Berthon, Claude Huriez Hospital, Lille; Stéphane de Botton, Institut Gustave Roussy, Villejuif; Denis Caillot, Dijon University Hospital, Dijon; Emilie Lemasle, Henri-Becquerel Center, Rouen; Jean-Pierre Marolleau, Amiens University Hospital, Amiens; Emmanuel Raffoux, Hervé Dombret, Jean-Michel Cayuela, Marie Magdeleine Coudé, Karine Celli-Lebras, and Nicolas Boissel, Hôpital Saint-Louis, AP-HP; Emmanuel Raffoux, Herve Dombret, and Nicolas Boissel, University 7 Paris Diderot; and Thorsten Braun, Hôpital Avicennes, AP-HP, Paris; Arnaud Pigneux, Haut-Leveque Hospital, Pessac; Norbert Vey, Paoli-Calmette Institute, Marseille; and Christine Terre, Hôpital de Versailles, Le Chesnay, France.

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.
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http://dx.doi.org/10.1200/JCO.2016.67.1875DOI Listing
January 2017

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study.

Cancer 2017 05 27;123(10):1791-1799. Epub 2016 Dec 27.

CEA, Institute of Emerging Diseases and Innovative Therapies, University Paris-Sud UMR 007, Fontenay-aux-Roses, France.

Background: We recently reported that peroxisome proliferator-activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification.

Methods: CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR ) defined by BCR-ABL1/ABL1 RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR over 12 months.

Results: Twenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR was 56% (95% confidence interval, 37%-76%) by 12 months, despite a wide range of therapy duration (1.9-15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR by 48 months. The cumulative incidence of MMR to MR spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients.

Conclusion: Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009-011675-79). Cancer 2017;123:1791-1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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http://dx.doi.org/10.1002/cncr.30490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434901PMC
May 2017

Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.

Blood 2016 08 27;128(6):774-82. Epub 2016 Apr 27.

Département d'Hématologie, d'Oncologie Médicale et de Radiothérapie Oncologique, Centre Hospitalier de Jolimont-Lobbes, Haine Saint Paul, Belgium;

Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
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http://dx.doi.org/10.1182/blood-2016-02-700153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085255PMC
August 2016

Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.

Blood 2016 06 25;127(26):3424-30. Epub 2016 Apr 25.

Department of Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Pediatrico Bambino Gesù, Rome, Italy; and University of Pavia, Pavia, Italy.

Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.
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http://dx.doi.org/10.1182/blood-2016-01-695551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161011PMC
June 2016

Natural killer cell licensing after double cord blood transplantation is driven by the self-HLA class I molecules from the dominant cord blood.

Haematologica 2016 05 27;101(5):e209-12. Epub 2016 Jan 27.

Université Paris-Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Amiens, France Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris, France Inserm, UMRS-1160, Institut Universitaire d'Hématologie, Paris LabEx Transplantex, University of Strasbourg, Paris, France.

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http://dx.doi.org/10.3324/haematol.2015.138883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004361PMC
May 2016

Recommendations for accreditation of laboratories in molecular biology of hematologic malignancies.

Ann Biol Clin (Paris) 2015 Sep-Oct;73(5):595-630

Laboratoire d'hématologie, Paris, France.

Over recent years, the development of molecular biology techniques has improved the hematological diseases diagnostic and follow-up. Consequently, these techniques are largely used in the biological screening of these diseases; therefore the Hemato-oncology molecular diagnostics laboratories must be actively involved in the accreditation process according the ISO 15189 standard. The French group of molecular biologists (GBMHM) provides requirements for the implementation of quality assurance for the medical molecular laboratories. This guideline states the recommendations for the pre-analytical, analytical (methods validation procedures, quality controls, reagents), and post-analytical conditions. In addition, herein we state a strategy for the internal quality control management. These recommendations will be regularly updated.
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http://dx.doi.org/10.1684/abc.2015.1067DOI Listing
August 2016

Genetic polymorphisms associated with increased risk of developing chronic myelogenous leukemia.

Oncotarget 2015 Nov;6(34):36269-77

Service d'Hématologie et d'Oncologie, Hôpital Mignot, Université Versailles, Saint-Quentin-en-Yvelines, France.

Little is known about inherited factors associated with the risk of developing chronic myelogenous leukemia (CML). We used a dedicated DNA chip containing 16 561 single nucleotide polymorphisms (SNPs) covering 1 916 candidate genes to analyze 437 CML patients and 1 144 healthy control individuals. Single SNP association analysis identified 139 SNPs that passed multiple comparisons (1% false discovery rate). The HDAC9, AVEN, SEMA3C, IKBKB, GSTA3, RIPK1 and FGF2 genes were each represented by three SNPs, the PSM family by four SNPs and the SLC15A1 gene by six. Haplotype analysis showed that certain combinations of rare alleles of these genes increased the risk of developing CML by more than two or three-fold. A classification tree model identified five SNPs belonging to the genes PSMB10, TNFRSF10D, PSMB2, PPARD and CYP26B1, which were associated with CML predisposition. A CML-risk-allele score was created using these five SNPs. This score was accurate for discriminating CML status (AUC: 0.61, 95%CI: 0.58-0.64). Interestingly, the score was associated with age at diagnosis and the average number of risk alleles was significantly higher in younger patients. The risk-allele score showed the same distribution in the general population (HapMap CEU samples) as in our control individuals and was associated with differential gene expression patterns of two genes (VAPA and TDRKH). In conclusion, we describe haplotypes and a genetic score that are significantly associated with a predisposition to develop CML. The SNPs identified will also serve to drive fundamental research on the putative role of these genes in CML development.
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http://dx.doi.org/10.18632/oncotarget.5915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742176PMC
November 2015

Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion.

J Immunol 2015 Sep 5;195(6):2580-90. Epub 2015 Aug 5.

INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Laboratoire d'Immunologie et Histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France;

Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule-1, NKp46, and NKG2D) and decreased IFN-γ production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.
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http://dx.doi.org/10.4049/jimmunol.1500262DOI Listing
September 2015

Novel fusion between the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with chronic myeloid leukemia-like neoplasm: undetectable residual disease after imatinib therapy.

Eur J Haematol 2015 Nov 20;95(5):480-3. Epub 2015 May 20.

Service d'Hématologie adulte, Hôpital Saint Louis, AP-HP, Paris, France.

Rare patients suffering from myeloid neoplasms share clinical and cytological features indistinguishable from chronic myeloid leukemia (CML) but lack the BCR-ABL1 fusion gene. Several studies provide evidence that alterations in genes encoding tyrosine kinase receptors such as the platelet-derived growth factor receptor (PDGFR) may be involved in the pathogenesis of these disorders. Here we describe a patient with a rare CML-like disease in whom we identified a novel in-frame BCR-PDGFRA rearrangement joining BCR exon 17 to PDGFRA exon 13, resulting in overexpression of PDGFRA. The design of a specific quantitative PCR assay to monitor the molecular response during treatment with imatinib, a multitargeted tyrosine kinase inhibitor (TKI) with activity against ABL, c-Kit, and PDGFRA revealed an outstanding disease control with durably undetectable BCR-PDGFRA transcripts. Multiple TKIs are currently available yet with distinct target profiles; thus, accurate molecular diagnosis and monitoring tools are essential to establish tailored treatments and assess response to therapy in this type of rare hematological malignancy.
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http://dx.doi.org/10.1111/ejh.12576DOI Listing
November 2015

Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.

Blood 2015 Jun 15;125(24):3711-9. Epub 2015 Apr 15.

Division of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Paris, France;

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.
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http://dx.doi.org/10.1182/blood-2015-02-627935DOI Listing
June 2015

A novel method for room temperature distribution and conservation of RNA and DNA reference materials for guaranteeing performance of molecular diagnostics in onco-hematology: A GBMHM study.

Clin Biochem 2015 Oct 12;48(15):982-7. Epub 2015 Apr 12.

Laboratory of Hematology, University Hospital Necker-Enfants-Malades, AP-HP, Paris, France.

Objectives: Performance of methods used for molecular diagnostics must be closely controlled by regular analysis of internal quality controls. However, conditioning, shipping and long lasting storage of nucleic acid controls remain problematic. Therefore, we evaluated the minicapsule-based innovative process developed by Imagene (Evry, France) for implementing DNA and RNA controls designed for clonality assessment of lymphoproliferations and BCR-ABL1 mRNA quantification, respectively.

Design & Methods: DNA samples were extracted from 12 cell lines selected for giving specific amplifications with most BIOMED-2 PCR tubes. RNA samples were extracted from 8 cell line mixtures expressing various BCR-ABL1 transcript levels. DNA and RNA were encapsulated by Imagene and shipped at room temperature to participating laboratories. Biologists were asked to report quality data of recovered nucleic acids as well as PCR results.

Results: Encapsulated nucleic acids samples were easily and efficiently recovered from minicapsules. The expected rearrangements at immunoglobulin, T-cell receptor and BCL2 loci were detected in DNA samples by all laboratories. Quality of RNA was consistent between laboratories and met the criteria requested for quantification of BCR-ABL1 transcripts. Expression levels measured by the 5 laboratories were within ±2 fold interval from the corresponding pre-encapsulation reference value. Moreover aging studies of encapsulated RNA simulating up to 100 years storage at room temperature show no bias in quantitative outcome.

Conclusions: Therefore, Imagene minicapsules are suitable for storage and distribution at room temperature of genetic material designed for proficiency control of molecular diagnostic methods based on end point or real-time quantitative PCR.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.04.004DOI Listing
October 2015

A CALR mutation preceding BCR-ABL1 in an atypical myeloproliferative neoplasm.

N Engl J Med 2015 Feb;372(7):688-90

INSERM Unité 1009, Villejuif, France.

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http://dx.doi.org/10.1056/NEJMc1413718DOI Listing
February 2015

Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react.

Br J Haematol 2015 Apr 19;169(2):249-61. Epub 2014 Dec 19.

Department of Paediatric Haematology/oncology, University Hospital of Nancy, Nancy, France.

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.
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http://dx.doi.org/10.1111/bjh.13272DOI Listing
April 2015