Publications by authors named "Philippe Rousselot"

133 Publications

Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy.

Blood 2021 Aug;138(7):507-519

Département d'Hématologie, Canther (Cancer Heterogeneity, Plasticity and Resistance to Therapies), Unité 1277, Centre Hospitalier Universitaire de Lille, Université de Lille, INSERM, Lille, France.

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10-4) allelic ratio, DNMT3A (HR, 1.86; P < 10-4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a "go-go" tier with a 2-year OS of 66.1%, 7.6% to the "no-go" group (2-year OS 2.8%), and 3.3% of to the "slow-go" group (2-year OS of 39.1%; P < 10-5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10-5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.
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http://dx.doi.org/10.1182/blood.2021011103DOI Listing
August 2021

Ponatinib Dose-Ranging Study in Chronic-Phase Chronic Myeloid Leukemia: A Randomized, Open-Label Phase 2 Clinical Trial.

Blood 2021 Aug 18. Epub 2021 Aug 18.

The University of Utah, Salt Lake City, Utah, United States.

In PACE, a phase 2 trial of ponatinib that included patients with chronic phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit:risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel response-based dose-reduction strategy for a TKI in CP-CML. Adults with CP-CML resistant/intolerant to at least 2 prior BCR-ABL1 TKIs, or with a BCR-ABL1 T315I mutation, were randomized 1:1:1 to ponatinib 45mg (45mg cohort), 30mg (30mg cohort), or 15mg (15mg cohort) once daily. Patients who received 45 or 30mg daily reduced their dose to 15mg upon achievement of response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. Between August 2015 and May 2019, 283 patients were randomized; 282 (94/group) received treatment (data cutoff, 5/31/20). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45mg cohort, 29.0% (18.4-41.6) in the 30mg cohort, and 23.1% (13.4-35.3) in the 15mg cohort. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45, 30, and 15mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit:risk outcomes occurred with the 45mg starting dose reducing to 15mg upon achievement of response (ClinicalTrials.gov number, NCT02467270).
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http://dx.doi.org/10.1182/blood.2021012082DOI Listing
August 2021

KMT2A-ARHGEF12, a therapy related fusion with poor prognosis.

Mol Biol Rep 2021 Aug 12. Epub 2021 Aug 12.

Department of Laboratory Medicine, Hemato-Oncologic Cytogenetics, Centre Hospitalier de Versailles, 2, rue JL Forain, 78150, Le Chesnay, France.

Background: The detection of KMT2A gene rearrangements have an important impact on the prognosis and management of acute leukemias. These alterations most commonly involve reciprocal translocations at specific breakpoint regions within KMT2A. To date, more than 100 translocation partner genes of KMT2A have been identified, with different effects on risk stratification.

Methods And Results: We report the case of a mature plasmacytoid dendritic cells proliferation associated with B lymphoblasts harboring a KMT2A-ARHGEF12 fusion. This rare rearrangement, resulting from a cryptic deletion on the long arm of chromosome 11, is located outside the known major and minor breakpoint regions of KMT2A, not reported to date. The review of the few cases of KMT2A-ARHGEF12 reveals the tendency of this deletion to occur in therapy related hematologic neoplasm and confer unfavorable prognosis.

Conclusion: This review sheds light into the rare KMT2A-ARHGEF12 fusion in leukemia. Reporting rare chimeras is essential to improve knowledge about the biological mechanism and associated clinical consequences.
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http://dx.doi.org/10.1007/s11033-021-06621-5DOI Listing
August 2021

Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy: A Randomized, Phase 3 Trial.

Hemasphere 2021 Aug 2;5(8):e617. Epub 2021 Aug 2.

Goethe University, Frankfurt/Main, Germany.

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1-10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95-2.89]; = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8-1.2]; = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.
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http://dx.doi.org/10.1097/HS9.0000000000000617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328241PMC
August 2021

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.

Br J Haematol 2021 Jul 30;194(2):393-402. Epub 2021 Jun 30.

Clinical Pharmacology Department, Centre Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France.

Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
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http://dx.doi.org/10.1111/bjh.17654DOI Listing
July 2021

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL.

Blood 2021 Jun 14. Epub 2021 Jun 14.

Institut Necker Enfants-Malades, Team 2, INSERM U1151, Paris, France.

T-cell acute lymphoblastic leukemia (T-ALL) are aggressive hematological cancers with dismal outcomes, and are in need of new therapeutic options. Polycomb Repressor Complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL; yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to ETP-ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients poorly respond to prednisone, have low bone marrow blast clearance, and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with Bromodomain and Extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data has uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.
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http://dx.doi.org/10.1182/blood.2020010081DOI Listing
June 2021

Genetic Identification of AML Patients Older than 60 years Achieving Long-term Survival with Intensive Chemotherapy.

Blood 2021 May 27. Epub 2021 May 27.

CHU Lille, INSERM, Lille, France.

To design a simple and reproducible classifier predicting the overall survival (OS) of AML patients ≥ 60 years old treated with 7+3, we sequenced 37 genes in 471 patients from the ALFA1200 study (NCT01966497, median age 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (N=13), intermediate (N=339) or unavailable (N=35) cytogenetic risk. TP53 (HR=2.49; P=0.0003) and KRAS (HR=3.60; P=0.001) mutations independently worsened OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR=0.57; P=0.0004), FLT3-ITDs with low (HR=1.85; P=0.0005) or high (HR=3.51; P<10-4) allelic ratio, DNMT3A (HR=1.86; P<10-4), NRAS (HR=1.54; P=0.019) and ASXL1 (HR=1.89; P=0.0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a 'go-go' tier with a 2-year OS of 66.1%, 7.6% to the 'no-go' group (2-year OS 2.8%) while the 53.3% 'slow-go' patients had a 2-year OS of 39.1% (P<10-5). Across three independent validation cohorts, 31.2-37.7% and 11.2-13.5% of patients were assigned to the 'go-go' and the 'no-go' tiers respectively, with significant differences in OS between tiers in all 3 cohorts (HDF, N=141, P=0.003, SAL N=466 and AMLSG N=223, both P<10-5). The ALFA decision tool is a simple, robust and discriminant prognostic model for AML patients older than 60 years treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7+3 standard of care with less intensive regimens.
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http://dx.doi.org/10.1182/blood.2021011103DOI Listing
May 2021

PPARγ agonists promote the resolution of myelofibrosis in preclinical models.

J Clin Invest 2021 06;131(11)

Division of Innovative Therapies, CEA/DRF/François Jacob Biology Institute, UMR1184 IMVA-HB/IDMIT, Université Paris-Saclay, Fontenay-aux-Roses, France.

Myelofibrosis (MF) is a non-BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.
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http://dx.doi.org/10.1172/JCI136713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159700PMC
June 2021

Ponatinib long-term follow-up of efficacy and safety in CP-CML patients in real world settings in France: The POST-PACE study.

Leuk Res 2021 05 2;104:106541. Epub 2021 Mar 2.

Département d'hématologie et and INSERM U1052, Centre Léon Bérard, CRCL, Lyon, France; Fi-LMC, Centre Léon Bérard, Lyon, France.

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http://dx.doi.org/10.1016/j.leukres.2021.106541DOI Listing
May 2021

BiTtEn by Src inhibitors.

Blood 2021 02;137(7):867-868

Centre Hospitalier de Versailles; Université Versailles Saint-Quentin-en-Yvelines et Paris-Saclay; UMR1184.

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http://dx.doi.org/10.1182/blood.2020008876DOI Listing
February 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 08 22;35(8):2332-2345. 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
August 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

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

Rapid screening of COVID-19 patients using white blood cell scattergrams, a study on 381 patients.

Br J Haematol 2020 09 5;190(5):718-722. Epub 2020 Jul 5.

Department of Pharmacology, CH Versailles, Le Chesnay, France.

Complementary tools are warranted to increase the sensitivity of the initial testing for COVID-19. We identified a specific 'sandglass' aspect on the white blood cell scattergram of COVID-19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID-19-positive or -negative based on reverse transcriptase polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the 'sandglass' aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non-invasive and simple tool to quickly categorize symptomatic patients as either COVID-19-probable or -improbable especially when RT-PCR and/or chest CT are not rapidly available.
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http://dx.doi.org/10.1111/bjh.16943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323204PMC
September 2020

Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors.

Eur Respir J 2020 10 29;56(4). Epub 2020 Oct 29.

INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
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http://dx.doi.org/10.1183/13993003.00279-2020DOI Listing
October 2020

Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients.

Clin Cancer Res 2019 11 10;25(22):6606-6613. Epub 2019 Jul 10.

Groupe Fi-LMC, Bergonié Institut, Bordeaux, France.

Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.

Patients And Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.

Results: A total of 218 patients with chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%-59%] at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of in 175 of 218 patients at imatinib cessation. To apply positive ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%) were the two identified predictive factors of molecular recurrence, with = 0.0366 (HR, 0.635; 95% CI, 0.415-0.972] and = 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively.

Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with chronic phase CML..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3373DOI Listing
November 2019

Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome.

Br J Haematol 2019 11 4;187(3):337-346. Epub 2019 Jul 4.

Bergonié Institute Cancer Center, Bordeaux, France.

The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO-SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO-SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02-2·74)] with a 93-month cut-off time, and history of osteoarticular symptoms [RR = 1·84 (1·04-3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre-existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.
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http://dx.doi.org/10.1111/bjh.16083DOI Listing
November 2019

Management of adverse events associated with bosutinib treatment of chronic-phase chronic myeloid leukemia: expert panel review.

J Hematol Oncol 2018 12 27;11(1):143. Epub 2018 Dec 27.

University of Milano-Bicocca, Milan, Italy.

Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.
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http://dx.doi.org/10.1186/s13045-018-0685-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307238PMC
December 2018

Ponatinib evaluation and safety in real-life chronic myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: the PEARL observational study.

Exp Hematol 2018 11 5;67:41-48. Epub 2018 Sep 5.

Hematology Department, Centre Léon Bérard, Lyon, France; INSERM U1052, CRCL, Lyon, France; French Group of CML (Fi-LMC), Institut Bergonié, Bordeaux, France. Electronic address:

Ponatinib represents a remarkable progress in the treatment of heavily pretreated chronic myelogenous leukemia (CML) and de novo Philadelphia chromosome-positive ALL patients despite significant toxicity in clinical trials. To date, "real-life" data remain few and the use of ponatinib in this setting and its consequences remain mostly unknown. We report, within a national observational study, the use of ponatinib in unselected CML patients who had previously failed ≥2 lines of tyrosine kinase inhibitor (TKI) therapy (or one line if an Abelson (ABL) mutation was identified), in real-life conditions (2013-2014) in a compassionate program. Our analysis has been focused on 48 chronic phase CML patients recorded. With a median follow-up of 26.5 months since ponatinib initiation, the overall survival (OS) rates (80.5% at 3 years) and cumulative incidence of major molecular response (81.8% at 18 months) were similar to those of the phase II study, with no influence of BCR-ABL mutations nor the reason of ponatinib prescription. A specific subanalysis of the preexisting cardiovascular risk factors and events occurring on ponatinib is described. These events occurred after a median time on ponatinib of 5.8 months (excluding hypertension) and were observed in 29/48 patients (47%), even in those already on anti-aggregants/coagulants. The majority were not severe and resolved, but two cases were fatal. Other hematological or nonhematological nonvascular adverse events were similar to those previously described in trials. This observational study reports similar rates of survival, molecular responses, and a slight increase in the cardiovascular toxicity of ponatinib in real-life conditions, prompting improved control of cardiovascular risk factors and selection of patients.
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http://dx.doi.org/10.1016/j.exphem.2018.08.006DOI Listing
November 2018

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia.

Haematologica 2019 01 9;104(1):93-101. Epub 2018 Aug 9.

University of Texas MD Anderson Cancer Center, Houston, TX, USA

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034/Dose-optimization. With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not. .
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http://dx.doi.org/10.3324/haematol.2018.188987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312029PMC
January 2019

Nivolumab to control molecular response in chronic myeloid leukemia.

Leuk Res 2018 09 26;72:5-6. Epub 2018 Jul 26.

General and Oncologic Dermatology department, Hôpital Ambroise-Paré, AP-HP, Boulogne, France.

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http://dx.doi.org/10.1016/j.leukres.2018.07.011DOI Listing
September 2018

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.

Leukemia 2018 08 20;32(8):1768-1777. Epub 2018 Jul 20.

City of Hope National Medical Center, Duarte, CA, USA.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
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http://dx.doi.org/10.1038/s41375-018-0210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087717PMC
August 2018

The story of tyrosine kinase inhibitors discontinuation in clinical practice.

Leuk Lymphoma 2018 12 18;59(12):2782-2791. Epub 2018 Jun 18.

a Department of Hematology and Oncology , Université Versailles Saint-Quentin-en-Yvelines, Université Paris Saclay, INSERM U1173, Centre Hospitalier de Versailles , Le Chesnay , France.

Chronic myeloid leukemia is the first example of successful clinical use of tyrosine kinase inhibitors (TKIs). Blockade of oncogenic BCR-ABL1 tyrosine kinase activity by imatinib translated into an impressive demonstration of clinical and biological control of the disease. Historically, the primary objective of TKIs use was to achieve long-term survival. Today this is a reality for the majority of patients. The rapid development of BCR-ABL1 quantification by RT-qPCR has facilitated the monitoring of residual disease. Molecular response has emerged as a new therapeutic objective, opening the door to TKIs discontinuation. The first prospective stop study in patients in deep molecular response was initiated in 2004, with today nearly 15 years of follow-up. The pioneering observations of this study followed by numerous stop-studies have led to a new therapeutic goal of treatment-free remission. Five cases of patients who discontinued TKIs are reviewed, illustrating the current issues and challenges surrounding this approach.
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http://dx.doi.org/10.1080/10428194.2018.1459611DOI Listing
December 2018

Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial.

J Clin Oncol 2018 08 4;36(24):2514-2523. Epub 2018 Jun 4.

Françoise Huguet, Eric Delabesse, Institut Universitaire du Cancer, Toulouse; Sylvie Chevret, Nicolas Boissel, Hervé Dombret, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP); Université Paris Diderot; Agnès Buzyn, Vahid Asnafi, Elizabeth Macintyre, Hôpital Necker, AP-HP; Université Paris Descartes, Paris; Thibaut Leguay, Centre Hospitalier Universitaire, Pessac; Xavier Thomas, Véronique Lhéritier, Hôpital Lyon-Sud, Pierre Bénite; Martine Escoffre-Barbe, Centre Hospitalier Universitaire, Rennes; Patrice Chevallier, Marie C. Béné, Centre Hospitalier Universitaire, Nantes; Mathilde Hunault, Norbert Ifrah, Centre Hospitalier Universitaire, Angers; Norbert Vey, Institut Paoli-Calmettes, Marseille; Caroline Bonmati, Centre Hospitalier Universitaire, Nancy; Stéphane Lepretre, Centre Henri Becquerel, Rouen; Jean-Pierre Marolleau, Centre Hospitalier Universitaire, Amiens; Philippe Rousselot, Centre Hospitalier, Versailles; Jean-Yves Cahn, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France; Thomas Pabst, Inselspital; Swiss Group for Clinical Cancer Research, Bern; and Yves Chalandon, Swiss Group for Clinical Cancer Research, Bern; Hôpital Universitaire, Geneva, Switzerland.

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.
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http://dx.doi.org/10.1200/JCO.2017.76.8192DOI Listing
August 2018

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.

Lancet Oncol 2018 07 31;19(7):889-903. Epub 2018 May 31.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

Background: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.

Methods: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.

Findings: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2.

Interpretation: Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses.

Funding: Ambit Biosciences/Daiichi Sankyo.
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http://dx.doi.org/10.1016/S1470-2045(18)30240-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152787PMC
July 2018

Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial.

Lancet Oncol 2018 06 4;19(6):747-757. Epub 2018 May 4.

Bergonié Cancer Institute, Inserm Unit 916, University of Bordeaux, Bordeaux, France. Electronic address:

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.

Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114.

Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported.

Interpretation: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.

Funding: ELN Foundation and France National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(18)30192-XDOI Listing
June 2018

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
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