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Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the inci-dence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients.Patients and methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP.Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative inci-dence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haemato-poietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome.Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis. (c) 2020 Elsevier Ltd. All rights reserved.

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 de novo 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 BCR-ABL1 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 BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 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 de novo chronic phase CML. See related commentary by Yan et al., p. 6561

International audience; 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).

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.

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.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (

International audience; Manganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted). In a large cohort of patients with chronic myeloid leukemia (CML), a significant decrease of SOD2 mRNA was observed. This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. The analysis of anti-oxidant gene expression analysis revealed a specific down-regulation of the expression of PRDX2 in UT7-BCR-ABL and UT7-T315I cells silenced for SOD2 expression. Gene set enrichment analysis performed between the two SOD2-dependent classes of CML patients revealed a significant enrichment of Reactive Oxygen Species (ROS) Pathway. Our data provide the first evidence for a link between SOD2 expression and genetic instability in CML. Consequently, SOD2 mRNA levels should be analyzed in prospective studies as patients with low SOD2 expression could be more prone to develop a mutator phenotype under TKI therapies.

Resume Objectifs Le Female Pelvic Floor Questionnaire (FPFQ) est un outil auto-administrable qui explore les symptomes perineaux. Notre objectif etait de realiser l’adaptation culturelle du FPFQ en langue francaise et d’evaluer ses proprietes psychometriques. Methodes Apres l’adaptation culturelle en francais, l’acceptabilite et la fiabilite du questionnaire ont ete evaluees dans un echantillon de 56 femmes dans le cadre d’un test–retest. La validite de construction discriminative a ete evaluee en comparant les resultats obtenus par le FPFQ a ceux d’autres questionnaires valides. Le suivi longitudinal des 282 femmes enceintes incluses dans l’etude prevention perineale prenatale (3PN) a permis l’evaluation de sa sensibilite aux changements. Resultats La proportion de donnees manquantes ne depassait pas 4 % pour les questions concernant le domaine urinaire, le domaine anorectal et le prolapsus genital ; 10 % pour les questions sur la sexualite. La question 9 a ete jugee difficile a comprendre par 14 % des femmes. Apres reformulation, cette question a ete testee dans un nouvel echantillon de 52 femmes et n’a pas pose de probleme de comprehension. Le coefficient de correlation intraclasse etait superieur ou egal a 0,7 pour tous les domaines au cours du test–retest. Le FPFQ etait fortement et significativement correle (Spearman r > 0,5) avec les autres questionnaires valides. La version francaise du FPFQ a enregistre des changements dans les symptomes urinaires et sexuels pour les femmes incluses dans l’essai 3PN avec une reponse moyenne standardisee egale a 0,83 et 0,44, respectivement. Conclusion La version francaise du FPFQ est auto-administrable, fiable, valide et peut detecter un changement de symptomatologie au cours d’un suivi longitudinal. Niveau de preuve Niveau 4.

Since tyrosine kinase inhibitors (TKI) have been introduced in the armamentarium of chronic myeloid leukemia (CML) therapy, CML patients can expect a life expectancy close to the healthy population...

Background In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. Methods The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry for Chronic Myeloid Leukemia in Children and Adolescents. Results Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation, children with ACAs, and children with a variant t(9;22) translocation who were treated with imatinib as frontline therapy, the probability of progression-free survival (PFS) was 95% (95% confidence interval [CI], 91%-97%), 100%, and 75% (95% CI, 13%-96%), respectively, and the probability of overall survival (OS) was 98% (95% CI, 95%-100%), 100% (95% CI, 43%-98%), and 75% (95% CI, 13%-96%), respectively. No statistical difference was observed between the patients with classic cytogenetic findings and those with additional chromosomal abnormalities in terms of PFS and OS. Conclusions In contrast to adults with CML, additional chromosomal abnormalities observed at diagnosis do not seem to have a significant prognostic impact. Cancer 2017;123:3609-16. © 2017 American Cancer Society.

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

Recent clinical findings in chronic myeloid leukemia (CML) patients suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitors (TKI) treatment substantially depend on an individual, leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will most likely remain in a long-term treatment free remission (TFR). Here, we use a mathematical model for CML, which explicitly includes an anti-leukemic (presumably immunological) effect and apply it to a set of patients (n=60) for whom BCR-ABL/ABL time courses had been quantified before and after TKI stop. We demonstrate that such a feedback control is conceptually necessary to explain long-term remission as observed in about half of the patients. Based on simulation results we classify the patient data sets into three different groups according to their predicted immune system configuration. While one class of patients requires a complete CML eradication to achieve TFR, other patients are able to control the leukemia after treatment cessation. Among them, we identified a third class of patients, which only maintains TFR if an optimal balance between leukemia abundance and immunological activation is achieved before treatment cessation. Further, we demonstrate that the immune response classification of the patients cannot be obtained solely from BCR-ABL measurements before treatment cessation. However, our results strongly suggest that changes in the BCR-ABL dynamics arising after system perturbations, such as TKI dose reduction, holds the information to predict the individual outcome after treatment cessation.

Recent clinical findings in patients with chronic myeloid leukemia (CML) suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitor (TKI) treatment substantially depends on an individual's leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will remain in treatment-free remission (TFR). Here, we used an ordinary differential equation model for CML, which explicitly includes an antileukemic immunologic effect, and applied it to 21 patients with CML for whom BCR-ABL1/ABL1 time courses had been quantified before and after TKI cessation. Immunologic control was conceptually necessary to explain TFR as observed in about half of the patients. Fitting the model simulations to data, we identified patient-specific parameters and classified patients into three different groups according to their predicted immune system configuration (“immunologic landscapes”). While one class of patients required complete CML eradication to achieve TFR, other patients were able to control residual leukemia levels after treatment cessation. Among them were a third class of patients that maintained TFR only if an optimal balance between leukemia abundance and immunologic activation was achieved before treatment cessation. Model simulations further suggested that changes in the BCR-ABL1 dynamics resulting from TKI dose reduction convey information about the patient-specific immune system and allow prediction of outcome after treatment cessation. This inference of individual immunologic configurations based on treatment alterations can also be applied to other cancer types in which the endogenous immune system supports maintenance therapy, long-term disease control, or even cure. Significance: This mathematical modeling approach provides strong evidence that different immunologic configurations in patients with CML determine their response to therapy cessation and that dose reductions can help to prospectively infer different risk groups. See related commentary by Triche Jr, p. 2083

Several studies have now shown that chronic myeloid leukaemia (CML) patients in deep molecular remission may discontinue tyrosine kinase inhibitor (TKI) treatment with a treatment free remission (TFR) rate of approximately 40-60 %. Some factors influencing the possibility of TFR have been described but better tools are needed for individual prediction of long-term TFR. Herein, two multiplex panels were utilised to analyse a total of 162 different plasma proteins from 56 patients included in the TKI stopping trial EURO-SKI (Saussele a al., 2018). The purpose was to identify possible plasma protein markers for prediction of successful TKI discontinuation and to evaluate effects of TKI discontinuation on plasma protein profiles. No protein biomarkers sampled before TKI discontinuation could separate relapse cases from non-relapse cases but some plasma proteins differed between patients who relapsed and those who remained in TFR when followed over time after TKI cessation. In conclusion, the plasma protein markers in this study could not predict relapse after TKI discontinuation but may be of use to understand the mechanisms involved in maintenance of TFR.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known on the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7 - 2.6]). Patients with 20-29% had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2 - 4.0], p = 0.008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs. non-high risk) with an HR of 3.01 (95%-CI: [1.81 - 5.00], p

Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

Aims: The Female pelvic floor questionnaire (FPFQ) is a self-administered tool on pelvic floor function. Our aim was to carry out a cultural adaptation of the FPFQ into French and to assess its psychometric properties. Methods: After cross-cultural adaptation into French, acceptability and reliability of the questionnaire were assessed through a sample of 56 women in a test-retest. Discriminative construct validity was evaluated by comparing the results obtained by the FPFQ to those of other validated questionnaires. Longitudinal follow-up of the 282 pregnant women included in the PreNatal Pelvic floor Prevention trial (3PN) was used to analyze responsiveness. Results: The proportion of missing data did not exceed 4% for questions about bladder function, bowel function and pelvic organ prolapse; 10% for issues related to sexual function. Question 9 was considered difficult to understand by 14% of women. After rewriting, this issue was retested in a new sample of 52 women and presented no further problems. The intra-class correlation coefficient was greater than or equal to 0.7 for all domains during the test-retest. The FPFQ was strongly and significantly correlated (Spearman r>0.5) with the other validated questionnaires. The French version of FPFQ recorded changes in urinary and sexual symptoms for the women involved in 3PN trial with a standardized response mean equal to 0.83 and 0.44, respectively. Conclusion: The French version of the FPFQ is self-administered, reliable, valid, and can detect a change in symptoms during follow-up.

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later. Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P 95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with 8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.

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 (

Background The pathological determinism of H. pylori infection is explained by complex interplay between bacterial virulence and host inflammatory response. In a large prospective multicenter clinical study, Th17 response, expression of antimicrobial peptides (AMPs), cagA and vacA status, and bacterial density were investigated in the gastric mucosa of H. pylori -infected patients. Materials and methods Gastric inflammatory response was analyzed by RT-qPCR for quantification of Th17 cytokines (IL-17A, IL-22), CXCL-8, and AMPs (BD2 and S100A9) mRNA levels in gastric biopsies. Detection and genotyping of H. pylori strains were achieved by bacterial culture and PCR. Results Among 787 patients screened for H. pylori, 269 were analyzed (147 H. pylori -infected and 122 uninfected patients). In H. pylori -infected patients, distribution was 83 gastritis, 12 duodenal ulcers, 5 gastric ulcers, and 47 precancerous and cancerous lesions. CXCL-8, IL-17A, BD2, and S100A9 mRNA levels were significantly increased in H. pylori -infected patients but, surprisingly, IL-22 was not, and no difference was shown between H. pylori -related diseases. A positive correlation was identified between S100A9 expression and bacterial density. Although expression of the virulence genes cagA and vacA did not impact inflammatory response, patients infected with a cagA-positive strain were associated with severe H. pylori -related diseases. Conclusion This study showed that CXCL-8, IL-17A, and AMPs are not differently expressed according to the various H. pylori -related diseases. The clinical outcome determinism of H. pylori infection is most likely not driven by gastric inflammation but rather tends to mainly influenced by bacterial virulence factors.

Background The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. Results Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-β1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-β1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-β1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. Conclusion Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0380-0) contains supplementary material, which is available to authorized users.

To compare, in an unselected population of nulliparous pregnant women, the postnatal effect of prenatal supervised pelvic floor muscle training with written instructions on postpartum urinary incontinence (UI).In a randomized controlled trial in two parallel groups, 282 women were recruited from five university teaching hospitals in France and randomized during the second trimester of pregnancy. The physiotherapy group received prenatal individually supervised exercises. Both groups received written instructions about how to perform exercises at home. Women were blindly assessed at baseline, end of pregnancy, and 2 and 12 months postpartum. The primary outcome measured was UI severity, assessed with an International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score (range 0-21; 1-5 is slight UI) at 12 months postpartum; other outcomes were UI prevalence and pelvic floor troubles assessed using self-administered questionnaires. To give a 1-point difference in UI severity score, we needed 91 women in each group (standard deviation 2.4, α=0.05, β=0.20, and bilateral analysis).Between February 2008 and June 2010, 140 women were randomized in the physiotherapy group and 142 in the control group. No difference was observed between the two groups in UI severity, prevalence, or pelvic floor troubles at baseline, end of pregnancy, and at 2 and 12 months postpartum. At 12 months postpartum, the primary outcome was available for 190 women (67.4%); mean UI severity was 1.9 in the physiotherapy group compared with 2.1 in the control group (P=.38).Prenatal supervised pelvic floor training was not superior to written instructions in reducing postnatal UI.ClinicalTrials.gov; www.clinicaltrials.gov, NCT00551551.I.

Purpose The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. Methods Retrospective data from 81 children less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). Results A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall ( p −4 ) irrespective of gender and pubertal age. The height SDS was significantly ( p −4 ) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. Conclusion Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%-99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%-98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents. Funding Agencies|Nordic Cancer Union; Finnish Society of Hematology; Biomedicum Helsinki Foundation; Research Foundation of Blood Diseases in Finland; Academy of Finland; Finnish Cancer Organizations; Signe and Ane Gyllenberg Foundation; Finnish Cancer Institute; Doctoral Programme in Clinical Research in the University of Helsinki

Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

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 (MR4.5) defined by BCR‐ABL1/ABL1 IS 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 MR4.5 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 MR4.5 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 MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 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., Pioglitazone is a peroxisome proliferator‐activated receptor gamma agonist that is able to target quiescent chronic myeloid leukemia stem cells. The combination of imatinib and pioglitazone was well tolerated in vivo and induced a cumulative incidence of conversion to molecular response 4.5 (MR4.5) of 56% by 12 months in 24 CML patients who had a major molecular response under imatinib alone.

Background TKI discontinuation is now a critical goal of CML management and several studies have demonstrated the feasibility of stopping safely imatinib (IM). A sustained deep molecular response (DMR) on long-term TKI therapy seems critical prior to attempting treatment-free remission (TFR). Results from different studies have been reported recently, but they failed to identify robust and reproducible predictive factors allowing a better selection of candidate patients for successful TFR. Aims We prospectively asked whether the use of IM first-line in de novo CP-CML patients and a systematic screen of patients with digital droplet quantitative PCR (ddPCR) for BCR-ABL1 would impact on the TFR rates. Methods In a national prospective phase II trial (Eudract # NCT01343173), we enrolled newly diagnosed CP-CML patients, in sustained MR4.5 (≥2 yrs on at least 5 consecutive points) according to the ELN criteria, checked centrally. Further molecular follow-up was performed in local laboratories, all ELN standardized and aligned on the international scale (IS). Molecular recurrence was defined as the positivity of BCR-ABL1/ABL1 transcripts with at least 1-log increase between 2 consecutive assessments or as loss of MMR on a single assessment. Duplex ddPCR was performed on screening samples after RT, using EAC primers and probes. Pre-mixes were transferred in aDG8 cartridge, and generation of droplets was made on the QX200 droplet generator. Each emulsion was transferred into a 96 wells ddPCR plate and amplified on the Biorad-C1000 Touch Thermocycler. Each patient was analyzed in duplicate. ddPCR was considered positive when the BCR-ABL1/ABL1 % was ≥3 SD. BCR-ABL1/ABL1 ratios were aligned on the IS, a conversion factor was calculated for the RT-ddPCR as previously described (S. Branford et al., Blood 2008). Impact of variables on the risk of relapse were assessed through univariate and multivariate analyses using SAS program. Results The median follow-up after IM cessation was 23.5 (1-64) Mo. One patient died from unrelated cause, and 107 experienced a loss of MMR. The molecular recurrence-free survival (RFS) was 52% (95%CI: 45-59%) at 6 months, and 50% (95%CI: 43-57%) at 24 months. The Sokal and the EUTOS long-term survival (ELTS) scores failed to discriminate patients but a trend was observed for ELTS score (p=0.0547). Other variables analysed such as gender (p=0.6246), age at diagnosis (p=0.966), age at IM cessation (p=0.6197), interval diagnosis-IM (p=0.9621), interval IM initiation-DMR (p=0.9978) did not impact on the rate of relapse. In contrast, IM and DMR duration before IM cessation significantly impacted on the rate of relapse, as this interval is redundant with IM duration (p=0.008). ddPCR was applied to 174 out of 218 patients at IM cessation. A cut-off of 0.0023%IS ratio (= median of positive ratios) was also associated with a higher risk of relapse. The RFS estimate according to this cut-off is shown in Figure 1. In a multivariate analysis, the duration of IM (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified significant predictive factors with respectively p=0.0366 [HR=0.635, 95%CI: 0.415-0.972] and p=0.0081 [HR=0.635, 95%CI: 0.415-0.972)]. No association was observed between a ddPCR ≥0.0023%IS and gender, Sokal or ELTS score, age at diagnosis, age at IM discontinuation, duration of IM treatment, DMR duration or the time-lapse for obtaining DMR. Conclusion We conclude that the duration of IM and the residual leukemic cell load as determined by a sensitive technique such as ddPCR are key factors for predicting TFR for de novo CP-CML patients who have been treated with IM front-line. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau. Dulucq:Incyte: Consultancy; BMS: Consultancy. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau.

Background. The Doxorubicin based R-CHOP regimen remains the standard of care for the upfront treatment of DLBCL. The advent of oral idarubicin permitted to develop an all-oral ambulatory oro-CIEP regimen. We hypothesized this regimen would improve the treatment of elderly DLBCL. Methods. We have performed a phase 1/2 study to determine the MTD of idarubicin in the oro-CIEP regimen. Idarubicin was orally administrated on day 1 with starting dose at 20mg/m2 and escalated per 10mg/m2 increment. Results. Twenty-six newly diagnosed patients were enrolled, median age of 71 years (range, 62-80). All first 3 patients developed a DLT at level 3 (40mg/m2), and 14 patients were then enrolled at RP2D 30mg/m² in the phase 2. The most significant hematological toxicities were thrombocytopenia grade 3 or 4 (3.3%) and neutropenia grade 3 or 4 (26%); and extra-hematological toxicities were infectious disease (5% grade 3 or 4). No toxic related death was observed. ORR and CR rates were 85% and 77%, respectively. The 5-year overall survival and event free survival were 65% (95%CI 41;81) and 65% (95%CI 42;81), respectively. Conclusion. This analysis shows that oral idarubicin at the MTD of 30 mg/m2 is safe and active in elderly DLBCL. The results we have observed, particularly overall survival seemed to be superimposable to previous publications with the regular CHOP-like regimens for this population. Further improvements in the protocol will be introduced with the subcutaneous anti-CD20 immunotherapy approach. This data needs to be confirmed in the context of a larger study. Disclosures Leleu: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: The pegylated form of interferon-α-2a (PegIFNa2a) in combination with imatinib has demonstrated a molecular improvement in patients with chronic-phase chronic myeloid leukemia. However, to the authors' knowledge, the appropriate dose of PegIFNa2a has not been established to date. METHODS: In the French SPIRIT trial, the authors compared 2 initial doses of PegIFNa2a, taking into account an amendment that recommended reducing that dose from 90 μg/week to 45 μg/week because of toxicities. Accordingly, 2 subgroups of patients were identified: the PegIFN90 group (171 patients who were treated with the 90-μg/week dose) and the PegIFN45 group (50 patients who were treated with the 45-μg/week dose). Both groups were compared for toxicity and efficacy. RESULTS: PegIFNa2a at a dose of 90 μg/week resulted in a rate of 54% of grade 3 to 4 hematologic toxicity compared with 27% with the dose of 45 μg/week (P < .001), leading to discontinuation rates of 40% and 10%, respectively, before 6 months. The dose reduction did not significantly affect the efficacy of the combination. By 12 months, the cumulative molecular response rates (ie, BCR-ABL/abl ≤ 0.01 [IS: molecular responses graded as molecular response 4 (MR4)]) were 14% and 25%, respectively, for the subgroup treated with imatinib at a dose of 400 mg and the PegIFN90 subgroup. After the amendment, the MR4 rates were 10% and 28%, respectively, for the subgroup treated with imatinib at the 400-mg dose and PegIFN45 subgroup (P < .0001). CONCLUSIONS: The results of the current study demonstrate that in combination with imatinib, the efficient dose of PegIFNa2a appears to be 45 μg/week. Society.

The epithelial to mesenchymal transition (EMT) enables epithelial cells with a migratory mesenchymal phenotype. It is activated in cancer cells and is involved in invasion, metastasis and stem-like properties. ZEB1, an E-box binding transcription factor, is a major suppressor of epithelial genes in lung cancer. In the present study, we show that in H358 non-small cell lung cancer cells, ZEB1 downregulates EpCAM (coding for an epithelial cell adhesion molecule), ESRP1 (epithelial splicing regulatory protein), ST14 (a membrane associated serine protease involved in HGF processing) and RAB25 (a small G-protein) by direct binding to these genes. Following ZEB1 induction, acetylation of histone H4 and histone H3 on lysine 9 (H3K9) and 27 (H3K27) was decreased on ZEB1 binding sites on these genes as demonstrated by chromatin immunoprecipitation. Of note, decreased H3K27 acetylation could be also detected by western blot and immunocytochemistry in ZEB1 induced cells. In lung cancers, H3K27 acetylation level was higher in the tumor compartment than in the corresponding stroma where ZEB1 was more often expressed. Since HDAC and DNA methylation inhibitors increased expression of ZEB1 target genes, targeting these epigenetic modifications would be expected to reduce metastasis.

Acute corticosteroid refractory GVHD (aGVHD) remains a challenging problem after allogeneic hematopoietic SCT. Even though immunosuppressive therapies may achieve a response, unsatisfactory aGVHD control and toxicity of high cumulative doses of corticosteroids are frequent, notably with an increased infection rate. We report long-term follow-up of 33 consecutive patients who developed corticosteroid refractory aGVHD in our institution, treated homogeneously according to a unique algorithm combining an induction treatment (Inolimomab, 0.3 mg/kg per day), an associated immunosuppression (Mycophenolate Mofetil) and a predefined management of partial responses (PR) by the switch from Cyclosporin to Tacrolimus, together with an intensive infectious monitoring and supportive care. In this cohort, 17 patients (52%) achieved a complete response (CR) and 14 patients (42%) a PR, which converted to CR for 12 patients after Tacrolimus introduction. Transplant related mortality (TRM) was 15.5% and 29.7% at 1 and 3 years, respectively. OS was 54.5% at 3 years. Multivariate analysis identified CR after Inolimomab therapy as the unique prognostic factor on OS. Among the 30 evaluable patients, 19 (63%) developed extensive chronic GVHD. This Inolimomab-based algorithm allows for an efficient control of corticosteroid refractory aGVHD in a high proportion of patients with low toxicity, and deserves further investigation.

STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.

© The Author 2016. Published by Oxford University Press.Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinibs price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness (×quot;imatinib-first×quot;) would be cost-effective compared with the current standard of care: ×quot;physicians choice×quot; of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physicians choice from a US commercial payer perspective, assuming 3% annual discounting (×dollar;US 2013). The models clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truvens MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of ×dollar;100 000/QALY. A panel of European LeukemiaNet experts oversaw the studys conduct. Results: Both strategies met the threshold. Imatinib-first (×dollar;277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of ×dollar;88 343 over five years to payers compared with physicians choice (×dollar;365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately ×dollar;883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

A high radiochemical purity (RCP) is recommended for radiopharmaceutical compounds used in the clinical practice of nuclear medicine. However, some preparations of (99m)Tc-sestamibi contain excess impurities (6%). To understand the origin of these impurities, we investigated the effect of sodium nitrate on the RCP of sestamibi preparations by testing eluates from 3 commercially available (99m)Tc generators.The sestamibi kits (Stamicis) were reconstituted with (99m)Tc eluate from nitrate-containing wet-column (NCWC), nitrate-free wet-column (NFWC), and nitrate-free dry-column (NFDC) generators. Sodium nitrate was 0.05 mg/mL in eluates from the NCWC generators. The RCP was determined using aluminum oxide sheets as the stationary phase and absolute ethanol as the mobile phase. Succimer, tetrofosmin, oxidronate, exametazine, albumin nanocolloid, and soluble albumin were also tested for their RCP values with eluates from the 3 different (99m)Tc generators.The RCP assessment of (99m)Tc-sestamibi was performed on 127 Stamicis preparations. Significantly lower RCP values were found for Stamicis kits prepared with the NCWC generator than for Stamicis prepared with the NFWC (P0.0001) and NFDC (P0.0001) generators. The number of Stamicis preparations with an RCP under 94% was greater with the NCWC generator (32 of 53 kits) than with the NFDC (2 of 51 kits) or NFWC (0 of 23 kits) generator. Furthermore, the addition of a 0.05 mg/mL concentration of nitrate in NFWC generator eluates significantly decreased the RCP of the Stamicis preparation. In the absence of nitrate in (99m)Tc eluate, no difference was observed between the RCP values of Stamicis kits prepared with the NFWC and NFDC generators. The (99m)Tc impurities generated by nitrates did not modify the quality of myocardial imaging (normal heart-to-lung ratio, 2.2), probably because these impurities are not in the heart field of view. No other tested (99m)Tc-radiopharmaceutical interfered with nitrates.We recommend using nitrate-free generator eluates in (99m)Tc-sestamibi preparations to improve the product quality and prevent unnecessary exposure of the patient to radiation.

Background Chronic myeloid leukemia is successfully managed by imatinib therapy, but the question remains whether treatment must be administered indefinitely. Imatinib discontinuation trials have led to two distinct outcomes: about 60% of patients experienced disease relapse within 6 months of treatment cessation, while the remaining 40% remained disease-free throughout the duration of follow-up. We aimed to investigate the mechanisms underlying these disparate clinical outcomes. Design and Methods We utilized molecular data from the “Stop Imatinib” trial together with a mathematical framework of chronic myeloid leukemia, based on a four-compartment model that can explain the kinetics of the molecular response to imatinib. This approach was complemented by statistical analyses to estimate system parameters and investigate whether chronic myeloid leukemia can be cured by imatinib therapy alone. Results We found that there are insufficient follow-up data from the “Stop Imatinib” trial in order to conclude whether the absence of a relapse signifies cure of the disease. We determined that selection of less aggressive leukemic phenotypes by imatinib therapy recapitulates the trial outcomes. This postulated mechanism agrees with the observation that most patients who have a complete molecular response after discontinuation of imatinib continue to harbor minimal residual disease, and might work in concert with other factors suppressing leukemic cell expansion when the tumor burden remains low. Conclusions Our analysis provides evidence for a mechanistic model of chronic myeloid leukemia selection by imatinib treatment and suggests that it may not be safe to discontinue therapy outside a clinical trial.

The use of tyrosine kinase inhibitors (TKIs) targeted against the BCR-ABL1 oncoprotein has proven remarkably successful in chronic myeloid leukemia (CML) and long-term survival has become a reality. Despite this outstanding progress, detection of minimal residual disease precludes therapy termination in most TKI-receiving patients. CML has thus turned into a chronic illness, raising concerns about long-term safety, medication adherence, and health care costs. Although treatment cessation may be feasible in few selected patients achieving deep molecular responses, a definitive cure remains elusive owing to the discovery that TKIs spare quiescent leukemic stem cells (LSC). Understanding mechanisms underlying LSC behavior in TKI-treated patients may provide important clues to develop an array of strategies that ensure the complete destruction of LSC reservoirs and thereby offer CML patients a definitive cure.

We appreciate the correspondence from Richter et al reporting for the first time a so-called tyrosine kinase inhibitor withdrawal syndrome consisting of musculoskeletal pain after imatinib discontinuation in patients with chronic myelogenous leukemia (CML). All patients (15 of 50; 30%) were graded as 1 to 2 on the Common Terminology Criteria for Adverse Events scale (version 4.0), and 11 patients (22%) did not experience any musculoskeletal pain before discontinuation. Richter et al ask whether such events were observed in the According to Stop Imatinib (A-STIM) study. The A-STIM study was not designed to collect data on low-grade events, either before discontinuation or after discontinuation. We thus tried to retrospectively collect this information and asked the A-STIM investigators to check their patients’ files. As a result, we estimated that four of 80 patients presented similar symptoms after discontinuation. Because of the retrospective collection of the data, we believe that this proportion may be underestimated. French investigators have pioneered the field of tyrosine kinase discontinuation from the first pilot study in 2007 to the multicentric Stop Imatinib 1 (STIM1) study. In none of these studies was the collection of data on low-grade adverse events planned. We are currently conducting the Stop Imatinib 2 (STIM2) study for patients treated only with imatinib and are prospectively recording events of all grades at the time of discontinuation and after discontinuation. We calculated that 400 patients were enrolled in discontinuation studies in France from 2007 to 2013. Few grade 3 or grade 4 events were reported as being possibly related to the discontinuation of tyrosine kinase inhibitors. Such events were mainly related to exacerbation of preexisting inflammatory diseases such as Crohn’s disease or rheumatoid arthritis, as reported. In a recently published study, thermal pain thresholds were significantly increased in 39 patients with CML who were treated with imatinib or nilotinib as compared with ageand sex-matched healthy controls. The authors suggested that c-Kit inhibition may modulate nociceptive sensitivity in humans, as reported in mice. Sudden discontinuation of imatinib may reverse this phenomenon. Prolonged inhibition of c-Kit signaling by imatinib may also suppress mast cell function and activation over the long term, as suggested by the observation that imatinib may improve asthma in asthmatic patients with CML. Taken together, these observations favor the hypothesis that c-Kit signaling may contribute to the symptoms that were observed by Richter et al after imatinib discontinuation.

Purpose: The aim of this study was to analyze the importance of donor factors and especially the potential role of hemodynamic management in regard to delayed graft function in paired kidney recipient patients after renal transplantation and to analyze the urine of organ donors by proton-nuclear magnetic resonance spectroscopy to identify urine markers potentially correlated with delayed graft function in recipient patients. Methods: A prospective multicenter epidemiologic study was conducted. A logistic regression model taking into account paired data was used. Results: Data from 72 donors and the 144 corresponding paired recipients were analyzed. Univariate analysis showed that age of donor, previous history of tobacco, ischemic cause of brain death, norepinephrine infusion, and recipient age were the risk factors for delayed graft function. After adjusting for correlated outcome data and controlling for other potential prognostic factors, 3 variables remained significantly associated with outcome: donor age (odds ratio [OR], 10.7), hemodynamic status (OR, 0.167), and hydroxyl-ethyl starch infusion (OR, 0.135). Proton-nuclear magnetic resonance analysis evidenced 3 metabolites of interest in donors (trimethylamine-N-oxide, citrate, and lactate). However, these peaks were not correlated the clinical parameters in donors. Conclusions: Paired analysis of kidney transplantation emphasizes the important role of factor donor associated with delayed graft function in recipient. Thus, a particular attention should be paid to the hemodynamic management of donor.

International audience; Imatinib has revolutionized the therapy of chronic myeloid leukaemia. However the complete eradication of leukaemic stem cells is still a matter of discussion. Interferon (IFN) has been used in the past with success. However the proportion of patients who achieved sustained complete cytogenetic response was small. Recently, in addition to its direct antineoplastic effect and immunomodulatory activity, IFN has been shown to stimulate the quiescent leukaemic stem cells. Thus there is now a rational for combining Imatinib and IFN. Large prospective phase III trials are in good progress to demonstrate in humans the usefullness of a combination therapy using Imatinib and IFN.