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In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at month 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the EUTOS long-term survival (ELTS) score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs. second-generation TKI [2G-TKI]). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.

Background: In the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient., Methods: The BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023., Discussion: The assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making., Trial Registration: ClinicalTrials.gov , ID NCT06130787; registered on November 14, 2023., (© 2024. The Author(s).)

Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR 4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR 4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR 4.5 or MR 4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Guidelines for tyrosine kinase inhibitor (TKI)-treated chronic phase-chronic myeloid leukemia (CML) management are essentially based on data from clinical research trials; however, real-world data should be valuable for optimizing such recommendations. Here, we analyzed the data collected in the French CML Observatory database, a multicenter real-world cohort (n = 646), using a first-line "intention-to-treat" analysis strategy. This cohort included patients treated with first-line imatinib (n = 484), nilotinib (n = 103), dasatinib (n = 17), imatinib and interferon (n = 9), or second-generation (2G)-TKIs and interferon (n = 29). The cumulative incidence of major molecular response (MMR), MR4, MR4.5 and MR5 confirmed the faster response kinetics with 2G-TKIs. Multivariate analysis identified being a woman and residual disease at month 6 as the main predictive factors of deep molecular response (DMR). Moreover, 30% of patients met the criteria for treatment discontinuation (5 years of treatment and ≥ 2 years of DMR), but only 38% of them stopped treatment. Among the 92 patients who actually discontinued treatment due to optimal response, 31.5% relapsed (48% of them after > 6 months of TKI discontinuation). Multivariate analysis identified age and TKI duration as factors positively correlated with treatment-free remission maintenance. Late (> 6 months) relapses were more frequent in patients with the e14a2 BCR::ABL transcript. Relapse rate was higher in patients who stopped TKI before than after 5 years of treatment (52.6% vs 26%; p = 0.040). These results advocate caution concerning early treatment withdrawal, including in patients receiving 2G-TKIs. This still recruiting database is a valuable source of information for the real-world follow-up of patients with CML., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34 + ) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34 +  cells. Moreover, in CD34 + cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34 + cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal., (Copyright© 2019 Ferrata Storti Foundation.)

Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

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) T315I 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., (Copyright © 2018 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating intraclonal heterogeneity in chronic-phase CML (CP-CML). To determine the basis of this heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP-CML CD34 + CD15 - (immature) and CD34 - CD15 + (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34 + CD15 - and CD34 - CD15 + cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP-CML and HD samples, with only a subset of them in common between CD34 + CD15 - and CD34 - CD15 + cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP-CML cells, among which 18 and 81, respectively, were in CP-CML CD34 + CD15 - cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP-CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP-CML., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Introduction: Malnutrition is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is a well-known prognostic factor for survival. The nutritional status of patients in a long term after allo-HSCT is less well documented. The main objective of this study was to evaluate the prevalence of malnutrition in adult patients who underwent allo-HSCT more than one year ago. Secondary objectives were to assess body composition, muscle strength, and factors associated with malnutrition., Patients & Methods: All allo-HSCT patients admitted into the University Hospital of Clermont-Ferrand between 1st January 1985 and 31st December 2012 were screened. Clinical and biological nutritional assessments included anthropometric measurements, serum nutritional proteins, body composition assessed by bioelectrical impedance, and upper-limb muscle strength (MS) measured by dynamometry. Hematological and nutritional data during and after hospital stay for allo-HSCT were retrospectively collected., Results: Eighty four allo-HSCT patients (52% men; mean age 54.4 ± 12.5 years) were enrolled. Average follow-up after allo-HSCT was 56.4 ± 47.5 months. Prevalence of malnutrition at the end of follow-up was 20%. Compared to well-nourished patients (WN group), undernourished patients (UN group) at the end of follow-up were significantly more likely to be undernourished (50% vs. 21%, p = 0.04) at hospital admission, and to have a Nutritional Risk Index of <97.5 (47% vs. 20%, p = 0.004). Compared to a reference population, mid-arm muscle circumference and MS were significantly more likely to be decreased in the UN group than in the WN group (35.3% vs. 8.9%, p = 0.017; 24% vs. 3%, p = 0.005, respectively); fat-free mass index and appendicular skeletal muscle mass index were decreased in 30.5% and 36.6% of all patients, respectively, with no difference between UN and WN groups. Chronic graft-versus-host disease was more frequent, although not significantly in the UN group (76% vs. 52%, p = 0.071). In multivariate analyses, the presence of malnutrition at hospital admission for allo-HSCT trended towards an increased risk of longer-term malnutrition (OR = 3.60 [0.95; 13.67], p = 0.06)., Conclusion: Malnutrition is a frequent consequence of allo-HSCT, and may occur several months or years after allo-HSCT, particularly if malnutrition existed before allo-HSCT. Our findings support the need for specialized nutritional care for both before and after allo-HSCT. Furthermore, assessment of muscle mass may be a pertinent parameter of malnutrition in this instance., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The French society of bone marrow transplantation and cell therapy (SFGM-TC) organizes annually workshops in the attempt to harmonize clinical practices between different francophone transplantation center. Here, we report our recommendations regarding the management of Epstein Barr virus reactivation and lymphoproliferative disorders, cytomegalovirus (CMV) and human herpes virus 6 (HHV6) after allogeneic stem cell transplantation., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

To understand the complex interactions between hematopoietic stem cells and the bone marrow niche, a human experimental model is needed. Our hypothesis is that hematons are an appropriate ex vivo model of human bone marrow. We analyzed the hierarchical hematopoietic cell content and the tissue organization of single hematons from healthy donors. Most (>90%) hematons contained precursors of all cell lineages, myeloid progenitors, and LTC-ICs without preferential commitment. Approximately, half of the hematons could generate significant levels of lympho-myeloid hematopoiesis after transplantation in an NSG mouse model, despite the low absolute numbers of transplanted CD34 + cells. Mesenchymal STRO-1 + and/or CD271 + cells formed a critical network that preserved hematon cohesion, and STRO-1 + cells colocalized with most hematopoietic CD34 + cells (68%). We observed an influence of age and gender. These structures represent a particularly attractive model for studying the homeostasis of the bone marrow niche and pathological changes that occur during diseases., (© 2017 Wiley Periodicals, Inc.)

Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile., (© 2017 by The American Society of Hematology.)

To harmonize clinical practice in hematopoietic stem cell transplantation, the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. The main aim of this session was to describe the impact, evaluation and treatment of post-transplant iron overload., (Copyright © 2016. Published by Elsevier Masson SAS.)

Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease., (© 2016 S. Karger AG, Basel.)

Background: Myeloablative allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a major procedure usually accompanied by multifactorial malnutrition, prompting the recommendation of systematic artificial nutritional support. Parenteral nutrition (PN) is usually administered during allo-HSCT, essentially for practical reasons. Recently published data suggest that enteral nutrition (EN), given as systematic artificial nutrition support, could decrease grade III-IV graft-versus-host disease (GVHD) and infectious events, which are associated with early toxicity after allo-HSCT and then have an impact on early transplant-related mortality (D100 mortality)., Methods/design: We report on the NEPHA trial: an open-label, prospective, randomised, multi-centre study on two parallel groups, which has been designed to evaluate the effect of EN compared to PN on early toxicity after an allo-HSCT procedure. Two hundred forty patients treated with allo-HSCT for a haematological malignancy will be randomly assigned to two groups to receive either EN or PN. The primary endpoint will assess the effect of EN on D100 mortality. Secondary endpoints will compare EN and PN with regards to the main haematological, infectious and nutritional outcomes., Discussion: The impacts of nutritional support should exceed the limits of nutritional status improvement: EN may directly reduce immunological and infectious events, as well as decrease early transplant-related morbidity and mortality. EN and PN need to be prospectively compared in order to assess their impacts and to provide treatment guidelines. (Clinical trials gov number: NCT01955772; registration: July 19th, 2013).

We investigated Syk as a potential marker of CML progression. We observed a significant over-expression of Syk mRNA and constitutive phosphorylation of Syk Y348 in blast cells from six AP or BP-CML, but not in 15 CML in chronic phase. We could follow in vivo the recurrence of pSyk(348) throughout blast cell escape, despite observing storage of dasatinib in blast cells. A combination of dasatinib and R406 did not improve therapeutic efficacy in vitro. Our results strongly suggest that Syk activation could be a relevant biomarker of disease progression and dasatinib resistance but is probably not a molecular target., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4·5 log (MR(4·5)), allowing the prospect of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR(4·5), avoid late side-effects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML)., Methods: In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR(4·5) at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modified intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28., Findings: Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR(4·5). Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the first 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints., Interpretation: The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic effects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial., Funding: Novartis Pharma., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

Background: Various late-onset noninfectious pulmonary complications may occur after allogeneic hematopoietic stem cell transplantation (HSCT). Interstitial lung diseases (ILD) are often overlooked, and few data are available., Methods: We retrospectively analyzed the clinical features, pulmonary function tests, radiological features and outcomes of allogeneic HSCT recipients who were diagnosed with a noninfectious ILD and were managed in our center between 2001 and 2010., Results: Forty patients were analyzed. The median time from transplant to ILD was 11.3 months. The donor hematopoietic stem cell source was peripheral blood stem cells in 75% of the cases. Seventy percent of the patients had extra-thoracic chronic graft versus host disease at ILD diagnosis. We identified two lung computed tomography (CT) scan patterns according to the predominance of ground glass opacities or alveolar consolidations. Restrictive ventilatory defect was the main pulmonary function pattern. Lung histology was available for seven patients and showed diffuse alveolar damage, non-specific interstitial pneumonia, organizing pneumonia or lymphoid interstitial pneumonia. Thirty-five patients (87.5%) were treated with systemic steroids. Thirteen patients died (32.5%), 10 of respiratory failure. The median survival rate at 24 months was 61%., Conclusion: This study highlights the existence of noninfectious post-allogeneic HSCT ILD and provides new insights into the characteristics of these illnesses., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille. Here, we report our recommendations regarding the use of donor lymphocyte injection (DLI) in the prophylactic, pre-emptive and curative settings. This work has been limited to allogeneic stem cell transplantations from an HLA-matched (10/10) or -one antigen-mismatched (9/10) donor., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is associated with frequent and severe malnutrition, which may contribute to transplant-related morbidity. While both enteral nutrition (EN) via a nasogastric tube and parenteral nutrition (PN) are effective, it remains unclear what is the optimal method of nutritional support., Aims: We propose to compare the impact of EN versus PN on early outcome after allo-HSCT., Methods: We evaluated the effect of initial nutritional support with EN versus PN on early outcome in 56 patients who required nutritional support after first allo-HSCT for haematological malignancies in our centre. Patients were offered EN but could decline and chose to be treated by PN., Results: Twenty patients received myeloablative conditioning and 36 received reduced-intensity conditioning. Twenty-eight patients received EN and 28 received PN. Compared with PN, EN was associated with a lower median duration of fever (2 versus 5 days; p < 0.01), a reduced need for empirical antifungal therapy (7 versus 17 patients; p < 0.01), a lower rate of central venous catheter replacement (9 versus 3 patients; p = 0.051) and a lower rate of transfer to intensive care (2 versus 8 patients; p = 0.036). The early death rate (<100 days) was the same in both groups (14%)., Conclusions: Compared with PN, EN was associated with a lower risk of infection in allo-HSCT, without an increase in the incidence of graft-versus-host disease., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on dyslipidemia and thyroid disorders post-transplant., (Copyright © 2013. Published by Elsevier SAS.)

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant., (Copyright © 2013. Published by Elsevier SAS.)

Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed.

One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology-dependent IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response., (Copyright © 2012 International Society for Advancement of Cytometry.)

Background: About 100 serotypes of human rhinovirus (HRV), classified into two species, have been identified by 1990. Uncultivable HRV variants have recently been identified and designated a new species. Recent improved diagnosis has led to a re-appraisal of the clinical impact of HRV infections in lower respiratory diseases., Objectives: To characterise clinical features in hospitalised patients with positive HRV RNA detection and to determine the distribution of HRV species in respiratory infections diagnosed during the winter of 2009-2010., Study Design: Prospective virus typing was conducted by sequencing the VP4/VP2 genomic regions, and clinical data were collected., Results: Fifty-eight patients (for 63 respiratory specimens) were included. Phylogenetic analysis identified 52% of HRV species A, 6% of species B and 40% of species C, and revealed the co-circulation of 34 different HRV types during the study period. Three infants had successive infections with two or three different types. Five patients were admitted to an intensive care unit, four of them on arrival. Bronchiolitis, pneumonia and exacerbation of asthma were observed in 34/45 children. Pneumonia and severe exacerbation of chronic lung disease were observed in 8/13 adults, of whom 1, with immunocompromised status, died of multivisceral failure., Conclusions: This study underlines the diversity of co-circulating strains and the potential severity of clinical presentations associated with HRV infections., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice of hematologic malignancies. Acute graft versus host disease (GvHD) is common after HSCT and directly related to graft versus leukemia effect. Little progress has been done in the treatment of acute GvHD. The first line treatment is usually high-dose steroids for patients presenting grade II or more GvHD. However, 40% of those patients are resistant to this treatment. Several approaches using monoclonal antibodies against cytokines or other molecules involved in the physiopathology of GvHD have been used. The aim of this review is an updated overview of the mainly used monoclonal antibodies in the prophylaxis or treatment of GvHD (e.g., anti-CD52, anti-TNFα, anti-CD25, anti-LFA3 and anti-CD20).

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.