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BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.FUNDING: Sierra Oncology.

International audience; Several scoring systems have been developed to assess suitability of individual patients for intensive acute myeloid leukemia (AML) therapy. We sought to compare the performance of these scores in a cohort of 428 consecutive adults with AML who received conventional induction chemotherapy in five academic centers in France. All scoring systems identified a subset of patients with increased 28 and 56-day mortality although the prediction accuracy was overall limited with C-statistics of ranging from 0.61 to 0.71 Overall survival (OS) prediction was more limited and restricted to scoring systems that include AML-related parameters. The outcome of 104 patients (24%) considered unsuitable for intensive chemotherapy based on criteria used in recent randomized trials was similar to that of the other 324 patients (28-day mortality, odds ratio [OR] = 1.88, P = 0.2; 56-day mortality, OR = 1.71, P = 0.21; event-free survival, hazard ratio [HR] = 1.08, P = 0.6; OS, HR = 1.25, P = 0.14) with low discrimination (C-statistic: 0.57, 0.56, 0.50, and 0.52 for 28-day, 56-day mortality, EFS, and OS, respectively). Together, our findings indicate that the accuracy of currently available approaches to identify patients at increased risk of early mortality and shortened survival after intensive AML therapy is relatively limited. Caution regarding the use of available scoring systems should be warranted in clinical decision-making.

In recent decades, follow-up of cancer survivors has taken on its full meaning with the gradual improvement in the survival of children and adolescents with cancer. This follow-up is associated specially for adolescents with a multitude of transitions: the transition from therapeutic management to the monitoring for possible relapse, the transition into long-term follow-up after childhood cancer, the transition from a pediatric system to an adult care system. If this transition can be perceived as difficult by patients, it gives young people the opportunity to access more autonomous follow-up and support in becoming an adult. Supporting the transition should make caregivers attentive to this time of consolidation of adolescence, favorable to the emergence of a sense of stable, mature identity that guarantees a certain autonomy. This is a key to a successful transition limiting breakdown of care and promoting "the work of the disease". The double contribution of adult and pediatric oncology provides support tailored to these psychic and societal issues. AYA teams can actively participate in this process by facilitating the acculturation of pediatric and adult care teams to the specificity of this group, thus allowing a continuum of care.

Resumo A consciência sobre a limitação e término dos recursos naturais fez com que as organizações buscassem novas alternativas e práticas para atenuar a degradação que causam ao meio ambiente. Nesse sentido, a Tecnologia da Informação (TI) pode aliar recursos disponíveis a políticas de sustentabilidade e à economia nas organizações, beneficiando o meio ambiente e as próprias instituições, através da utilização de tecnologias e práticas ambientais aplicadas à área de TI. Neste estudo, objetivou-se identificar diferentes motivos que influenciam as organizações a adotarem práticas sustentáveis na área de TI, o que vem sendo comumente chamado de TI Verde. A metodologia utilizada foi a pesquisa survey, realizada junto a 88 organizações localizadas no RS. Identificou-se que a principal motivação para a adoção da TI Verde é a questão financeira, seguida pela motivação ambiental. Por outro lado, as pressões de mercado e de legislação ainda se mostram pouco influentes na decisão de adotar essas práticas, com exceção das instituições públicas, as quais são influenciadas pela legislação vigente com mais intensidade que as demais. Espera-se que este estudo proporcione uma maior visibilidade da TI Verde, servindo como norteador para a adoção de práticas sustentáveis na área de TI, destacando as diferentes motivações organizacionais para tal. Palavras-chave: Sustentabilidade. TI Verde. Adoção. Práticas sustentáveis.

International audience; Purpose: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients.Methods: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach.Results: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship.Conclusion: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.

International audience; Background: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo-HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo-HSCT.Methods: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically.Results: Average gamma globulin levels between D-7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P = .65). Gamma globulin level

Après allogreffe de cellules souches hématopoïétiques (allo-CSH), la rechute de la maladie initiale et le dysfonctionnement du greffon restent aujourd’hui parmi les causes majeures d’échec de cette thérapeutique tant pour les hémopathies malignes que non malignes. Une seconde allo-CSH est une option pour pallier ces situations. Dans le cadre des 8e ateliers d’harmonisation des pratiques de greffe de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC), le groupe de travail s’est basé sur les données de la littérature, afin d’élaborer des recommandations concernant la faisabilité, les indications, le choix du donneur et le conditionnement de la seconde allo-CSH. En cas de rechute de la maladie, une seconde allogreffe avec conditionnement à intensité réduite ou non myéloablatif est une option raisonnable, en particulier chez les patients en bon état général (Karnofsky/Lansky > 80 %), avec un faible score de comorbidités (score EBMT ≤ 3), ayant une longue rémission après la première greffe (> 6 mois) et une faible masse tumorale au moment de seconde allogreffe. Un donneur géno-identique tend à donner une meilleure survie globale. En cas de dysfonctionnement du greffon (rejet primaire et secondaire), un conditionnement immunoablatif est recommandé. Un changement de donneur reste une option valide, en particulier, en l’absence de maladie du greffon contre l'hôte après la première allo-CSH. [Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. 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.

IDH1 and IDH2 mutations (IDH1/2Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2Mut. Mutational patterns of IDH1/2Mut in T-ALL present some specific features compared to AML. Whereas IDH2R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

International audience; Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long-term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient’s DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p

Introduction Citrulline, a non-essential amino acid produced exclusively by enterocytes in the small intestine and involved in the synthesis of L-arginine, is not metabolized by the liver. Therefore citrulline serum concentration is highly correlated with functional enterocyte mass, and decreases with digestive toxicity induced by conditioning therapy (radiotherapy and/or chemotherapy) for hematopoietic stem cell transplantation (HSCT) . Acute Graft-versus-host disease (GvHD), one of the major complications of HSCT, is correlated to conditioning-induced gut barrier damage and may be predicted by pre-transplant serum citrulline level (Rashidi, BBMT 2018). It could be interesting to know whether citrulline kinetics could also represent a biomarker for conditioning toxicity, non-relapse mortality (NRM), and GvHD. The aim of this study is thus to define group-based trajectory modeling, to identify clusters of individual serum citrulline kinetics in the early phase of allogeneic HCST, and to test whether these unsupervised trajectories were correlated with these early complications. Materials and Methods Serum citrulline was quantified by liquid chromatography in blood samples collected from consecutive patients who received an allogeneic HSCT in our institution between July 2014 and November 2019. These samples were drawn at different time-points: pre-transplant (D-7, D-3); day of transplant (D0), and post-transplant (D7, D15, D21). Distinct trajectories were identified for serum citrulline by using the semiparametric mixture model described by Nagin (Nagin, Stat Methods Med Res 2018). Results Among 161 patients (pts) included in the study, with a median age of 53 years (17-72), 98 pts (60.9%) received a reduced-intensity conditioning (RIC), 36 pts (22.4%) reduced-toxicity conditioning (RTC), 18 pts (11.1 %) sequential conditioning, and 9 pts (5.6%) myeloablative conditioning (MAC). Donor were identical sibling (22%), matched unrelated donor (52%) and haploidentical sibling (25%). Graft source was peripheral blood mononuclear cells in 144 pts (89.4%) and bone marrow in 17 pts (10.6%) respectively. HCT-CI score was low, intermediate and high-risk in 38%, 32%, and 30% of pts respectively. Disease-Risk Index (DRI) was low/intermediate in 111 pts (69%) and high/very-high in 50 pts (31%). With a median follow up of 29.1 month, 3-year overall survival (OS), disease-free survival (DFS), and NRM rates were 64.5%, 58.3%, and 18.9%, respectively. The median number of citrulline samples per patient was 7 [3-16]. Median citrulline concentrations before conditioning and at D-3, D0, D7 and D15 were statistically different during RIC, RTC, MAC, and sequential conditioning (p In the whole cohort, 3 citrulline trajectories were determined in an unsupervised method. Patients belonging to these 3 trajectories were different according to intensity of conditioning received with lower citrulline trajectories during MAC and sequential conditioning (p After restricting the analysis to pts who received RIC conditioning (n=98), higher pre-HSCT citrulline concentrations were associated with a lower NRM (p=0.042). Unsupervised analysis in this setting individualized 4 clusters of individual trajectories (figure 1), that did neither distinguish age (p=0.28), DRI (p=0.87), HCT-CI score (p=0.81) nor the incidence of acute (p=0.6) or chronic (p=0.4) GvHD. However, the lowest citrulline trajectory contained significantly more haploidentical transplantations (p=0.004) and less pts who received antithymocyte globulin for GvHD prophylaxis (p=0.005). Interestingly in this RIC cohort, cumulative incidence of NRM at 12 months was 23%, 21%, 8%, and 0% respectively according to the 4 citrulline trajectories (figure 2). Conclusion In patients receiving allogeneic HSCT, the variation of serum citrulline concentrations depends on the intensity of the conditioning regimen. In patients who received RIC conditioning, lower plasma citrulline trajectories are associated with higher NRM. In this setting, citrulline may be an attractive biomarker for predicting conditioning toxicity and NRM. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria.

Introduction: Pre-transplant comorbidities, which may impact the success of allogeneic stem cell transplantation (AlloSCT) can be appreciated through 3 different scoring systems. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) allows to predict non-relapse mortality (NRM) and survival (Sorror, Blood 2005). Its prognostic value was further augmented by the addition of donor age (< vs ≥40 yo) (Comorbidity/Age index, C/AI, Sorror, JCO 2014) then of pre-transplant ferritin (< or >2500 µg/L) and albumin (3.5g/dL) serum levels as well as platelet count (< vs >100 109/L) (Augmented Comorbidity/Age index, AC/AI, Elsawy, BBMT 2019). The performance of these 3 scores has not been evaluated in haploASCT using post-transplant cyclophosphamide (PTCY), a procedure in constant expansion worldwide. Material and Methods: We studied retrospectively the impact on non-relapse mortality (NRM), overall (OS) and disease-free (DFS) survival of the 3 comorbidity scores on a cohort of 223 patients (pts) having received a haploSCT with PTCY. All pts had pre-transplant ferritin and albumin levels and platelet counts available. These parameters were evaluated at the time of the pre-transplant check-up or just before conditioning (median from transplant: 20 days, range: 4-49). Results: Pts were recruited in 4 French centers (Nantes n=127; Angers n=45; Besançon n=29, Brest n=22). They had received haploSCT between October 2013 and January 2020. There were 136 males and 87 females with a median age of 55 yo (16-71, >40 years n=172). The majority of pts had a myeloid disease (n=157) and received a reduced intensity regimen (n=161, myeloablative n=30; sequential n=32). Respectively, 132 and 91 pts had low/intermediate and high/very-high Disease-Risk Index (DRI). All pts received PTCY, cyclosporine and mycophenolate mofetyl as graft versus host disease (GVHD) prophylaxis. Donors had a median age of 40.8 years (19.4-71.7). Median HCT-CI, C/AI and AC/AI scores were 2 (0-8), 3 (0-9) and 3 (0-11), respectively. The HCT-CI score was 5 in 110, 83 and 30 pts, respectively, while the AC/AI score was With a median follow-up for alive patients of 35.6 months (6-77), 3-year OS, DFS and NRM were 47.8+3%, 46+3% and 29.4+6%, respectively. In univariate analysis, better 3-year OS and DFS were associated with lymphoid diseases (OS: 60.4+6% vs 42.3+4%, p=0.02; DFS: 56.2+6% vs 41.6+4%, p=0.04), low/intermediate DRI (OS: 59.1+4% vs 30.1+7%, p3.5g/dL 50.1+4%, p=0.03; 3.5g/dL 47.4+3%, p=0.05). OS and DFS were not impacted by ferritin levels, platelet count, recipient age, gender, nor any of the 3 comorbidity scores. A lower 3-year NRM was observed in younger pts ( In multivariate analysis, each comorbidity score was compared to DRI, donor and patient age, type of disease and pre-transplant albumin levels. DRI and donor age remained associated with OS and DFS. This was also the case for recipient age, except when considering a high C/AI index score. Finally, an older age of recipients and donors remained associated with higher NRM. Conclusion: HCT-CI, C/AI and AC/AI do not to predict survivals nor NRM in haploSCT with PTCY, suggesting that pre-transplant comorbidities should not be a contra-indication to this procedure. As donor age is the only factor predicting survivals and NRM in this series, while multiple donors are generally available in the haploSCT setting, the selection of a younger donor should be the rule whenever possible for all patients. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Deconinck:ImmunoGen: Consultancy, Research Funding; Stemline: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Chevallier:Incyte Corporation: Honoraria.

Background : Atherosclerosis is an inflammatory disease that affects the arterial wall leading to myocardial, cerebral, and peripheral ischemic syndromes. The use of low doses of aspirin inhibits platelet aggregation and inflammation and prevents cardiovascular mortality. However, ASA may produce hemorrhagic events. Thus, several studies have sought new natural compounds to suppress platelet aggregation without causing serious adverse effects. Purpose : In this sense, this study aims to compare the effects of Campomanesia xanthocarpa plant extract with those of acetylsalicylic acid (ASA) on inflammatory parameters observed in homozygous mice knockout for the low-density lipoprotein receptor (LDLr-KO) treated with a hypercholesterolemic diet. Material and Methods : In this study, 28 male LDLr-KO mice were divided into three groups and fed a hypercholesterolemic diet for 4 weeks. Thereafter, the animals that received the hypercholesterolemic diet were treated for 5 days with (1) distilled water, (2) C. xanthocarpa extract, or (3) acetylsalicylic acid. The levels of inflammatory markers were assessed in the blood samples. The gastric tolerability of the animals after oral administration of the treatments was assessed through quantification of the lesions in the gastric mucosa. Results : The levels of proinflammatory cytokines IL-1, IL-6, TNF-α, and INF-γ were reduced to 19.2 ± 3%, 20.4 + 1.3%, 24.7 ± 1.2%, and 20.8 ± 1.7%, respectively, in the group treated with C. xanthocarpa, when compared to control group. Furthermore, treatment with plant extract significantly increased the levels of the anti-inflammatory cytokine IL-10 by 27.3 ± 5.9%, but ASA showed no significant effect on the same cytokines when compared to the control group, with the exception of IL-10, which presented an increase of 8.6 ± 3.5%. Treatments with C. xanthocarpa and ASA also caused significant reductions of 26.4 ± 3% and 38.4± 6% in the serum levels of oxLDL, respectively. However, only treatment with C. xanthocarpa reduced the levels of anti-oxLDL antibodies when compared with the control (25.8 ± 6%). In addition, the analyzed extract did not induce ulcerogenic activity, while ASA induced the formation of lesions. Conclusion : In conclusion, treatment with C. xanthocarpa causes anti-inflammatory activity in hypercholesterolemic animals, with results superior to those obtained with the use of ASA.

An acute myeloid leukemia was diagnosed in a 53-year-old female patient. She received an allogeneic stem cell transplant. After this transplant, some neutrophils with hyposegmented nucleus and abnormal chromatin clumping appeared in the peripheral blood, and their number gradually increased. The hypothesis of early relapse after transplant was ruled out and drug-related anomaly was suspected. The authors discuss about morphological features of constitutional and acquired Pelger-Huët anomaly. In the patient reported here, ciclosporine seemed to be involved in the phenomenon, as the morphological anomaly of the neutrophils gradually decreased after the drug was discontinued.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

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/Lansky80%), 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.

Importance Pathogen reduction of platelet concentrates may reduce transfusion-transmitted infections but is associated with qualitative impairment, which could have clinical significance with regard to platelet hemostatic capacity. Objective To compare the effectiveness of platelets in additive solution treated with amotosalen–UV-A vs untreated platelets in plasma or in additive solution in patients with thrombocytopenia and hematologic malignancies. Design, Setting, and Participants The Evaluation of the Efficacy of Platelets Treated With Pathogen Reduction Process (EFFIPAP) study was a randomized, noninferiority, 3-arm clinical trial performed from May 16, 2013, through January 21, 2016, at 13 French tertiary university hospitals. Clinical signs of bleeding were assessed daily until the end of aplasia, transfer to another department, need for a specific platelet product, or 30 days after enrollment. Consecutive adult patients with bone marrow aplasia, expected hospital stay of more than 10 days, and expected need of platelet transfusions were included. Interventions At least 1 transfusion of platelets in additive solution with amotosalen–UV-A treatment, in plasma, or in additive solution. Main Outcomes and Measures The proportion of patients with grade 2 or higher bleeding as defined by World Health Organization criteria. Results Among 790 evaluable patients (mean [SD] age, 55 [13.4] years; 458 men [58.0%]), the primary end point was observed in 126 receiving pathogen-reduced platelets in additive solution (47.9%; 95% CI, 41.9%-54.0%), 114 receiving platelets in plasma (43.5%; 95% CI, 37.5%-49.5%), and 120 receiving platelets in additive solution (45.3%; 95% CI, 39.3%-51.3%). With a per-protocol population with a prespecified margin of 12.5%, noninferiority was not achieved when pathogen-reduced platelets in additive solution were compared with platelets in plasma (4.4%; 95% CI, −4.1% to 12.9%) but was achieved when the pathogen-reduced platelets were compared with platelets in additive solution (2.6%; 95% CI, −5.9% to 11.1%). The proportion of patients with grade 3 or 4 bleeding was not different among treatment arms. Conclusions and Relevance Although the hemostatic efficacy of pathogen-reduced platelets in thrombopenic patients with hematologic malignancies was noninferior to platelets in additive solution, such noninferiority was not achieved when comparing pathogen-reduced platelets with platelets in plasma. Trial Registration clinicaltrials.gov Identifier:NCT01789762

A consciência sobre a limitação ou término dos recursos naturais e a necessidade de criar modelos econômicos e sociais originais, e tecnologias inovadoras que tragam benefícios nítidos para assegurar a sustentabilidade ambiental fez com que as organizações buscassem novas alternativas e práticas. Nesse sentido, a Tecnologia da Informação (TI) pode ser vista como uma forma de aliar recursos disponíveis a políticas de sustentabilidade e economia nas organizações, gerando benefícios para o meio ambiente e para as organizações, especialmente no que tange às organizações públicas, que além do compromisso com o meio ambiente incutido em suas ações, necessitam atender o cumprimento de legislações, normas e políticas específicas. Nesse sentido, esta pesquisa busca analisar a relação entre a adoção da TI Verde pelas organizações públicas e o seu impacto na sustentabilidade ambiental. É um estudo exploratório descritivo, tipo survey, aplicado em servidores e usuários da Tecnologia de Informação lotados em instituições públicas Federais do RS, que buscou identificar as principais práticas de TI Verde adotadas pelas organizações públicas; analisar as ações implementadas pelas organizações públicas que influenciam a adoção da TI Verde e analisar o impacto da adoção de práticas de TI Verde na sustentabilidade ambiental, sob dois modelos estruturais distintos, sendo o primeiro baseado no Desenvolvimento Ambiental e Imagem institucional e o segundo calcado nos Impactos Ambientais Positivos e Impactos Ambientais Negativos. Os resultados mostraram que apesar de todas as instituições pesquisadas adotarem algumas das 22 práticas listadas no instrumento de coleta, estas não são desenvolvidas na sua totalidade, sendo utilizadas pelas instituições públicas apenas algumas das práticas e em níveis diferentes de desenvolvimento. O destaque foi para as práticas de substituição de monitores CRT por LCD ou LED, a digitalização de documentos, a consolidação de impressoras ou uso de multifuncionais e o descarte correto de materiais e equipamentos de informática, aparecendo como as práticas de TI Verde mais disseminadas, enquanto a terceirização de servidores, a terceirização de impressoras, a preferência por fornecedores verdes e a consolidação de desktops destacam-se como as práticas menos disseminadas. Percebeu-se, também, que quanto mais efetivas forem as atividades voltadas à Orientação Governamental e à Orientação Ambiental em TI, maior será o seu efeito na adoção de ações de TI Verde pelas instituições públicas. Quanto ao impacto na sustentabilidade ambiental, percebeu-se que a adoção da TI Verde tem se refletido principalmente nos aspectos referentes aos impactos ambientais positivos da TI (como o aumento do número de videoconferências, processos de digitalização, uso de papel reciclado e da impressão frente e verso), bem como a uma melhor imagem institucional e desempenho ambiental. Awareness of the finiteness of natural resources and the need to create unique economic and social models and innovative technologies that bring clear benefits to ensure environmental sustainability have led organizations to seek new alternatives and practices. In this sense, Information Technology (IT) be a way of allying resources available to sustainability policies and the economy in organizations, generating benefits for the environment and for organizations, especially regarding public organizations, which in addition to the commitment to the environment in its actions, needs to comply with specific laws, regulations and policies. In this sense, this research seeks to analyze the relationship between the adoption of Green IT by public organizations and their impact on environmental sustainability. It is an exploratory descriptive study, type survey, applied in servers and Information Technology users crowded in Federal public institutions of RS, which sought to identify the main Green IT practices adopted by public organizations; to analyze the actions implemented by public organizations that influence the adoption of Green IT and to analyze the impact of adopting Green IT practices on environmental sustainability under two distinct structural models, the first one being based on Environmental Development and Institutional Image and the second one based on Impacts Environmental Positives and Negative Environmental Impacts. The result showed that although all the institutions studied adopt some of the 22 practices listed in the collection instrument, they do not develop in their entirety, being used by public institutions only some of the practices and at different levels of development. The highlight was the practice of replacing CRT monitors with LCD or LED, scanning documents, consolidating printers or using multifunction devices, and correctly discarding computer materials and equipment, with Green IT practices being more widespread and outsourcing of servers, outsourcing of printers, preference for green vendors, consolidation of desktops as less widespread practices. It was also realized that the more effective the activities focused on Government Guidance and Environmental Guidance in IT, the greater its effect on the adoption of Green IT actions by public institutions. Regarding the Environmental Impact, it was noticed that the adoption of the Green IT is only reflected in the aspects related to the Positive Environmental Impact of TI.

To detect early changes in the metabolic profile of pregnant ewes subject to acute feed restriction at 130 days of gestation, and to establish indicators of risk for ovine pregnancy toxaemia (OPT) for diagnostic purposes.Twenty Corriedale ewes with known mating dates, carrying a single fetus, were used. Ewes were maintained on meadow grasslands and at 130 days of gestation were randomly divided in two groups of 10 ewes. The control group had ad libitum access to pasture. Ewes in the restricted group were subjected to an acute feed restriction for a maximum of 144 hours (6 days), with free access to water. From the start (0 hours) until the end of feed restriction, blood samples were collected from all ewes to monitor concentrations of cortisol, non-esterified fatty acids (NEFA), ß-hydroxybutyrate (BOHB) daily, and glucose in plasma every 6 hours; urinary pH was also measured. Every 6 hours the food restricted ewes were observed to detect clinical signs of OPT e.g. apathy, grinding teeth, empty chewing movements, head leaning against the wall, tachypnea and not drinking water.In food-restricted ewes, concentrations of glucose decreased and differed from control ewes from 54 to 90 hours (p0.001), and 96 to 102 hours (p0.05). Concentrations of BOHB, cortisol and NEFA increased following feed restriction and differed from control ewes after 48 to 144 hours (p0.01). Eight of the 10 restricted ewes showed clinical signs of OPT after 102-132 hours. Mean concentrations of glucose, BOHB and cortisol differed between control and restricted ewes prior to the onset of clinical signs of OPT, after 48-96 hours of feed restriction (p0.01). Mean gestational length, and time from birth to placental expulsion was not affected by the feed restriction.Our results suggest that concentrations of glucose, BOHB and cortisol in plasma may provide a precocious diagnosis of subclinical OPT, using values of 1.59 (SD 0.24) mmol/L, 2.26 (SD 1.03) mmol/L and 15.09 (SD 7.75) nmol/L, respectively. The identification of a potentially harmful metabolic imbalance could lead to the improvement of treatment success.

Background. We previously reported that IL7R-pathway genes are mutated in 29% of T-ALL and that surface IL7R is expressed in 53% of T-ALL (Rathana K et al. abstract S131, EHA 2019). In these samples, in vitro and in vivo (IL7R+PDX T-ALL) sensitivity to JAK inhibitors is determined by the expression of IL7R regardless of the IL7Rp genomic status. BCL2 inhibition has been shown to be synergistic with the IL7R pathway inhibition (Degrise S et al., Leukemia 2018;32(3):788-800). We therefore explored whether the combination of tofacitinib, a potent JAK3 inhibitor, with venetoclax may improve the hematological status of patients with relapse/refractory T-ALL. Methods. Patients with relapse/refractory T-ALL, with surface IL7R expression or IL7R-pathway mutations and BCL2 expression were eligible if they had failed all available therapeutic options (including clofarabine and/or allogenic HSCT if eligible). Patients were offered to be treated with venetoclax, 100 mg/d day1; 200 mg/d day2; 300 mg/d day3 and 400 mg/day thereafter and for subsequent 28 days cycles combined with tofacitinib, 10mg twice a day started from day 5 cycle 1 (off-label use). Responses were assessed after cycle 1 and cycle 3. Responding patients may continue therapy until relapse, death or allogenic HSCT if eligible. Results. Eight patients were treated including 7 ETP-ALL and 1 T-cell lymphoblastic lymphoma. Median age was 56 years (27-69) and sex ratio (M/F) was 4/4. Four patients were refractory to at least 2 lines of therapy and 4 patients relapsed, all on therapy. Relapsing patients were in failure after at least one salvage therapy. All patients expressed BCL2. A mutation of JAK3 L857P was found in 5 cases including one patient with both JAK3 and JAK1 mutations. except one with a mutation of IL7-R. Other patients expressed IL7R. A response to therapy was observed in 5 out of seven evaluable cases (71%) including 2 CR associated with a negative MRD (sensitivity 10-4) and 3 partial responses (medullar blasts less than 15%). The remaining patient has just started the first cycle of therapy. Duration of responses was 10 months and +6 months (allo HSCT planned) for the 2 patients in CR and 3 months or less for the partial responders. No serious adverse event related to therapy was observed. Conclusion. IL7-pathway is a possible target for therapy with JAK inhibitors in patients with T-ALL in relapse or refractory to conventional therapy. A combination of venetoclax and tofacitinib may offer a potential savage for these patients with limited therapeutic options. Disclosures Chevallier: Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria. Dombret:Institut de Recherches Internationales Servier (IRIS): Research Funding; AGIOS: Honoraria; CELGENE: Consultancy, Honoraria. Boissel:NOVARTIS: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Venetoclax in T-ALL Tofacitinib in T-ALL

Invasive fungal infections (IFIs) remain a major clinical burden due to their morbidity and mortality, particularly in patients with acute leukemias and allogeneic HSCT which represent the main risk factors for proven/probable IFI in hematology. We conducted a study in France which enrolled 677 patients with acute myeloid leukemia (AML) receiving intensive chemotherapy from 34 ALFA centers. This study confirmed the significant lower rate of proven/probable IFI in patients who received antifungal prophylaxis (AFP), and that IFI was associated with an increased early mortality rate. The trial recommended laminar air flow rooms and posaconazole AFP according to the 2009 recommendations of the European Conference on Infections in Leukaemia (ECIL). IFI were graded as proven/probable or possible by local investigators. Two central review processes were performed. All study data were centrally reviewed by hematological expert according to the EORTC classification. In parallel, available CT-scans were reviewed by two independent experts (hematologist and pneumologist). We showed three supplementary important observations: (1) Despite the ECIL recommendations, 30% of patients (203/677) did not receive any AFP, and 91 patients (13%) received another antifungal agent than the one recommended. (2) with regards to the IFI grading (Figure 1), 71 IFI were diagnosed and graded by the investigators. After review by the experts, the grade was maintained for 49/71 IFI [69%, 20 possible and 28 proven/probable IA and 1 proven/probable invasive candidiasis (IC)], while 9 possible IFI (13%) (8 IA and 1 IC) were upgraded as proven/probable, and 13 proven/probable IFI (18%) (13 IA) were downgraded as possible. Twenty-five IFI were not graded by the investigators including 3 cases of IA graded by the experts (2 proven/probable and 1 possible) for whom antifungal prophylaxis was pursued, and 22 cases of other IFI graded only by the experts: 15 IC and 7 invasive mucormycosis (IM) all proven/probable, for whom AFP was modified for a curative therapy. In addition, chest imaging data of 37 patients were centrally reviewed, and 21 (57%) were reclassified. The review of imaging data was 100% consistent with the EORTC-based expert review. The experts graded more proven/probable IFI than the investigators with 9.0% (61/677) versus 6.2% (42/677). (3) Among patients without IFI, the rate of complete hematological remission was higher (513/581, 88.3%) versus those with IFI (77/96, 80.2%) (p=0.04). Among patients with IFI, the rate of posaconazole-based AFP was 45.5% (35/77) for those who achieved CR, vs. 63.2% (12/19) for those who did not achieve CR. In conclusion, we showed in this very high-risk population, ECIL recommendations were followed only in 57% of patients. The frequent "misgrading" of the IFI (33% of IA up or downgraded and 92% of other IFI) has an impact on their appropriate management. Another important message is that haematological failure is associated with more IFI despite the AFP. Disclosures De Botton: Pierre Fabre: Consultancy; AbbVie: Consultancy; Forma: Consultancy, Research Funding; Daiichi: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Agios: Consultancy, Research Funding; Servier: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Syros: Consultancy; Astellas: Consultancy. Bertoli:Astellas: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Consultancy. Castaigne:Pfizer: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding. Thomas:DAICHI: Honoraria; ABBVIE: Honoraria; PFIZER: Honoraria; INCYTE: Honoraria.

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p < 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p < 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

Summary The optimal management of relapsed diffuse large B-cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leucet aAutres Maladies du Sang developed a combination of vinorelbine, ifosfa- mide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18-75 years. Patients received rituximab 375 mg/m² day 1, ifosfamide 1000 mg/m² days 1-5, vinorelbine 25 mg/m² days 1 and 15, mitoxantrone 10 mg/m² day 1, and prednisone 1 mg/kg days 1-5, every 28 days for three cycles. Responding patients underwent autologous trans- plantation or received three additional R-NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non-germinal centre B immunophenotype was associated with shorter progression-free survival. in conclusion, the R-NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.

Use of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) filgrastim accelerates neutrophil recovery following myelosuppressive chemotherapy. Since filgrastim requires multiple daily administrations, forms of rhG-CSF with a longer half life, including pegfilgrastim, have been developed. Pegfilgrastim is safe and effective in supporting neutrophil recovery and reducing febrile neutropenia after conventional chemotherapy. Pegfilgrastim has also been successfully used to support patients undergoing peripheral blood stem cell (PBSC) transplantation for haematological malignancies. To our knowledge, no cost-effectiveness analysis (CEA) of pegfilgrastim in this setting has been published yet.We undertook a CEA to compare a single injection of pegfilgrastim versus repeated administrations of filgrastim in patients who had undergone PBSC transplantation for lymphoma or myeloma. The CEA was set in France and covered a period of 100 ± 10 days from transplant.The CEA was designed as part of an open-label, multicentre, randomized phase II trial. Costs were assessed from the hospital's point of view and are expressed in 2009 euros. Costs computation focused on inpatient, outpatient, and home care. Costs in the two arms of the study were compared using the Mann-Whitney test. When differences were statistically significant, multiple regression analyses were performed in order to identify cost drivers. Incremental cost-effectiveness ratios (ICER) were calculated for the major endpoints of the trial; i.e., duration of febrile neutropenia (absolute neutrophil count [ANC]0.5 × 10(9)/L and temperature ≥38 °C), duration of neutropenia (ANC1.0 × 10(9)/L and ANC0.5 × 10(9)/L), duration of thrombopenia (platelets50 × 10(9)/L and20 × 10(9)/L), and days with a temperature ≥38 °C). Uncertainty around the ICER was captured by a probabilistic analysis using a non-parametric bootstrap method.151 patients were enrolled at ten French centres from October 2008 to September 2009. The mean total cost in the pegfilgrastim arm of the study (n = 74) waseuro25,024 (SD 9,945). That in the filgrastim arm (n = 76) waseuro28,700 (SD 20,597). Pegfilgrastim strictly dominated filgrastim for days of febrile neutropenia avoided, days of neutropenia (ANC1.0 × 10(9)/L) avoided, days of thrombopenia (platelets20 × 10(9)/L) avoided, and days with temperature ≥38 °C) avoided. Pegfilgrastim was less costly and less effective than filgrastim for the number of days with ANC0.5 × 10(9)/L avoided and the number of days with platelets50.0 × 10(9)/L avoided. Taking uncertainty into account, the probabilities that pegfilgrastim strictly dominated filgrastim were 67 % for febrile neutropenia, 86 % for neutropenia (ANC1.0 × 10(9)/L), 59 % for thrombopenia (platelets20 × 10(9)/L), 86 % for temperature ≥38 °C, 32 % for neutropenia (ANC0.5 × 10(9)/L), and 43 % for thrombopenia (platelets50 × 10(9)/L). Conversely, the probability that filgrastim strictly dominated pegfilgrastim for neutropenia (ANC0.5 × 10(9)/L) is 5 %.This study found no evidence that the use of pegfilgrastim is associated with greater cost in lymphoma and myeloma patients after high-dose chemotherapy and PBSC transplantation.

Purpose To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. Patients and Methods Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m2 per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). Conclusion Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.

Background: Complex hemostatic mechanisms are involved in the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activity is linked to the progression of atherosclerosis and mainly involves platelet aggregation and a decrease in blood flow in the vascular endothelium. The major platelet activation pathways mediated by agonists involve the arachidonic acid pathway, adenosine diphosphate pathway, serotonin pathway, nitric oxide pathway, and action of free radicals on molecules involved in platelet aggregation. These mechanisms have been widely studied and discussed because they are inhibited by the use of medicinal plants in complementary and alternative medicine, thus reducing platelet aggregation. Results: Of the main plants discussed in this review, which have antiplatelet activity, some include saffron, garlic, green tea, St. John's wort, ginger, ginkgo biloba, ginseng, and guavirova. These herbal medicines have phytochemical components, which are directly related to the antiplatelet activity of the plant, such as flavonoids, curcumins, catechins, terpenoids, polyphenols, and saponins. While the majority of the medicinal plants mentioned here were native to the Asian continents, some are distributed worldwide, and found to a smaller extent throughout the American continent, European continent, Mediterranean, African continent, and the Middle East. Conclusion: This review showed that several plants and/or compounds exhibit anti-platelet activity, and are therefore potential research targets for developing drugs to treat diseases related to aggregation disorders.

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1mut patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2mut patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2mut patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2mut patients. U2AF35mut patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2mut/TET2wt (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

We treated 95 RBC transfusion dependent lower risk MDS with del 5q with Lenalidomide (10mg/day, 3 weeks/4 weeks). Median age was 70.4, median interval from diagnosis 29 months. IPSS was low in 31% and intermediate-1 in 69% patients. Del 5q was isolated, with 1 additional and >1 additional abnormality in 79%, 14%, and 6% patients, respectively. 62 (65%) patients achieved transfusion independence (TI). The only significant factor predicting TI was baseline platelet count >150 G/L and platelet decrease by at least 50% during the first weeks of treatment (p=0.001). Grade III-IV neutropenia and thrombocytopenia were seen in 74% and 37.9% of the cases, respectively, and 3 deaths were attributed to cytopenias. Eight (8%) patients developed deep venous thrombosis (DVT). Platelet decrease by less than 50% predicted a higher risk of DVT. Only 6 patients (6.3%) patients progressed to AML, but median follow-up time was short (18 months). We confirm the high rate of TI with Lenalidomide in lower risk MDS with del 5q. Very close patient monitoring for cytopenias and DVT is mandatory, especially during the first weeks of treatment.

Context. Congenital neutropenia (CN) is a heterogeneous group of diseases characterized by low neutrophil count, severe bacterial infections, increased risk of leukemic transformation and various extra-hematopoietic organ dysfunctions. Even if 24 different genes have been linked to the etiology of CN, in many patients the genetic causes of CN remain unknown. Methods. Whole-exome sequencing (WES) was performed on a trio-based approach in 8 sporadic cases and 6 multiplex families. Sanger sequencing was performed in a second phase on 66 additional patients from the French CN registry. Structural and functional studies were performed using primary cells from patients including fibroblasts and hematopoietic cells. In vitro granulocytic differentiation was conducted by culturing CD34+ in serum-free medium with SCF, IL-3 and G-CSF for 21 days. Results. WES analysis identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and an autosomal dominant family. Considering these results we directly sequenced SRP54 in the French CN cohort and identified 13 additional sporadic cases and 2 multiplex families, thus reaching a total of 23 cases carrying a SRP54 mutation (19 families, Figure 1A). The Thr117del in-frame deletion was found in 12 probands. In all patients, neutropenia was profound (mean neutrophil absolute count 0.23x109/L), diagnosed in the neonate period or during childhood (mean age 4.2 months), and required long-term G-CSF therapy (mean dose 9 µg/kg/day). Bone marrow examination showed a maturation arrest at the promyelocytic stage. In contrast to CN associated with ELANE mutations, SRP54-mutated patients presented an important degree of dysgranulopoiesis (abnormal localization and number of mature granules) and enlarged endoplasmic reticulum (ER) in promyelocytes as well as dystrophic neutrophils (Figure 1B-1C). No evolution into acute myeloid leukemia was observed in this cohort after a median follow-up period of 14.8 years despite high doses of G-CSF. Six out of the 23 patients had extra-hematopoietic manifestations comprising severe neurodevelopmental delay (n=5) and/or exocrine pancreatic insufficiency (n=3), and/or bone abnormalities (n=2) (Figure 1A). The SRP54 protein is a key component of the ribonucleoprotein complex SRP that mediates the co-translational targeting and the insertion of secretory and membrane proteins to the ER. We identified 7 distinct mutations that affect highly conserved residues within or interacting with G motifs involved in the GTPase activity of SRP54. Of note, 17 out of 18 patients with mutations located within the G1 element and predicted to affect the structure and/or stability of the NG domain presented only a severe neutropenia. In contrast, the other 5 patients with mutations affecting either the magnesium-binding or the guanine-binding site and/or implied in the heterodimeric association with the receptor of SRP54, were associated with Shwachman-Diamond-like syndrome features. During the in vitro granulocytic differentiation of both normal and mutated hematopoietic progenitors, we found a strong increase in SRP54 mRNA expression levels associated with a slight decrease in the protein level in patients compared to controls. Moreover, SRP54 mutations induced a major deleterious effect on proliferation (Figure 1D) and a delay in the differentiation associated with increased apoptosis. Using both in vitro-derived granulocytic cells and primary fibroblasts, we also observed that SRP54 mutations led to ER stress (increased eIF2a phosphorylation, XBP1 splicing, ATF4 and CHOP expression) and enhanced autophagy (higher levels of LC3-II and ULK1 expression). Conclusions. This study thus identifies a novel pathological pathway implicating the co-translational process of protein targeting. This new genetic subtype which represents the second cause of CN in the French registry (prevalence 6.9%), is characterized by a promyelocytic maturation arrest with dysgranulopoiesis leading to a profound neutropenia, with a poor response to G-CSF, and in few patients, is associated with severe neurodevelopmental delay and exocrine pancreatic insufficiency. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder of the haematopoietic stem cell which can be associated with marrow fibrosis and/or osteosclerosis. Because bone progenitors and mature bone cells are influenced by the marrow microenvironment, cellular and tissular changes were assessed by histomorphometry in MMM. Thirteen patients, with a clinical proven MMM, had a bone biopsy of the iliac crest with double tetracycline labelling and osteoclast count. Histomorphometry was done at the 2D level (bone volume, osteoid parameters, bone histodynamic parameters and osteoclast count) and 3D level by microcomputed tomography. All patients had clusters of abnormal megakaryocytes in bone marrow. Newly apposed bone packets were observed in 12 patients and corresponded to an increased thickness of some bone units with new lamellae or focal areas of woven bone anchored on the pre-existing trabeculae. Osteoid parameters were unchanged, only bone formation rate appeared considerably increased in seven patients. There was a net tendency for decrease in osteoclast number and conversion of trabecular pillars into plates. An uncoupling of bone remodelling was evidenced with an increased life-span of osteoblasts associated with a normal/reduced osteoclast activity. A very complex network of factors is candidate to explain bone changes observed in MMM.

Adult Acute Lymphoblastic Leukemia (ALL) therapies have been improved by pediatric-like approaches. However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The p16(INK4A)/CDK4-6/pRb pathway and telomerase activity, which are implicated in cell activation and aging, were analyzed to identify new prognostic markers. Proteins of the p16(INK4A)/CDK4-6/pRb pathway and telomerase activity were analyzed in 123 adult B-cell precursor (BCP) ALL cases included in the GRAALL/GRAAPH trials. We found a significantly increased expression of p16(INK4A) in BCP-ALLs with MLL rearrangement. Telomerase activity was significantly lower in Philadelphia chromosome-negative/IKAROS-deleted (BCR-ABL1(-)/IKAROS(del)) cases compared to Philadelphia chromosome-positive (BCR-ABL1+) BCP-ALLs. In BCR-ABL1+ ALLs, high CDK4 expression, phosphorylated pRb (p-pRb) and telomerase activity were significantly associated with a shorter disease-free survival (DFS) and event-free survival (EFS). Enhanced p16(INK4A) expression was only related to a significantly shorter DFS. In vitro analyses of normal stimulated lymphocytes after short- and long-term cultures demonstrated that the observed protein variations of poor prognosis in BCR-ABL1+ ALLs may be related to cell activation but not to cell aging. For these patients, our findings argue for the development of therapeutic strategies including the addition of new lymphocyte activation inhibitors to current treatments.

Background. Primary bone lymphoma (PBL) is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL.Patients and Methods. The GOELAMS prospective multicenter study (1986–1998) enrolled adults with localized high-grade PBL according to age and performance status (PS). Patients Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7), 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS.Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.