Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

UNLABELLED Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. SIGNIFICANCE We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101

Is the posaconazole conjugated fraction of analytical relevance ? Is the posaconazole conjugated fraction of clinical relevance ?

International audienc

Is there an interest of new techniques for dosing posaconazole in invasive fungal infection prophylaxis?

International audience: Invasive fungal infections (IFI) are a major causeof morbidity and mortality in patients treated for acuteS393myeloid leukemia (AML) or those receiving allogeneic stemcell transplant (SCT). The interest of IFI prophylaxis byposaconazole (PCZ), an anti-fungal molecule with intramembrane mechanism of action, in these settings is wellproved. Despite the threshold of 0.7 mg/l considered to thegoal in prophylaxis indication, usefulness of therapeutic drugmonitoring (TDM) of PCZ is still questionable because bothpoor plasma levels reached in practice and the absence ofdemonstrated correlation between blood and membranelevels. We evaluate the interest of the dosage of differentsub-fractions of posaconazole and correlate them withconfusion parameters known to influence results of PCZmonitoring.Material (or patients) and methods: Samples from the TDM ofPCZ (oral suspension) performed in hematological malignanciesbetween January and April 2015 in our laboratory wereprospectively collected. In more, we measured the total fraction(TF) after hydrolysis of the glucuroconjugate, and the fraction inerythrocyte membrane (EF) of PCZ. We calculated theconjugated fraction (GF = TF - UF) and the ratio of conjugation.Results were correlated with 13 confusion parameters: indication of prophylaxis, body-mass index and surface area, ethnicity,fever, nutrition mode, hemoglobin concentration, white bloodcell count, glomerular filtration rate (GFR), albumin, intake ofproton pump inhibitors, immunosuppressive drugs (IS), andcorticosteroids

Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance

Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery

Les eaux en bouteille exposent-elles les patients immunodéprimés à un risque infectieux ?

International audienceLes services d’hématologie accueillent des patients immunodéprimés, dont l’environnement et l’alimentation sont contrôlés. Ils consomment de l’eau en bouteille, aux normes européennes pour la population générale. Nous étudions ici la microbiologie de ces eaux pour évaluer le risque infectieux chez les patients immunodéprimés. 144 bouteilles de marques françaises ont été analysées, eaux plates et gazeuses, durant deux périodes. Après filtration de 250 ml d’eau, les membranes étaient déposées sur milieux Cétrimide, MacConkey et plate count agar (PCA), puis incubées 72 h à 30 °C. Un dénombrement bactérien était réalisé. Tous les morphotypes étaient identifiés par spectrométrie de masse. La sensibilité aux antibiotiques des bactéries opportunistes était également testée. La flore mésophile totale variait entre 0 et 104 UFC/100 ml, selon les périodes, les lots et les marques. Trois bactéries pathogènes opportunistes ont été identifiées dans 13,2 % des eaux : Pseudomonas aeruginosa, Stenotrophomonas maltophilia et Citrobacter freundii. Leur taux maximal était respectivement de 3,20 et 76 UFC/100 ml. Ces bactéries présentaient un phénotype de résistance sauvage. Deux marques présentaient un faible inoculum et l’absence de bactéries pathogènes opportunistes. La présence de ces dernières dans les eaux en bouteille suggère un risque d’infection chez des patients immunodéprimés et incite à réaliser des contrôles microbiologiques périodiques pour leur proposer l’eau la moins contaminée

Cutaneous presentation preceding acute myeloid leukemia with CD4+/CD56+ expression misdiagnosed as a blastic plasmocytoid dendritic cell neoplasm: A case report

International audienceAcute myeloid leukemia (AML) may initially present as cutaneous lesions corresponding to blasts involving the skin as the first clinical manifestation prior to blood and bone marrow (BM) infiltration. Such presentation is known as myeloid leukemia cutis (LC). Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is an aggressive tumor derived from the precursors of plasmocytoid dendritic cells with cutaneous and BM involvement and leukemic dissemination. Myeloid LC and BPDCN may be difficult to distinguish as they share similar clinical and histopathological features, in particular AML with monocytic differentiation. Nevertheless, the correct diagnosis has to be made to determine adequate and effective therapy. Here, we report the case of a 61-year-old woman who presented with an AML with MLL rearrangement and CD4+/CD56+ expression presenting as LC and that was misdiagnosed as BPDCN. We emphasize that careful and exhaustive analyses should be performed to make the correct diagnosis

The survey of bacterial contamination of bottled water intended for haematopoietic stem-cell transplant patients

International audienc

Niches environnementales et circuit de transmission des bactéries hydriques dans un service hospitalier à réseau d’eau protégé.

International audiencePseudomonas aeruginosa est une bactérie hydrique en causedans les infections et les épidémies associées aux soins.Le génotype ST308 colonise le réseau d’eau d’un serviced’oncologie-hématologie. Les points d’eau utilisés pour lessoins ont été équipés de filtres antimicrobiens mais un patienta déclaré une bactériémie à P. aeruginosa ST308, ce quisuggère un défaut de filtration ou une circulation secondairedes pathogènes hydriques.L’objectif est d’évaluer l’efficacité de la filtration antimicrobienneterminale et les circuits secondaires de circulation et detransmission de bactéries hydriques dans un service à réseaud’eau protégé

High-dose methotrexate and risk factors for intoxication.

International audienc

Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies

International audienceUbiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cell response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict acute myeloid leukemias (AML) response to standard chemotherapy (daunorubicin-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9,000 proteins spotted on protein arrays. We identified 122 proteins whose conjugation by these posttranslational modifiers marks AML resistance to DNR and/or Ara-C. Based on this signature, we defined a statistical score predicting AML patient response to standard chemotherapy. We finally developed a miniaturized assay allowing for easy assessment of modification levels of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patient response to treatments