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

Evaluation du kit FMH quikquant pour la quantification de l'hémorragie fœto-maternelle et des hématies contenant un fort taux d'hémoglobine fœtale (F cells)

La détection de l'hémorragie fœto-maternelle (HFM) est essentielle à la prise en charge obstétricale des femmes rhésus D-négatif, pour optimiser la prévention de l'allo-immunisation. Bien que peu reproductible et subjectif, le test de Kleihauer (TK) consistant en une numération microscopique des hématies fœtales (HF) reste le test de référence. Nous avons évalué le kit FMH QuikQuant, basé sur l'utilisation d'un anticorps anti-HbF, pour la quantification de l'HFM en cytométrie en flux. Nous avons testé en parallèle, en cytométrie et en microscopie, 58 dilutions de sang de cordons dans du sang adulte et 83 prélèvements de femmes enceintes. Nous concluons que la quantification des HF en cytométrie i) est corrélée au TK mais plus reproductible et fiable ii) permet d'éviter la surestimation systématiquement observée avec le TK. Enfin, les F-cells (hématies maternelle contenant un fort taux d' HbF) pourrait être un marqueur spécifique de syndrome myélodysplasique.The detection of fetomaternal hemorrage (FMH) is a crucial test for the obstetrical management of Rhesus D-negative women. Indeed, the amount of fetal erythrocytes in maternal blood samples determines the dose of anti-D immunoglobulin to prevent allo-immunization. The Kleihauer-Betke test (KBT) is the most widely used assay, althought it is not reproductible and labour extensive. In the current study, we sought to evaluate the performance of a flow cytometry (FCM) kit, FMH QuikQuant, using an anti-Hemoglobin F antibody. Blood samples from 83 pregnant women and 58 ombilical cord blood dilutions in adult blood were tested in parallel by KBT and FCM. Firstly, FCM showed a good correlation with KBT, a higher accuracy and reproducibility than the standard method. Moreover, we reported a systematic over-estimation with KBT, probably leading to inappropriate treatments. Finally, F-cells (maternal erythrocytes with high amount of HbF) could be a specific marker of myelodysplastic syndromes.RENNES1-BU Santé (352382103) / SudocSudocFranceF

Toward a Better Classification System for NK-LGL Disorders

International audienceLarge granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by a clonal expansion of T-lineage lymphocyte or natural killer (NK) cells in 85 and 15% of cases respectively. T and NK large granular leukemia share common pathophysiology, clinical and biological presentation. The disease is characterized by cytopenia and a frequent association with autoimmune manifestations. Despite an indolent course allowing a watch and wait attitude in the majority of patients at diagnosis, two third of the patient will eventually need a treatment during the course of the disease. Unlike T lymphocyte, NK cells do not express T cell receptor making the proof of clonality difficult. Indeed, the distinction between clonal and reactive NK-cell expansion observed in several situations such as autoimmune diseases and viral infections is challenging. Advances in our understanding of the pathogenesis with the recent identification of recurrent mutations provide new tools to prove the clonality. In this review, we will discuss the pathophysiology of NK large granular leukemia, the recent advances in the diagnosis and therapeutic strategies

Ruxolitinib for refractory large granular lymphocyte leukemia

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Five new F10 variants in hereditary factor x deficiency detected by high-throughput sequencing

International audienceFactor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10-gene variant database.This study aimed to describe new F10 variants.The gene was analysed 16 consecutive families with FX by targeted high-throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated haematological malignancies.We identified 19 (17 missense, one nonsense frameshift) two copy number variations. Two patients presenting combined FVII-FX showed loss of (del13q34) associated missense on remaining allele, leading FX:C significantly lower than FVII:C level explaining their unusual history. We five novel variants. Three (p.Glu22Val affecting signal peptide cleavage site, p.Cys342Tyr removing disulphide bond between heavy light chains, p.Val385Met located peptidase S1 domain) were detected at compound heterozygosis status three severe symptoms below 10 IU/dL. truncating p.Tyr279* p.Thr434Aspfs*13 an altered protein found heterozygous state mild history.This feasibility interest approach for disorders, enabling report screening 3-weeks delay, suitable clinical use. The description may contribute better understanding phenotype-genotype correlation deficiency

Reliable IGHV status assessment by next generation sequencing in routine practice for chronic lymphocytic leukemia

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Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia

International audienceLarge granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia

Diversity of TP53 Mutations in CLL: Retrospective Analysis of 450 Mutations from the French Innovative Leukemia Organization (FILO) Group

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