Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT

Chronic Disseminated Candidiasis During Hematological Maligancies: An Immune Reconstitution Inflammatory Syndrome with Expansion of Pathogen-Specific TH1 T Cells

International audienceChronic disseminated candidiasis (CDC) is a rare disease mostly occurring after chemotherapy-induced prolonged neutropenia in patients with hematological malignancies. It is believed to ensue from Candida colonization, breach of the intestinal epithelial barrier and venous translocation to organs. Fungal blood or liver biopsy cultures are generally negative, suggesting the absence of an ongoing invasive fungal disease. To unravel the contribution of the immune system to CDC pathogenesis, we undertook a prospective multicentric exploratory study in 44 CDC patients at diagnosis and 44 matched controls (CANHPARI NCT01916057). Analysis of Candida-specific T cell responses using Elispot assays revealed higher numbers of IFNγ-producing T cells reactive to mp65 or candidin in 27 CDC cases as compared to 33 controls. Increased plasma levels of sCD25, IL-6, IL-1β, TNFα and IL-10 and lower levels of IL-2 were observed in CDC patients versus controls. Neutrophilia and higher level of CD4 and CD8 T cell activation were found in CDC patients as well as increased proportions of CXCR3-expressing TCRγδ+Vδ2+ cells. The expansion of Candida-specific IFNγ-producing T cells together with features of T cell activation and systemic inflammation identified here support the view that CDC belongs to the broad spectrum of fungal-associated immune reconstitution inflammatory syndromes (IRIS)

Outcome of febrile neutropenic patients treated for bacteriuria in hematology

International audienceIntroduction: Positive urine sample is a frequent finding in post-chemotherapy febrile neutropenia (FN) and can lead to prolonged antibiotic therapy. The aim of this study was to assess the outcome of bacteriuria episodes in FN patients receiving targeted antibiotic therapy.Materials and methods: A multi-centric retrospective study was conducted over a four-year period (2014-2019) on systematic urinalysis. All consecutive first bacteriuria episodes (≤ 2 bacteria with at least ≥ 103 CFU/mL) during FN in hospitalized adult patients for hematological malignancies were included. Relapse and recurrence were defined by fever or urinary tract symptoms (UTS) with the same bacterial subspecies in urine occurring ≤ 7 days and ≤ 30 days, respectively, after antibiotic discontinuation. Mortality rate was determined at 30 days. Targeted antibiotic therapy ≤ 10 days for women and ≤ 14 for men was considered as short course.Results: Among 97 patients, 105 bacteriuria episodes on systematic urinalysis were analyzed; 67.6% occurred in women, 41.9% in AML patients, 17.1% were bacteremic, 14.2% presented with UTS, and 61.9% were treated with short-course antibiotic treatment. One death was reported. In men, no relapse/recurrence was noted, even in the short-course antibiotic group. In women, 2.8% of episodes treated with short-course antibiotic led to relapse or recurrence.Conclusions: Relapse, recurrence, and mortality were uncommon events in FN patients experiencing bacteriuria episode, whatever the antibiotic duration. To distinguish asymptomatic bacteriuria from infection remained challenging in women. In men, systematic urinalysis at onset of FN could be useful

Ulceroglandular Infection and Bacteremia Caused by Francisella salimarina in Immunocompromised Patient, France

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Long‐term molecular remission in a patient with acute myeloid leukemia harboring a new NUP98‐LEDGF

Abstract A large variety of molecular rearrangements of the NUP98 gene have been described in the past decades (n = 72), involving fusion partners coding for different transcription factors, chromatin modifying enzymes, as well as various cytosolic proteins. Here, we report the case of an AML‐M2 patient with a variant NUP98‐LEDGF/PSIP1 gene fusion (N9‐L10). In this patient, three different NUP98-LEDGF fusion mRNAs were characterized due to alternative splicing in LEDGF exon 11. Targeted high‐throughput sequencing revealed the presence of IDH1, SRSF2, and WT1 additional pathogenic mutations. To improve the therapeutic monitoring, quantification of NUP98‐LEDGF mRNA by real‐time PCR was developed. Because of poor response to conventional chemotherapy, allogeneic stem cell transplantation was performed, followed by 20 cycles of azacitidine‐based preemptive treatment of relapse. More than 31 months after diagnosis, corresponding to 25 months post SCT and 4 months after the last cycle of azacytidine, the patient is in complete molecular remission (undetectable NUP98‐LEDGF mRNA transcripts). This study highlights the considerable variability in breakpoint location within both NUP98 and LEDGF, associated with alternative splicing affecting LEDGF. It also emphasizes the need to fully characterize the breakpoints within the two genes and the identification of all fusion mRNAs, particularly for the development of a molecular monitoring assay. All these data seem critical for the optimal management of NUP98‐LEDGF + hematological malignancies commonly associated with a poor prognosis

Cytogenetic risk score maintains its prognostic significance in aml patients with detectable measurable residual disease undergoing transplantation in remission: on behalf of the alwp/ebmt

International audienceWhile evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Canaani et al. Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD+wtwt

Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML

International audienceThe treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids ( p &lt; 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients. ClinicalTrials.gov identifier: NCT01999413