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Galia Stemer,1 Jacob M Rowe,2– 4 Yishai Ofran2,4 1Institute of Hematology, Ha’Emek Medical Center, Afula, Israel; 2Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; 3Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel; 4The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, IsraelCorrespondence: Jacob M RoweDepartment of Hematology, Shaare Zedek Medical Center, Shmu’el Bait St 12, Jerusalem, 91031, IsraelTel +972-2-6555204Fax +972-2-6555755Email rowe@rambam.health.gov.ilAbstract: The isocitrate dehydrogenase enzyme, catalyzing isocitrate conversion to α-ketoglutarate (αKG) in both the cell cytoplasm and mitochondria, contributes to the production of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as a reductive potential in various cellular processes. IDH1 gene mutations are revealed in up to 20% of the patients with acute myeloid leukemia (AML). A mutant IDH enzyme, existing in the cell cytoplasm and possessing neomorphic activity, converts αKG into oncometabolite R-2-hydroxyglutarate (R-2-HG) that accumulates in high amounts in the cell and inhibits αKG-dependent enzymes, including epigenetic regulators. The resultant alteration in gene expression and blockade of differentiation ultimately lead to leukemia development. Myeloid differentiation capacity can be restored by obstruction of the mutant enzyme, inducing substantial reduction in R-2-HG levels. Ivosidenib, a potent selective inhibitor of mutant IDH1, is a differentiating agent shown to be clinically effective in newly diagnosed AML (ND-AML) and relapsed/refractory (R/R) AML harboring this mutation. The drug is approved by the Food and Drug Administration (FDA) as a single-agent treatment for R/R AML. Significance of mutated IDH1 targeting and a potential role of ivosidenib in AML management, when used either as a single agent or as part of combination therapies, will be reviewed herein.Keywords: mutant IDH1, acute myeloid leukemia, ivosidenib

Excessive ingestion of salt is a well-recognized cause of hypernatraemia in children, is uncommonly recognized in debilitated elderly persons, but is rarely diagnosed in healthy, independent adults. We report a case of fatal salt poisoning in a 20-year-old lady who suffered of post-natal depression and ingested large quantities of salt as part of exorcism ritual. She presented with the highest ever documented serum sodium level of 255 mmol L(-1), associated with severe neurological impairment that was unresponsive to aggressive hypotonic fluid replacement. Post-mortem examination ruled out any other possible probable cause of death. The medical literature was reviewed, and 16 previous cases of severe hypernatraemia in adults secondary to excessive salt ingestion were retrieved. Common features of all reported cases included female gender (95% of cases) and evidence of underlying cognitive or psychiatric disorders (all reported cases). We conclude that women with documented cognitive or psychiatric disorders, in particular depression, are susceptible for psychogenic salt poisoning. Awareness should be raised to the potentially life-risking use of salty beverages as emetics or as part of 'exorcism' rituals. [ABSTRACT FROM AUTHOR]

Ofran Y, Lavi D, Opher D, Weiss TA, Elinav E (Hadassah University Hospital, Jerusalem, Israel). Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol L−1): a disorder linked to female gender and psychiatric disorders (Case Report).J Intern Med2004;256: 525–528.Excessive ingestion of salt is a well-recognized cause of hypernatraemia in children, is uncommonly recognized in debilitated elderly persons, but is rarely diagnosed in healthy, independent adults. We report a case of fatal salt poisoning in a 20-year-old lady who suffered of post-natal depression and ingested large quantities of salt as part of exorcism ritual. She presented with the highest ever documented serum sodium level of 255 mmol L−1, associated with severe neurological impairment that was unresponsive to aggressive hypotonic fluid replacement. Post-mortem examination ruled out any other possible probable cause of death. The medical literature was reviewed, and 16 previous cases of severe hypernatraemia in adults secondary to excessive salt ingestion were retrieved. Common features of all reported cases included female gender (95% of cases) and evidence of underlying cognitive or psychiatric disorders (all reported cases). We conclude that women with documented cognitive or psychiatric disorders, in particular depression, are susceptible for psychogenic salt poisoning. Awareness should be raised to the potentially life-risking use of salty beverages as emetics or as part of‘exorcism’ rituals. [ABSTRACT FROM AUTHOR]

BACKGROUND Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. METHODS We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bio-equivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. RESULTS A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. CONCLUSIONS CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZARAML-001 ClinicalTrials.gov number, NCT01757535.) [ABSTRACT FROM AUTHOR]

Molecular assessment of measurable residual disease (MRD) in NPM1-mutated AML patients is a powerful prognostic tool to identify the risk of relapse. There is limited data regarding MRD-guided decisions against alloSCT in elderly patients and FLT3-ITD co-mutation. We describe the outcome of NPM1-mutated AML patients in whom alloSCT was deferred based on ELN 2017 risk and MRD response. We report a relapse rate of 53% in this group, with a much higher incidence for older than 60 years patients than for younger patients (73% vs. 37%). When comparing outcomes of alloSCT in CR1 to intensive chemotherapy consolidation within each age group, patients over 60 years and patients with FLT3-ITD co-mutation had significantly lower RFS with intensive consolidation. Yet, in all subgroups, the lower RFS did not translate into OS difference, suggesting that relapsed NPM1 patients can often be salvaged and consequently achieve long-term remission. Our study supports the use of MRD response along with FLT3-ITD status in the decision to use post-remission therapy. We demonstrate that older patients and patients with FLT3-ITD-mutated AML have a high relapse rate but can be salvaged, leading to long-term survival., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

This pilot study evaluated CPX-351 in adults with newly diagnosed, favourable-intermediate risk, FLT3-ITD-negative AML. Twenty patients received CPX-351 for induction, with six also receiving gemtuzumab ozogamicin (GO). The complete response rate was 95%, with 42% achieving flow-based minimal residual disease (MRD) negativity post-induction. The 18-month leukaemia-free and overall survival estimates were 80% and 95% respectively. Adding GO appeared safe without prolonged cytopenias. Subclinical cardiotoxicity was observed in 25% of patients. The study demonstrated CPX-351's feasibility, with response and MRD-negativity rates comparable to standard '7 + 3' induction., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Venetoclax (Ven) plus hypomethylating agents are considered standard-of-care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, since patterns of patient selection, treatment-exposure and post-remission management may vary. This prospective observational multi-center study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range 0.1-43), median overall-survival (mOS) was 11.7 months (95% Confidence Interval [CI] 9.9,15.4). Composite complete remission (CRc) was achieved in 65.2% (CR 44.4%; CRi 20.8%). Of responding patients, 21.1% underwent stem-cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (p=0.027). AML ontogeny (p=0.024), reduced kidney function (p=0.001), Charlson co-morbidity index (CCI; p=0.0017), ELN-risk (p=0.01) and body-mass index (p=0.0298) were significantly associated with OS. Multivariant Cox-regression analysis confirmed independent association of OS with AML ontogeny (p=0.012), CCI (p=0.033) and ELN-risk (p=0.019). Patients enrolled in the latter half of the study period demonstrated improved OS compared to those enrolled earlier (p=0.026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. (clinicaltrials.gov: #NCT03987958)., (Copyright © 2024 American Society of Hematology.)

Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.