Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study.

DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

Allogeneic transplantation in acute myelogenous leukemia: a comprehensive single institution's experience.

Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults.

Benefits of dexamethasone on early outcomes in patients with acute myeloid leukemia with hyperleukocytosis: a propensity score matched analysis.

Hyperleukocytosis is associated with a significant early mortality rate in patients with acute myeloid leukemia (AML). To date, no controlled trial has ever evaluated a strategy to reduce this risk, and the initial management of these patients remains heterogeneous worldwide. The aim of the present study was to evaluate the influence of a short course of intravenous dexamethasone on the early outcomes of patients with hyperleukocytic AML with white blood cell (WBC) count above 50 × 109/L. Clinical and biological data of all consecutive patients (1997-2017) eligible for intensive chemotherapy from a single center were retrospectively collected. A total of 251 patients with a median age of 51 years and a median WBC count of 120 × 109/L were included, 95 of whom received dexamethasone. Patients treated with dexamethasone had higher WBC count and a more severe disease compared with those who did not, and they presented more often with leukostasis and hypoxemia, resulting in a more frequent need for life-sustaining therapies (p < 0.001). To account for these imbalances, patients were compared after adjusting for a propensity score, which included all variables with a prognostic influence in the overall cohort. In the matched cohort, dexamethasone was associated with lower early death (OR = 0.34, p = 0.0026) and induction failure rate (OR = 0.44, p = 0.02) and better overall survival (HR = 0.60, p = 0.011), with no impact on relapse risk (cHR = 0.73, p = 0.39). The overall survival benefit was confirmed among all tested subgroups. This study suggests that dexamethasone administration is safe and associated with a lower risk of induction mortality in patients with hyperleukocytic AML and deserves prospective evaluation.

The transfusion of non-prophylactically RH-KEL1 antigen-matched red blood cells is feasible in selected myelodysplastic syndrome and acute myeloid leukaemia patients.

BACKGROUND AND OBJECTIVES: Most myelodysplastic syndromes (MDS) patients become red blood cell (RBC) transfusion-dependent. Transfusing MDS patients with prophylactically RH-KEL1 antigen-matched (PAM) RBC units is recommended to avoid RBC allo-immunization. D+C-E-c+e+, D+C-E+c+e- and D+C+E-c-e+ phenotypes are infrequent among French blood donors. To preserve infrequent phenotype RBC units for patients other than MDS, and to manage frequent phenotype RBC unit stocks, we let, for 1 year, higher-risk non-immunized chronically transfused MDS and acute myeloid leukaemia (AML) patients receive RBC transfusions matched only for D. Our objectives were to evaluate the impact of non-PAM transfusions on the transfusion policy (which would be modified in case of RBC allo-immunization) for frequent and infrequent phenotypes patients and to estimate the number of infrequent phenotypes RBC units that could be redistributed to other patients. RESULTS: Ninety patients were enrolled. Thirty-five patients had infrequent phenotypes, nine received only PAM RBC (143 units) and 26 PAM and non-PAM RBC (415 and 532, respectively): none developed allo-immunization. Fifty-five patients had frequent RBC phenotypes, 34 received only PAM RBC (561 units) and three developed antibodies (2 non-RH-KEL1 and one anti-E); 21 received PAM and non-PAM RBC (436 and 109, respectively) and one developed allo-immunization (unknown specificity). Our strategy enabled us to preserve 532 infrequent phenotypes RBC units: 216 D+C-E-c+e+, 33 D+C-E+c+e- and 283 D+C+E-c-e+ units, representing 48.8% of the total number of RBC units received by infrequent phenotypes patients during the study period. CONCLUSION: Allowing the transfusion of non-PAM RBC in selected chronically transfused MDS and AML patients was feasible and enabled to redistribute infrequent phenotypes RBC units to other patients in need.

Germline DDX41 mutations define a significant entity within adult MDS/AML patients.

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.

A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure.

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676).

Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies.

Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1-3 in cohort 1, escalated to 60 mg/m2/day, days 1-3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1-7) and lenalidomide (10 mg/day, days 1-21 in cohorts 1 and 2, escalated to 25 mg/day, days 1-21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508.

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin.

In mammals, melatonin is the pivotal messenger synchronizing biological functions, notably reproductive activity, with annual daylength changes. Recently, two major findings clarified melatonin's mode of action. First, melatonin controls the production of thyroid stimulating hormone (TSH) by the pars tuberalis of the adenohypophysis. This TSH regulates local thyroid hormone availability in the mediobasal hypothalamus. Second, the RF-amides kisspeptin and RFRP-3, recently discovered regulators of the gonadotropic axis, are involved in the melatonin control of reproduction. This study aims to establish a mechanistic link between the melatonin-driven TSH and the RF-amide control of reproduction. We treated short-day-adapted male Djungarian and Syrian hamsters with a chronic central infusion of TSH. In both hamster species, the central administration of 5 mIU/d TSH for 4 to 6 wk restored the summer phenotype of both testicular activity and kisspeptin and RFRP expression. Vehicle treated hamsters remain sexually inactive. Furthermore, the TSH treatment increased the body weight of lean short-day-adapted Djungarian hamsters and reduced hypothalamic somatostatin expression to the summer phenotype. In summary, our study demonstrates the pivotal role of melatonin-driven TSH for the seasonal regulation of reproduction and body weight, and uncovers the neuropeptides relaying this signal within the hypothalamus.

Phase to phase: Navigating drug combinations with hypomethylating agents in higher-risk MDS trials for optimal outcomes.

Recent developments in high-risk Myelodysplastic Neoplasms (HR MDS) treatment are confronted with challenges in study design due to evolving drug combinations with Hypomethylating Agents (HMAs). The shift from the International Prognostic Scoring System (IPSS) to its molecular revision (IPSS-M) has notably influenced research and clinical practice. Introducing concepts like the MDS/AML overlap complicate classifications and including chronic myelomonocytic leukemia (CMML) in MDS studies introduces another layer of complexity. The International Consortium for MDS emphasizes aligning HR MDS criteria with the 2022 ELN criteria for AML. Differences in advancements between AML and MDS treatments and hematological toxicity in HR MDS underline the importance of detailed trial designs. Effective therapeutic strategies require accurate reporting of adverse events, highlighting the need for clarity in criteria like the Common Terminology Criteria for Adverse Events (CTCAE). We provide an overview on negative clinical trials in HR MDS, analyze possible reasons and explore possibilities to optimize future clinical trials in this challenging patient population.

Targeting a lineage-specific PI3KÉ£-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

Next-generation therapy for lower-risk MDS.

Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor ß pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.