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NRAS and KRAS activating point mutations are present in 10-30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting., (© 2024. The Author(s).)

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2 P95H with Jak2 V617F , we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2 P95H unexpectedly delayed myelofibrosis induced by Jak2 V617F and decreased TGFβ1 serum level. Srsf2 P95H reduced the competitiveness of transplanted Jak2 V617F hematopoietic stem cells while preventing their exhaustion. RNA sequencing of sorted megakaryocytes identified an increased number of splicing events when the two mutations were combined. Focusing on JAK/STAT pathway, Jak2 exon 14 skipping was promoted by Srsf2 P95H , an event detected in patients with JAK2 V617F and SRSF2 P95 co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2 P95H delays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2 wild-type animals. These results unveil JAK2 exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies., Competing Interests: LZ and CB designed research and wrote the paper. CB, YH, CT, AC, RB, PL, CF, IL, MM performed research, and analyzed the data. EDS and MM provided critical expertise and reagents. AT, CCL, SDB, CF, AB, LD, JL, AM, and VR managed the patient’s information and data. All authors provided critical revision of the manuscript and had final approval of the manuscript for publication., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were TP53 (31%), DNMT3A (19%), IDH1/2 (13%), NRAS (13%), TET2 (12%), NPM1 (10%), PPM1D (9%), and PTPN11 (9%). CHIP-AMs were detected in 66% of TRMN patients, with no impact on OS. Yet, patients with CHIP-AM were older and had a longer time interval between solid tumor diagnosis and TRMN. According to our modified ontogeny-based classifier, we observed that the patients with TP53 or PPM1D mutations had more treatment lines and complex karyotypes, the "MDS-like" patients were older with more gene mutations, while patients with "De novo/pan-AML" mutations were younger with more balanced chromosomal translocations. Median OS within each subgroup was 7.5, 14.5, and 25.2 months, respectively, with statistically significant difference in multivariate analysis. These results support the integration of cytogenetic and molecular markers into the future TRMN classification to reflect the biological diversity of TRMN and its impact on outcomes., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Objectives: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context., Methods: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight., Results: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease., Conclusion: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R-mini-CYVE) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL)., Methods: We included pretreated adult patients with B-cell NHL who were ineligible for high-dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered., Results: Between 2013 and 2019, 56 patients with diffuse large B-cell lymphoma (n = 45, 80%) and indolent B-cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36-88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R-mini-CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression-free survival and overall survival times were 5.7 (95% CI: 0.5-10.9) and 14.7 (95% CI: 3.5-25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non-haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine-related neurotoxicity (5%)., Conclusion: R-mini-CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B-cell NHL who were ineligible for HDT., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m 2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m 2 /d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14 Low CD16 High monocytes, accumulation of HLA-DR Low classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10 Low CD101 - CXCR4 +/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation., Competing Interests: Declaration of Interests A. Silvin, N.C., M.F., E. Solary, and F. Ginhoux are inventors of patent EP 20305624.7, “Methods for detecting and treating COVID patients requiring intensive care,” submitted on June 9, 2020 under Gustave Roussy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: High-dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high-dose cyclophosphamide to treat relapsed or refractory lymphoma., Methods: A phase II study included adult patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High-dose cyclophosphamide was given intravenously 3 g/m 2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m 2 intravenously was added in patients not refractory to anti-CD20 antibody., Results: Forty-two patients with median age 65 [56-70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B-cell lymphoma (n = 26; 62%), indolent B-cell non-Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non-hematologic grade 3-5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%., Conclusion: One to two cycles of high-dose cyclophosphamide in hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR-T cell., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Islands of CD123 high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123 + mononucleated cells that are lineage-negative, CD45 + , CD11c - , CD33 - , HLA-DR + , BDCA-2 + , BDCA-4 + in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34 + cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes.

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

Background: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1., Methods: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up., Results: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment., Conclusions: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recurrent mutations in isocitrate dehydrogenase 2 ( IDH2 ) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant- IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498., (© 2017 by The American Society of Hematology.)

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34 + cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2rγnull) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Scopulariopsis brevicaulis onychomycosis with local cutaneous invasion was diagnosed in an acute leukemia patient and unsuccessfully treated with high-dose micafungin, based on antifungal susceptibility testing. This case should alert clinicians to the possible severe evolution of onychomycosis in neutropenic patients and suggests that surgery should be preferred in such a situation.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit α-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.

In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558)., (Copyright© Ferrata Storti Foundation.)

Purpose: Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen., Methods: An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone., Results: Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non-haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%., Conclusions: With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Importance: Constitutional mismatch repair deficiency (CMMRD) syndrome is a disorder with recessive inheritance caused by biallelic mismatch repair gene mutations, in which mismatch repair defects are inherited from both parents. This syndrome is associated with multiple cancers occurring in childhood. The most common tumors observed with CMMRD include brain tumors, digestive tract tumors, and hematological malignancies. The aim of this study was to report new phenotypic expressions of CMMRD syndrome and add new insight to the existing knowledge about this disease. A review of the literature was conducted and recommendation for surveillance and follow-up in patients with CMMRD are proposed., Clinical Presentation: We report for the first time in the literature, the case of a 22-year-old female patient who was diagnosed with CMMRD syndrome, with the development of 2 unusual tumors: an anaplastic ganglioglioma and an osteosarcoma. She presented initially with an anaplastic ganglioglioma and later developed several malignancies including colonic adenocarcinoma, osteosarcoma, and acute myeloid leukemia. The patient had an atypical course of her disease with development of the initial malignancy at an older age and a remarkably long survival period despite developing aggressive tumors., Conclusion: Many aspects of this disease are still unknown. We identified a case of CMMRD in a patient presenting with an anaplastic ganglioglioma, who underwent successful surgical resection, chemotherapy, and radiotherapy and has had one of the longest survival periods known with this disease. This case broadens the tumor spectrum observed with CMMRD syndrome with anaplastic ganglioglioma and osteosarcoma as new phenotypic expressions of this genetic defect.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood monocytes to >1 × 10(9)/L, measured for ≥3 months. Diagnosis can be ambiguous; for example, with prefibrotic myelofibrosis or reactive monocytosis. We set up a multiparameter flow cytometry assay to distinguish CD14(+)/CD16(-) classical from CD14(+)/CD16(+) intermediate and CD14(low)/CD16(+) nonclassical monocyte subsets in peripheral blood mononucleated cells and in total blood samples. Compared with healthy donors and patients with reactive monocytosis or another hematologic malignancy, CMML patients demonstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells (cutoff value, 94.0%). The associated specificity and sensitivity values were 95.1% and 90.6% in the learning cohort (175 samples) and 94.1% and 91.9% in the validation cohort (307 samples), respectively. The accumulation of classical monocytes, which demonstrate a distinct gene expression pattern, is independent of the mutational background. Importantly, this increase disappears in patients who respond to hypomethylating agents. We conclude that an increase in the fraction of classical monocytes to >94.0% of total monocytes is a highly sensitive and specific diagnostic marker that rapidly and accurately distinguishes CMML from confounding diagnoses., (© 2015 by The American Society of Hematology.)

The introduction of tyrosine kinase inhibitor (TKI) therapy has markedly reduced the use of allogeneic (allo) hematopoietic stem cell transplantation (HSCT), which is no longer standard practice in the first chronic phase in chronic myelogenous leukemia and is currently reserved after failure of TKI or in advanced phase of disease. We compared the outcome of Philadelphia chromosome-positive (Ph+) leukemia patients who received a first allo-HSCT in our center in both the pre-TKI era and the TKI era. The primary end point was to compare the 2 groups' overall survival (OS), leukemia-free survival (LFS), cumulative incidence of nonrelapse mortality, and relapse incidence. The secondary end point was to underline in the TKI era the impact of the pretransplantation minimal residual disease (MRD) on the outcomes. A total of 69 patients with Ph+ leukemia were included and their outcomes analyzed. For the purpose of this analysis, we defined 2 groups: group A (n = 39) included patients treated in the pre-TKI era, treated from January 1989 until December 2001, and group B (n = 30) included patients treated in the TKI era, treated from January 2002 until December 2013. Additional analysis was performed in group B for whom detailed TKIs and MRD data were collected. The study took place in our cancer center in the department of HSCT, Villejuif, France. The median follow-up duration for group A was 116.1 months (range, 1.1 to 240.1 months) and for group B was 8.3 months (range, 3.5 to 141.7 months). At 3 years, the LFS and OS were higher in group B (respectively, 66% and 71%) than in group A (respectively, 63% and 57%) (P > .05). The LFS and OS at 3 years of the pretransplantation MRD-negative (< 0.01%) patients were significantly (P < .05) higher (respectively, 83% and 94%) than the pretransplantation MRD-positive patients (respectively, 43% and 46%). Our data, although statistically not significant, suggest better outcomes for Ph+ leukemia patients undergoing allo-HSCT in the TKI era. Mostly TKI does not adversely affect the transplantation outcomes and can be used successfully as a bridge to allo-HSCT, especially in advanced disease. In addition, we highlight the importance of obtaining deep pretransplantation MRD negativity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0-28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC<13G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1-27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2-5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response., (© 2014 Wiley Periodicals, Inc.)

Core-binding factor acute myeloid leukemia (CBF-AML) - including AML with t(8;21) and AML with inv(16) - accounts for about 15% of adult AML and is associated with a relatively favorable prognosis. Nonetheless, relapse incidence may reach 40% in these patients. In this context, identification of prognostic markers is considered of great interest. Due to similarities between their molecular and prognostic features, t(8;21) and inv(16)-AML are usually grouped and reported together in clinical studies. However, considerable experimental evidences have highlighted that they represent two distinct entities and should be considered separately for further studies. This review summarizes recent laboratory and clinical findings in this particular subset of AML and how they could be used to improve management of patients in routine practice.

Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses., (© 2014 by The American Society of Hematology.)

Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing. RUNX1-RUNX1T1 DNA quantification was performed by real-time quantitative PCR using patient-specific primers and probe. MRD levels were evaluated in 71 follow-up samples from 16 patients, with a median of four samples [range 2-7] per patient. RUNX1 breakpoints were located in intron 5 in all cases. RUNX1T1 breakpoints were located in intron 1b in 15 cases and in intron 1a in two cases. RUNX1-RUNX1T1 MRD levels measured on DNA and RNA were strongly correlated (r = 0.8, P < 0.0001). Discordant MRD results were observed in 10/71 (14%) of the samples: in three samples from two patients who relapsed, RUNX1-RUNX1T1 was detectable only on DNA, while RUNX1-RUNX1T1 was detectable only on RNA in seven samples. MRD monitoring on genomic DNA is feasible, but with sensitivity variations depending on the patient breakpoint sequence and the qPCR assay efficiency. Although interpretation of the results is easier because it is closely related to the number of leukemic cells, this method greatly increases time, cost and complexity, which limits its interest in routine practice., (© 2014 Wiley Periodicals, Inc.)

Background: The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C-reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly., Method: The PINI score was determined in 231 previously untreated patients with MM, of whom 112 were ≥65 yrs old. The serum albumin, prealbumin, orosomucoid (human α1-acid glycoprotein), and hsCRP are measured routinely by immunonephelometry., Results: In the overall population and the elderly subset, PINI ≥ 4 ('high PINI') was correlated with a shorter median survival, 26 vs. 65 months in the high and low PINI groups, respectively. The prognostic impact of PINI index was dramatic in the elderly MM subgroup, 6 and 45 months, respectively. The high PINI index also predicted for shorter survival in various groups with good prognostic, such as low International Staging System (ISS) stages, low b2m, and absence of del17p and t(4;14), further demonstrating its prognostic impact on overall survival. In multivariate analysis, PINI index provided additional survival prognostic information to b2m in a b2m/PINI model., Conclusion: PINI index appears to be a useful and easy-to-perform marker in routine to determine the prognosis of patients with MM, especially in the elderly population. PINI might represent an alternative to ISS score, especially in elderly patients, in the future., (© 2012 John Wiley & Sons A/S.)

Introduction: Hemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant., Case Presentation: A 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration., Conclusions: Influenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians.

A 37-year-old man presented a slight debility. The hemogram showed a phenotype of beta-thalassemia minor: Hb (13.1 g/dL), mean corpuscular volume (MCV) (62 fL) with low mean corpuscular hemoglobin (MCH) (20.8 pg), associated with a high level of Hb A(2) of 5.3%. The serum ferritin level was 1,072 ng/mL. The sequencing of the mutated fragment revealed a duplication of four bases of codons 7/8 involving a shift in the open reading frame starting from codon 9 with a TGA stop codon at codon 23: codons 7/8/9 (+AGAA); GAG.AAG.TCT(Gly-Lys-Ser)>GAG.AAAGAAG. The human hemoglobin (Hb) instability tests were negative. The patient did not present the high iron Fe (HFE) mutation (C282Y, H63D). The same mutation was found in five other unrelated families (representing a total of 23 patients). All of their ancestors came from the north of France. This mutation has not been described before and could have its origins in the native populations of Northern France.

Despite advances in therapy, Waldenstrom's macroglobulinemia (WM) remains incurable. Guidelines on therapeutic alternatives in WM recommended the use of alkylating agents, rituximab, nucleoside analogues and anthracyclins either in first line or at relapse and in combination in fit patients. While the overall response rates of combination regimens reached up to 80 - 90% in some studies, the complete response rate is low, no greater than 10 - 20%; and the disease-related median survival for symptomatic patients is approximately 6 years. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, advances were made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. Several preclinical studies have demonstrated that the NFkappaB pathway is a potential target for therapeutics in WM. Bortezomib (Velcade) is the first approved proteasome inhibitor for treating relapse/refractory multiple myeloma and, among other mechanisms of action, significantly inhibits the NFkB pathway. This report provides an update on biological studies and clinical efforts to develop bortezomib as a new treatment of Waldenstrom's macroglobulinemia.