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Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children’s Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (

Background Acute myeloid leukemia (AML) is a malignancy commonly seen in adults. Previous studies indicated that TRIM14 played a tumorigenic role in various types of cancer and miR-23b-5p was down-regulated in human mesenchymal stem cell-derived exosomes (HMSC-exos) of AML patients. However, their roles in AML remains unclear. Our study aims to investigate the role of TRIM14 and miR-23b-5p in the pathogenesis of AML. Materials and methods The blood specimen was collected from de novo AML patients and healthy donators. Exosomes were extracted from the culture medium of human mesenchymal stem cells under ultracentrifugation. Then exosomes were co-cultured with AML cells to determine the effect of their contents. The cell proliferation was detected by cell counting kit-8 assay, whereas the cell apoptosis was detected by flow cytometry. The expression of miR-23b-5p and TRIM14 was silenced or overexpressed to explore their biological functions in AML. Luciferase reporter assay was conducted to validate the interaction between miR-23b-5p and TRIM14. Gene expression was determined by quantitative real-time PCR and immunoblots. Results TRIM14 was significantly increased in AML patients and cell lines. The inhibition of TRIM14 significantly reduced the proliferation and induced the apoptosis of AML cells via activating PI3K/AKT pathway, whereas its overexpression exhibited reversed effects. HMSC-exos could suppress the proliferation of AML cells through the delivery of miR-23b-5p. Moreover, miR-23b-5p inhibited the transcription of TRIM14 by binding on its 3’UTR region. Overexpression of TRIM14 exhibited reversed effect against the function of miR-23b-5p mimic. Conclusion TRIM14 could promote the proliferation of AML cells via activating PI3K/AKT pathway, which was reversed by HMSC-exos through delivering miR-23b-5p. These findings indicated that miR-23b-5p and TRIM14 could be applied as potential targets for the treatment of AML.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs., The mutational effects of chemotherapies on healthy cells are unclear. Here, the authors show that the mutational signature of platinum-based drugs -but not 5-fluorouracil- is detectable in secondary acute myeloid leukemia, implying that the clonal expansion begins after the start of therapy.

Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p

There is paucity of data regarding the diagnostic yield and safety of skin biopsies in patients with acute myeloid leukemia (AML), though skin eruptions are common in these patients. We evaluated 216 patients treated in our hemato-oncology unit at a tertiary medical center between 2007 and 2018 and identified 35 patients who underwent 37 skin biopsies. The majority of biopsies were performed during induction treatment for AML (n = 26, 70%), whereas the remainder of biopsies were done prior to induction initiation (n = 8, 22%) or during consolidation chemotherapy (n = 3, 8%). Pathology findings were inconclusive in 13 cases (35%), while diagnostic biopsies were positive for drug eruptions (24%), leukemia cutis (16%), infections (11%), reactive processes (8%) and Sweet syndrome (5.5%). In almost half of cases (16/37) tissue cultures were performed. Of those, only a quarter (4/16) were positive. Histopathology and tissue culture results altered immediate patient care in 3 cases (8%), yet information obtained from biopsies had potential to affect long term patient care in 8 additional cases (21.6%). Although most skin biopsies were performed while patients had severe thrombocytopenia and neutropenia, only one patient had a complication due to the biopsy (fever and local bleeding). With the limitation of a retrospective analysis, our study suggests that skin biopsies in patients treated for AML are relatively safe. Although biopsy results infrequently alter immediate patient management, long term effect on patient care expand the potential diagnostic yield of skin biopsies.

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level., The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial.

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

Background: Aspergillus species meet the most important group of invasive fungal diseases (IFD) in immunosuppressed patients. Galactomannan is a polysaccharide antigen located in the wall structure of Aspergillus. The most commonly used method for antigen detection is enzymelinked immunoassay (ELISA). Aspergillus galactomannan Lateral Flow Assay (LFA) constitutes one of the new methods in the diagnosis of invasive aspergillosis (IA). The goal of this study is to demonstrate efficacy of LFA in our patients and to compare it to synchronous ELISA results. Methods: Galactomannan antigen was examined using both LFA and ELISA in serum samples taken from patients who were followed up in our hematology clinic. All patients are classified in subgroups as "proven", "probable", and “possible" patients according to the last EORTC / MSG guideline. Patients who met the “proven" IA criteria were included in the study as the gold standard. Results: A total of 87 patients were included in the study. Majority of patients had acute myeloid leukemia (AML) (56.3%). Eleven (12.6%) were in "proven" IA group. LFA test showed a superior diagnostic performance compared to ELISA (LFAAUC = 0.934 vs ELISAAUC = 0.545; p

Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity. Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models. Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.

Background Therapeutic cancer vaccines are an attractive approach for treating malignant tumours, and successful tumour eradication depends primarily on controlling tumour immunosuppression status as well as heterogeneity of tumour cells driven by epigenetic alterations. Methods Peptide-loaded dendritic cell (DC) prime and non-infectious peptide booster heterologous immunisations were assessed for the immunogenicity of polo-like kinase-1 (PLK1)-derived peptides. Heterologous vaccination regimen targeting multiple shared tumour antigens simultaneously with PD-L1 blockade was assessed against murine myeloid leukaemia. Results A synthetic PLK1122 (DSDFVFVVL)-based heterologous vaccination generated large numbers of long-lasting antigen-specific CD8 T-cells eliciting therapeutic effects against various established tumours. The therapeutic efficacy of single antigen-targeting PLK1122-based vaccine with sufficient endurance of PD-L1 blockade toward C1498 leukaemia relied on the heterogeneous clonal levels of MHC-I and PD-L1 expression. A novel multi-peptide-based vaccination targeting PLK1 and survivin simultaneously along with PD1 blockade led to complete tumour eradication and long-term survival in mice with clonally heterologous C1498 myeloid leukaemia. Conclusions Our findings suggest that PLK1 could be an attractive immunotherapeutic target antigen for cancer immunotherapy, and that similar strategies would be applicable for the optimisation of cancer vaccines for the treatment of numerous viral diseases and malignant tumours.

Platelet (PLT) recovery after chemotherapy is associated with the prognosis of patients with acute myeloid leukaemia (AML). This study aimed to explore the prognostic significance of early high PLT values in patients with de novo non-M3 AML who achieved first complete remission (CR).A total of 206 patients with de novo non-M3 AML were analysed in this retrospective study. A receiver operating characteristic (ROC) curve was used to determine the optimal PLT cut-off. The overall survival (OS) and relapse-free survival (RFS) were assessed using Kaplan-Meier and Cox regression analyses.312×10Our results showed that early high PLT count recovery at first CR in non-adverse-risk AML patients is a positive prognostic marker for survival outcomes.

We studied 79 patients with AML-MRC or RAEB-T, who were later reclassified according to the WHO classification. Marrow slides were examined cytomorphologically with regard to dysplasia. Patients were followed up until March 2020. Thirty-one patients underwent allogeneic stem cell transplantation (median survival (ms) 16 months), 14 were treated with induction chemotherapy (ms 8.4 months), 18 received hypomethylating agents (ms 9.2 months), 16 received low dose chemotherapy or best supportive care (ms 2.4 months). Only 30.4% fulfilled the morphologic WHO criteria. 46.8% were classified as AML-MRC by an antecedent MDS, 54.4% of the pts were classified by MDS-related chromosomal abnormalities. 5% did not fulfill any of the criteria and were entered based on 20-29% medullary blasts. There was no difference in ms between pts presenting with > 50% dysplasia as compared to pts with dysplasia between 10% and 50% (ms 9.1 vs 9.9 months, p = n.s.) or for pts with antecedent MDS (ms 9.1 vs 8.9 months, p = n.s.). Myelodysplasia-related cytogenetic abnormalities were associated with a worse outcome (ms 8.1 vs 13.5 months, p = 0.026). AML-MRC in its current definition is a heterogenous entity. Dysplasia of ≥ 50% in ≥ two lineages is not helpful for diagnostics and prognostication and therefore should be deleted in future classifications. We recommend utilizing the WHO guidelines for defining dysplasia (10% or greater in ≥ 1 of the three myeloid cell lines) assisting in establishing the diagnosis of MDS.

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211

Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100–200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.

Despite the great advance in treatment, cytogenetically normal Acute myeloid leukemia (CN-AML) is still a challenging entity. The discovery of IDH1 mutation in AML together with the frequent co-mutations; NPM1 and FLT3-ITD throughs a new insight into the pathogenesis and outcome of CN-AML. Recently, there has been an increasing number of recurring mutations in other genes for which the forecasting effect is still required. Despite the large number of risk variables established, there are relatively few prognostic indicators that can help in treatment decisions in AML patients. This study aimed at recording the frequency of IDH1 and NPM1 mutations in newly diagnosed AML and, dual clinicopathological significance. IDH1 and NPM1 mutations were analyzed using High-Resolution Melting curve analysis PCR in 78 newly diagnosed AML patients; 30 pediatric and 48 adult AML patients. IDH1 mutation was detected in 6 out of the 48 adult AML cases (12.5%) and all of them had intermediate cytogenetic prognostic stratification. 5/6 mutant IDH1 patients showed NPM1 co-mutation (P-value= 0.008). Mutant IDH1 patients showed significant resistance to induction therapy (P-value

MECOM rearrangements are recurrent in myeloid neoplasms and associated with poor prognosis. However, only inv(3)(q21q26.2) and t(3;3)(q21;q26.2), the classic MECOM rearrangements resulting in RPN1-MECOM rearrangement with Mecom overexpression and GATA2 haploinsufficiency, define the distinct subtype of acute myeloid leukemia (AML), and serve as presumptive evidence for myelodysplastic syndrome based on the current World Health Organization classification. Myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements have been found to be clinically aggressive, but comparative analysis of clinicopathologic and genomic features is limited. We retrospectively studied cohorts of myeloid neoplasms with classic and nonclassic MECOM rearrangements. Cases with classic rearrangements consisted predominantly of AML, often with inv(3) or t(3;3) as the sole chromosome abnormality, whereas the group of nonclassic rearrangements included a variety of myeloid neoplasms, often with complex karyotype without TP53 mutations and similarly dismal overall survival. Immunohistochemistry revealed Mecom protein overexpression in both groups, but overexpression in cases with nonclassic rearrangements was mediated through a mechanism other than GATA2 distal enhancer involvement typical for classic rearrangement. Our results demonstrated that myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements encompass a diverse group of diseases with poor clinical outcome, overexpression of Mecom protein as a result of the nonclassic mechanism of MECOM activation.

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

BACKGROUND The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). METHODS The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. RESULTS A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P

Background The addition of midostaurin to induction chemotherapy improves survival in younger patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Sorafenib is a potent multikinase inhibitor with efficacy when given as monotherapy. The authors investigated whether the addition of sorafenib to intensive induction chemotherapy improves outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated AML. Methods In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. Of these, 79 patients (43%) underwent intensive chemotherapy with the addition of sorafenib, and 104 (57%) received intensive chemotherapy alone. Propensity score matching identified 42 patients in each cohort. Results The overall response rate was 98% in the sorafenib cohort and 83% in the intensive chemotherapy cohort (P = .057). The median follow-up was 54 months. The median event-free survival was 35 months in the sorafenib cohort and 8 months in the intensive chemotherapy cohort (P = .019), and the median overall survival was 42 and 13 months, respectively (P = .026). With censoring at the time of allogeneic stem cell transplantation, the median event-free survival was 31 and 8 months in the sorafenib and intensive therapy cohorts, respectively (P = .031), and the median overall survival was not reached and 10 months, respectively (P = .001). Multivariate Cox proportional hazards models confirmed that treatment with sorafenib was a favorable prognostic factor (P = .009; hazard ratio, 0.558; 95% CI, 0.360-0.865). Conclusions The addition of sorafenib improves survival in patients with FLT3-ITD-mutated AML regardless of whether they undergo allogeneic stem cell transplantation.

Leukemia is a complex genetic disease caused by errors in differentiation, growth, and apoptosis of hematopoietic cells in either lymphoid or myeloid lineages. Large-scale genomic characterization of thousands of leukemia patients has produced a tremendous amount of data that have enabled a better understanding of the differences between adult and pediatric patients. For instance, although phenotypically similar, pediatric and adult myeloid leukemia patients differ in their mutational profiles, typically involving either chromosomal translocations or recurrent single-base-pair mutations, respectively. To elucidate the molecular mechanisms underlying the biology of this cancer, continual efforts have been made to develop more contextually and biologically relevant experimental models. Leukemic cell lines, for example, provide an inexpensive and tractable model but often fail to recapitulate critical aspects of tumor biology. Likewise, murine leukemia models of leukemia have been highly informative but also do not entirely reproduce the human disease. More recent advances in the development of patient-derived xenografts (PDXs) or human models of leukemias are poised to provide a more comprehensive, and biologically relevant, approach to directly assess the impact of the in vivo environment on human samples. In this review, the advantages and limitations of the various current models used to functionally define the genetic requirements of leukemogenesis are discussed.

KIT mutations are observed in about 20-40% of acute myeloid leukemia with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 [abbreviated AML t(8;21) here] with mutations involving exon 17 being the most common. Despite high frequencies of KIT mutations in both AML t(8;21) and systemic mastocytosis (SM), AML t(8;21) associated with SM is uncommon, and restricted to KIT exon 17 mutated cases. In this study, we report two cases of AML t(8;21) associated SM that KIT mutation occurred in exon 8 (T417_D419delinsY). In both patients, the bone marrow displayed increased round/ovoid mast cells with bilobated nuclei and absence of CD2 and CD25 expression. RUNX1/RUNX1T1 fusion was shown in both myeloblasts and mast cells by FISH. Patient #1 was refractory to induction chemotherapy and died at day 50; patient #2 had residual AML, marked SM, and persistent RUNX1/RUNX1T1 fusion after induction therapy.

Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response.Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).

Allogeneic hematopoietic cell transplant (HCT) is a curative procedure for myeloid malignant neoplasms, but relapse after HCT remains critical. A conditioning regimen involving granulocyte colony-stimulating factor-combined high-dose cytarabine, cyclophosphamide, and total body irradiation (G-CSF–combined high-dose cytarabine/cyclophosphamide/total-body irradiation [HDCA/CY/TBI]) was reported to improve outcomes after cord blood transplant (CBT) for myeloid malignant neoplasms, but this regimen was not previously evaluated among patients undergoing bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT). Methods We retrospectively analyzed 28 patients who underwent allogeneic HCT including BMT from a related (1 patient) or unrelated donor (9 patients), PBSCT from a related donor (7 patients), or single-unit CBT from an unrelated donor (11 patients) after a G-CSF–combined HDCA/CY/TBI regimen. Results All patients achieved neutrophil and platelet engraftment, which were significantly more rapid in the BMT/PBSCT group than in the CBT group. Eighteen patients were alive at a median follow-up of 54.3 months. The 3-year relapse and nonrelapse mortality rates were 28.6% and 7.1%, respectively, which were similar between the BMT/PBSCT and CBT groups. Overall survival and disease-free survival at 5 years after HCT were 62.6% and 64.3%, respectively, which were also similar between the BMT/PBSCT and CBT groups. Only disease status at HCT had a significant impact on overall survival and disease-free survival (86.7% with standard risk vs 38.5% with high risk and 86.7% with standard risk vs 38.5% with high risk, respectively). Conclusion A G-CSF–combined HDCA/CY/TBI regimen is a promising conditioning in patients with myeloid malignant neoplasms who undergo not only CBT but also BMT or PBSCT.

The aim of this study was to define a population-based frequency of TAM in DS newborns. The Dutch Pediatric Surveillance Unit (DPSU) registers newborns with DS and TAM screening was added to this registration from Jan 1, 2008, until Jan 1, 2013 (Erasmus MC MEC-2007-168, Netherlands Trial Register NL1587). Based on the live birth prevalence of DS in the Netherlands, an estimated 1211 DS children were born in the Netherlands during the screening period. Between 2008 and 2013, 803 neonates with DS were included in the DPSU registry. Therefore ~66% of the neonates with DS were registered. Of the 803 registered neonates, TAM screening blood samples were received for 368 neonates (46% of the registered cases). The low inclusion rate could give rise to a selection bias, as pediatricians are probably more likely to include neonates with symptoms or abnormal PB values compared to healthy DS neonates. Therefore, the incidence of TAM could be overestimated in this study.

A decreased percentage of CD177

HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, BCL2 and SOX4 synergistically induced leukemia with MYC. Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.

This chapter describes a real-time, bioluminescent apoptosis assay technique, which circumvents the well-documented "timing condundrum" encountered when employing traditional apoptosis detection chemistries after exposures with inducers of unknown potential. The assay continuously reports the translocation of phosphatidylserine (PS) from the inner membrane leaflet of a cell to the exofacial surface during apoptosis. This homogenous, no-wash, plate-based assay is made possible by two different annexin V fusion proteins, which contain complementing NanoBiT™ luciferase enzyme subunits, a time-released luciferase substrate, and a fluorescent membrane integrity reagent. During apoptosis, luminescence signal is proportional to PS exposure and fluorescence intensity correlated with the degree of secondary necrosis. Altogether, the measures provide exquisite kinetic resolution of dose- and agent-dependent apoptotic responses, from early through late phases. At exposure termination, other compatible reagents can be applied to measure additional orthogonal correlates of cell health.

Purpose of Review Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of conventional chemotherapy and a broadening use of allogeneic hematopoietic cell transplantation (allo-HCT) whereas the results remained dismal and very stable in patients older than 60 years. The current review highlights the recent developments in standard intensive post-remission chemotherapy, evidence for the use of recently approved agents, and discusses the relevance of measurable residual disease (MRD) measurement in treatment adaptation. Recent Findings Current approvals of midostaurin, venetoclax, gemtuzumab ozogamicin, VYXEOS, ivosidenib, enasidenib, glasdegib, and CC-486 have changed the structure, aim, and schedule of consolidation therapy, and new, well-tolerated agents are being evaluated as maintenance therapies. Furthermore, MRD assessment has been implemented to guide the duration and type of consolidation and maintenance therapy as well as indicate the optimal timing of allo-HCT. Summary Novel therapies have changed the structure and perspective of post-remission therapy in AML for both young and elderly patients. In addition, MRD assessment could guide the type, duration, and intensity of consolidation and maintenance therapy.

PURPOSE The COVID-19 pandemic is a colossal challenge for global health; nonetheless, specific subgroups face considerably higher risks for infection and mortality. Among patients with malignant diseases, those with hematologic neoplasms are at a higher risk for poor outcomes. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and their short-term consequences in Latin America. METHODS Multicenter, prospective, observational, cohort study including patients older than 14 years from 14 centers in four countries (Mexico, Peru, Guatemala, and Panama) who had a confirmed diagnosis of acute leukemia, and who were undergoing active treatment since the first COVID-19 case in each country until the cutoff on July 15, 2020. RESULTS We recruited 635 patients. Treatment modifications because of the COVID-19 pandemic were reported in 40.8% of cases. The main reason for such modifications was logistic issues (55.0%) and the most frequent modification was chemotherapy delay (42.0%). A total of 13.1% patients developed COVID-19 disease, with a mortality of 37.7%. Several factors were identified as independently associated with mortality, including a diagnosis of acute myeloid leukemia (odds ratio 2.38 [95% CI, 1.47 to 3.84]; P < .001), while the use of telemedicine was identified as a protective factor (odds ratio 0.36 [95% CI, 0.18 to 0.82]; P = .014). CONCLUSION These results highlight the collateral damage of COVID-19 in oncology patients.

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors. Epigenetic changes are implicated in Acute myeloid leukemia (AML) tumorigenesis. Here, the authors show that the ubiquitin ligase RNF5 and its substrate RBBP4 contribute to AML development by regulating epigenetic-controlled transcription which determines AML sensitivity to HDAC inhibitors.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.

Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34+ progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.

Immunosuppressed patients like patients with leukemia or lymphoma, but also patients after autologous or allogeneic stem cell transplantation are at particular risk for an infection with COVID‐19. We describe a COVID‐19 outbreak on our leukemia and stem cell transplantation unit (LSCT‐Unit) originating from a patient with newly diagnosed acute myeloid leukemia. The patient was treated with intensive induction chemotherapy and we characterize the subsequent outbreak of COVID‐19 on a LSCT‐Unit. We describe the characteristics of the 36 contacts among the medical team, the results of their PCR and antibody tests and clinical aspects and features of infected employees. Of these 36 close contacts, 9 employees of the LSCT‐Unit were infected and were tested positive by PCR and/or antibody‐testing. 8/9 of them were symptomatic, 3/9 with severe, 5/9 with mild symptoms, and one person without symptoms. Due to stringent hygiene measures, the outbreak did not lead to infections of other patients despite ongoing clinical work. Moreover, we demonstrate that incubation period and clinical course of a COVID‐19 infection in an immunosuppressed patient could be unusual compared to that of immunocompetent patients. Consistent PCR and antibody testing are helpful to understand, control, and prevent outbreaks. For the safety of health‐care workers and patients alike, all employees wore FFP2 masks and were trained to adhere to several further safety guidelines. The implementation of rigorous hygiene measures is the key to controlling an outbreak and preventing infections of other patients.

To determine if the immunophenotype of monocytes and granulocytes could help differentiate between reactive conditions and myeloid neoplasms.We analyzed 94 patients including acute myeloid leukemia (n=53), myelodysplastic syndrome (n=19), chronic myelomonocytic leukemia (n=13), and chronic myelogenous leukemia (n=9). Twenty-five cases of reactive condition were included as controls.Myeloid neoplasm cases showed significantly altered expression patterns including overexpression of CD56, altered expression of HLA-DR, underexpression of CD14, CD64, and altered expression of CD33 when compared to controls.There are significant and consistent differences in immunophenotype of monocytes and granulocytes in neoplastic groups versus controls. Immunophenotypic evaluation of monocytes and granulocytes in addition to blasts may be useful in flow cytometric assessment of minimal residual disease in myeloid neoplasms.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve long-term survival of patients with chronic-phase (CP) chronic myeloid leukemia (CML). Recently, the treatment goal for patients with CML-CP became safe discontinuation of TKIs. Several clinical trials have shown that approximately half of patients who experience a durable deep molecular response during TKI treatment maintain molecular remission after discontinuation of TKIs. However, the factors responsible for successful treatment-free remission (TFR) remain unclear. This study reviews very recent TKI discontinuation studies, focusing on factors responsible for TFR in patients with CML-CP. Longer TKI treatment duration, time of deep molecular response, presence of withdrawal syndrome, deeper molecular response, lower Sokal score, interferon α treatment before TKI administration, and favorable natural killer or T-cell profiles may be associated with TFR. However, different study designs have generated inconsistent data. Further investigations are needed to identify factors that consistently favor achievement of TFR.

BACKGROUND Abnormalities involving chromosome 7 are one of the most frequent chromosomal aberrations in myeloid neoplasms including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and are associated with an adverse prognosis. Immunophenotyping by flow cytometry provides data that can assist in the diagnosis and classification of myeloid neoplasms. The immunophenotypic features of myeloid neoplasms with monosomy 7 or del(7q) have not been previously described in a comprehensive fashion. METHODS We retrospectively analyzed flow cytometric data of myeloid neoplasms with monosomy 7 or del(7q) and summarized associated immunophenotypic features. RESULTS Myeloid neoplasms with monosomy 7 typically demonstrate multiple immunophenotypic abnormalities on myeloid blasts and maturing myelomonocytic cells. Increased CD14 expression on maturing granulocytic cells was characteristically seen in myeloid neoplasms with monosomy 7. This abnormality was significantly more frequent in myeloid neoplasms with monosomy 7 than in those with del(7q) (92.9% vs. 8.2%, P

Extramedullary hematopoeisis (EMH), also known as myeloid metaplasia can be seen in association with various hematological disorders. The common sites of EMH are liver, spleen and lymph nodes; but it can occur in almost any organ and in numerous locations. Involvement of the thyroid gland with EMH has rarely been reported. We present a case of EMH in the thyroid gland in an adult female diagnosed on fine-needle aspiration cytology (FNAC) which further helped in revealing an underlying myeloproliferative neoplasm; chronic myeloid leukemia (CML).

目的 探讨伴有t（3;21）（q26;q22）髓系肿瘤的临床特征。 方法 回顾性分析2011年1月至2018年3月北京大学人民医院收治的19例伴有t（3;21）（q26;q22）血液恶性肿瘤患者的临床资料，并汇总文献报道的有详细生存资料的48例患者，采用Kaplan-Meier法进行生存分析。 结果 19例患者中男15例，女4例，中位年龄36（22~68）岁，包括原发急性髓系白血病（AML）4例，骨髓增生异常综合征（MDS）4例，MDS转化的AML3例，慢性髓性白血病（CML）急变8例。19例患者染色体核型均可见t（3;21）（q26;q22），其中13例伴有附加异常。19例中9例进行AML1-MDS1融合基因检测均阳性。9例患者有随访资料，6例接受化疗的患者中4例无效，2例获得完全缓解。随访期内除1例MDS患者因随访期短（6个月）仍存活，其余8例均死亡，中位生存时间为6（4.5~22）个月。汇总文献生存分析结果显示伴有t（3;21）（q26;q22）的髓系肿瘤患者整体预后差，中位生存时间为7个月，尤以AML/治疗相关的AML预后最差，移植和非移植组中位生存时间分别为20.9和4.7个月，差异有统计学意义（P

Leukemias are malignancies in which abnormal white blood cells are produced in the bone marrow, resulting in compromise of normal bone marrow hematopoiesis and subsequent cytopenias. Leukemias are classified as myeloid or lymphoid depending on the type of abnormal cells produced and as acute or chronic according to cellular maturity. The four major types of leukemia are acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Clinical manifestations are due to either bone marrow suppression (anemia, thrombocytopenia, or neutropenia) or leukemic organ infiltration. Imaging manifestations of leukemia in the thorax are myriad. While lymphadenopathy is the most common manifestation of intrathoracic leukemia, leukemia may also involve the lungs, pleura, heart, and bones and soft tissues. Myeloid sarcomas occur in 5%-7% of patients with acute myeloid leukemia and represent masses of myeloid blast cells in an extramedullary location. ©RSNA, 2019.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.

Background Mutations in splicing factor 3b subunit 1 (SF3B1) have been reported to be associated with a favorable prognosis, while the prognostic impact of tet methylcytosine dioxygenase 2 (TET2) mutations is still controversial. The clinical significance of combined SF3B1 and TET2 mutation is even more uncertain. In this study, the clinical consequences of concurrent double SF3B1/TET2 mutation were compared with isolated SF3B1 or TET2 mutation. Materials and methods The demographics, diagnosis, cytogenetic abnormalities, and overall survival time of 130 patients with isolated SF3B1 (n=48) or TET2 mutation (n=54), or double SF3B1/TET2 mutation (n=28) were compared by next-generation sequencing. Results Patients with double mutation were found to be significantly older than patients with isolated TET2 mutation. Patients with double mutation or isolated SF3B1 mutation were less likely to be diagnosed with acute myeloid leukemia than patients with isolated TET2 mutation. Patients with myelodysplasia had a higher percentage of double or isolated SF3B1 mutation, while patients with myeloproliferative neoplasms had a higher percentage of isolated TET2 mutation. Patients with double mutation more frequently had increased ring sideroblasts similarly to patients with isolated SF3B1 mutation. The percentage of patients with normal cytogenetics or good cytogenetic abnormalities was significantly higher in patients with double mutation than those with isolated mutation. Finally, in patients with myelodysplasia and normal cytogenetics, the median survival time in those with double mutation was significantly longer than in those with isolated SF3B1 mutation, even though the overall survival curve was not statistically significant. Conclusion TET2 mutation appeared not to have additional effects when combined with SF3B1, and patients with double mutation appeared to have at least as, good as or even better prognosis than patients with isolated mutation.

DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.

Here we report a C-terminal RUNX1 mutation in a family with platelet disorder and predisposition to myeloid malignancies. We identified the mutation c.866delG:p.Gly289Aspfs*22 (NM_001754) (RUNX1 b-isoform NM_001001890; c.785delG:p.Gly262Aspfs*22) using exome sequencing of samples obtained from eight members of a single family. The mutation found in our pedigree is within exon eight and the transactivation domain of RUNX1. One of the affected individuals developed myelodysplastic syndrome (MDS), which progressed to acute myelogenous leukemia (AML). A search for the second hit which led to the development of MDS and later AML in this individual revealed the PHF6 gene variant (exon9:c.872G > A:p.G291E; NM_001015877), BCORL1 (exon3:c.1111A > C:p.T371P; NM_001184772) and BCOR gene variant (exon4:c.2076dupT:p.P693fs; NM_001123383), which appear to be very likely second hits participating in the progression to myeloid malignancy.

We have been using a combination of fludarabine/busulfan plus low-dose total body irradiation (TBI) as the reduced-intensity conditioning (RIC) regimen for patients age ≥ 60 years undergoing allogeneic hematopoietic cell transplantation (HCT) for myeloid malignancies. We retrospectively analyzed outcomes of 116 older patients (median age 64 years) who underwent HCT from 2006 to 2015 for myeloid malignancies, including acute myeloid leukemia (AML) in first complete remission (CR1). On univariate analysis, overall survival (OS) for the cohort at 3 years was 33% (95% CI 25-42). Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years were 24% (95% CI 16-32) and 43% (95% CI 34-52), respectively. Multivariable analysis for OS demonstrated AML patients to have superior outcome (HR 1.60 for other myeloid, 95% CI 1.01-2.54, p = 0.045), as well as related donors (HR 1.92 for unrelated, 95% CI 1.22-3.03, p = 0.005). For NRM, AML patients had superior outcome (HR 1.76 for other myeloid, 95% CI 1.03-3.01, p = 0.038), as well as patients with related donors (HR 1.81 for unrelated, 95% CI 1.07-3.07, p = 0.028). We then demonstrated that AML patients with related donors (n = 45) had superior 3-year OS of 51% (95% CI 36-65), compared to 21% (95% CI 12-32) for all other patients (p = 0.0003). We conclude that the RIC regimen used is effective for older patients, particularly AML patients in CR1 with matched related donors.