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Purpose: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined., Methods: We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration., Results: The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined., Conclusion: We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS., Competing Interests: Ryotaro NakamuraConsulting or Advisory Role: Viracor Eurofins, Magenta Therapeutics, Kadmon, Napajen PharmaResearch Funding: Helocyte, Miyarisan PharmaceuticalTravel, Accommodations, Expenses: Kyowa Hakko Kirin, Alexion Pharmaceuticals Bart ScottHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Celgene, Acceleron Pharma, Astex Pharmaceuticals, NovartisSpeakers' Bureau: Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, NovartisResearch Funding: Celgene Betul OranResearch Funding: AROG Phamarceuticals, Astex Pharmaceuticals Asmita MishraResearch Funding: Novartis Richard T. MaziarzHonoraria: Novartis, Omeros, PACT PharmaceuticalsConsulting or Advisory Role: Novartis, Incyte, Kite, a Gilead company, Bristol Myers Squibb, Intellia Therapeutics, ArtivaPatents, Royalties, Other Intellectual Property: Athersys Inc shared patent re: use of mesenchymal stromal cells for treatment of GVHDTravel, Accommodations, Expenses: Novartis, Incyte, Kite, a Gilead company Joseph McGuirkHonoraria: Kite, a Gilead company, AlloVir, Juno Therapeutics, Magenta TherapeuticsConsulting or Advisory Role: Kite, a Gilead company, Juno Therapeutics, AlloVir, Magenta Therapeutics, EcoR1 CapitalSpeakers' Bureau: Kite/GileadResearch Funding: Novartis, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Therapeutics, Kite, a Gilead company, AlloVirTravel, Accommodations, Expenses: Kite, a Gilead company Peter WesterveltConsulting or Advisory Role: Pfizer Sumithira VasuConsulting or Advisory Role: Omeros, Johnson & JohnsonPatents, Royalties, Other Intellectual Property: The Ohio State University has entered into an exclusive licensing agreement with Kiadis Inc Mrinal PatnaikHonoraria: Kura OncologyConsulting or Advisory Role: Kura OncologyResearch Funding: Stemline Therapeutics Stephen J. FormanStock and Other Ownership Interests: MustangBio, Lixte BiotechnologyConsulting or Advisory Role: Alimera Sciences, Lixte Biotechnology, MustangBioResearch Funding: MustangBioPatents, Royalties, Other Intellectual Property: MustangBio Mikkael A. SekeresConsulting or Advisory Role: Celgene, Millennium, Pfizer, NovartisResearch Funding: Takeda, Pfizer, Bristol Myers Squibb Frederick AppelbaumStock and Other Ownership Interests: Jasper Therapeutics Brent LoganConsulting or Advisory Role: Daiichi Sankyo, Enlivex Therapeutics Ltd, Gamida Cell Mary HorowitzConsulting or Advisory Role: Magenta Therapeutics, Janssen Research & Development, MedacResearch Funding: Biovitrum, Jazz Pharmaceuticals, Magenta Therapeutics, Novartis, Kite/Gilead, Actinium Pharmaceuticals, Amgen, Amneal Pharmaceuticals, Anthem, Bluebird Bio, Bristol Myers Squibb, Chimerix, CSL Behring, Cyto-Sen Therapeutics, Daiichi Sankyo, Gamida Cell, GlaxoSmithKline, Mesoblast, Miltenyi Biotec, Neovii, Oncoimmune, Pfizer, Pharmacyclics, Regeneron, Sanofi, Seattle Genetics, Shire Corey CutlerStock and Other Ownership Interests: Bluebird Bio, Idera, Verastem, Northwest Biotherapeutics, Actinium PharmaceuticalsHonoraria: Omeros, PfizerConsulting or Advisory Role: Incyte, Jazz Pharmaceuticals, CareDX, Mesoblast, Syndax, MedsenicNo other potential conflicts of interest were reported.

HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet-derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT., (© 2018 by The American Society of Hematology.)

Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.

Background: The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT., Methods: A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model., Results: Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy., Conclusions: The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia., Methods: We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37)., Results: The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse., Conclusions: We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Presents a study which aimed to investigate the biological role of a bcr-3 isoform of RAR...-PML for the development of acute promyelocytic leukemia (APML) in a transgenic mouse model. Information on APML; Construction of the transgene; Detection of transgene expression in bone marrow cells; Treatment of APML cells in vitro; Results.

Abstract: The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with varying degrees of mono- to trilineage cytopenias and bone marrow dysplasia. In recent years much progress has been made in the treatment of MDS and there are now several therapeutic compounds used with varying levels of success. These compounds typically cause side effects that make them unattractive for treatment of patients in the early stages of MDS. Naturally occurring compounds that are not toxic may provide a means to treat patients in the initial stages of disease. We conducted a pilot study to test the efficacy of coenzyme Q10 (coQ10) in MDS patients with low to intermediate-2 risk disease. A variety of responses were observed in 7 of 29 patients including two trilineage and two cytogenetic responses. Sequencing mitochondrial DNA (mtDNA) from pretreatment bone marrows showed multiple mutations, some resulting in amino acid changes, in 3/5 nonresponders, 1/4 responders and in two control samples. We conclude that coQ10 may be of clinical benefit in a subset of MDS patients, but responders cannot be easily pre-selected on the basis of either the conventional clinical and pathologic characteristics or mtDNA mutations. [Copyright &y& Elsevier]

Summary DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A R882H , has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A R882 mutations. Non-leukemic hematopoietic cells with DNMT3A R882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A R882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3A R882 , while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression. [ABSTRACT FROM AUTHOR]