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The WHO and International Consensus Classification 2022 classifications of myelodysplastic syndromes enhance diagnostic precision and refine decision-making processes in these diseases. However, some discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. We adopted a data-driven approach to provide a harmonisation between these two classification systems. We investigated the importance of genomic features and their effect on the cluster assignment process to define harmonised entity labels. A panel of expert haematologists, haematopathologists, and data scientists who are members of the International Consortium for Myelodysplastic Syndromes was formed and a modified Delphi consensus process was adopted to harmonise morphologically defined categories without a distinct genomic profile. The panel held regular online meetings and participated in a two-round survey using an online voting tool. We identified nine clusters with distinct genomic features. The cluster of highest hierarchical importance was characterised by biallelic TP53 inactivation. Cluster assignment was irrespective of blast count. Individuals with monoallelic TP53 inactivation were assigned to other clusters. Hierarchically, the second most important group included myelodysplastic syndromes with del(5q). Isolated del(5q) and less than 5% of blast cells in the bone marrow were the most relevant label-defining features. The third most important cluster included myelodysplastic syndromes with mutated SF3B1. The absence of isolated del(5q), del(7q)/-7, abn3q26.2, complex karyotype, RUNX1 mutations, or biallelic TP53 were the basis for a harmonised label of this category. Morphologically defined myelodysplastic syndrome entities showed large genomic heterogeneity that was not efficiently captured by single-lineage versus multilineage dysplasia, marrow blasts, hypocellularity, or fibrosis. We investigated the biological continuum between myelodysplastic syndromes with more than 10% bone marrow blasts and acute myeloid leukaemia, and found only a partial overlap in genetic features. After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting., Competing Interests: Declaration of interests UG reports speaker honoraria from Novartis, AbbVie, and BMS; and institutional research support from BMS, AbbVie, and Jazz Pharmaceuticals. FE reports consultancy or advisory roles for AbbVie, Incyte, Syros, Novartis, and Jazz Pharmaceuticals. SH reports research support from STORM Therapeutics and AstraZeneca. EAG reports honoraria from AAMDS, MedscapeLIVE!, MediCom Worldwide, MJH Life Sciences, ASH, MDS International Foundation, and Physicians’ Education Resource; consulting fees from AbbVie, Alexion, Apellis, Takeda Oncology, Astex/Taiho Oncology, Alexion/AstraZeneca Rare Disease, Celgene/BMS, CTI BioPharma, Novartis, Partner Therapeutics, Picnic Health, and Servier; and research funding from Alexion, Apellis, Astex /Otsuka/Taiho Oncology, Blueprint Medicines, Celldex Therapeutics, Genentech, and NextCure. MAS reports participation on advisory boards for BMS, Kurome, Schrödinger, and Karyopharm. MD-C reports participation on a data safety monitoring board or advisory board for BMS, Novartis, Blueprint Medicines, GSK, Agios, Hemavan, Syros, Keros, Curis, and Astex/Otsuka; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events for BMS, Novartis, and Keros. UP reports research support and honoraria from BMS, Geron, Curis, AbbVie, and Janssen. RBe reports employment or equity from Aptose Biosciences; participation on advisory boards for BMS, Servier, NeoGenomics, and Geron; being Data Monitoring Committee Chair for Gilead, Ipsen, and Keros; and consultancy for TenSixteen. YM reports honoraria from Nippon Shinyaku, BMS, Novartis, Sumitomo Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Takeda, Janssen, Astellas, Pfizer, Eisai, and Otsuka; and research funding from Chugai. AED reports participation on advisory boards, consultancy, or honoraria from Celgene/BMS, Agios, Novartis, Astellas, and Gilead; and participation on clinical trial committees or data safety monitoring boards for Novartis, AbbVie, Kura, Geron, Servier, Keros, and Celgene/BMS. DPS reports employment by Ajax Therapeutics; former employment by Novartis; and minor equity in Arrowhead and Bluebird. TKK reports consultancy for Agenus and ImmunoBiome. AK reports research support from Novartis and BMS; consulting fees from Alexion, Novartis, Amgen, Agios, Pfizer, Samsung, Celgene, F Hoffmann-La Roche, and Sobi; honoraria from Alexion, Novartis, Pfizer, Amgen, Samsung, Celgene, F Hoffmann-La Roche, BMS, Sobi, and Silence Therapeutics; and speakers fees from Alexion, Novartis, Amgen, Pfizer, Celgene, F Hoffmann-La Roche, and Sobi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The current World Health Organization (WHO) classification of myeloid malignancies includes myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) as a distinct entity. Previous literature on predictors of survival was based on the provisional category of refractory anemia with ring sideroblast and thrombocytosis (RARS-T), which was not subject to MDS/MPN-RS-T exclusionary criteria such as PB blast% ≥1, BM blast% ≥5 or cytogenetic abnormalities such as t(3;3)(q21.2;q26.2), inv(3)(q21.23q26.2) or isolated del(5q). We examined overall (OS) and leukemia-free (LFS) survival and its predictors, among 158 patients with WHO-defined MDS/MPN-RS-T. In univariate analysis, age ≥70 years (P = 0.006), hemoglobin (Hb) ≤10 g/dL (P = 0.03) and abnormal karyotype (excluding -Y, P = 0.008) were associated with shortened OS, which was otherwise not affected by either ASXL1 (P = 0.7), SF3B1 (P = 0.4) or JAK2 V617F (P = 0.7) mutations; in multivariable analysis, Hb ≤ 10 g/dL (P = 0.03) and abnormal karyotype (P = 0.001) remained significant, and thus allowed the development of an operational survival model with low (0 risk factors, median OS 10.5 years), intermediate (1 risk factor, median OS 4.8 years) and high risk (2 risk factors, median OS 1.4 years) categories (P = 0.0009). Comparison of MDS/MPN-RS-T (n = 158) and MDS/MPN-U with BM RS ≥ 15% (MDS/MPN-U-RS; n = 25) did not reveal significant differences in frequency of thrombosis, OS, or LFS, although SF3B1 mutation frequency was higher in the former (93% versus 59%; P = 0.0005). These data suggest limited survival impact for molecular abnormalities and the morphological distinction between MDS/MPN-RS-T and MDS/MPN-U-RS., (© 2022. The Author(s).)

Recent studies demonstrated that MYC epigenetically regulates AML cell survival and differentiation by suppressing IDH1/2-TET2-5hmC signaling and that MYC overexpression is associated with poor survival outcomes in multiple AML patient cohorts. However, the oncogenic roles of MYC in MDS remain to be explored. A total of 41 patients with de novo MDS were retrospectively identified using the Total Cancer Care database at the Moffitt Cancer Center. A total of 61 % of patients had low MYC expression and 39 % of patients had high MYC expression defined as MYC reactivity by immunohistochemical staining in ≥5% of bone marrow (BM) cells at the time of MDS diagnosis. The median MDS-to-AML progression free survival (PFS) was significantly shorter in the high MYC group (median PFS 9.3 vs. 17.7 months, HR = 2.328, p = 0.013). Further, overall survival (OS) was also shorter in the high MYC patients (median OS 19.7 vs. 51.7 months, HR = 2.299, p = 0.053). Multivariate analyses demonstrated that high MYC expression is an independent poor prognostic factor for the MDS-to-AML progression (HR = 2.275, p = 0.046). Our observations indicate that MYC may play a crucial role in MDS transformation to AML and the underlying mechanisms of MYC-driven MDS clonal expansion and leukemic transformation require further investigation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Approximately 20% of patients with TP53 -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53 -mutant cells., Methods: This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53 -mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043)., Results: Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%)., Conclusion: Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53 -mutant MDS and oligoblastic AML., Competing Interests: David A. SallmanConsulting or Advisory Role: Celyad, Agios, Abbvie, Aprea AB, Bristol-Myers Squibb, Gilead Sciences, Intellia Therapeutics, Kite Pharma, Magenta Therapeutics, Novartis, SyndaxSpeakers' Bureau: Agios, Incyte, Bristol-Myers SquibbResearch Funding: Celgene, Jazz PharmaceuticalsPatents, Royalties, Other Intellectual Property: Intellectual Property Patent for LB-100 in MDS Amy E. DeZernConsulting or Advisory Role: Celgene, Novartis, Gilead SciencesResearch Funding: Celgene, Astex PharmaceuticalsTravel, Accommodations, Expenses: Abbvie Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbvieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol-Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, Abbvie, Bristol-Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck David P. SteensmaStock and Other Ownership Interests: Arrowhead Pharmaceuticals, Sage TherapeuticsHonoraria: Daiichi Sankyo, Summer Road, Stemline Therapeutics, Celgene, Astex PharmaceuticalsConsulting or Advisory Role: Pfizer, Janssen Oncology, Agios, Onconova Therapeutics, Geron, Astex PharmaceuticalsResearch Funding: Aprea AB, Celgene/BMS, H3 Biomedicine Gail J. RobozConsulting or Advisory Role: Amphivena, Janssen, Amgen, Astex Pharmaceuticals, Celgene, Genoptix, MedImmune, Novartis, Pfizer, Abbvie, Argenx, Array BioPharma, Bayer, Celltrion, Jazz Pharmaceuticals, Orsenix, Genentech/Roche, Sandoz, Actinium Pharmaceuticals, Astellas Pharma, Eisai, Bayer, Daiichi Sankyo, MEI Pharma, Otsuka, Takeda, Roche, Agios, Trovagene, GlaxoSmithKline, Bristol-Myers Squibb, Helsinn Therapeutics, MesoblastResearch Funding: Abbvie, Agios, Astex Pharmaceuticals, Celgene, CTI, Karyopharm Therapeutics, MedImmune, MEI Pharma, Moffitt, Novartis, Onconova Therapeutics, Pfizer, Sunesis Pharmaceuticals, Tensha Therapeutics, Cellectis, Janssen, AmphivenaTravel, Accommodations, Expenses: Amphivena, Astex Pharmaceuticals, Janssen, Pfizer, Array BioPharma, Novartis, Abbvie, Jazz Pharmaceuticals, Celgene, Celltrion, Roche/Genentech, Sandoz, Bayer, Clovis Oncology, Amgen, Sunesis Pharmaceuticals, Eisai, Agios Mikkael A. SekeresConsulting or Advisory Role: Celgene, Millennium, Syros PharmaceuticalsResearch Funding: Takeda, Pfizer, Bristol-Myers Squibb Thomas CluzeauConsulting or Advisory Role: Abbvie, Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche, Takeda, Syros PharmaceuticalsSpeakers' Bureau: Novartis, Amgen, Sanofi, Astellas PharmaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Pfizer, Sanofi Kendra L. SweetLeadership: ImmtechConsulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Novartis, Takeda, Stemline TherapeuticsResearch Funding: Incyte Kathy L. McGrawResearch Funding: Genentech, Celgene Eric PadronHonoraria: Stemline Therapeutics, Blueprint MedicinesSpeakers' Bureau: Novartis, Taiho PharmaceuticalResearch Funding: Incyte, Bristol-Myers Squibb, Kura Oncology Greg KorbelEmployment: Aprea Therapeutics, IncLeadership: Aprea Therapeutics, IncStock and Other Ownership Interests: Aprea Therapeutics, Inc Eyal C. AttarEmployment: Agios, Aprea ABLeadership: Aprea ABStock and Other Ownership Interests: Agios, Aprea ABConsulting or Advisory Role: TeladocTravel, Accommodations, Expenses: Aprea AB, Agios Hagop M. KantarjianHonoraria: Abbvie, Amgen, ARIAD, Bristol-Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol-Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, Abbvie, Agios, Cyclacel, Immunogen, Jazz Pharmaceuticals Jeffrey E. LancetStock and Other Ownership Interests: ArvinasConsulting or Advisory Role: Jazz Pharmaceuticals, Astellas Pharma, Abbvie, Agios, BerGenBio, Daiichi Sankyo, ElevateBioResearch Funding: Pfizer Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Alan F. ListHonoraria: Celgene, Aileron Therapeutics, Cellular Biomedicine GroupConsulting or Advisory Role: Celgene, Cellular Biomedicine Group, Aileron Therapeutics, Acceleron Pharma, International Personalized Cancer Center, Precision Biosciences, CTI BioPharma Corp, Prelude TherapeuticsResearch Funding: CelgeneTravel, Accommodations, Expenses: Celgene, Cellular Biomedicine GroupOther Relationship: Thousand Talents Award Rami S. KomrokjiStock and Other Ownership Interests: AbbvieConsulting or Advisory Role: Novartis, Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Abbvie, Geron, Acceleron PharmaSpeakers' Bureau: Jazz Pharmaceuticals, Bristol-Myers Squibb, AgiosTravel, Accommodations, Expenses: Incyte, Jazz Pharmaceuticals, Bristol-Myers Squibb, AgiosNo other potential conflicts of interest were reported.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)-inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death., (© 2021 by The American Society of Hematology.)

The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS [n = 95]; sAML [n = 52]; CMML [n = 10]) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03-0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05-0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher-risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first-line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first-line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher-risk MDS pts treated at Moffitt Cancer Center who received first-line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation., (© 2020 by The American Society of Hematology.)

Background: Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset., Patients and Methods: Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts)., Results: Specific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3-MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P  =  .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P  =  .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs., Conclusion: Patients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Immunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients with lower-risk myelodysplastic syndrome (MDS). Age, human leukocyte antigen (HLA)-DR15 positivity, and duration of transfusion dependence are putative clinical variables predictive for response. We investigated the effect of somatic gene mutations on response to IST in lower-risk MDS., Patients and Methods: Forty of 66 patients who received antithymocyte globulin with or without cyclosporine A identified at the Moffitt Cancer Center were molecularly profiled using a 49-gene myeloid panel. All patients profiled received antithymocyte globulin, and cyclosporine A was provided to 60% of patients., Results: The overall frequency of HI was 42%. Presence of a large granular lymphocytic clone, hypocellular bone marrow, HLA-DR15 positivity, trisomy 8, and age had no influence on response to IST. Among 40 patients evaluated by next-generation sequencing, the presence of an SF3B1 mutation (MT) was significantly associated with IST nonresponse (1 of 9 SF3B1 MT, 11% vs. 21 of 31 wild type, 68%; P = .002). All patients with SF3B1 MT had ring sideroblasts > 15% (RS) by morphology; the corresponding HI rate was 20% among patients with RS versus 50% for those without RS (P = .09)., Conclusion: These findings support the clinical implementation of genomics in MDS. The presence of an SF3B1 mutation adversely influences response to IST and should be incorporated into treatment decisions upon validation of these findings., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: To test the hypothesis that combination treatment with lenalidomide and prednisone will yield a higher erythroid response rate in patients with non-del(5q) lower-risk myelodysplastic syndromes compared to the historical clinical trial data with lenalidomide monotherapy, which reported a 26% transfusion independence rate., Patients and Methods: The study enrolled 25 patients with lower-risk myelodysplastic syndromes by the International Prognostic Scoring System who were transfusion dependent or who had symptomatic anemia and prior erythroid stimulating agent failure or low chance of response. The planned dose of lenalidomide was 10 mg per day. Prednisone dose was 30 mg by mouth, daily cycle 1 tapered by 10 mg after each cycle to 5 mg by mouth every other day for those with response beyond cycle 6. The primary objective was best response (hematologic improvement-erythroid, HI-E) by International Working Group 2006 criteria within 24 weeks., Results: The HI-E rate was 20% (5/25) and was 22% (5/23) for patients with evaluable data. All those with response became red blood cell-transfusion independent (5/23). The median time to response was 57 days. The median duration of response was 80 days (95% confidence interval, 69-91). Three of 5 of those with response did not have prior hypomethylating agent, while 14 of 20 those without response received a hypomethylating agent., Conclusion: The combination was relatively well tolerated, with no additional observed toxicity to single-agent lenalidomide., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.

In patients with acute myeloid leukemia (AML), the presence of residual disease at day 14 after primary induction therapy warrants consideration of a second induction cycle. However, data to guide retreatment decisions in such patients are presently limited. Here, we retrospectively reviewed data from 176 patients with AML treated at our institution with a second induction chemotherapy regimen because of day 14 residual disease. Clinical variables and nadir bone marrow features were assessed for correlations with complete remission (CR) and overall survival (OS). In our patient group, 59% achieved CR after a second induction course. Median OS for the entire group was 12.40 months (95% CI, 9.90-14.90) but 19.07 months (95% CI, 13.13-25.01) for those who attained a CR. Nadir marrow hypocellularity (P < 0.001) at day 14, absolute blast reduction of >50% (P = 0.030), and de novo disease status (P = 0.018) were significantly correlated with CR achievement after re-induction. Marrow hypocellularity at day 14 was the most significant predictor of CR on multivariate analysis (P < 0.001). Nadir marrow features did not independently correlate with OS when accounting for CR status. Re-induction was successful in achieving CR in most patients. Study patients who did not achieve CR were more likely to have nonhypocellular marrows., (© 2016 Wiley Periodicals, Inc.)

The few studies that have examined rates of acute myeloid leukemia (AML) transformation in lenalidomide-treated myelodysplastic syndrome (MDS) patients have been limited to deletion 5q MDS. The association between lenalidomide and subsequent primary malignancies (SPMs) in MDS patients has not been evaluated previously. We conducted a retrospective cohort study to evaluate the risk of both SPM and AML in association with lenalidomide. A cohort of MDS patients (n = 1248) treated between 2004 and 2012 at Moffitt Cancer Center were identified, and incident cases of SPM and AML transformation were ascertained. Using a nested case-control design, MDS controls were 1:1 matched to SPM (n = 41) and AML (n = 150) cases, on age and date of MDS diagnosis, gender, follow-up time, IPSS, and del (5q). Associations between lenalidomide and (1) SPM incidence and (2) AML transformation were estimated with hazards ratios (HR) and 95% confidence intervals (CIs) in the cohort and odds ratios (OR) in the case-control analysis. SPM incidence did not differ significantly between cohort MDS patients treated with (0.7 per 100 person-years) or without lenalidomide (1.4 per 100 person-years) (HR = 1.04, 95% CI = 0.40-2.74), whereas a significantly reduced SPM risk was observed in the case-control sample (OR = 0.03, 95% CI = <0.01-0.63). Lenalidomide was not associated with AML transformation in the cohort analysis (HR = 0.75, 95% CI = 0.44-1.27) or in the case-control analyses (OR = 1.16, 95% CI = 0.52-2.56), after adjustment for potential confounders. Lenalidomide was not associated with increased risk of SPM or AML transformation in a large cohort of MDS patients mostly including nondeletion 5q MDS., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation., (© 2016 Wiley Periodicals, Inc.)

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

Treatment with hypomethylating agents (HMAs) improves overall survival (OS) in patients who achieve a response of stable disease (SD) or better (complete remission [CR], partial remission [PR], or hematologic improvement [HI]). It is not well established if patients who achieve SD at 4-6 months of therapy should be offered different therapies to optimize their response or continue with the same regimen. Clinical data were obtained from the MDS Clinical Research Consortium database. SD was defined as no evidence of progression and without achievement of any other responses. Of 291 patients treated with AZA or DAC, 55% achieved their best response (BR) at 4-6 months. Among patients with SD at 4-6 months, 29 (20%) achieved a better response at a later treatment time point. Younger patients with lower bone marrow blast percentages, and intermediate risk per IPSS-R were more likely to achieve a better response (CR, PR, or HI) after SD at 4-6 months. Patients with SD who subsequently achieved CR had superior OS compared to patients who remained with SD (28.1 vs. 14.4 months, respectively, p=.04). In conclusion, patients treated with HMAs who achieves CR after a SD status had longer survival with continuous treatment after 6 months., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Lenalidomide and azanucleosides are commonly used to treat anemic patients with lower-risk myelodysplastic syndromes (LR-MDS) without chromosome 5q deletion (non-del5q) after failure of treatment with erythropoiesis-stimulating agents (ESAs). Nonetheless, response rates to lenalidomide after azanucleosides treatment failure and their optimal sequencing after failure of treatment with ESAs is unknown., Patients and Methods: We identified patients with LR-MDS in the Moffitt Cancer Center Clinical Database who received lenalidomide and azacitidine after ESA treatment failure. Rates of erythroid hematologic improvement (HI-E) in patients who received lenalidomide first followed by azacitidine (group 1) and those who received lenalidomide after azacitidine (group 2) were examined according to the International Working Group 2006 criteria., Results: Sixty-three patients (37 in group 1 and 26 in group 2) were identified. The HI-E rate with lenalidomide as first-line therapy was 38% versus only 12% when lenalidomide was used as second-line therapy (P = .04). There were no significant differences in overall survival (OS; median OS, 104 vs. 87 months, respectively; P = .55), rates of leukemic progression, or in HI-E rates after azacitidine use (38% when azacitidine was used after lenalidomide vs. 35% when azacitidine was administered before lenalidomide, P = .69)., Conclusion: Lenalidomide appears to yield a higher HI-E rate in non-del5q LR-MDS when used as first-line therapy after ESA treatments failure. If validated in larger cohorts, lenalidomide rather than azacitidine should be considered for first-line therapy after ESA treatment failure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

We hypothesized that tobacco usage is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). To evaluate the impact of tobacco usage in this population, we identified patients diagnosed with MDS in our Center's MDS database and reviewed individual charts retrospectively. Of the 767 MDS patients identified, 743 patients (97%) had a known tobacco usage history. Given that the majority of tobacco users were smokers, we stratified patients as having never smoked (never-smoker group) versus current or former smokers (ever-smoker group). Greater than 60% of ever-smokers were risk stratified as having low or intermediate-1 (int-1) risk at diagnosis based on the International Prognostic Scoring System for MDS. In patients with lower-risk MDS, we found that ever-smokers had an increased proportion of poor-risk karyotypes (8.8%) compared with never-smokers (2.4%) (P=0.003). The adverse effect of smoking was greatest in the low-risk and int-1-risk groups, where median overall survival was 69 months (95% CI 42-96) in never-smokers versus 48 months (95% CI 41-55) in ever-smokers (P=0.006). The median overall survival for never-smokers, former smokers, and current smokers was 69 months (95% CI 42-96), 50 months (95% CI 43-57), and 38 months (95% CI 23-53), respectively, in patients risk stratified as lower-risk MDS (P=0.01). Our findings suggest that tobacco usage negatively impacts overall survival in patients with lower-risk MDS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The hypomethylating agents (HMAs) azacitidine and decitabine are most commonly used to treat patients with higher-risk myelodysplastic syndromes (MDS). To the authors' knowledge, the prognosis of patients with low-risk and intermediate-1-risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure has not been explored comprehensively., Methods: The clinical characteristics and treatment outcome of 438 patients with low-risk and intermediate-1-risk MDS who were treated with HMAs were retrospectively analyzed., Results: Using the International Working Group response criteria, the overall objective response to HMA was 35% with a median of 6 cycles of HMA administered, and the median response duration was 7 months. Only 7% of patients had disease that transformed into acute myeloid leukemia while receiving therapy. Of the 290 patients who were evaluable at the time of HMA failure, 77% remained in the lower-risk disease categories. On multivariate analysis, baseline neutropenia, intermediate-risk and poor-risk baseline karyotype, and lack of response to HMA were found to be independently associated with a higher risk of disease progression. With a median follow-up of 16 months, the median transformation-free survival and overall survival (OS) after HMA failure were 15 months and 17 months, respectively. On multivariate analysis, only The University of Texas MD Anderson Global Scoring System was found to be independently predictive of outcome, with patients with higher-risk categories having poor transformation-free survival (hazards ratio [HR], 1.5; P = .003) and OS (HR, 1.8; P = .002). The administration of salvage therapy was independently associated with better OS only (HR, 0.8; P = .01)., Conclusions: Outcomes of patients with lower-risk MDS after HMA failure are poor and the treatment of these patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population., (© 2014 American Cancer Society.)

Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (KDMs). In this single-institution retrospective analysis, patients with KDMs were identified from a cohort of patients treated for CML at our institution. Clinical outcomes were assessed based on the characteristics of the KDMs and results of cytogenetic analysis. In total, we compared 26 patients with KDM to those without; 46 % (n = 12) versus 20 % (n = 57) progressed to advanced phase (P = 0.003). Median overall survival was 22 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations (P = 0.127). KDM patients had a median progression-free survival (PFS) and overall survival of 75 and 109 months; however, neither was reached in the non-mutation cohort (P = 0.0007, P = 0.235). Median PFS in patients with single versus compound or double mutations was not reached versus 10 months (P = 0.014). We conclude that T315I, P-loop, and compound mutations may worsen prognosis in CML.

For patients with acute myeloid leukemia from antecedent myelodysplastic syndrome particularly after azanucleoside treatment failure, outcome is poor. Here, we conducted a case-control study in these patients to compare the efficacy of CLAG-M induction (28 patients) versus standard 3+7 induction chemotherapy (24 patients). Response rates (P=0.014) and median overall survival (P=0.025) were 64% and 202 days (95% CI 37-367 days) versus 29% and 86 days (95% CI 36-136) in the CLAG-M and 3+7 cohorts, respectively. Median overall survival was 202 (95% CI 37-367 days) versus 86 days (95% CI 36-136) (P=0.025), respectively. CLAG-M has encouraging activity in this patient group., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Limited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed., Patients and Methods: This was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method., Results: A total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%., Conclusion: Patients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = -0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS.

Azacitidine's efficacy in therapy-related myeloid neoplasms (t-MN) has not been well-studied. In our retrospective review of 84 t-MN patients treated with azacitidine, median overall survival (OS) was 14.5 months and overall response rate was 43%, including 11% complete remission, 4% marrow complete remission, and 11% partial remission. In patients who underwent allogeneic transplant (25%), median OS was 19.2 versus 12.8 months (P=0.023) for those who did not. Response rates were comparable to those reported for de novo myelodysplastic syndrome. When we analyzed outcomes according to five scoring systems, only the Global MD Anderson Risk Model predicted survival with statistical significance., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We hypothesized that hypoalbuminemia is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). We analyzed records of 767 patients treated at Moffitt Cancer Center between January 2001 and December 2009 to evaluate the relationship between serum albumin (SA) at the time of presentation and overall survival (OS). Patients (median age of 69 years) were stratified into three groups based on SA concentration (≤3.5, 3.6-4.0, and >4.0 g/dL). Two-thirds of the patients had low or intermediate-1 International Prognostic Scoring System (IPSS)-based risk for MDS. Median OS by SA concentration of ≤3.5, 3.6-4.0, and >4.0 g/dL was 11, 23, and 34 months, respectively (P < 0.005), whereas rate of acute myeloid leukemia progression was highest in patients with low SA (≤3.5 g/dL). The SA level offered prognostic discrimination for outcomes within the lower and higher IPSS risk groups, as well as with the MD Anderson risk model. In multivariable analysis, SA was a significant independent co-variate for OS after adjustment for IPSS, age, serum ferritin, and transfusion dependence (hazard ratio = 0.8; 95% CI 0.6-0.9; P = 0.004). Our findings indicate that hypoalbuminemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology or comorbidities in patients with MDS., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) outcome in the United States has not been reported outside the context of clinical trials., Patients and Methods: We reviewed the Surveillance, Epidemiology, and End Results (SEER) registry and compared survival trends among DLBCL patients from 1973 to 2004., Results: We identified 59,728 patients (mean age, 63 years; 54.4% men, 86.7% white) and had staging information for 57%, including 30% early-stage (I/II) and 27% advanced-stage (III/IV). Median overall survival (OS) from 1973 to 1979, 1980 to 1989,1990 to 1999, and 2000 to 2004 was 15, 18, 20, and 47 months, respectively (P < .005). For the period from 2000 to 2004, 4-year OS was 46%. Outcome was better in white patients than in black (47 months versus 29 months) (P = .001). Median OS for patients younger than 60 years old was not reached versus 23 months for patients older than 60 years., Conclusion: The outcome of DLBCL in the United States has improved significantly in the era of monoclonal antibodies; however, racial disparities remain., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Epidemiology and outcome of myelodysplastic syndromes (MDS) in the United States is not well recognized. MDS became reportable to the Surveillance, Epidemiology, and End Results Program (SEER) in 2001. We report first study of MDS among large population in the Veteran Affair system., Patients and Methods: There are approximately 127 VA Medical Centers diagnosing and/or treating Cancer patients. The data collected by the medical centers cancer registries is aggregated as the VA Central Cancer Registry (VACCR). We used the VACCR to analyze VA patients with MDS diagnosed between 1995 and 2006. The cases were identified using ICD-03 histology codes for MDS., Results: A total of 2242 MDS cases were registered during the period analyzed. The median overall survival (OS) was 2.1 years, but varied by French-American-British category. Median OS for patients with RA, RARS and RAEB was 3.4, 4.9, and 0.7 years, respectively. No differences in OS were observed by race., Conclusion: Outcome of MDS in the VA was similar to what is described in literature and reported by the SEER Program. Appropriate coding for WHO subtypes, IPSS and treatment details are needed in all MDS registries to facilitate comparisons across populations., (2009 Elsevier Ltd. All rights reserved.)