1 960 168 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 2 961 76 CHRONIC MYELOMONOCYTIC LEUKEMIA: A GENETIC AND CLINICAL UPDATE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER, CHARACTERIZED BY PERIPHERAL BLOOD MONOCYTOSIS AND OVERLAPPING FEATURES BETWEEN MYELODYSPLASTIC SYNDROMES (MDS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CLONAL CYTOGENETIC CHANGES ARE SEEN IN UP TO 30 % PATIENTS, WHILE APPROXIMATELY 90 % HAVE DETECTABLE MOLECULAR ABNORMALITIES. MOST PATIENTS ARE DIAGNOSED IN THE SEVENTH DECADE OF LIFE. GENE MUTATIONS IN TEN-ELEVEN TRANSLOCATION (TET) ONCOGENE FAMILY MEMBER 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), AND RAS (20-30 %) ARE FREQUENT, WITH ONLY FRAME SHIFT AND NONSENSE ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. WITH THE LACK OF FORMAL GUIDELINES, MANAGEMENT AND RESPONSE CRITERIA ARE OFTEN EXTRAPOLATED FROM MDS AND MPN. CONTEMPORARY MOLECULARLY INTEGRATED CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) MODEL AND THE MOLECULAR MAYO MODEL, BOTH INCORPORATING ASXL1 MUTATIONAL STATUS. HYPOMETHYLATING AGENTS AND ALLOGENEIC STEM CELL TRANSPLANT REMAIN THE TWO MOST COMMONLY USED TREATMENT STRATEGIES, WITH SUBOPTIMAL RESULTS. CLINICAL TRIALS EXPLOITING EPIGENETIC AND SIGNAL PATHWAY ABNORMALITIES, FREQUENT IN CMML, OFFER HOPE AND PROMISE. 2015 3 12 38 2017 CLINICAL TRIALS UPDATE IN NEW TREATMENTS OF BETA-THALASSEMIA. THE UNDERLYING BASIS OF BETA-THALASSEMIA PATHOLOGY IS THE DIMINISHED BETA-GLOBIN SYNTHESIS LEADING TO ALPHA-GLOBIN ACCUMULATION AND PREMATURE APOPTOTIC DESTRUCTION OF ERYTHROBLASTS, CAUSING OXIDATIVE STRESS-INDUCED INEFFECTIVE ERYTHROPOIESIS, BONE MARROW HYPERPLASIA, SPLENOMEGALY, AND INCREASED INTESTINAL IRON ABSORPTION WITH PROGRESSIVE IRON OVERLOAD. BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE LED TO THE RECOGNITION OF NEW TARGETS WITH POTENTIAL THERAPEUTIC UTILITY. AGENTS SUCH AS JAK2 INHIBITORS AND TGF-BETA LIGAND TRAPS THAT REDUCE THE INEFFECTIVE ERYTHROPOIESIS PROCESS ARE ALREADY BEING TESTED IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS THAT AIM TO REDUCE OXIDATIVE STRESS (ACTIVATORS OF FOXO3, HRI-EIF2AP, PRX2, HSP70, AND PK ANTI-OXIDANT SYSTEMS AND INHIBITORS OF HO-1) AND TO DECREASE IRON OVERLOAD (HEPCIDIN AGONISTS, ERYTHROFERRONE INHIBITORS AND EXOGENOUS TRANSFERRIN) ARE ALSO UNDER EXPERIMENTAL INVESTIGATION. SIGNIFICANT PROGRESS HAS ALSO BEEN MADE IN THE AREA OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH SEVERAL ONGOING CLINICAL TRIALS EXAMINING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONOR SELECTION AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS REACHED A CRITICAL POINT AND PHASE 1 CLINICAL TRIALS HAVE RECENTLY BEEN LAUNCHED TO EXAMINE THE EFFECTIVENESS AND ESPECIALLY LONG TERM SAFETY. EPIGENETIC MANIPULATION AND GENOMIC EDITING OF THE GAMMA- OR BETA-GLOBIN GENE ARE NOVEL AND PROMISING EXPERIMENTAL GENE THERAPY APPROACHES FOR BETA-THALASSEMIA GIVING HOPE FOR CURE FOR THIS CHRONIC DISEASE. THIS REVIEW OUTLINES THE KEY POINTS OF THE MOLECULAR MECHANISMS UNDERLYING BETA-THALASSEMIA IN RELATION TO THE DEVELOPMENT OF NEW THERAPIES AND AN UPDATE IS GIVEN BOTH AT THE PRE-CLINICAL AND CLINICAL LEVEL. AM. J. HEMATOL. 91:1135-1145, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 4 4562 76 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED. 2020 5 962 75 CHRONIC MYELOMONOCYTIC LEUKEMIA: FOCUS ON CLINICAL PRACTICE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER WITH FEATURES THAT OVERLAP THOSE OF MYELODYSPLASTIC SYNDROMES (MDSS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CHRONIC MYELOMONOCYTIC LEUKEMIA OFTEN RESULTS IN PERIPHERAL BLOOD MONOCYTOSIS AND HAS AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CLONAL CYTOGENETIC CHANGES ARE SEEN IN APPROXIMATELY 30% OF PATIENTS, AND MOLECULAR ABNORMALITIES ARE SEEN IN MORE THAN 90%. GENE MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT, WITH NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS BEING THE ONLY MUTATIONS IDENTIFIED THUS FAR TO HAVE AN INDEPENDENT NEGATIVE PROGNOSTIC EFFECT ON OVERALL SURVIVAL. CONTEMPORARY MOLECULARLY INTEGRATED PROGNOSTIC MODELS (INCLUSIVE OF ASXL1 MUTATIONS) INCLUDE THE MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. GIVEN THE LACK OF FORMAL TREATMENT AND RESPONSE CRITERIA, MANAGEMENT OF CMML IS OFTEN EXTRAPOLATED FROM MDS AND MPN, WITH ALLOGENEIC STEM CELL TRANSPLANT BEING THE ONLY CURATIVE OPTION. HYDROXYUREA AND OTHER CYTOREDUCTIVE AGENTS HAVE BEEN USED TO CONTROL MPN-LIKE FEATURES, WHILE EPIGENETIC MODIFIERS SUCH AS HYPOMETHYLATING AGENTS HAVE BEEN USED FOR MDS-LIKE FEATURES. GIVEN THE RELATIVELY POOR RESPONSE TO THESE AGENTS AND THE INHERENT RISKS ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT, NEWER DRUGS EXPLOITING MOLECULAR AND EPIGENETIC ABNORMALITIES IN CMML ARE BEING DEVELOPED. THE CREATION OF CMML-SPECIFIC RESPONSE CRITERIA IS A MUCH NEEDED STEP IN ORDER TO IMPROVE CLINICAL OUTCOMES. 2016 6 1266 67 CYTOGENETIC AND MOLECULAR ABNORMALITIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER ASSOCIATED WITH PERIPHERAL BLOOD MONOCYTOSIS AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CMML HAS OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. CLONAL CYTOGENETIC CHANGES ARE SEEN IN ~30%, WHEREAS GENE MUTATIONS ARE SEEN IN >90% OF PATIENTS. COMMON CYTOGENETIC ABNORMALITIES INCLUDE; TRISOMY 8, -Y, -7/DEL(7Q), TRISOMY 21 AND DEL(20Q), WITH THE MAYO-FRENCH RISK STRATIFICATION EFFECTIVELY RISK STRATIFYING PATIENTS BASED ON CYTOGENETIC ABNORMALITIES. GENE MUTATIONS FREQUENTLY INVOLVE EPIGENETIC REGULATORS (TET2 ~60%), MODULATORS OF CHROMATIN (ASXL1 ~40%), SPLICEOSOME COMPONENTS (SRSF2 ~50%), TRANSCRIPTION FACTORS (RUNX1 ~15%) AND SIGNAL PATHWAYS (RAS ~30%, CBL ~15%). OF THESE, THUS FAR, ONLY NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS HAVE BEEN SHOWN TO NEGATIVELY IMPACT OVERALL SURVIVAL. THIS HAS RESULTED IN THE DEVELOPMENT OF CONTEMPORARY, MOLECULARLY INTEGRATED (INCLUSIVE OF ASXL1 MUTATIONS) CMML PROGNOSTIC MODELS, INCLUDING MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. BETTER UNDERSTANDING OF THE PREVALENT GENETIC AND EPIGENETIC DYSREGULATION HAS RESULTED IN EMERGING TARGETED TREATMENT OPTIONS FOR SOME PATIENTS. THE DEVELOPMENT OF AN INTEGRATED (CYTOGENETIC AND MOLECULAR) PROGNOSTIC MODEL ALONG WITH CMML-SPECIFIC RESPONSE ASSESSMENT CRITERIA ARE MUCH NEEDED FUTURE GOALS. 2016 7 3871 39 JUVENILE MYELOMONOCYTIC LEUKEMIA - A BONA FIDE RASOPATHY SYNDROME. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROME WITH SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS, AGGRESSIVE FEATURES, AND POOR OUTCOMES. IN >90% OF CASES JMML IS DRIVEN BY GERMLINE OR SOMATIC MUTATIONS INVOLVING THE CANONICAL RAS PATHWAY (PTPN11, NRAS, CBL, KRAS AND NF1), WITH SOMATIC MUTATIONS/ALTERATIONS IN RAS PATHWAY GENES (SECOND HIT), SETBP1, ASXL1 AND JAK3 RESULTING IN DISEASE PROGRESSION. WHILE SPONTANEOUS REGRESSION HAS BEEN SEEN IN GERMLINE PTPN11 AND CBL MUTANT JMML, IN MOST PATIENTS, ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY CURATIVE MODALITY. JMML SHARES SEVERAL PHENOTYPIC FEATURES WITH ITS ADULT COUNTERPART PROLIFERATIVE, CHRONIC MYELOMONOCYTIC LEUKEMIA (PCMML). PCMML LARGELY OCCURS DUE TO RAS PATHWAY MUTATIONS THAT OCCUR IN THE CONTEXT OF AGE RELATED CLONAL HEMATOPOIESIS (TET2, SRSF2, ASXL1), WHILE JMML IS A BONA FIDE RASOPATHY, WITH ADDITIONAL SOMATIC MUTATIONS, INCLUDING IN EPIGENETIC REGULATORS GENES RESULTING IN DISEASE PROGRESSION. 2020 8 4748 37 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION. 2010 9 5246 45 PROGNOSTIC SCORE INCLUDING GENE MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE: SEVERAL PROGNOSTIC SCORING SYSTEMS HAVE BEEN PROPOSED FOR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A DISEASE IN WHICH SOME GENE MUTATIONS-INCLUDING ASXL1-HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS IN UNIVARIABLE ANALYSES. WE DEVELOPED AND VALIDATED A PROGNOSTIC SCORE FOR OVERALL SURVIVAL (OS) BASED ON MUTATIONAL STATUS AND STANDARD CLINICAL VARIABLES. PATIENTS AND METHODS: WE GENOTYPED ASXL1 AND UP TO 18 OTHER GENES INCLUDING EPIGENETIC (TET2, EZH2, IDH1, IDH2, DNMT3A), SPLICING (SF3B1, SRSF2, ZRSF2, U2AF1), TRANSCRIPTION (RUNX1, NPM1, TP53), AND SIGNALING (NRAS, KRAS, CBL, JAK2, FLT3) REGULATORS IN 312 PATIENTS WITH CMML. GENOTYPES AND CLINICAL VARIABLES WERE INCLUDED IN A MULTIVARIABLE COX MODEL OF OS VALIDATED BY BOOTSTRAPPING. A SCORING SYSTEM WAS DEVELOPED USING REGRESSION COEFFICIENTS FROM THIS MODEL. RESULTS: ASXL1 MUTATIONS (P < .0001) AND, TO A LESSER EXTENT, SRSF2 (P = .03), CBL (P = .003), AND IDH2 (P = .03) MUTATIONS PREDICTED INFERIOR OS IN UNIVARIABLE ANALYSIS. THE RETAINED INDEPENDENT PROGNOSTIC FACTORS INCLUDED ASXL1 MUTATIONS, AGE OLDER THAN 65 YEARS, WBC COUNT GREATER THAN 15 X10(9)/L, PLATELET COUNT LESS THAN 100 X10(9)/L, AND ANEMIA (HEMOGLOBIN < 10 G/DL IN FEMALE PATIENTS, < 11G/DL IN MALE PATIENTS). THE RESULTING FIVE-PARAMETER PROGNOSTIC SCORE DELINEATED THREE GROUPS OF PATIENTS WITH MEDIAN OS NOT REACHED, 38.5 MONTHS, AND 14.4 MONTHS, RESPECTIVELY (P < .0001), AND WAS VALIDATED IN AN INDEPENDENT COHORT OF 165 PATIENTS (P < .0001). CONCLUSION: A NEW PROGNOSTIC SCORE INCLUDING ASXL1 STATUS, AGE, HEMOGLOBIN, WBC, AND PLATELET COUNTS DEFINES THREE GROUPS OF CMML PATIENTS WITH DISTINCT OUTCOMES. BASED ON CONCORDANCE ANALYSIS, THIS SCORE APPEARS MORE DISCRIMINATIVE THAN THOSE BASED SOLELY ON CLINICAL PARAMETERS. 2013 10 3872 49 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 11 4553 39 MUTATIONAL LANDSCAPE OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN CHINESE PATIENTS. BACKGROUND: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A RARE AND HETEROGENEOUS HEMATOLOGICAL MALIGNANCY. IT HAS BEEN SHOWN THAT THE MOLECULAR ABNORMALITIES SUCH AS ASXL1, TET2, SETBP1, AND SRSF2 MUTATIONS ARE COMMON IN CAUCASIAN POPULATION. METHODS: WE RETROSPECTIVELY ANALYZED 178 CHINESE CMML PATIENTS. THE TARGETED NEXT GENERATION SEQUENCING (NGS) WAS USED TO EVALUATE 114 GENE VARIATIONS, AND THE PROGNOSTIC FACTORS FOR OS WERE DETERMINED BY COX REGRESSION ANALYSIS. RESULTS: THE CMML PATIENTS SHOWED A UNIQUE MUTATIONAL SPECTRUM, INCLUDING TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), AND RUNX1 (21.9%). OF THE 102 PATIENTS WITH CLONAL ANALYSIS, THE ANCESTRAL EVENTS PREFERENTIALLY OCCURRED IN TET2 (18.5%), SPLICING FACTORS (16.5%), RAS (14.0%), AND ASXL1 (7.8%), AND THE SUBCLONAL GENES WERE MAINLY ASXL1, TET2, AND RAS. IN ADDITION, THE SECONDARY ACUTE MYELOID LEUKEMIA (SAML) TRANSFORMED FROM CMML OFTEN HAD MUTATIONS IN DNMT3A, ETV6, FLT3, AND NPM1, WHILE THE PRIMARY AML (PAML) DEMONSTRATED MORE MUTATIONS IN CEBPA, DNMT3A, FLT3, IDH1/2, NPM1, AND WT1. IT WAS OF NOTE THAT A SERIES OF CLONES WERE EMERGED DURING THE PROGRESSION FROM CMML TO AML, INCLUDING DNMT3A, FLT3, AND NPM1. BY UNIVARIATE ANALYSIS, ASXL1 MUTATION, INTERMEDIATE- AND HIGH-RISK CYTOGENETIC ABNORMALITY, CMML-SPECIFIC PROGNOSTIC SCORING SYSTEM (CPSS) STRATIFICATIONS (INTERMEDIATE-2 AND HIGH GROUP), AND TREATMENT OPTIONS (BEST SUPPORTIVE CARE) PREDICTED FOR WORSE OS. MULTIVARIATE ANALYSIS REVEALED A SIMILAR OUTCOME. CONCLUSIONS: THE COMMON MUTATIONS IN CHINESE CMML PATIENTS INCLUDED EPIGENETIC MODIFIERS (TET2 AND ASXL1), SIGNALING TRANSDUCTION PATHWAY COMPONENTS (NRAS), AND SPLICING FACTOR (SRSF2). THE CMML PATIENTS WITH DNMT3A, ETV6, FLT3, AND NPM1 MUTATIONS TENDED TO PROGRESS TO SAML. ASXL1 MUTATION AND THERAPEUTIC MODALITIES WERE INDEPENDENT PROGNOSTIC FACTORS FOR CMML. 2022 12 1311 55 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION. 2023 13 5980 32 TET2 MUTATIONS WERE PREDICTIVE OF INFERIOR PROGNOSIS IN THE PRESENCE OF ASXL1 MUTATIONS IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. BACKGROUND: SOMATIC MUTATIONS INVOLVING EPIGENETIC REGULATORS, HISTONE MODIFICATION AND CHROMATIN REGULATION, SPLICING COMPONENTS, TRANSCRIPTION FACTORS AND SIGNALING REGULATOR GENES ARE COMMON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IT HAS BEEN CONSENSUS THAT ASXL1 MUTATIONS HAVE ADVERSELY IMPACT ON OVERALL SURVIVAL (OS), WHILE THE EFFECT OF TET2 MUTATIONS REMAINS CONTROVERSIAL AND UNDEFINED. METHODS: ASXL1 AND TET2 MUTATIONS WERE ANALYZED IN 141 PATIENTS WITH CMML USING SANGER SEQUENCING, WITH THE AIM TO IDENTIFY THE INTERPLAY OF ASXL1 AND TET2 MUTATIONS IN THE PROGNOSIS OF CMML. RESULTS: SIXTY-FIVE (46.1%) OF THE CMML PATIENTS HARBORED ASXL1 MUTATIONS (FRAMESHIFT AND NONSENSE), AND 46 (32.6%) HAD TET2 MUTATIONS (FRAME SHIFT, NONSENSE AND MISSENSE). IN A SEPARATE MULTIVARIABLE ANALYSIS THAT INCLUDED THE MAYO PROGNOSTIC MODEL AS A SINGLE VARIABLE ALONG WITH ASXL1WT/TET2WT, THE RESPECTIVE HAZARD RATIOS OF ASXL1MUT/TET2MUT, ASXL1MUT/TET2WT AND ASXL1WT/TET2MUT WERE 4.7 (95% CI, 2.2-10.3; P<0.001), 2.2 (95% CI, 1.1-4.2; P=0.025) AND 1.3 (95% CI, 0.6-2.5; P=0.521). CONCLUSIONS: OUR STUDY SHOWED THAT ASXL1 MUTATIONS PREDICT INFERIOR OS, AND ADDITIONAL TET2 MUTATIONS WERE ASSOCIATED WITH POOR SURVIVAL IN THE PRESENCE OF ASXL1 MUTATIONS OF CMML PATIENTS. 2016 14 5244 49 PROGNOSTIC INTERACTION BETWEEN ASXL1 AND TET2 MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. MUTATIONS INVOLVING EPIGENETIC REGULATORS (TET2~60% AND ASXL1~40%) AND SPLICING COMPONENTS (SRSF2~50%) ARE FREQUENT IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). ON A 27-GENE TARGETED CAPTURE PANEL PERFORMED ON 175 CMML PATIENTS (66% MALES, MEDIAN AGE 70 YEARS), COMMON MUTATIONS INCLUDED: TET2 46%, ASXL1 47%, SRSF2 45% AND SETBP1 19%. A TOTAL OF 172 (98%) PATIENTS HAD AT LEAST ONE MUTATION, 21 (12%) HAD 2, 24 (14%) HAD 3 AND 30 (17%) HAD >3 MUTATIONS. IN A UNIVARIATE ANALYSIS, THE PRESENCE OF ASXL1 MUTATIONS (P=0.02) AND THE ABSENCE OF TET2 MUTATIONS (P=0.03), ADVERSELY IMPACTED SURVIVAL; WHILE THE NUMBER OF CONCURRENT MUTATIONS HAD NO IMPACT (P=0.3). IN A MULTIVARIABLE ANALYSIS THAT INCLUDED HEMOGLOBIN, PLATELET COUNT, ABSOLUTE MONOCYTE COUNT AND CIRCULATING IMMATURE MYELOID CELLS (MAYO MODEL), THE PRESENCE OF ASXL1 MUTATIONS (P=0.01) AND ABSENCE OF TET2 MUTATIONS (P=0.003) RETAINED PROGNOSTIC SIGNIFICANCE. PATIENTS WERE STRATIFIED INTO FOUR CATEGORIES: ASXL1WT/TET2WT (N=56), ASXL1MUT/TET2WT (N=31), ASXL1MUT/TET2MUT (N=50) AND ASXL1WT/TET2MUT (N=38). SURVIVAL DATA DEMONSTRATED A SIGNIFICANT DIFFERENCE IN FAVOR OF ASXL1WT/TET2MUT (38 MONTHS; P=0.016), COMPARED WITH THOSE WITH ASXL1WT/TET2WT (19 MONTHS), ASXL1MUT/TET2WT (21 MONTHS) AND ASXL1MUT/TET2MUT (16 MONTHS) (P=0.3). WE CONFIRM THE NEGATIVE PROGNOSTIC IMPACT IMPARTED BY ASXL1 MUTATIONS AND SUGGEST A FAVORABLE IMPACT FROM TET2 MUTATIONS IN THE ABSENCE OF ASXL1 MUTATIONS. 2016 15 4557 25 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT. 2012 16 4753 31 NOVEL THERAPEUTIC ADVANCES IN BETA-THALASSEMIA. THE MAIN CHARACTERISTIC OF THE PATHOPHYSIOLOGY OF BETA-THALASSEMIA IS REDUCED BETA-GLOBIN CHAIN PRODUCTION. THE INEVITABLE IMBALANCE IN THE ALPHA/BETA-GLOBIN RATIO AND ALPHA-GLOBIN ACCUMULATION LEAD TO OXIDATIVE STRESS IN THE ERYTHROID LINEAGE, APOPTOSIS, AND INEFFECTIVE ERYTHROPOIESIS. THE RESULT IS COMPENSATORY HEMATOPOIETIC EXPANSION AND IMPAIRED HEPCIDIN PRODUCTION THAT CAUSES INCREASED INTESTINAL IRON ABSORPTION AND PROGRESSIVE IRON OVERLOAD. CHRONIC HEMOLYSIS AND RED BLOOD CELL TRANSFUSIONS ALSO CONTRIBUTE TO IRON TISSUE DEPOSITION. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS LED TO THE DETECTION OF NEW CURATIVE OR "DISEASE-MODIFYING" THERAPEUTIC OPTIONS. SUBSTANTIAL EVOLVEMENT HAS BEEN MADE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH CURRENT CLINICAL TRIALS INVESTIGATING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONORS AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS ALSO MOVED FORWARD, AND PHASE 2 CLINICAL TRIALS WITH THE USE OF BETA-GLOBIN INSERTION TECHNIQUES HAVE RECENTLY BEEN SUCCESSFULLY COMPLETED LEADING TO APPROVAL FOR USE IN TRANSFUSION-DEPENDENT PATIENTS. GENETIC AND EPIGENETIC MANIPULATION OF THE GAMMA- OR BETA-GLOBIN GENE HAVE ENTERED THE CLINICAL TRIAL SETTING. AGENTS SUCH AS TGF-BETA LIGAND TRAPS AND PYRUVATE KINASE ACTIVATORS, WHICH REDUCE THE INEFFECTIVE ERYTHROPOIESIS, HAVE BEEN TESTED IN CLINICAL TRIALS WITH FAVORABLE RESULTS. ONE TGF-BETA LIGAND TRAP, LUSPATERCEPT, HAS BEEN APPROVED FOR USE IN ADULTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA. THE INDUCTION OF HBF WITH THE PHOSPHODIESTERASE 9 INHIBITOR IMR-687, WHICH INCREASE CYCLIC GUANOSINE MONOPHOSPHATE, IS CURRENTLY BEING TESTED. ANOTHER THERAPEUTIC APPROACH IS TO TARGET THE DYSREGULATION OF IRON HOMEOSTASIS, USING, FOR EXAMPLE, HEPCIDIN AGONISTS (INHIBITORS OF TMPRSS6 AND MINIHEPCIDINS) OR FERROPORTIN INHIBITORS (VIT-2763). THIS REVIEW PROVIDES AN UPDATE ON THE NOVEL THERAPEUTIC OPTIONS THAT ARE PRESENTLY IN DEVELOPMENT AT THE CLINICAL LEVEL IN BETA-THALASSEMIA. 2021 17 5911 29 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES. 2016 18 6780 30 [BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM ACCOMPANIED BY CHRONIC MYELOMONOCYTIC LEUKEMIA SUCCESSFULLY TREATED WITH AZACITIDINE]. BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN) IS A RARE DISEASE THAT DEVELOPS WITH A SKIN LESION AND IS OFTEN ACCOMPANIED BY LEUKEMIC TRANSFORMATION. THE NORMAL COUNTERPARTS OF BPDCN TUMOR CELLS ARE PROGENITORS OF PLASMACYTOID DENDRITIC CELLS, WHEREAS THE ORIGINS ARE THOUGHT TO BE HEMATOPOIETIC STEM CELLS. APPROXIMATELY 10%-20% OF BPDCN PATIENTS DEVELOP OTHER HEMATOLOGIC MALIGNANCIES, INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). MUTATIONS IN EPIGENETIC REGULATORS ARE FREQUENTLY OBSERVED IN BOTH BPDCN AND CMML TUMORS. AZACITIDINE, A DRUG THAT TARGETS EPIGENETIC DYSREGULATION, IS KNOWN TO BE AN EFFECTIVE TREATMENT FOR CMML. HOWEVER, IT HAS BEEN USED IN FEW BPDCN PATIENTS. HERE, WE REPORT A BPDCN PATIENT WITH SKIN LESIONS, BONE MARROW INFILTRATION, AND LYMPHADENOPATHY. CMML ALSO DEVELOPED DURING THE COURSE OF BPDCN. AZACITIDINE HAD POSITIVE EFFECTS ON CMML; HOWEVER, BPDCN AGGRESSIVELY RELAPSED DURING TREATMENT. TWO TET2 MUTATIONS WERE FOUND IN BOTH BPDCN AND CMML TUMORS; ONE OF WHICH WAS COMMONLY IDENTIFIED IN BOTH TUMORS. 2018 19 957 45 CHRONIC MYELOMONOCYTIC LEUKAEMIA: A CONCISE CLINICAL AND PATHOPHYSIOLOGICAL REVIEW. CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) IS A CLONAL HAEMATOPOIETIC STEM CELL DISORDER WITH MYELODYSPLASTIC AND MYELOPROLIFERATIVE OVERLAP FEATURES, AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKAEMIA. APPROXIMATELY 30% OF PATIENTS PRESENT WITH CLONAL CYTOGENETIC ABNORMALITIES, WHILE ALMOST 90% HAVE MOLECULAR ABERRATIONS INVOLVING EPIGENETIC REGULATION, THE SPLICEOSOME COMPONENT MACHINERY, TUMOUR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS/REGULATORS. NUMEROUS PROGNOSTIC MODELS EXIST FOR CMML, WITH MORE RECENT MODELS INCORPORATING PROGNOSTIC MUTATIONS, SUCH AS THOSE INVOLVING ASXL1. OTHER VARIABLES THAT SEEM TO CONSISTENTLY AFFECT OUTCOMES INCLUDE THE DEGREE OF LEUCOCYTOSIS/MONOCYTOSIS, ANAEMIA AND THROMBOCYTOPENIA. ALLOGENEIC STEM CELL TRANSPLANT REMAINS THE ONLY CURATIVE OPTION FOR CMML, WHILE HYPOMETHYLATING AGENTS CAN BE USED FOR TRANSPLANT-INELIGIBLE PATIENTS OR THOSE WITHOUT SUITABLE STEM CELL SOURCES. TARGETING BIOLOGICAL PATHWAYS ACTIVATED IN CMML OFFERS POTENTIAL HOPE FOR MORE EFFECTIVE AND LESS TOXIC THERAPIES. 2014 20 4686 34 NEW THERAPEUTIC TARGETS IN TRANSFUSION-DEPENDENT AND -INDEPENDENT THALASSEMIA. BETA-THALASSEMIAS ARE CHARACTERIZED BY REDUCED PRODUCTION OF BETA-GLOBIN CHAIN, RESULTING IN ALPHA/BETA-CHAIN UNBALANCE AND PRECIPITATION OF ALPHA-GLOBIN-HEME COMPLEXES AND DETERMINING INEFFECTIVE ERYTHROPOIESIS. INEFFECTIVE ERYTHROPOIESIS, CHRONIC HEMOLYTIC ANEMIA, AND COMPENSATORY HEMATOPOIETIC EXPANSION ARE THE DISEASE HALLMARKS, AND THEY ARE RELATED TO THE SEVERITY OF THE CHAIN UNBALANCE. SEVERAL CLINICAL FORMS OF BETA-THALASSEMIA, INCLUDING THE COINHERITANCE OF BETA-THALASSEMIA WITH HEMOGLOBIN E RESULTING IN HEMOGLOBIN E/BETA-THALASSEMIA, HAVE BEEN DESCRIBED. CLINICALLY, BETA-THALASSEMIAS CAN BE CLASSIFIED AS TRANSFUSION-DEPENDENT THALASSEMIA (TDT) AND NON-TRANSFUSION-DEPENDENT THALASSEMIA (NTDT) ACCORDING TO THE SEVERITY OF THE PHENOTYPE, WHICH IS CAUSED BY A WIDE SPECTRUM OF MUTATIONS IN A HOMOZYGOUS OR COMPOUND HETEROZYGOUS STATE. CURRENT TREATMENT OF TDT CONSISTS OF REGULAR TRANSFUSIONS THAT LEAD TO IRON OVERLOAD, REQUIRING IRON CHELATION TO PREVENT IRON-RELATED ORGAN TOXICITY. NTDT PATIENTS DO NOT REQUIRE TRANSFUSIONS OR ONLY OCCASIONALLY REQUIRE THEM; HOWEVER, THEY DEVELOP IRON OVERLOAD AS WELL BECAUSE OF INCREASED INTESTINAL IRON ABSORPTION CAUSED BY CHRONIC ANEMIA. HEMATOPOIETIC STEM CELL ALLOGENIC TRANSPLANT IS THE ONLY APPROVED CURE FOR BETA-THALASSEMIA; HOWEVER, IT IS STILL LIMITED BY CLINICAL CONDITIONS AND THE AVAILABILITY OF MATCHED DONORS AS WELL AS BY POTENTIAL GRAFT-VERSUS-HOST DISEASE (GVHD). GENE THERAPY COULD AVOID THE GVHD RISK, ALTHOUGH HEMATOPOIETIC STEM CELLS MUST BE GENETICALLY MODIFIED EX VIVO. EPIGENETIC MANIPULATION AND GENOMIC EDITING ARE NOVEL EXPERIMENTAL APPROACHES. AN INCREASED UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT CONTROLS THE DISEASE PROCESS PROMPTED US TO EXPLORE ALTERNATIVE THERAPEUTIC APPROACHES THAT ADDRESS THE UNDERLYING CHAIN UNBALANCE, INEFFECTIVE ERYTHROPOIESIS, AND IRON DYSREGULATION. MOLECULES, SUCH AS JAK2 INHIBITORS AND THE ACTIVIN-RECEPTOR LIGAND TRAP THAT TARGET INEFFECTIVE ERYTHROPOIESIS, ARE ALREADY IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS AIMED TO GENERATE IRON-RESTRICTED ERYTHROPOIESIS ARE ALSO UNDER EXPERIMENTAL EVALUATION. 2017