1 1242 140 CURRENT AND NOVEL THERAPEUTIC APPROACHES IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC NEOPLASMS WITH AN ANNUAL INCIDENCE OF 4.1 CASES PER 100,000 AMERICANS. PATIENTS WITH MDS SUFFER FROM CHRONIC CYTOPENIAS THAT MAY LEAD TO RECURRENT TRANSFUSIONS, INFECTIONS, AND INCREASED RISK FOR BLEEDING. THEY ARE ALSO AT RISK FOR PROGRESSION TO ACUTE MYELOID LEUKEMIA. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IS THE ONLY POTENTIALLY CURATIVE TREATMENT FOR MDS, ALTHOUGH 3 DRUGS HAVE BEEN APPROVED BY THE US FOOD AND DRUG ADMINISTRATION FOR ITS TREATMENT: LENALIDOMIDE, 5-AZACITIDINE, AND DECITABINE. THESE THERAPIES CAN BE EFFECTIVE IN THE RELIEF OF CYTOPENIAS, ACHIEVEMENT OF CYTOGENETIC REMISSIONS, AND REDUCTION IN BONE MARROW BLASTS. 5-AZACITIDINE HAS ALSO BEEN SHOWN TO IMPROVE OVERALL SURVIVAL. HOWEVER, THERE REMAIN MANY UNMET NEEDS IN THE TREATMENT OF MDS. BREAKTHROUGHS IN OUR UNDERSTANDING OF THE COMPLEX PATHOGENESIS OF MDS THROUGH EPIGENETIC, GENETIC, IMMUNOLOGIC, AND OTHER BIOLOGICAL MECHANISMS HAVE ALLOWED US TO DEVELOP NEW THERAPEUTIC STRATEGIES THAT CAN LEAD TO IMPROVEMENTS IN OUTCOMES IN MDS. IN THIS REVIEW, WE AIM TO PROVIDE AN OVERVIEW OF THE EVOLUTION IN CLASSIFCATION AND RISK STRATIFCATION IN MDS AND TO ILLUSTRATE HOW WE CAN USE THIS TO GUIDE US IN TAILORING THERAPEUTIC CHOICES IN THIS DISEASE. RESPONSES AND OUTCOMES RELATED TO COM MONLY USED MDS THERAPIES WILL BE DISCUSSED TOGETHER WITH NOVEL THERAPIES THAT HAVE EVOLVED WITH THE IMPROVED UNDERSTANDING OF MDS PATHOPHYSIOLOGY. 2014 2 4681 42 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY). 2005 3 5284 44 PROPOSALS FOR CLINICAL TRIALS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGIC MALIGNANCY OF MOSTLY OLDER INDIVIDUALS THAT EXHIBITS BOTH MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES. CMML PRESENTATION AND OUTCOME ARE VARIABLE, REFLECTING GENETIC AND CLINICAL HETEROGENEITY. HYPOMETHYLATING AGENTS ARE THE MAINSTAY OF THERAPY BUT INDUCE COMPLETE REMISSIONS IN LESS THAN 20% OF PATIENTS AND DO NOT PROLONG SURVIVAL COMPARED TO HYDROXYUREA. ALLOGENEIC STEM CELL TRANSPLANT (ASCT) IS POTENTIALLY CURATIVE, BUT FEW PATIENTS QUALIFY DUE TO ADVANCED AGE AND/OR COMORBIDITIES. WORK OF THE PAST SEVERAL YEARS HAS IDENTIFIED KEY MOLECULAR PATHWAYS THAT DRIVE DISEASE PROLIFERATION AND TRANSFORMATION TO ACUTE LEUKEMIA, INCLUDING JAK/STAT AND MAPK SIGNALING AND EPIGENETIC DYSREGULATION. THERE IS INCREASINGLY COMPELLING EVIDENCE THAT INFLAMMATION IS A MAJOR DRIVER OF CMML PROGRESSION. THUS FAR HOWEVER, THIS MECHANISTIC KNOWLEDGE HAS NOT YET BEEN TRANSLATED INTO IMPROVED OUTCOMES, SUGGESTING THAT FUNDAMENTALLY NEW APPROACHES ARE REQUIRED. IN THIS REVIEW, WE DISCUSS THE DISEASE COURSE, NEW CLASSIFICATIONS, AND CURRENT TREATMENT LANDSCAPE OF CMML. WE REVIEW ONGOING CLINICAL STUDIES AND DISCUSS OPTIONS FOR RATIONALLY BASED FUTURE CLINICAL TRIALS. 2023 4 2547 33 EPIGENETICS IN MYELOID MALIGNANCIES. MYELOID HEMATOLOGICAL MALIGNANCIES ARE AMONG THE EPIGENETICALLY BEST CHARACTERIZED NEOPLASMS. THE COMPARATIVELY LOW NUMBER OF RECURRING BALANCED AND UNBALANCED CHROMOSOMAL ABNORMALITIES AS WELL AS COMMON GENETIC MUTATIONS HAS ENABLED SCIENTISTS TO RELATE EPIGENETIC STATES TO THESE. THE EASE OF ACCESSING MALIGNANT CELLS THROUGH BONE MARROW ASPIRATION HAS CERTAINLY CONTRIBUTED TO THE FAST EXPANSION OF KNOWLEDGE. EVEN SO, THE CLINICAL AND PATHOGENETIC RELEVANCE OF EPIGENETIC CHANGES IS STILL NOT KNOWN, AND THE FIELD WILL CERTAINLY EVOLVE VERY FAST WITH THE DEVELOPMENT OF NEW ANALYTIC TECHNIQUES. THE FIRST EXAMPLE OF SUCCESSFUL EPIGENETIC THERAPY IS SEEN IN MYELOID MALIGNANCIES, IN THE HIGH-RISK MYELODYSPLASTIC SYNDROMES (MDS) WHICH ARE ROUTINELY TREATED WITH THE DEMETHYLATING AGENT AZACYTIDINE.THIS CHAPTER WILL CONCENTRATE ON DESCRIBING THE EPIGENETIC CHANGES IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML) AND MDS. AN OVERVIEW OF CLINICAL RELEVANCE AND EPIGENETIC THERAPEUTIC APPROACHES IS ALSO MADE. 2012 5 963 34 CHRONIC MYELOMONOCYTIC LEUKEMIA: INSIGHTS INTO BIOLOGY, PROGNOSTIC FACTORS, AND TREATMENT. PURPOSE OF REVIEW: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGICAL MALIGNANCY CHARACTERIZED BY BOTH DYSPLASTIC AND PROLIFERATIVE FEATURES, WITH AN INHERENT RISK FOR LEUKEMIC TRANSFORMATION. WITH THE HELP OF THIS REVIEW, WE AIM TO SUMMARIZE KEY CONCEPTS WITH REGARDS TO CMML BIOLOGY, DIAGNOSIS, RISK STRATIFICATION, AND THERAPEUTICS. RECENT FINDINGS: BASED ON RECENT STUDIES, CMML IS HALLMARKED BY A RELATIVELY LOW GENETIC COMPLEXITY, WHICH CONTRASTS WITH A COMPELLING PHENOTYPICAL HETEROGENEITY, LARGELY DRIVEN BY EPIGENETIC MECHANISMS. RECENT ADVANCES IN THE CHARACTERIZATION OF CMML BIOLOGY HAS LED TO AN IMPROVEMENT IN RISK-STRATIFICATION, BY MEANS OF INCORPORATING PROGNOSTICALLY RELEVANT GENE MUTATIONS. THIS, HOWEVER, HAS NOT SIGNIFICANTLY IMPACTED AVAILABLE THERAPIES AND OUTCOMES CONTINUE TO REMAIN POOR. ADVANCES IN CMML BIOLOGY HAVE BETTER EXPLAINED THE PHENOTYPIC HETEROGENEITY, WHILE CONTINUING TO DEFINE THE GENETIC AND EPIGENETIC LANDSCAPE. IN SPITE OF RECENT ADVANCES, LIMITED EFFECTIVE THERAPIES EXIST AND DEVELOPING RATIONALLY DERIVED THERAPEUTIC APPROACHES IS MUCH NEEDED. 2019 6 6573 38 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020 7 1882 40 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML. 2004 8 958 50 CHRONIC MYELOMONOCYTIC LEUKEMIA - A REVIEW. INTRODUCTION: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL MYELOID NEOPLASM, DENOTED BY OVERLAPPING MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES, WITH POOR OVERALL SURVIVAL AND HIGH TRANSFORMATION RATE TO ACUTE MYELOID LEUKEMIA. AREAS COVERED: THIS REVIEW, FOLLOWING A THOROUGH MEDLINE SEARCH OF PERTINENT PUBLISHED LITERATURE, DISCUSSES THE DIAGNOSTIC CRITERIA, THE PATHOGENESIS, AND THE COMPLEX GENETIC LANDSCAPE OF THE DISEASE. PROGNOSTICATION, RESPONSE CRITERIA, THERAPEUTIC MANAGEMENT OF PATIENTS, EFFICACY OF ESTABLISHED AND NOVEL TREATMENT MODALITIES ARE THOROUGHLY REVIEWED. EXPERT OPINION: CYTOGENETIC ABNORMALITIES AND MUTATIONS IN GENES INVOLVED IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION, AND CELL-SIGNALING ARE ABUNDANT IN CMML AND IMPLICATED IN ITS COMPLEX PATHOGENESIS. AS PRESENCE OF THESE MUTATIONS CARRY A PROGNOSTIC IMPACT, THEY ARE INCREASINGLY INCORPORATED IN RISK-STRATIFICATION SCHEMES. NOVEL RESPONSE CRITERIA HAVE BEEN PROPOSED, CONSIDERING THE UNIQUE FEATURES OF THE DISEASE. ALTHOUGH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION REMAINS THE ONLY TREATMENT WITH CURATIVE INTENT, IT IS RESERVED FOR A MINORITY OF PATIENTS; THEREFORE, THERE IS AN UNMET NEED FOR OPTIMIZING TREATMENT MODALITIES, SUCH AS HYPOMETHYLATING AGENTS, AND INTRODUCING NOVEL AGENTS, WHICH COULD SUBSTANTIALLY IMPROVE SURVIVAL AND QUALITY OF LIFE OF CMML PATIENTS. CLINICAL TRIALS DEDICATED SPECIFICALLY TO CMML ARE NEEDED TO EXPLORE THE EFFICACY AND SAFETY OF NOVEL TREATMENT MODALITIES. 2021 9 1616 38 DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES. THE RECENTLY APPROVED DRUGS 5-AZACITIDINE (5AC) AND 5-AZA-2'-DEOXYAZACYTIDINE (DAC) ARE IN WIDE CLINICAL USE FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME (MDS) OF ALL TYPES AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). THESE AGENTS WERE DEVELOPED BASED UPON AN UNDERSTANDING OF THE IMPORTANCE OF EPIGENETIC CHANGES IN MALIGNANCY, AND THEY HAVE BEEN EVALUATED IN RANDOMIZED CLINICAL TRIALS, WHICH DEMONSTRATE RESPONSE RATES BETWEEN 20% AND 40% IN PATIENTS FOR WHOM NO PREVIOUS STANDARD OF CARE WAS AVAILABLE. AS UNDERSTANDING OF THE EPIGENETIC CHANGES CHARACTERISTIC OF THE MALIGNANT PHENOTYPE IMPROVES, WE ARE ABLE TO TARGET OTHER REGULATORS OF CHROMATIN CONFORMATION THAT CONTRIBUTE TO ABERRANT GENE TRANSCRIPTION AND DYSREGULATED CELL GROWTH. THE HISTONE DEACETYLASE (HDAC) INHIBITORS BELONG TO ONE CLASS OF THERAPEUTICS DEVELOPED USING THIS PARADIGM. ALTHOUGH RESPONSES USING HDAC INHIBITORS ALONE IN MDS HAVE BEEN MODEST, ROBUST PRECLINICAL DATA DRIVE CLINICAL TRIALS IN WHICH THEY ARE UTILIZED IN COMBINATION WITH DNA METHYLTRANSFERASE (DNMT) INHIBITORS. COMBINATION THERAPY OFFERS THE POSSIBILITY OF HEMATOLOGIC IMPROVEMENT AND REMISSION TO MYELODYSPLASTIC PATIENTS WITH PREVIOUSLY UNTREATABLE DISEASE. 2008 10 2582 38 EPIGENETICS OF MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE CLONAL DISEASES OF THE ELDERLY CHARACTERIZED BY CHRONIC CYTOPENIAS, DYSPLASIA AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML). ABERRANT METHYLATION OF TUMOR-SUPPRESSOR GENE PROMOTERS HAS BEEN ESTABLISHED FOR MANY YEARS AND RECENTLY TRACKED TO THE MOST IMMATURE CELLS OF MDS, SUGGESTING THAT THESE ALTERATIONS ARE DRIVERS OF MDS PATHOGENESIS. IN RECENT YEARS, RECURRENT SOMATIC MUTATIONS IN GENES ENCODING PROTEINS INVOLVED IN DNA METHYLATION AND DEMETHYLATION AND IN COVALENT HISTONE MODIFICATIONS HAVE BEEN REPORTED IN MYELOID MALIGNANCIES, INCLUDING MDS. WHOLE-GENOME EPIGENETIC PROFILES OF MDS ARE ALSO EMERGING. IN PARALLEL WITH THESE ADVANCES IN THE MOLECULAR PATHOGENESIS OF MDS, CLINICAL TRIALS HAVE ESTABLISHED HYPOMETHYLATING AGENTS (HMAS) AS THE MAINSTAY OF THERAPY IN THE ADVANCED FORMS OF THE DISEASE. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR MACHINERY INVOLVED IN EPIGENETIC REGULATION, DISCUSS HOW EPIGENETIC ALTERATIONS ARISE IN MDS AND CONTRIBUTE TO ITS PATHOGENESIS AND THEN DISCUSS THE MODE OF ACTION OF HMAS IN MDS. 2014 11 3575 49 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 12 3565 45 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 13 5913 31 TARGETED THERAPY IN LEUKEMIA. RESEARCH CONDUCTED OVER THE LAST TWO DECADES HAS YIELDED A DETAILED UNDERSTANDING OF THE MOLECULAR LESIONS THAT CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITORS INTO THE VARIOUS FORMS OF ACUTE AND CHRONIC LEUKEMIA. ALTHOUGH OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LEUKEMIA REMAINS INCOMPLETE, THE INFORMATION GAINED TO DATE HAS HAD A PROFOUND IMPACT ON THE WAY THESE MALIGNANCIES ARE BOTH DIAGNOSED AND MONITORED DURING THERAPY. MORE RECENTLY, TARGETED THERAPIES HAVE BEEN DEVELOPED AGAINST SOME OF THE IDENTIFIED GENETIC LESIONS. THESE THERAPIES HAVE LED TO SIGNIFICANT IMPROVEMENTS IN PATIENT OUTCOMES WHILE SIMULTANEOUSLY DECREASING THERAPY-RELATED TOXICITY. WITH THE ADVENT OF GENOME-WIDE METHODS TO DEFINE THE TOTAL COMPLEMENT OF GENETIC AND EPIGENETIC LESIONS INVOLVED IN LEUKEMOGENESIS, NEW TARGETED THERAPIES CAN BE ANTICIPATED. THIS REVIEW HIGHLIGHTS SOME OF THE TARGETED THERAPIES THAT ARE PRESENTLY BEING USED TO TREAT HEMATOPOIETIC MALIGNANCIES AND DESCRIBES SOME OF THE RECENT ADVANCES THAT SHOULD HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT OF FUTURE TARGET THERAPIES. 2008 14 2237 47 EPIGENETIC MODIFIERS IN MYELOID MALIGNANCIES: THE ROLE OF HISTONE DEACETYLASE INHIBITORS. MYELOID HEMATOLOGICAL MALIGNANCIES ARE CLONAL BONE MARROW NEOPLASMS, COMPRISING OF ACUTE MYELOID LEUKEMIA (AML), THE MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), THE MYELOPROLIFERATIVE NEOPLASMS (MPN) AND SYSTEMIC MASTOCYTOSIS (SM). THE FIELD OF EPIGENETIC REGULATION OF NORMAL AND MALIGNANT HEMATOPOIESIS IS RAPIDLY GROWING. IN RECENT YEARS, HETEROZYGOUS SOMATIC MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS HAVE BEEN FOUND IN ALL SUBTYPES OF MYELOID MALIGNANCIES, SUPPORTING THE RATIONALE FOR TREATMENT WITH EPIGENETIC MODIFIERS. HISTONE DEACETYLASE INHIBITORS (HDACI) ARE EPIGENETIC MODIFIERS THAT, IN VITRO, HAVE BEEN SHOWN TO INDUCE GROWTH ARREST, APOPTOTIC OR AUTOPHAGIC CELL DEATH, AND TERMINAL DIFFERENTIATION OF MYELOID TUMOR CELLS. THESE EFFECTS WERE OBSERVED BOTH AT THE BULK TUMOR LEVEL AND IN THE MOST IMMATURE CD34(+)38(-) CELL COMPARTMENTS CONTAINING THE LEUKEMIC STEM CELLS. THUS, THERE IS A STRONG RATIONALE SUPPORTING HDACI THERAPY IN MYELOID MALIGNANCIES. HOWEVER, DESPITE INITIAL PROMISING RESULTS IN PHASE I TRIALS, HDACI IN MONOTHERAPY AS WELL AS IN COMBINATION WITH OTHER DRUGS, HAVE FAILED TO IMPROVE RESPONSES OR SURVIVAL. THIS REVIEW PROVIDES AN OVERVIEW OF THE RATIONALE FOR HDACI IN MYELOID MALIGNANCIES, CLINICAL RESULTS AND SPECULATIONS ON WHY CLINICAL TRIALS HAVE THUS FAR NOT MET THE EXPECTATIONS, AND HOW THIS MAY BE IMPROVED IN THE FUTURE. 2018 15 6320 48 THE ROCKY ROAD TO PERSONALIZED MEDICINE IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS A MALIGNANT DISORDER OF THE MYELOID BLOOD LINEAGE CHARACTERIZED BY IMPAIRED DIFFERENTIATION AND INCREASED PROLIFERATION OF HEMATOPOIETIC PRECURSOR CELLS. RECENT TECHNOLOGICAL ADVANCES HAVE LED TO AN IMPROVED UNDERSTANDING OF AML BIOLOGY BUT ALSO UNCOVERED THE ENORMOUS CYTOGENETIC AND MOLECULAR HETEROGENEITY OF THE DISEASE. DESPITE THIS HETEROGENEITY, AML IS MOSTLY MANAGED BY A 'ONE-SIZE-FITS-ALL' APPROACH CONSISTING OF INTENSIVE, HIGHLY TOXIC INDUCTION AND CONSOLIDATION CHEMOTHERAPY. THESE TREATMENT PROTOCOLS HAVE REMAINED LARGELY UNCHANGED FOR THE PAST SEVERAL DECADES AND ONLY LEAD TO A CURE IN APPROXIMATELY 30-35% OF CASES. THE ADVENT OF TARGETED THERAPIES IN CHRONIC MYELOID LEUKAEMIA AND OTHER MALIGNANCIES HAS SPARKED HOPE TO IMPROVE PATIENT OUTCOME IN AML. HOWEVER, THE IMPLEMENTATION OF TARGETED AGENTS IN AML THERAPY HAS BEEN UNEXPECTEDLY CUMBERSOME AND REMAINS A DIFFICULT TASK DUE TO A VARIETY OF DISEASE- AND PATIENT-SPECIFIC FACTORS. IN THIS REVIEW, WE DESCRIBE CURRENT STANDARD AND INVESTIGATIONAL THERAPEUTIC STRATEGIES WITH A FOCUS ON TARGETED AGENTS AND HIGHLIGHT POTENTIAL TOOLS THAT MIGHT FACILITATE THE DEVELOPMENT OF TARGETED THERAPIES FOR THIS FATAL DISEASE. THE CLASSES OF AGENTS DESCRIBED IN THIS REVIEW INCLUDE CONSTITUTIVELY ACTIVATED SIGNALLING PATHWAY INHIBITORS, SURFACE RECEPTOR TARGETS, EPIGENETIC MODIFIERS, DRUGS TARGETING THE INTERACTION OF THE HEMATOPOIETIC PROGENITOR CELL WITH THE STROMA AND DRUGS THAT TARGET THE APOPTOTIC MACHINERY. THE CLINICAL CONTEXT AND OUTCOME WITH THESE AGENTS WILL BE EXAMINED TO GAIN INSIGHT ABOUT THEIR OPTIMAL UTILIZATION. 2018 16 957 35 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 17 1164 29 CONTRIBUTION OF CHRONIC MYELOID LEUKAEMIA (CML) AS A DISEASE MODEL TO DEFINE AND STUDY CLONAL HETEROGENEITY. ALTHOUGH TUMOUR CELL INTRA-CLONAL HETEROGENEITY HAS BEEN KNOWN FOR MANY YEARS, ITS APPLICATION IN THE ONCOLOGY CLINICAL PRACTICE (PATIENT MANAGEMENT, PROGNOSIS, ETC.) REMAINS LIMITED. FOR THIS, CHRONIC MYELOID LEUKAEMIA (CML) IS A REMARKABLE MODEL. BASIC RESEARCH STUDIES REVEALED THE HETEROGENEITY OF THE INITIAL CLONE, AND LED TO THE HYPOTHESIS OF THE EXISTENCE OF LEUKEMIC STEM CELLS. NEVERTHELESS, THE INDISPUTABLE EVIDENCE OF THE INTRA-CLONAL HETEROGENEITY ROLE IN THE THERAPEUTIC RESPONSE CAME FROM THE OUTCOMES OF THE TREATMENT WITH TYROSINE KINASE INHIBITORS (THE FIRST TARGETED THERAPY IN MEDICINE) COMBINED WITH THE EARLY AND RIGOROUS CLINICAL AND MOLECULAR MONITORING OF THESE PATIENTS. CML MANAGEMENT ALREADY TAKES THIS HETEROGENEITY INTO ACCOUNT FOR PERSONALIZED PATIENT FOLLOW-UP. THE ADVENTURE CONTINUES WITH THE OBJECTIVES OF BETTER TAILORING THE TREATMENT AND OF CURING THE DISEASE IN MOST OF THE PATIENTS. 2019 18 1046 45 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES. 2005 19 4660 51 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW. 2002 20 2981 29 GENETIC COMPLEXITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA. IN RECENT YEARS CMML HAS RECEIVED INCREASED ATTENTION AS THE MOST COMMONLY OBSERVED MDS/MPN OVERLAP SYNDROME. RENEWED INTEREST HAS OCCURRED IN PART DUE TO WIDESPREAD ADOPTION OF NEXT-GENERATION SEQUENCING PANELS THAT HELP RENDER THE DIAGNOSIS IN THE ABSENCE OF MORPHOLOGIC DYSPLASIA. ALTHOUGH MOST CMML PATIENTS EXHIBIT SOMATIC MUTATIONS IN EPIGENETIC MODIFIERS, SPLICEOSOME COMPONENTS, TRANSCRIPTION FACTORS AND SIGNAL TRANSDUCTION GENES, IT IS INCREASINGLY CLEAR THAT A SMALL SUBSET HARBORS AN INHERITED PREDISPOSITION TO CMML AND OTHER MYELOID NEOPLASMS. MORE INTRIGUING IS THE FACT THAT THE MUTATIONAL SPECTRUM OBSERVED IN CMML IS FOUND IN OTHER TYPES OF MYELOID LEUKEMIAS, BEGGING THE QUESTION OF HOW SIMILAR GENETIC BACKGROUNDS CAN LEAD TO SUCH DIVERGENT CLINICAL PHENOTYPES. IN THIS REVIEW WE PRESENT A CONTEMPORARY SNAPSHOT OF THE GENETIC COMPLEXITY INHERENT TO CMML, EXPLORE THE RELATIONSHIP BETWEEN GENOTYPE-PHENOTYPE AND PRESENT A STEPWISE MODEL OF CMML PATHOGENESIS AND PROGRESSION. 2021