1  3178 128 HAEMATOLOGIC MALIGNANCIES WITH UNFAVOURABLE GENE MUTATIONS BENEFIT FROM DONOR LYMPHOCYTE INFUSION WITH/WITHOUT DECITABINE FOR PROPHYLAXIS OF RELAPSE AFTER ALLOGENEIC HSCT: A PILOT STUDY. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE FOR LEUKAEMIA PATIENTS WITH UNFAVOURABLE GENE MUTATIONS WHO RECEIVE ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT). THERE IS NO CONSENSUS ON THE INDICATION OF DONOR LYMPHOCYTE INFUSION (DLI) FOR PROPHYLAXIS OF RELAPSE AFTER ALLO-HSCT. TO EVALUATE THE TOLERANCE AND EFFICACY OF PROPHYLACTIC DLI IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS SUCH AS FLT3-ITD, TP53, ASXL1, DNMT3A OR TET2, WE PERFORMED A PROSPECTIVE, SINGLE-ARM STUDY. PROPHYLACTIC USE OF DECITABINE FOLLOWED BY DLI WAS PLANNED IN PATIENTS WITH TP53 OR EPIGENETIC MODIFIER GENE MUTATIONS. THE PROPHYLAXIS WAS PLANNED IN 46 RECIPIENTS: IT WAS ADMINISTERED IN 28 PATIENTS AND IT WAS NOT ADMINISTERED IN 18 PATIENTS DUE TO CONTRAINDICATIONS. NO DLI-ASSOCIATED PANCYTOPENIA WAS OBSERVED. THE CUMULATIVE INCIDENCES OF GRADE II-IV AND III-IV ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD) AT 100 DAYS POST-DLI WERE 25.8% AND 11.0%, RESPECTIVELY. THE RATES OF CHRONIC GVHD, NON-RELAPSE MORTALITY AND RELAPSE AT 3 YEARS POST-DLI WERE 21.6%, 25.0% AND 26.1%, RESPECTIVELY. THE 3-YEAR RELAPSE-FREE SURVIVAL AND OVERALL SURVIVAL (OS) RATES WERE 48.9% AND 48.2%, RESPECTIVELY. ACUTE GVHD (HR: 2.30, P = 0.016) AND RELAPSE (HR: 2.46, P = 0.003) AFTER DLI WERE INDEPENDENTLY ASSOCIATED WITH INFERIOR OS. DATA IN THE CURRENT STUDY SHOWED THE FEASIBILITY OF PROPHYLACTIC DLI WITH/WITHOUT DECITABINE IN THE EARLY STAGE AFTER ALLO-HSCT IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  5283  48 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE.	2021	
                                                                                                                                                                                                                                                                                                                            
3  1735  42 EARLY AND SUSTAINED EXPANSION OF ADAPTIVE NATURAL KILLER CELLS FOLLOWING HAPLOIDENTICAL TRANSPLANTATION AND CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS DISSOCIATE GRAFT-VERSUS-LEUKEMIA AND GRAFT-VERSUS-HOST EFFECTS. BACKGROUND: ADAPTIVE OR MEMORY NATURAL KILLER (NK) CELLS WITH EPIGENETIC IMPRINTS SIMILAR TO MEMORY T CELLS HAVE BEEN SHOWN TO DEVELOP IN RESPONSE TO CYTOMEGALOVIRUS (CMV) INFECTION WITH UPREGULATION OF ACTIVATING RECEPTOR NKG2C. THESE CELLS HAVE BEEN SHOWN TO POSSESS STRONG ANTI-TUMOUR EFFICACY BOTH IN-VITRO AS WELL AS IN-VIVO. OBJECTIVES: TO DETERMINE IF RECONSTITUTION OF ADAPTIVE NK CELLS (CD56(DIM)NKG2C(+)NKG2A(-)) IN PATIENTS WITH ADVANCED LEUKEMIA UNDERGOING HAPLOIDENTICAL HCT HAD ANY IMPACT ON DISEASE PROGRESSION (DP). STUDY DESIGN: THE STUDY COHORT COMPRISED OF 60 PATIENTS WITH ADVANCED ACUTE LEUKEMIA, AGED 2-65 YEARS, RECEIVING MYELOABLATIVE PTCY BASED HAPLOIDENTICAL TRANSPLANTATION FROM CMV SEROPOSITIVE DONORS, FOLLOWED BY CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS (DLI). THEY WERE EVALUATED FOR THE KINETICS OF RECONSTITUTION OF ADAPTIVE NK CELLS, BOTH PHENOTYPIC AND FUNCTIONAL, AT DAYS +30,+60, +90 AND AT REGULAR INTERVALS, TO 3 YEARS OF FOLLOW-UP, IN RELATION TO DP. RECONSTITUTION OF ADAPTIVE NK CELLS WAS COMPARED WITH A RETROSPECTIVE COHORT OF PATIENTS IN THE SAME PROTOCOL RECEIVING DLI WITHOUT CTLA4IG. RESULTS: NON-RELAPSE MORTALITY, ACUTE AND CHRONIC GVHD WERE 5.1%, 10.3% AND 14.5%. DP WAS 17.5% AT A MEDIAN FOLLOW-UP OF 28 MONTHS. ADAPTIVE NK CELLS WERE SIGNIFICANTLY HIGHER IN PATIENTS WITHOUT DP AT DAYS+30, +60 AND +90 (P = 0.0001), IRRESPECTIVE OF CMV REACTIVATION AND REMAINED ELEVATED UNTIL 36 MONTHS POST-HCT. THESE CELLS MAINTAINED THEIR FUNCTIONAL COMPETENCE AS MEASURED BY ROBUST INTERFERON-GAMMA PRODUCTION WITH HIGHER EXPRESSIONS OF KIR, NKG2D AND CD57, WITHOUT ANY INCREASE IN PD1 EXPRESSION. GRAFTS FROM DONORS WITH HIGHER ADAPTIVE NK CELLS WERE ASSOCIATED WITH A LOWER RISK OF DP (P = 0.0001). IN MULTIVARIATE ANALYSIS, ADAPTIVE NK CELL RECOVERY AT DAY +90 HAD THE MOST FAVORABLE IMPACT ON DP (HR-0.7). TREGS RECONSTITUTED BRISKLY ALONG WITH THE ADAPTIVE NK CELLS AND WERE SUSTAINED AS WELL, WITHOUT COMPROMISING THE GVL EFFECT. COMPARISON WITH A RETROSPECTIVE COHORT RECEIVING THE SAME PROTOCOL WITH DLI WITHOUT CTLA4IG, SHOWED A SUPERIOR RECONSTITUTION OF ADAPTIVE NK CELLS IN THOSE RECEIVING CTLA4IG-DLI (P < 0.0001). CONCLUSION: OUR STUDY SUGGESTS THAT MYELOABLATIVE TRANSPLANTATION FROM CMV SEROPOSITIVE HAPLOIDENTICAL DONORS AUGMENTED WITH CTLA4IG-PRIMED DLI MIGHT FAVOR EARLY AND SUSTAINED EXPANSION OF FUNCTIONALLY COMPETENT ADAPTIVE NK CELLS IRRESPECTIVE OF CMV REACTIVATION, WITH A FAVORABLE OUTCOME.	2021	

4  1286  42 DECITABINE IN COMBINATION WITH DONOR LYMPHOCYTE INFUSIONS CAN INDUCE REMISSIONS IN RELAPSED MYELOID MALIGNANCIES WITH HIGHER LEUKEMIC BURDEN AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION. THE COMBINATION OF 5-AZACYTIDINE (AZA) WITH DONOR LYMPHOCYTE INFUSIONS (DLIS) CAN INDUCE REMISSIONS IN PATIENTS WITH RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT. AS DECITABINE (DAC) IS KNOWN TO BE EFFECTIVE ALSO IN AML/MDS WITH LEUKOCYTOSIS, WE INVESTIGATED THE COMBINATION OF DAC WITH DLIS FOR RELAPSE AFTER ALLO-HCT. BETWEEN 2006 AND 2016, 26 PATIENTS (MEDIAN AGE 59 YEARS) WITH AML (N = 18), MDS (N = 6), OR MPN (N = 2) AND OVERT HEMATOLOGICAL RELAPSE AFTER ALLO-HCT WERE TREATED. MEDIAN DURATION FROM ALLO-HCT TO RELAPSE WAS 306 DAYS (RANGE, 76-4943). EIGHTEEN PATIENTS RECEIVED DAC + DLIS, 8 DAC-ONLY (MEDIAN NUMBER CYCLES OF DAC: 2, RANGE 1-13, MEDIAN NUMBER OF DLIS: 2, RANGE 1-10). THE INCIDENCE OF ACUTE AND CHRONIC GVHD IN PATIENTS RECEIVING DLI WAS 17% (3/18) AND 6% (1/18), RESPECTIVELY. CR/CRI WAS ACHIEVED IN 15% (4/26), PR IN 4% (1/26), AND STABLE DISEASE IN 58% (15/26) OF PATIENTS. EIGHT PATIENTS RECEIVED A SECOND ALLO-HCT. MEDIAN OVERALL SURVIVAL WAS 4.7 MONTHS. ELEVATED PD-L1 PROTEIN EXPRESSION IN BONE MARROW CELLS WAS DETECTED IN 4/8 PATIENTS WITH >20% BLAST INFILTRATION PRIOR TO DAC, WITHOUT A CLEAR ASSOCIATION WITH RESPONSE. IN CONCLUSION, THE DAC + DLI REGIMEN PROVED FEASIBLE AND EFFECTIVE IN RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT, WITH EFFICACY NOT RESTRICTED TO PATIENTS WITH LOW LEUKEMIC BURDEN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5   765  44 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  2769  38 EXTENDED DOSING WITH CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH MYELOID MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN CLINICAL DEVELOPMENT FOR TREATMENT OF HEMATOLOGICAL CANCERS. THIS STUDY OF EXTENDED CC-486 DOSING INCLUDED PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDSS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), OR ACUTE MYELOID LEUKEMIA (AML). AFTER A PHARMACOKINETIC ASSESSMENT PERIOD, 31 PATIENTS (MDS N = 18, CMML N = 4, AND AML N = 9) ENTERED A CLINICAL PHASE IN WHICH THEY RECEIVED CC-486 300 MG ONCE-DAILY FOR 21 DAYS OF REPEATED 28-DAY CYCLES. MEDIAN AGE WAS 71 YEARS (RANGE: 53-93); 42% OF PATIENTS WERE AGED >/=75 YEARS. A TOTAL OF 5 PATIENTS WITH AML (63%) HAD PRIOR MDS. MEDIAN NUMBER OF CC-486 TREATMENT CYCLES WAS 4 (RANGE: 1-32). THE MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) WERE GASTROINTESTINAL (84% OF PATIENTS) AND HEMATOLOGIC (81%). MOST COMMON GRADE 3-4 TEAES WERE NEUTROPENIA (N = 13, 42%) AND ANEMIA (N = 9, 29%). TEN PATIENTS EXPERIENCED GRADE 4 NEUTROPENIA. INFREQUENTLY, CC-486 DOSE WAS INTERRUPTED OR REDUCED DUE TO GASTROINTESTINAL (N = 5, 16%) OR HEMATOLOGIC (N = 6, 19%) TEAES. OVERALL RESPONSE RATE (COMPLETE REMISSION [CR], CR WITH INCOMPLETE HEMATOLOGICAL RECOVERY [CRI], PARTIAL REMISSION [PR], MARROW CR) IN THE MDS/CMML SUBGROUPS WAS 32% AND IN THE AML SUBGROUP (CR/CRI/PR) WAS 22%. RED BLOOD CELL TRANSFUSION INDEPENDENCE RATES IN THE MDS/CMML AND AML SUBGROUPS WERE 33% AND 25%, RESPECTIVELY, AND 2 MDS/CMML PATIENTS ATTAINED HEMATOLOGIC IMPROVEMENT AS A BEST RESPONSE ON-STUDY. NO BASELINE GENE MUTATION WAS PREDICTIVE OF RESPONSE/NONRESPONSE. CC-486 ALLOWS FLEXIBLE DOSING AND SCHEDULES TO IMPROVE TOLERABILITY OR RESPONSE. NEUTROPENIA IN EARLY TREATMENT CYCLES DESERVES SCRUTINY AND MAY WARRANT INITIATION OF PROPHYLACTIC ANTIBIOTICS. KEY POINTS: THE SAFETY PROFILE OF ORAL CC-486 WAS COMPARABLE TO THAT OF INJECTABLE AZACITIDINE; MOST ADVERSE EVENTS WERE HEMATOLOGICAL AND GASTROINTESTINAL. EXTENDED (21-DAY/CYCLE) CC-486 DOSING INDUCED RESPONSES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES, MANY OF WHOM HAD PRIOR DNMTI FAILURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  1959  36 EPIGENETIC AGING AND HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH SEVERE APLASTIC ANEMIA. CELLULAR AGING IN HEMATOPOIETIC CELL TRANSPLANTATION (HCT) IS IMPORTANT IN THE CONTEXT OF IMMUNE RECONSTITUTION AND AGE-RELATED COMPLICATIONS. RECENTLY, SEVERAL DNA-METHYLATION (DNAM)-BASED BIOMARKERS OF AGING KNOWN AS "EPIGENETIC CLOCKS" HAVE BEEN INTRODUCED AS NOVEL TOOLS TO PREDICT CELLULAR AGE. HERE, WE USED COX PROPORTIONAL HAZARDS MODELS TO ASSESS THE POSSIBLE ASSOCIATIONS OF DONOR PRE-HCT DNAM AGE, AND ITS POST-HCT CHANGES, USING THE RECENTLY PUBLISHED LIFESPAN-ASSOCIATED EPIGENETIC CLOCK KNOWN AS "DNAM-GRIMAGE," WITH OUTCOMES AMONG PATIENTS WITH SEVERE APLASTIC ANEMIA (SAA). THE STUDY INCLUDED 732 SAA PATIENTS FROM THE TRANSPLANT OUTCOMES IN APLASTIC ANEMIA PROJECT, WHO UNDERWENT UNRELATED DONOR HCT AND FOR WHOM A DONOR PRE-HCT BLOOD DNA SAMPLE WAS AVAILABLE; 41 ALSO HAD A POST-HCT SAMPLE COLLECTED AT DAY 100. IN MULTIVARIABLE ANALYSES, WE FOUND SIMILAR ASSOCIATIONS FOR DONOR CHRONOLOGICAL AGE AND PRE-HCT DNAM-GRIMAGE WITH POST-HCT SURVIVAL (HAZARD RATIO [HR] PER DECADE = 1.13; 95% CONFIDENCE INTERVAL [CI], 0.99-1.28; P = .07 AND HR = 1.14; 95% CI, 0.99-1.28; P = .06, RESPECTIVELY). IN DONORS WITH 10+ YEARS OF GRIMAGE ACCELERATION (IE, DEVIATION FROM EXPECTED DNAM AGE FOR CHRONOLOGICAL AGE), ELEVATED RISKS OF CHRONIC GRAFT VERSUS HOST DISEASE (HR = 2.4; 95% CI, 1.21-4.65; P = .01) AND POSSIBLY POST-HCT MORTALITY (HR = 1.79; 95% CI, 0.96-3.33; P = .07) WERE OBSERVED. IN THE SUBSET WITH POST-HCT SAMPLES, WE OBSERVED A SIGNIFICANT INCREASE IN DNAM-GRIMAGE IN THE FIRST 100 DAYS AFTER HCT (MEDIAN CHANGE 12.5 YEARS, RANGE 1.4 TO 26.4). HIGHER DNAM-GRIMAGE AFTER HCT WAS ASSOCIATED WITH INFERIOR SURVIVAL (HR PER YEAR = 1.11; 95% CI, 1.02-1.21; P = .01), PREDOMINANTLY WITHIN THE FIRST YEAR AFTER HCT. THIS STUDY HIGHLIGHTS THE POSSIBLE ROLE CELLULAR AGING MAY PLAY IN HCT OUTCOMES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  5044  29 PHARMACOKINETICS AND PHARMACODYNAMICS WITH EXTENDED DOSING OF CC-486 IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN DEVELOPMENT FOR PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA. IN PART 1 OF THIS TWO-PART STUDY, A 7-DAY CC-486 DOSING SCHEDULE SHOWED CLINICAL ACTIVITY, WAS GENERALLY WELL TOLERATED, AND REDUCED DNA METHYLATION. EXTENDING DOSING OF CC-486 BEYOND 7 DAYS WOULD INCREASE DURATION OF AZACITIDINE EXPOSURE. WE HYPOTHESIZED THAT EXTENDED DOSING WOULD THEREFORE PROVIDE MORE SUSTAINED EPIGENETIC ACTIVITY. REPORTED HERE ARE THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROFILES OF CC-486 EXTENDED DOSING SCHEDULES IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) OR ACUTE MYELOID LEUKEMIA (AML) FROM PART 2 OF THIS STUDY. PK AND/OR PD DATA WERE AVAILABLE FOR 59 PATIENTS WHO WERE SEQUENTIALLY ASSIGNED TO 1 OF 4 EXTENDED CC-486 DOSING SCHEDULES: 300MG ONCE-DAILY OR 200MG TWICE-DAILY FOR 14 OR 21 DAYS PER 28-DAY CYCLE. BOTH 300MG ONCE-DAILY SCHEDULES AND THE 200MG TWICE-DAILY 21-DAY SCHEDULE SIGNIFICANTLY (ALL P < .05) REDUCED GLOBAL DNA METHYLATION IN WHOLE BLOOD AT ALL MEASURED TIME POINTS (DAYS 15, 22, AND 28 OF THE TREATMENT CYCLE), WITH SUSTAINED HYPOMETHYLATION AT CYCLE END COMPARED WITH BASELINE. CC-486 EXPOSURES AND REDUCED DNA METHYLATION WERE SIGNIFICANTLY CORRELATED. PATIENTS WHO HAD A HEMATOLOGIC RESPONSE HAD SIGNIFICANTLY GREATER METHYLATION REDUCTIONS THAN NON-RESPONDING PATIENTS. THESE DATA DEMONSTRATE THAT EXTENDED DOSING OF CC-486 SUSTAINS EPIGENETIC EFFECTS THROUGH THE TREATMENT CYCLE. TRIAL REGISTRATION: CLINICALTRIALS.GOV NCT00528983.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9    87  33 A PHASE 1 STUDY OF AZACITIDINE WITH HIGH-DOSE CYTARABINE AND MITOXANTRONE IN HIGH-RISK ACUTE MYELOID LEUKEMIA. IN THIS PHASE 1 STUDY, AZACITIDINE (AZA) WAS GIVEN BEFORE HIGH-DOSE CYTARABINE (HIDAC) AND MITOXANTRONE (MITO) BASED ON THE HYPOTHESIS THAT EPIGENETIC PRIMING WITH A HYPOMETHYLATING AGENT BEFORE CYTOTOXIC CHEMOTHERAPY WOULD IMPROVE RESPONSE RATES IN PATIENTS WITH HIGH-RISK ACUTE MYELOID LEUKEMIA (AML), INCLUDING RELAPSED/REFRACTORY DISEASE. THE PRIMARY OBJECTIVE WAS TO ESTABLISH THE RECOMMENDED PHASE 2 DOSE OF AZA GIVEN BEFORE STANDARD HIDAC/MITO. IN A DOSE ESCALATION SCHEME, 46 PATIENTS (MEDIAN AGE, 66 YEARS) RECEIVED AZA AT 37.5, 50, OR 75 MG/M2 SUBCUTANEOUSLY OR IV ONCE DAILY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10 (THE HIDAC/MITO DOSE WAS REDUCED 33% IN ELDERLY SUBJECTS). TWO DOSE-LIMITING TOXICITIES OCCURRED (BOTH IN THE SAME PATIENT): ACUTE LIVER FAILURE AND KIDNEY INJURY AT THE 50 MG/M2 DOSE. THE 30-DAY INDUCTION DEATH RATE WAS 2.2% (1 OF 46). THE OVERALL RESPONSE RATE, INCLUDING COMPLETE REMISSION AND COMPLETE REMISSION WITH INCOMPLETE COUNT RECOVERY, WAS 61% (28 OF 46). PREVIOUSLY UNTREATED PATIENTS AGED >/=60 YEARS WITH THERAPY-RELATED AML AND DE NOVO AML WERE MORE LIKELY TO RESPOND THAN UNTREATED PATIENTS WITH AML PROGRESSING FROM AN ANTECEDENT HEMATOLOGIC DISORDER (MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA). PATIENTS WITH FAVORABLE EUROPEAN LEUKEMIA NETWORK RISK (P = .008), NPM1 MUTATIONS (P = .007), OR IDH2 MUTATIONS (P = .03) WERE MORE LIKELY TO RESPOND, AND THOSE WITH TP53 MUTATIONS (P = .03) WERE LESS LIKELY TO RESPOND. THE RECOMMENDED PHASE 2 DOSE OF AZA IS 75 MG/M2 PER DAY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10. THIS TRIAL WAS REGISTERED AT WWW.CLINICALTRIALS.GOV AS #NCT01839240.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  5478  32 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  5246  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  5244  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  1469  34 DISTINCT EVOLUTIONARY PATHS IN CHRONIC LYMPHOCYTIC LEUKEMIA DURING RESISTANCE TO THE GRAFT-VERSUS-LEUKEMIA EFFECT. LEUKEMIC RELAPSE REMAINS A MAJOR BARRIER TO SUCCESSFUL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT) FOR AGGRESSIVE HEMATOLOGIC MALIGNANCIES. THE BASIS FOR RELAPSE OF ADVANCED LYMPHOID MALIGNANCIES REMAINS INCOMPLETELY UNDERSTOOD AND MAY INVOLVE ESCAPE FROM THE GRAFT-VERSUS-LEUKEMIA (GVL) EFFECT. WE HYPOTHESIZED THAT FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH ALLO-HSCT, LEUKEMIC CELL-INTRINSIC FEATURES INFLUENCE TRANSPLANT OUTCOMES BY DIRECTING THE EVOLUTIONARY TRAJECTORIES OF CLL CELLS. INTEGRATED GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ANALYSES OF CLL CELLS FROM 10 PATIENTS REVEALED THAT THE CLINICAL KINETICS OF POST-HSCT RELAPSE ARE SHAPED BY DISTINCT MOLECULAR DYNAMICS. EARLY RELAPSES AFTER ALLO-HSCT EXHIBITED NOTABLE GENETIC STABILITY; SINGLE CLL CELL TRANSCRIPTIONAL ANALYSIS DEMONSTRATED A CELLULAR HETEROGENEITY THAT WAS STATIC OVER TIME. IN CONTRAST, CLL CELLS RELAPSING LATE AFTER ALLO-HSCT DISPLAYED NOTABLE GENETIC EVOLUTION AND EVIDENCE OF NEOANTIGEN DEPLETION, CONSISTENT WITH MARKED SINGLE-CELL TRANSCRIPTIONAL SHIFTS THAT WERE UNIQUE TO EACH PATIENT. WE OBSERVED A GREATER RATE OF EPIGENETIC CHANGE FOR LATE RELAPSES NOT SEEN IN EARLY RELAPSES OR RELAPSES AFTER CHEMOTHERAPY ALONE, SUGGESTING THAT THE SELECTION PRESSURES OF THE GVL BOTTLENECK ARE UNLIKE THOSE IMPOSED BY CHEMOTHERAPY. NO SELECTIVE ADVANTAGE FOR HUMAN LEUKOCYTE ANTIGEN (HLA) LOSS WAS OBSERVED, EVEN WHEN PRESENT IN PRETRANSPLANT SUBPOPULATIONS. GAIN OF STEM CELL MODULES WAS A COMMON SIGNATURE ASSOCIATED WITH LEUKEMIA RELAPSE REGARDLESS OF POSTTRANSPLANT RELAPSE KINETICS. THESE DATA ELUCIDATE THE BIOLOGICAL PATHWAYS THAT UNDERLIE GVL RESISTANCE AND POSTTRANSPLANT RELAPSE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  5056  27 PHASE I TRIAL OF LOW DOSE DECITABINE TARGETING DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA AND NON-HODGKIN LYMPHOMA: DOSE-LIMITING MYELOSUPPRESSION WITHOUT EVIDENCE OF DNA HYPOMETHYLATION. TARGETING ABERRANT DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN LYMPHOMA (NHL) WITH DECITABINE MAY REVERSE EPIGENETIC SILENCING IN B-CELL MALIGNANCIES. TWENTY PATIENTS WERE ENROLLED IN TWO PHASE I TRIALS TO DETERMINE THE MINIMUM EFFECTIVE PHARMACOLOGICAL DOSE OF DECITABINE IN PATIENTS WITH RELAPSED/REFRACTORY CLL (N = 16) AND NHL (N = 4). PATIENTS RECEIVED 1-3 CYCLES OF DECITABINE. DOSE-LIMITING TOXICITY (DLT) WAS OBSERVED IN 2 OF 4 CLL AND 2 OF 2 NHL PATIENTS RECEIVING DECITABINE AT 15 MG/M(2) PER D DAYS 1-10, CONSISTING OF GRADE 3-4 THROMBOCYTOPENIA AND HYPERBILIRUBINAEMIA. SIX PATIENTS WITH CLL RECEIVED DECITABINE AT 10 MG/M(2) PER D DAYS 1-10 WITHOUT DLT; HOWEVER, RE-EXPRESSION OF METHYLATED GENES OR CHANGES IN GLOBAL DNA METHYLATION WERE NOT OBSERVED. THEREFORE, A 5-DAY DECITABINE SCHEDULE WAS EXAMINED. WITH 15 MG/M(2) PER D DECITABINE DAYS 1-5, DLT OCCURRED IN 2 OF 6 CLL AND 2 OF 2 NHL PATIENTS, CONSISTING OF GRADE 3-4 NEUTROPENIA, THROMBOCYTOPENIA, AND FEBRILE NEUTROPENIA. EIGHT PATIENTS HAD STABLE DISEASE. IN 17 PATIENTS, THERE WERE NO SIGNIFICANT CHANGES IN GENOME-WIDE METHYLATION OR IN TARGET GENE RE-EXPRESSION. IN CONCLUSION, DOSE-LIMITING MYELOSUPPRESSION AND INFECTIOUS COMPLICATIONS PREVENTED DOSE ESCALATION OF DECITABINE TO LEVELS ASSOCIATED WITH CHANGES IN GLOBAL METHYLATION OR GENE RE-EXPRESSION IN CLL AND NHL.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  5980  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  3560  34 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17  2678  31 EVALUATION OF A PROGNOSTIC EPIGENETIC CLASSIFICATION SYSTEM IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. BACKGROUND: METHYLATION AT 5 CPG SITES WAS PREVIOUSLY SHOWN TO CLASSIFY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO 3 PROGNOSTIC SUBGROUPS. HERE, WE AIMED TO VALIDATE THE MARKER SET IN AN ADDITIONAL COHORT AND TO EVALUATE ITS CLINICAL UTILITY FOR CLL PATIENT STRATIFICATION. METHODS: WE EVALUATED THIS EPIGENETIC MARKER SET IN 79 GERMAN PATIENTS USING BISULFITE TREATMENT FOLLOWED BY PYROSEQUENCING AND CLASSIFICATION USING A SUPPORT VECTOR MACHINE-LEARNING TOOL. RESULTS: THE N-CLL, I-CLL, AND M-CLL CLASSIFICATION WAS DETECTED IN 28 (35%), 10 (13%), AND 41 (51%) PATIENTS, RESPECTIVELY. EPIGENETIC GROUPING WAS ASSOCIATED WITH IGHV MUTATIONAL STATUS (P = 2 X 10(-12)), ISOLATED DEL13Q (P = 9 X 10(-6)), DEL17P (P = .015), COMPLEX KARYOTYPE (P = .005), VH-USAGE, AND CLINICAL OUTCOME AS TIME TO FIRST TREATMENT (P = 1.4 X 10(-12)) AND OVERALL SURVIVAL (P = .003). MULTIVARIATE COX REGRESSION ANALYSIS IDENTIFIED N-CLL AS A FACTOR FOR EARLIER TREATMENT HAZARD RATIO (HR), 6.3 (95% CONFIDENCE INTERVAL [CI] 2.4-16.4; P = .0002) COMPARED TO IGHV MUTATIONAL STATUS (HR 4.6, 95% CI 1.9-11.3, P = .0008). IN ADDITION, WHEN COMPARING THE PROGNOSTIC VALUE OF THE EPIGENETIC CLASSIFICATION SYSTEM WITH THE IGHV CLASSIFICATION, EPIGENETIC GROUPING PERFORMED BETTER COMPARED TO IGHV MUTATIONAL STATUS USING KAPLAN-MEIER ESTIMATION AND ALLOWED THE IDENTIFICATION OF A THIRD, INTERMEDIATE (I-CLL) GROUP. THUS, OUR STUDY CONFIRMED THE PROGNOSTIC VALUE OF THE EPIGENETIC MARKER SET FOR PATIENT STRATIFICATION IN ROUTINE CLINICAL DIAGNOSTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  6689  32 VALPROIC ACID AT THERAPEUTIC PLASMA LEVELS MAY INCREASE 5-AZACYTIDINE EFFICACY IN HIGHER RISK MYELODYSPLASTIC SYNDROMES. PURPOSE: EPIGENETIC CHANGES PLAY A ROLE AND COOPERATE WITH GENETIC ALTERATIONS IN THE PATHOGENESIS OF MYELODYSPLASTIC SYNDROMES (MDS). WE CONDUCTED A PHASE II MULTICENTER STUDY ON THE COMBINATION OF THE DNA-METHYLTRANSFERASE INHIBITOR 5-AZACYTIDINE (5-AZA) AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID (VPA) IN PATIENTS WITH HIGHER RISK MDS. EXPERIMENTAL DESIGN: WE ENROLLED 62 PATIENTS WITH MDS (REFRACTORY ANEMIA WITH EXCESS BLASTS, 39 PATIENTS; REFRACTORY ANEMIA WITH EXCESS BLASTS IN TRANSFORMATION, 19 PATIENTS; AND CHRONIC MYELOMANOCYTIC LEUKEMIA (CMML), 4 PATIENTS) AND AN INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS) RATING OF INTERMEDIATE-2 (42 PATIENTS) OR HIGH (20 PATIENTS). VPA WAS GIVEN TO REACH A PLASMA CONCENTRATION OF >50 MICROG/ML, THEN 5-AZA WAS ADDED S.C. AT 75 MG/M(2) FOR 7 DAYS IN EIGHT MONTHLY CYCLES. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS 14.4 MONTHS. AT A MEDIAN FOLLOW-UP OF 12 MONTHS (RANGE, 0.7-21.0), THE DISEASE PROGRESSED IN 20 PATIENTS, WITH 21% CUMULATIVE INCIDENCE OF PROGRESSION. OF 26 PATIENTS WHO COMPLETED EIGHT CYCLES, 30.7% OBTAINED COMPLETE OR PARTIAL REMISSION, 15.4% HAD A MAJOR HEMATOLOGIC IMPROVEMENT, WHEREAS 38.5% SHOWED STABLE DISEASE. DRUG-RELATED TOXICITY WAS MILD. FAVORABLE PROGNOSTIC FACTORS FOR SURVIVAL WERE IPSS INTERMEDIATE-2 AND PLASMA VPA OF > OR =50 MICROG/ML (LOG RANK = 0.013 AND 0.007, RESPECTIVELY). ANALYSIS OF POLYMORPHISMS IMPORTANT FOR THE METABOLISM OF THE DRUGS USED IN THE TRIAL SHOWED THAT CARRIERS OF THE CYP2C19*2 VARIANT OF CYTOCHROME P450 REQUIRED HIGHER VPA DOSES TO ACHIEVE THE TARGET VPA PLASMA CONCENTRATION OF 50 MICROG/ML ON DAY 1 OF 5-AZA TREATMENT (P = 0.0021). CONCLUSION: OUR DATA SHOW THAT THE 5-AZA/VPA COMBINATION IS ACTIVE AND SAFE IN PATIENTS WITH MDS WITH A POOR PROGNOSIS. ACHIEVEMENT OF VPA THERAPEUTIC LEVELS MAY INDEED INCREASE 5-AZA EFFICACY.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  1953  27 EPIGENETIC AGE ACCELERATION AND CHRONIC HEALTH CONDITIONS AMONG ADULT SURVIVORS OF CHILDHOOD CANCER. BACKGROUND: MOUNTING EVIDENCE SUPPORTS THE OCCURRENCE OF ACCELERATING AGING AMONG LONG-TERM SURVIVORS OF CHILDHOOD CANCER. WE AIMED TO INVESTIGATE EPIGENETIC AGE ACCELERATION (EAA) IN SURVIVORS AND EVALUATE ASSOCIATIONS BETWEEN EAA, TREATMENT EXPOSURES, HEALTH BEHAVIORS, AND CHRONIC HEALTH CONDITIONS (CHCS). METHODS: GENOME-WIDE METHYLATION DATA WERE GENERATED WITH INFINIUM EPIC BEADCHIP ON BLOOD-DERIVED DNA FROM 2139 SURVIVORS AND 282 FREQUENCY MATCHED CONTROLS FROM THE ST JUDE LIFETIME COHORT STUDY. EAAS WERE ESTIMATED AS RESIDUALS FROM A LINEAR REGRESSION OF EPIGENETIC AGE (LEVINE'S CLOCK) AGAINST CHRONOLOGICAL AGE. ADJUSTED LEAST SQUARE MEAN (ALSM) OF EAA WAS CALCULATED AND COMPARED BETWEEN SURVIVORS AND CONTROLS, ACROSS TREATMENT EXPOSURES AND HEALTH BEHAVIORS. ASSOCIATIONS OF EAA WITH 20 CLINICALLY ASSESSED CHCS WERE EVALUATED WITH MULTIVARIABLE PIECEWISE-EXPONENTIAL MODELS. ALL STATISTICAL TESTS FOR P VALUES BELOW WERE 2-SIDED. RESULTS: EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS THAN CONTROLS (ALSM = 0.63, 95% CONFIDENCE INTERVAL [CI] = 0.26 TO 1.01 VS -3.61, 95% CI = -4.43 TO 2.80). IN A MULTIVARIABLE MODEL AMONG SURVIVORS, STATISTICALLY SIGNIFICANTLY HIGHER EAA (P < .05) WAS OBSERVED IN THOSE EXPOSED TO CHEST RADIOTHERAPY, ABDOMEN OR PELVIC RADIOTHERAPY, ALKYLATING AGENTS, GLUCOCORTICOIDS, OR EPIPODOPHYLLOTOXINS. COMPARED WITH SURVIVORS WITH FAVORABLE HEALTH BEHAVIORS (ALSM = 0.26, 95% CI=-0.36 TO 0.87), EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG SURVIVORS WITH INTERMEDIATE (ALSM = 1.07, 95% CI = 0.59 TO 1.54) OR UNFAVORABLE HEALTH BEHAVIORS (ALSM = 1.45, 95% CI = 0.60 TO 2.30). IN TIME-TO-EVENT ANALYSES, STATISTICALLY SIGNIFICANT ASSOCIATIONS WERE IDENTIFIED BETWEEN EAA TERTILES AND INCIDENCE OF 7 CHCS: HYPERTENSION (3RD VS 1ST TERTILE, RELATIVE RATE [RR] = 1.83, 95% CI = 1.17 TO 2.83), MYOCARDIAL INFARCTION (RR = 2.91, 95% CI = 1.27 TO 7.21), OBESITY (RR = 1.39, 95% CI = 1.17 TO 1.66), OBSTRUCTIVE PULMONARY DEFICIT (RR = 1.86, 95% CI = 0.95 TO 3.77), PERIPHERAL MOTOR NEUROPATHY (RR = 2.89, 95% CI = 1.24 TO 6.97), PERIPHERAL SENSORY NEUROPATHY (RR = 2.04, 95% CI = 0.99 TO 4.26), AND PULMONARY DIFFUSION DEFICITS (RR = 2.75, 95% CI = 0.95 TO 7.63). CONCLUSIONS: EAA IS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS OF CHILDHOOD CANCER THAN IN NONCANCER CONTROLS AND IS ASSOCIATED WITH SPECIFIC TREATMENT EXPOSURES, UNFAVORABLE HEALTH BEHAVIORS, AND PRESENCE OF SPECIFIC CHCS.	2021	
                                                                                                                                 
20   960  34 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