19 results on '"Jacoby, Meagan A."'
Search Results
2. A randomized phase II/III study of 'novel therapeutics' versus azacitidine in newly diagnosed patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML), age 60 or older: a report of the comparison of azacitidine and nivolumab to azacitidine: SWOG S1612.
- Author
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Assouline S, Michaelis LC, Othus M, Hay AE, Walter RB, Jacoby MA, Schroeder MA, Uy GL, Law LY, Cheema F, Sweet KL, Asch AS, Liu JJ, Moseley AB, Maher T, Kingsbury LL, Fang M, Radich J, Little RF, and Erba HP
- Subjects
- Humans, Middle Aged, Azacitidine adverse effects, Nivolumab therapeutic use, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic drug therapy, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute chemically induced
- Published
- 2023
- Full Text
- View/download PDF
3. Convergent Clonal Evolution of Signaling Gene Mutations Is a Hallmark of Myelodysplastic Syndrome Progression.
- Author
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Menssen AJ, Khanna A, Miller CA, Nonavinkere Srivatsan S, Chang GS, Shao J, Robinson J, O'Laughlin M, Fronick CC, Fulton RS, Brendel K, Heath SE, Saba R, Welch JS, Spencer DH, Payton JE, Westervelt P, DiPersio JF, Link DC, Schuelke MJ, Jacoby MA, Duncavage EJ, Ley TJ, and Walter MJ
- Subjects
- Clonal Evolution genetics, Disease Progression, Humans, Mutation genetics, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Neoplasms, Second Primary
- Abstract
Progression from myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (AML) is associated with the acquisition and expansion of subclones. Our understanding of subclone evolution during progression, including the frequency and preferred order of gene mutation acquisition, remains incomplete. Sequencing of 43 paired MDS and secondary AML samples identified at least one signaling gene mutation in 44% of MDS and 60% of secondary AML samples, often below the level of standard sequencing detection. In addition, 19% of MDS and 47% of secondary AML patients harbored more than one signaling gene mutation, almost always in separate, coexisting subclones. Signaling gene mutations demonstrated diverse patterns of clonal evolution during disease progression, including acquisition, expansion, persistence, and loss of mutations, with multiple patterns often coexisting in the same patient. Multivariate analysis revealed that MDS patients who had a signaling gene mutation had a higher risk of AML progression, potentially providing a biomarker for progression., Significance: Subclone expansion is a hallmark of progression from MDS to secondary AML. Subclonal signaling gene mutations are common at MDS (often at low levels), show complex and convergent patterns of clonal evolution, and are associated with future progression to secondary AML. See related article by Guess et al., p. 316 (33). See related commentary by Romine and van Galen, p. 270. This article is highlighted in the In This Issue feature, p. 265., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
4. Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
- Author
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Huselton E, Rettig MP, Campbell K, Cashen AF, DiPersio JF, Gao F, Jacoby MA, Pusic I, Romee R, Schroeder MA, Uy GL, Marcus S, and Westervelt P
- Subjects
- Aged, Aged, 80 and over, Anticoagulants therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Biomarkers, Tumor, Chemokine CXCL12 antagonists & inhibitors, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Pilot Projects, Prognosis, Receptors, CXCR4 antagonists & inhibitors, Survival Rate, Azacitidine therapeutic use, DNA Methylation, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic drug effects, Heparin therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
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5. Frequency of infusion-related reactions with CPX-351 treatment in an observational study in adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC).
- Author
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Jacoby MA, Finn L, Emadi A, Saba NS, Powell BL, Seiter K, Garcia R, Faderl S, and Male HJ
- Subjects
- Adult, Cytarabine, Daunorubicin, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute etiology, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes etiology
- Published
- 2021
- Full Text
- View/download PDF
6. A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.
- Author
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Garcia JS, Swords RT, Roboz GJ, Jacoby MA, Garcia-Manero G, Hong WJ, Yang X, Zhou Y, Platzbecker U, Steensma DP, Wolff JE, and Fenaux P
- Subjects
- Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, Clinical Trials as Topic, Disease-Free Survival, Humans, Survival Rate, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes mortality
- Abstract
The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10
-14 ). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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7. Daratumumab in transfusion-dependent patients with low or intermediate-1 risk myelodysplastic syndromes.
- Author
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Garcia-Manero G, Diez-Campelo M, Vellenga E, Jacoby MA, Merchan B, Breems D, Cortelezzi A, Doronin V, Gomez V, Beckers M, Della Porta MG, Varsos H, Xiu L, DeAngelis N, Nnane I, Rose E, and van Eygen K
- Subjects
- ADP-ribosyl Cyclase 1 antagonists & inhibitors, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Female, Fever chemically induced, Follow-Up Studies, Humans, Immunologic Factors adverse effects, Male, Membrane Glycoproteins antagonists & inhibitors, Middle Aged, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes therapy, Neutropenia chemically induced, Pneumonia chemically induced, Proof of Concept Study, Risk, Thrombocytopenia chemically induced, Antibodies, Monoclonal therapeutic use, Erythrocyte Transfusion, Immunologic Factors therapeutic use, Myelodysplastic Syndromes drug therapy
- Published
- 2021
- Full Text
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8. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
- Author
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Duncavage EJ, Schroeder MC, O'Laughlin M, Wilson R, MacMillan S, Bohannon A, Kruchowski S, Garza J, Du F, Hughes AEO, Robinson J, Hughes E, Heath SE, Baty JD, Neidich J, Christopher MJ, Jacoby MA, Uy GL, Fulton RS, Miller CA, Payton JE, Link DC, Walter MJ, Westervelt P, DiPersio JF, Ley TJ, and Spencer DH
- Subjects
- Feasibility Studies, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Survival Analysis, Cytogenetic Analysis, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Whole Genome Sequencing methods
- Abstract
Background: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated., Methods: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing., Results: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different., Conclusions: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.)., (Copyright © 2021 Massachusetts Medical Society.)
- Published
- 2021
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9. Identifying Molecular Markers of Relapse in Myelodysplastic Syndrome.
- Author
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Jacoby MA and Walter M
- Subjects
- Humans, Recurrence, Biomarkers analysis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology
- Published
- 2018
10. Mutation Clearance after Transplantation for Myelodysplastic Syndrome.
- Author
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Jacoby MA, Trinkaus K, and Walter MJ
- Subjects
- Humans, Mutation, Myelodysplastic Syndromes, Transplantation Conditioning
- Published
- 2018
- Full Text
- View/download PDF
11. Mutation Clearance after Transplantation for Myelodysplastic Syndrome.
- Author
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Duncavage EJ, Jacoby MA, Chang GS, Miller CA, Edwin N, Shao J, Elliott K, Robinson J, Abel H, Fulton RS, Fronick CC, O'Laughlin M, Heath SE, Brendel K, Saba R, Wartman LD, Christopher MJ, Pusic I, Welch JS, Uy GL, Link DC, DiPersio JF, Westervelt P, Ley TJ, Trinkaus K, Graubert TA, and Walter MJ
- Subjects
- Adult, Bone Marrow Examination, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Humans, Leukemia, Myeloid, Acute genetics, Middle Aged, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Skin pathology, Survival Analysis, Transplantation Conditioning, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Mutation, Myelodysplastic Syndromes genetics
- Abstract
Background: Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for patients with myelodysplastic syndrome (MDS). The molecular predictors of disease progression after transplantation are unclear., Methods: We sequenced bone marrow and skin samples from 90 adults with MDS who underwent allogeneic hematopoietic stem-cell transplantation after a myeloablative or reduced-intensity conditioning regimen. We detected mutations before transplantation using enhanced exome sequencing, and we evaluated mutation clearance by using error-corrected sequencing to genotype mutations in bone marrow samples obtained 30 days after transplantation. In this exploratory study, we evaluated the association of a mutation detected after transplantation with disease progression and survival., Results: Sequencing identified at least one validated somatic mutation before transplantation in 86 of 90 patients (96%); 32 of these patients (37%) had at least one mutation with a maximum variant allele frequency of at least 0.5% (equivalent to 1 heterozygous mutant cell in 100 cells) 30 days after transplantation. Patients with disease progression had mutations with a higher maximum variant allele frequency at 30 days than those who did not (median maximum variant allele frequency, 0.9% vs. 0%; P<0.001). The presence of at least one mutation with a variant allele frequency of at least 0.5% at day 30 was associated with a higher risk of progression (53.1% vs. 13.0%; conditioning regimen-adjusted hazard ratio, 3.86; 95% confidence interval [CI], 1.96 to 7.62; P<0.001) and a lower 1-year rate of progression-free survival than the absence of such a mutation (31.3% vs. 59.3%; conditioning regimen-adjusted hazard ratio for progression or death, 2.22; 95% CI, 1.32 to 3.73; P=0.005). The rate of progression-free survival was lower among patients who had received a reduced-intensity conditioning regimen and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 than among patients with other combinations of conditioning regimen and mutation status (P≤0.001). Multivariate analysis confirmed that patients who had a mutation with a variant allele frequency of at least 0.5% detected at day 30 had a higher risk of progression (hazard ratio, 4.48; 95% CI, 2.21 to 9.08; P<0.001) and a lower 1-year rate of progression-free survival than those who did not (hazard ratio for progression or death, 2.39; 95% CI, 1.40 to 4.09; P=0.002)., Conclusions: The risk of disease progression was higher among patients with MDS in whom persistent disease-associated mutations were detected in the bone marrow 30 days after transplantation than among those in whom these mutations were not detected. (Funded by the Leukemia and Lymphoma Society and others.).
- Published
- 2018
- Full Text
- View/download PDF
12. Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant.
- Author
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Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, Robinson J, Fulton RS, Fronick CC, O'Laughlin M, Heath SE, Pusic I, Welch JS, Link DC, DiPersio JF, Westervelt P, Ley TJ, Graubert TA, and Walter MJ
- Subjects
- Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, Clonal Evolution drug effects, Clone Cells drug effects, Clone Cells immunology, DNA Mutational Analysis, Disease Progression, Female, Humans, Male, Middle Aged, Mutation drug effects, Myeloablative Agonists administration & dosage, Myeloablative Agonists adverse effects, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes pathology, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Clonal Evolution immunology, Hematopoietic Stem Cell Transplantation, Myelodysplastic Syndromes therapy, Neoplasm Recurrence, Local genetics
- Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.
- Published
- 2018
- Full Text
- View/download PDF
13. Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.
- Author
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Ali AM, Weisel D, Gao F, Uy GL, Cashen AF, Jacoby MA, Wartman LD, Ghobadi A, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Schroeder MA, Westervelt P, DiPersio JF, and Welch JS
- Subjects
- Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Azacitidine administration & dosage, Azacitidine adverse effects, Decitabine, Drug Administration Schedule, Female, Fever chemically induced, Fever mortality, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections mortality, Gram-Positive Bacterial Infections microbiology, Gram-Positive Bacterial Infections mortality, Humans, Incidence, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Missouri, Mycoses chemically induced, Mycoses microbiology, Mycoses mortality, Myelodysplastic Syndromes diagnosis, Neutropenia chemically induced, Neutropenia mortality, Opportunistic Infections diagnosis, Opportunistic Infections microbiology, Opportunistic Infections mortality, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Virus Diseases chemically induced, Virus Diseases mortality, Virus Diseases virology, Antimetabolites, Antineoplastic adverse effects, Azacitidine analogs & derivatives, Gram-Negative Bacterial Infections chemically induced, Gram-Positive Bacterial Infections chemically induced, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Opportunistic Infections chemically induced
- Abstract
Decitabine has been explored as a reduced-intensity therapy for older or unfit patients with acute myeloid leukemia (AML). To better understand the risk of infections during decitabine treatment, we retrospectively examined the culture results from each infection-related serious adverse event that occurred among 85 AML and myelodysplastic syndromes (MDS) patients treated in a prospective clinical study using 10-day cycles of decitabine at Washington University School of Medicine. Culture results were available for 163 infection-related complications that occurred in 70 patients: 90 (55.2%) events were culture-negative, 32 (19.6%) were gram-positive bacteria, 20 (12.3%) were gram-negative bacteria, 12 (7.4%) were mixed, 6 (3.7%) were viral, 2 (1.2%) were fungal, and 1 (0.6%) was mycobacterial. Infection-related mortality occurred in 3/24 (13%) of gram-negative events, and 0/51 gram-positive events. On average, nearly one third of patients experienced an infection-related complication with each cycle, and the incidence did not decrease during later cycles. In summary, in patients receiving 10-day decitabine, infectious complications are common and may occur during any cycle of therapy. Although febrile events are commonly culture-negative, gram-positive infections are the most frequent source of culture-positive infections, but gram-negative infections represent a significant risk of mortality in AML and MDS patients treated with decitabine., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
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14. Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy.
- Author
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Duncavage EJ, Uy GL, Petti AA, Miller CA, Lee YS, Tandon B, Gao F, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Jacoby MA, Cashen AF, Wartman LD, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ, and Welch JS
- Subjects
- Azacitidine administration & dosage, Decitabine, Female, Humans, Male, Azacitidine analogs & derivatives, Blood Cells metabolism, Blood Cells pathology, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mutation, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Neoplasm Proteins blood, Neoplasm Proteins genetics
- Published
- 2017
- Full Text
- View/download PDF
15. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
- Author
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Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee YS, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, and Ley TJ
- Subjects
- 5-Methylcytosine analysis, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, Biomarkers, Tumor analysis, Bone Marrow chemistry, Decitabine, Exome, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Prospective Studies, Risk Factors, Survival Rate, Antimetabolites, Antineoplastic administration & dosage, Azacitidine analogs & derivatives, Bone Marrow pathology, Leukemia, Myeloid, Acute drug therapy, Mutation, Myelodysplastic Syndromes drug therapy, Tumor Suppressor Protein p53 genetics
- Abstract
Background: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear., Methods: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols., Results: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles., Conclusions: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
- Published
- 2016
- Full Text
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16. A study of high-dose lenalidomide induction and low-dose lenalidomide maintenance therapy for patients with hypomethylating agent refractory myelodysplastic syndrome.
- Author
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Cherian MA, Tibes R, Gao F, Fletcher T, Fiala M, Uy GL, Westervelt P, Jacoby MA, Cashen AF, Stockerl-Goldstein K, DiPersio JF, and Vij R
- Subjects
- Aged, Aged, 80 and over, DNA Methylation drug effects, Drug Resistance, Neoplasm, Female, Humans, Immunologic Factors adverse effects, Lenalidomide, Maintenance Chemotherapy, Male, Middle Aged, Myelodysplastic Syndromes genetics, Remission Induction, Retreatment, Thalidomide administration & dosage, Thalidomide adverse effects, Treatment Outcome, Immunologic Factors administration & dosage, Myelodysplastic Syndromes drug therapy, Thalidomide analogs & derivatives
- Abstract
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by bone marrow failure which frequently progress to acute myeloid leukemia. Patients who fail to respond to, or progress on first-line DNA hypomethylating agents (HMA) have a poor prognosis. Conventionally dosed lenalidomide has activity in 5q-MDS. In other subtypes, it may reduce RBC transfusion requirements but does not result in cytogenetic responses. We previously reported that high-dose lenalidomide induction (50 mg/day) results in complete remissions in a high fraction of patients. We, therefore, conducted a Phase 2 trial of the same regimen in MDS refractory to HMA. Marrow complete remissions were seen in 33% of patients and hematological improvement in 8% of patients. Significant infections complicated more than 50% of cases. Future trials to explore alternative dosing schedules of high-dose lenalidomide to increase efficacy while decreasing toxicity are warranted.
- Published
- 2016
- Full Text
- View/download PDF
17. Detection of copy number alterations in acute myeloid leukemia and myelodysplastic syndromes.
- Author
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Jacoby MA and Walter MJ
- Subjects
- Comparative Genomic Hybridization methods, Gene Dosage, High-Throughput Nucleotide Sequencing methods, Humans, Oligonucleotide Array Sequence Analysis methods, Polymorphism, Single Nucleotide, Sequence Deletion, DNA Copy Number Variations, Genome, Human, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
- Abstract
Chromosomal deletions and amplifications that occur in affected cells from patients with myelodysplastic syndromes and acute myeloid leukemia often contain genes that contribute to disease pathogenesis. Identification of copy number alterations (deletions and amplifications) and regions of copy neutral loss of heterozygosity using array-based platforms has led to the identification of genes that are commonly mutated in myeloid malignancies. In this article, we review the literature and highlight the array-based studies that directly compare matched normal and tumor samples from the same individual to identify somatic alterations. We also discuss the use of next-generation sequencing to identify all types of structural variants, including copy number alterations and copy neutral loss of heterozygosity, and provide an outlook for how this technology may be used to interrogate cancer genomes.
- Published
- 2012
- Full Text
- View/download PDF
18. Mutation Clearance after Transplantation for Myelodysplastic Syndrome.
- Author
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Fozza, Claudio, Zhu, Xiaolin, Jacoby, Meagan A, Trinkaus, Kathryn, and Walter, Matthew J
- Subjects
- *
IMMUNOSUPPRESSION , *GENETIC mutation , *MYELODYSPLASTIC syndromes - Published
- 2018
- Full Text
- View/download PDF
19. Corrigendum to "A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival" [Leukemia Res. 104 March (2021)].
- Author
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Garcia, Jacqueline S., Swords, Ronan T., Roboz, Gail J., Jacoby, Meagan A., Garcia-Manero, Guillermo, Hong, Wan-Jen, Yang, Xiaoqing, Zhou, Ying, Platzbecker, Uwe, Steensma, David P., Wolff, Johannes E., and Fenaux, Pierre
- Subjects
- *
OVERALL survival , *MYELODYSPLASTIC syndromes , *AZACITIDINE , *CLINICAL trials , *LEUKEMIA - Published
- 2021
- Full Text
- View/download PDF
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