16 results on '"Uy, Geoffrey L."'
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
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- 2023
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3. Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
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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
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- 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.)
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- 2021
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4. A phase I trial evaluating the effects of plerixafor, G-CSF, and azacitidine for the treatment of myelodysplastic syndromes.
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Huselton E, Rettig MP, Fletcher T, Ritchey J, Gehrs L, McFarland K, Christ S, Eades WC, Trinkaus K, Romee R, Kulkarni S, Ghobadi A, Abboud C, Cashen AF, Stockerl-Goldstein K, Uy GL, Vij R, Westervelt P, DiPersio JF, and Schroeder MA
- Subjects
- Azacitidine adverse effects, Benzylamines, Cyclams, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Humans, Heterocyclic Compounds adverse effects, Myelodysplastic Syndromes drug therapy
- Abstract
Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design. Subjects received G-CSF 10 mcg/kg D1-D8, plerixafor D4-D8, and azacitidine 75 mg/m
2 D4-D8, but the trial was amended to reduce G-CSF dose to 5 mcg/kg for 5 days after 2 patients had significant leukocytosis. Plerixafor was dose escalated to 560 mcg/kg/day without dose limiting toxicity. Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients, and ORR of 53% in patients receiving the triplet. Evidence of mobilization correlated with a higher ORR, 60% vs. 17%. Plerixafor, G-CSF and azacitidine appears tolerable when given over 5 days and has encouraging response rates.KEY POINTSPlerixafor and G-CSF can be safely combined with azacitidine for 5 days in patients with MDS.The overall response rate of 53% for evaluable patients with this regimen is higher than expected and more responses were seen in patients with blast mobilization.- Published
- 2021
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5. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.
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Lin TL, Rizzieri DA, Ryan DH, Schiller GJ, Kolitz JE, Uy GL, Hogge DE, Solomon SR, Wieduwilt MJ, Ryan RJ, Faderl S, Cortes JE, and Lancet JE
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- Aged, Cytarabine, Daunorubicin, Humans, Middle Aged, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes
- Abstract
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084., (© 2021 by The American Society of Hematology.)
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- 2021
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6. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
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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
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- 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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7. Mutation Clearance after Transplantation for Myelodysplastic Syndrome.
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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
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8. Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.
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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
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9. Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy.
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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
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- 2017
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10. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
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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
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11. A study of high-dose lenalidomide induction and low-dose lenalidomide maintenance therapy for patients with hypomethylating agent refractory myelodysplastic syndrome.
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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
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- 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
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12. Chemotherapy versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome after Allogeneic Stem Cell Transplant.
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Motabi IH, Ghobadi A, Liu J, Schroeder M, Abboud CN, Cashen AF, Stockler-Goldstein KE, Uy GL, Vij R, Westervelt P, and DiPersio JF
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- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Myelodysplastic Syndromes drug therapy, Recurrence, Transplantation, Homologous, Treatment Outcome, Young Adult, Antimetabolites, Antineoplastic therapeutic use, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Lymphocyte Transfusion methods, Myelodysplastic Syndromes therapy, Salvage Therapy methods
- Abstract
Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplantation, intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High-intensity chemotherapy and less aggressive therapy with hypomethylating agents (HAs) with and without DLI are often used for relapse after allo-SCT. Here we compared the treatment outcomes of intensive chemotherapy with that of HAs in relapsed AML and MDS after allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression-free survival (PFS). One hundred patients were included: 73 patients received chemotherapy and 27 patients received an HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least 1 DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% versus 19%, P = .004) and a higher CR rate (40% versus 7%, P = .002). The median OS (6 versus 3.9 months, P = .01) and PFS (4.9 versus 3.8 months, P = .02) were longer in the chemotherapy group. Similar benefit of chemotherapy over HAs was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI offered the greatest benefit (ORR, 68%; CR, 59%, 1-year OS, 44%; and median OS, 9.8 months). In conclusion, in our hands, with limited numbers, the use of more conventional salvage chemotherapy, with DLI when possible, for the treatment of relapsed AML and MDS after allo-SCT is associated with better outcomes than nonchemotherapy (HA) options., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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13. Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies.
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Pasquini MC, Zhang MJ, Medeiros BC, Armand P, Hu ZH, Nishihori T, Aljurf MD, Akpek G, Cahn JY, Cairo MS, Cerny J, Copelan EA, Deol A, Freytes CO, Gale RP, Ganguly S, George B, Gupta V, Hale GA, Kamble RT, Klumpp TR, Lazarus HM, Luger SM, Liesveld JL, Litzow MR, Marks DI, Martino R, Norkin M, Olsson RF, Oran B, Pawarode A, Pulsipher MA, Ramanathan M, Reshef R, Saad AA, Saber W, Savani BN, Schouten HC, Ringdén O, Tallman MS, Uy GL, Wood WA Jr, Wirk B, Pérez WS, Batiwalla M, and Weisdorf DJ
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Karyotype, Male, Middle Aged, Myelodysplastic Syndromes mortality, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation methods, Myelodysplastic Syndromes therapy, Transplantation Conditioning methods
- Abstract
The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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14. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.
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Churpek JE, Pyrtel K, Kanchi KL, Shao J, Koboldt D, Miller CA, Shen D, Fulton R, O'Laughlin M, Fronick C, Pusic I, Uy GL, Braunstein EM, Levis M, Ross J, Elliott K, Heath S, Jiang A, Westervelt P, DiPersio JF, Link DC, Walter MJ, Welch J, Wilson R, Ley TJ, Godley LA, and Graubert TA
- Subjects
- Adolescent, Adult, Aged, Base Sequence, Child, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins genetics, Female, Hematopoiesis genetics, Humans, Male, Middle Aged, Molecular Sequence Data, Repressor Proteins genetics, Transcription Factors genetics, Exome, Genetic Diseases, Inborn genetics, Germ-Line Mutation, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Neoplasm Proteins genetics
- Abstract
Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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15. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.
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Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, Vij R, Abboud CN, Stockerl-Goldstein KE, Jacoby MA, Uy GL, Westervelt P, and DiPersio JF
- Subjects
- Adult, Aged, Allografts, Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, Azacitidine therapeutic use, Combined Modality Therapy, Decitabine, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Gastrointestinal Diseases chemically induced, Graft vs Host Disease etiology, Hematologic Diseases chemically induced, Humans, Infusions, Intravenous, Leukemia, Myeloid, Acute therapy, Male, Maximum Tolerated Dose, Middle Aged, Myelodysplastic Syndromes therapy, Prospective Studies, Young Adult, Antimetabolites, Antineoplastic therapeutic use, Azacitidine analogs & derivatives, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Maintenance Chemotherapy methods, Myelodysplastic Syndromes drug therapy
- Abstract
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
16. A phase II study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes.
- Author
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Martin MG, Walgren RA, Procknow E, Uy GL, Stockerl-Goldstein K, Cashen AF, Westervelt P, Abboud CN, Kreisel F, Augustin K, Dipersio JF, and Vij R
- Subjects
- Aged, Antimetabolites, Antineoplastic, Azacitidine pharmacokinetics, Humans, Injections adverse effects, Methylation, Middle Aged, Myelodysplastic Syndromes mortality, Remission Induction, Risk Assessment, Survival Analysis, Azacitidine administration & dosage, Myelodysplastic Syndromes drug therapy
- Abstract
The approved 7-day schedule of subcutaneous azacitidine for myelodysplastic syndrome is associated with injection site reactions and bruising and may be inconvenient because of the need for weekend doses. Although pharmacokinetic data with IV azacitidine suggests equivalence, there are no efficacy data published. Patients with all myelodysplastic syndromes (MDS) FAB subtypes were enrolled and received 75 mg/m(2)/d of azacitidine by 20-min intravenous infusion for 5 days in every 28 days. Global methylation studies were performed at baseline and prior to Cycle 3. Twenty-five patients were enrolled and 22 were evaluable. Median age was 69.5 years; 9 (41%) patients had lower-risk disease (IPSS Low or Int-1) and 13 (59%) had higher-risk disease (IPSS Int-2 or High). Twenty-seven percent of patients responded (5 CRs and 1 PR). The median time to response was 108 days. The median PFS was 339 days (11.3 months), the median OS was 444 days (14.8 months) and the median duration of response (DOR) was 450 days (15.0 months). Global methylation studies suggest a greater degree of demethylation in responders. This regimen appeared to offer a PR + CR rate and median DOR somewhat similar to what has been reported with the 7-day subcutaneous regimen; however, OS was shorter., (2009 Wiley-Liss, Inc.)
- Published
- 2009
- Full Text
- View/download PDF
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