28 results on '"Jacoby, Meagan A."'
Search Results
2. Exome analysis of treatment‐related AML after APL suggests secondary evolution.
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Wang, Tianjiao, Jacoby, Meagan A., Duncavage, Eric J., Miller, Christopher A., Heath, Sharon, Rahme, Ramy, Fenaux, Pierre, Ades, Lionel, Renneville, Aline, Cassinat, Bruno, Takeshita, Akihiro, Asou, Norio, Miyazaki, Yasushi, Kiyoi, Hitoshi, Ravandi, Farhad, Westervelt, Peter, Wartman, Lukas D., and Welch, John S.
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ACUTE promyelocytic leukemia , *CANCER genetics , *REVERSE transcriptase polymerase chain reaction - Abstract
The article presents a case study of an older woman who initially presented with dysplasia and she developed acute promyelocytic leukaemia (APL) and was treated with all-trans retinoic acid and arsenic trioxide (ATRA/ATO). Information about treatment-related acute myeloid leukaemia (tAML) and treatment-related myelodysplastic syndrome is presented.
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- 2019
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3. The Murine Gammaherpesvirus 68 M2 Gene Is Required for Efficient Reactivation from Latently Infected B Cells.
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Herskowitz, Jeremy, Jacoby, Meagan A., and Speck, Samuel H.
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HERPESVIRUSES , *B cells , *MICE , *ANTIGENS , *LYMPHOID tissue , *INJECTIONS - Abstract
Murine gammaherpesvirus 68 (γHV68) infection of mice provides a tractable small-animal model system for assessing the requirements for the establishment and maintenance of gammaherpesvirus latency within the lymphoid compartment. The M2 gene product of γHV68 is a latency-associated antigen with no discernible homology to any known proteins. Here we focus on the requirement for the M2 gene in splenic B-cell latency. Our analyses showed the following. (i) Low-dose (100 PFU) inoculation administered via the intranasal route resulted in a failure to establish splenic B-cell latency at day 16 postinfection. (ii) Increasing the inoculation dose to 4 × 105 PFU administered via the intranasal route partially restored the establishment of B-cell latency at day 16, but no virus reactivation was detected upon explant into tissue cultures. (iii) Although previous data failed to detect a phenotype of the M2 mutant upon high-dose intraperitoneal inoculation, decreasing the inoculation dose to 100 PFU administered intraperitoneally revealed a splenic B-cell latency phenotype at day 16 that was very similar to the phenotype observed upon high-dose intranasal inoculation. (iv) After low-dose intraperitoneal inoculation, fractionated B-cell populations showed that the M2 mutant virus was able to establish latency in surface immunoglobulin D-negative (sIgD-) B cells; by 6 months postinfection, equivalent frequencies of M2 mutant and marker rescue viral genome-positive sIgD- B cells were detected. (v) Like the marker rescue virus, the M2 mutant virus also established latency in splenic naive B cells upon low-dose intraperitoneal inoculation, but there was a significant lag in the decay of this latently infected reservoir compared to that seen with the marker rescue virus. (vi) After low-dose intranasal inoculation, by day 42 postinfection, latency was observed in the spleen, although at a frequency significantly lower than that in the marker rescue virus-infected mice; by 3 months postinfection, nearly equivalent levels of viral genome-positive cells were observed in the spleens of marker rescue virus- and M2 mutant virus-infected mice, and these cells were exclusively sIgD- B cells. Taken together, these data convincingly demonstrate a role for the M2 gene product in reactivation from splenic B cells and also suggest that disruption of the M2 gene leads to dose- and route-specific defects in the efficient establishment of splenic B-cell latency. [ABSTRACT FROM AUTHOR]
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- 2005
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4. Virescent tongue.
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Ali, Alaa, Jacoby, Meagan, Romee, Rizwan, and Ali, Alaa M
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TONGUE abnormalities , *TASTE buds , *MOUTH , *GANGRENE - Abstract
The article discusses the case of a 55-year-old man presented in a hospital with a rapidly growing tongue lesion over one week. The patient's intraoral examination revealed a necrotic mass infiltrated and surrounded by green areas and that histology shows diffuse infiltration by large cells. The article discusses a case of virescent tounque.
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- 2017
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5. The authors reply.
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Jacoby, Meagan A., Trinkaus, Kathryn, and Walter, Matthew J.
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- 2018
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6. Clinical whole-genome sequencing and FISH identify two different fusion partners for NUP98 in a patient with acute myeloid leukemia: A case report.
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Mojarad, Bahareh A., Crees, Zachary D., Schroeder, Molly C., Xiang, Zhifu, Vader, Justin, Sina, Jason, Jacoby, Meagan, Frater, John L., Duncavage, Eric J., Spencer, David H., Lavine, Kory, Neidich, Julie A., and Amarillo, Ina
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ACUTE myeloid leukemia , *NUCLEOTIDE sequencing , *FLUORESCENCE in situ hybridization , *ACUTE leukemia , *SEQUENCE analysis , *CHROMOSOMES - Abstract
Only rare cases of acute myeloid leukemia (AML) have been shown to harbor a t(8;11)(p11.2;p15.4). This translocation is believed to involve the fusion of NSD3 or FGFR1 with NUP98; however, apart from targeted mRNA quantitative PCR analysis, no molecular approaches have been utilized to define the chimeric fusions present in these rare cases. Here we present the case of a 51-year-old female with AML with myelodysplastic-related morphologic changes, 13q deletion and t(8;11), where initial fluorescence in situ hybridization (FISH) assays were consistent with the presence of NUP98 and FGFR1 rearrangements, and suggestive of NUP98/FGFR1 fusion. Using a streamlined clinical whole-genome sequencing approach, we resolved the breakpoints of this translocation to intron 4 of NSD3 and intron 12 of NUP98 , indicating NUP98 / NSD3 rearrangement as the likely underlying aberration. Furthermore, our approach identified small variants in WT1 and STAG2 , as well as an interstitial deletion on the short arm of chromosome 12, which were cryptic in G-banded chromosomes. NUP98 fusions in acute leukemia are predictive of poor prognosis. The associated fusion partner and the presence of co-occurring mutations, such as WT1 , further refine this prognosis with potential clinical implications. Using a clinical whole-genome sequencing analysis, we resolved t(8;11) breakpoints to NSD3 and NUP98 , ruling out the involvement of FGFR1 suggested by FISH while also identifying multiple chromosomal and sequence level aberrations. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Hand-foot syndrome following decitabine.
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Ali, Alaa, Jacoby, Meagan, Welch, John, Ali, Alaa M, and Welch, John S
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HAND-foot syndrome , *DECITABINE , *THERAPEUTICS , *ANTIMETABOLITES , *ANTINEOPLASTIC agents , *AZACITIDINE , *DIAGNOSIS - Abstract
A letter to the editor is presented which discusses the occurrence of a case of hand-foot syndrome due to decitabine infusion.
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- 2016
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8. Persistent Molecular Disease in Adult Patients With AML Evaluated With Whole-Exome and Targeted Error-Corrected DNA Sequencing.
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Slade, Michael J., Ghasemi, Reza, O'Laughlin, Michelle, Burton, Tasha, Fulton, Robert S., Abel, Haley J., Duncavage, Eric J., Ley, Timothy J., Jacoby, Meagan A., and Spencer, David H.
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DNA sequencing , *ACUTE myeloid leukemia , *ADULTS , *INDUCTION chemotherapy , *BONE marrow - Abstract
PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML. MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq). RESULTS: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (>2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in DNMT3A , ASXL1 , and TET2 (ie, DTA mutations) were persistent in 16 of 17 patients, but WES also detected non-DTA mutations in 14 of these patients, which for some patients distinguished residual AML cells from clonal hematopoiesis. Surprisingly, MyeloSeq detected additional variants not identified at presentation in 73% of patients that were consistent with new clonal cell populations after chemotherapy. CONCLUSION: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML. Persistent molecular disease and clonal hematopoiesis are common in patients with AML in remission after chemotherapy. [ABSTRACT FROM AUTHOR]
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- 2023
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9. 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
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Assouline, Sarit, Michaelis, Laura C., Othus, Megan, Hay, Annette E., Walter, Roland B., Jacoby, Meagan A., Schroeder, Mark A., Uy, Geoffrey L., Law, Lisa Y., Cheema, Faisal, Sweet, Kendra L., Asch, Adam S., Liu, Jijun, Moseley, Anna B., Maher, Tracy, Kingsbury, Laura L., Fang, Min, Radich, Jerald, Little, Richard F., and Erba, Harry P.
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MYELODYSPLASTIC syndromes , *ACUTE myeloid leukemia , *CHRONIC leukemia , *NIVOLUMAB , *AZACITIDINE , *HYPERKALEMIA - Abstract
Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 phase III study. Acute myeloid leukemia (AML) primarily affects older adults, for whom lower intensity therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, or best supportive care have often been selected. In arm B, three patients had an FLT3-ITD mutation and died within 28 days of therapy initiation, one patient with FLT3-ITD mutation was randomized to the azacitidine alone arm. The study was closed prematurely after an observed excess early mortality in arm B, where six patients (24%) died within 28 days of initiating therapy versus one patient (4%) in arm A ( I p i = 0.098). [Extracted from the article]
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- 2023
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10. Mutation Clearance after Transplantation for Myelodysplastic Syndrome.
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Fozza, Claudio, Zhu, Xiaolin, Jacoby, Meagan A, Trinkaus, Kathryn, and Walter, Matthew J
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IMMUNOSUPPRESSION , *GENETIC mutation , *MYELODYSPLASTIC syndromes - Published
- 2018
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11. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
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Duncavage, Eric J., Schroeder, Molly C., O'Laughlin, Michele, Wilson, Roxanne, MacMillan, Sandra, Bohannon, Andrew, Kruchowski, Scott, Garza, John, Feiyu Du, Hughes, Andrew E. O., Robinson, Josh, Hughes, Emma, Heath, Sharon E., Baty, Jack D., Neidich, Julie, Christopher, Matthew J., Jacoby, Meagan A., Uy, Geoffrey L., Fulton, Robert S., and Miller, Christopher A.
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ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *TREATMENT effectiveness , *GENOMICS , *TURNAROUND time , *PILOT projects , *RESEARCH , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *SURVIVAL analysis (Biometry) , *RESEARCH funding , *CYTOGENETICS , *PROPORTIONAL hazards models - 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.). [ABSTRACT FROM AUTHOR]- Published
- 2021
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12. A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.
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Shea, Lauren, Watkins, Marcus P., Wan, Fei, Cashen, Amanda F., Wagner-Johnston, Nina D., Jacoby, Meagan A., Abboud, Camille N., Dipersio, John F., Hurd, David D., Jaglowski, Samantha M., Bartlett, Nancy L., and Fehniger, Todd A.
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AUTOTRANSPLANTATION , *HODGKIN'S disease , *STEM cell transplantation , *PILOT projects , *MULTIPLE myeloma , *MEDICAL quality control - Abstract
• We performed a pilot clinical trial to determine the feasibility of maintenance lenalidomide after autologous stem cell transplant in relapsed/refractory classical Hodgkin lymphoma (rel/ref cHL). • An unexpectedly high frequency of hematologic toxicities resulting in early lenalidomide discontinuation was observed. • The lenalidomide maintenance dose and schedule used in this study are not feasible in rel/ref cHL. For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL. Image, graphical abstract [ABSTRACT FROM AUTHOR]
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- 2020
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13. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia.
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Chen, Christine, Siegel, David, Gutierrez, Martin, Jacoby, Meagan, Hofmeister, Craig C., Gabrail, Nashat, Baz, Rachid, Mau-Sorensen, Morten, Berdeja, Jesus G., Savona, Michael, Savoie, Lynn, Trudel, Suzanne, Areethamsirikul, Nuchanan, Unger, T. J., Rashal, Tami, Hanke, Tim, Kauffman, Michael, Shacham, Sharon, and Reece, Donna
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MULTIPLE myeloma , *MULTIPLE myeloma treatment , *HEMATOLOGIC malignancies , *DRUG efficacy , *NUCLEAR nonproliferation , *WALDENSTROM'S macroglobulinemia , *PATIENTS - Abstract
Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ‡partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR550%). Furthermore, 46% of all patients showed a reduction inMM markers from baseline. Based on these findings,we conclude that selinexor in combinationwith dexamethasone is active in heavily pretreatedMMand propose a RP2D of 45mg/m2 (80mg) plus 20 mg dexamethasone given twiceweekly. This trial was registered at clinicaltrials.gov as #NCT01607892. (Blood. 2018;131(8):855-863) [ABSTRACT FROM AUTHOR]
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- 2018
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14. Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.
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Ali, Alaa M., Weisel, Daniel, Gao, Feng, Uy, Geoffrey L., Cashen, Amanda F., Jacoby, Meagan A., Wartman, Lukas D., Ghobadi, Armin, Pusic, Iskra, Romee, Rizwan, Fehniger, Todd A., Stockerl‐Goldstein, Keith E., Vij, Ravi, Oh, Stephen T., Abboud, Camille N., Schroeder, Mark A., Westervelt, Peter, DiPersio, John F., and Welch, John S.
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DECITABINE , *ACUTE myeloid leukemia treatment , *MYELODYSPLASTIC syndromes treatment , *INFECTION risk factors , *GRAM-positive bacteria , *GRAM-negative bacteria , *THERAPEUTICS - 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. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma.
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Kuruvilla, John, Martin, Peter, Flinn, Ian, Jacoby, Meagan, Unger, Thaddeus J., Saint-Martin, Jean-Richard, Rashal, Tami, Friedlander, Sharon, Carlson, Robert, Kauffman, Michael, Shacham, Sharon, Gutierrez, Martin, Savona, Michael, Baz, Rachid, Mau-Sorensen, Paul Morten, Gabrail, Nashat, Garzon, Ramiro, Stone, Richard, Wang, Michael, and Savoie, Lynn
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LYMPHOMA treatment , *LYMPHOMAS , *ANTINEOPLASTIC agents , *CANCER relapse , *CANCER prognosis , *PATIENTS - Abstract
Patients with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B cell lymphoma (DLBCL), Richter's transformation, mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) were enrolled. In the dose escalation phase, patients received 3-80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics and anti-tumor activity. In the dose expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3-4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%) and hyponatremia (10%). Tumor biopsies showed decreases in cell signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN) and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective response (OR), including 4 complete responses (CR) and 18 partial responses (PR), which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anti-cancer activity in patients with R/R NHL. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy.
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Duncavage, Eric J., Uy, Geoffrey L., Petti, Allegra A., Miller, Christopher A., Yi-Shan Lee, Tandon, Bevan, Feng Gao, Fronick, Catrina C., O'Laughlin, Michelle, Fulton, Robert S., Wilson, Richard K., Jacoby, Meagan A., Cashen, Amanda F., Wartman, Lukas D., Walter, Matthew J., Westervelt, Peter, Link, Daniel C., DiPersio, John F., Ley, Timothy J., and Welch, John S.
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GENETIC mutation , *BONE marrow , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *LEUCOCYTOSIS , *PATIENTS - Abstract
The article discusses comparison of mutation burden in paired serial peripheral blood (PB) and bone marrow (BM) samples in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). It mentions clonal architecture of diagnostic BM samples in AML patients with leukocytosis is recapitulated in their simultaneously obtained PB. It adds that targeted PB sequencing recapitulates the major genomic events observed in the BM cells of AML and MDS patients.
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- 2017
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17. Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy.
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Duncavage, Eric J., Uy, Geoffrey L., Petti, Allegra A., Miller, Christopher A., Yi-Shan Lee, Tandon, Bevan, Feng Gao, Fronick, Catrina C., O'Laughlin, Michelle, Fulton, Robert S., Wilson, Richard K., Jacoby, Meagan A., Cashen, Amanda F., Wartman, Lukas D., Walter, Matthew J., Westervelt, Peter, Link, Daniel C., DiPersio, John F., Ley, Timothy J., and Welch, John S.
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DECITABINE , *ENZYME inhibitors - Published
- 2017
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18. 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, Mathew A., Tibes, Raoul, Gao, Feng, Fletcher, Theresa, Fiala, Mark, Uy, Geoffrey L., Westervelt, Peter, Jacoby, Meagan A., Cashen, Amanda F., Stockerl-Goldstein, Keith, DiPersio, John F., and Vij, Ravi
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MYELODYSPLASTIC syndromes treatment , *MYELODYSPLASTIC syndromes , *RED blood cell transfusion , *ACUTE myeloid leukemia diagnosis , *CYTOGENETICS , *TREATMENT effectiveness , *CANCER chemotherapy , *PROGNOSIS - 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. [ABSTRACT FROM PUBLISHER]
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- 2016
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19. Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation.
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Ghobadi, Armin, Choi, Jaebok, Fiala, Mark A., Fletcher, Theresa, Liu, Jingxia, Eissenberg, Linda G., Abboud, Camille, Cashen, Amanda, Vij, Ravi, Schroeder, Mark A., Pusic, Iskra, Stockerl-Goldstein, Keith, Jacoby, Meagan, Uy, Geoffrey, DiPersio, John, and Westervelt, Peter
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ACUTE myeloid leukemia treatment , *AZACITIDINE , *STEM cell transplantation , *LYMPHOCYTES , *CANCER relapse , *GRAFT versus host disease , *THERAPEUTICS - Abstract
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3 + 3 design with three AzaC dose levels: 30 mg/m 2 (level −1), 45 mg/m 2 (level 1) and 75 mg/m 2 (level 2). Three patients were treated in the 45 mg/m 2 dose level and 5 patients were treated in the 75 mg/m 2 dose level; no DLTs or grade 3–5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III–IV aGVHD and no patients died of aGVHD. Six out of 8 patients in the treatment group responded to treatment including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete count recovery. In conclusion, administration of AzaC early post DLI is well tolerated and can potentially prevent GVHD after DLI. Further studies are required to evaluate the effect of azacitidine early post DLI on GVHD and GVL. [ABSTRACT FROM AUTHOR]
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- 2016
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20. Protective Effect of Cytomegalovirus Reactivation on Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients Is Influenced by Conditioning Regimen.
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Manjappa, Shivaprasad, Bhamidipati, Pavan Kumar, Stokerl-Goldstein, Keith E., DiPersio, John F., Uy, Geoffrey L., Westervelt, Peter, Liu, Jingxia, Schroeder, Mark A., Vij, Ravi, Abboud, Camille N., Fehniger, Todd A., Cashen, Amanda F., Pusic, Iskra, Jacoby, Meagan, Meera, Srinidhi J., and Romee, Rizwan
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CYTOMEGALOVIRUSES , *HEMATOPOIETIC stem cell transplantation , *ACUTE myeloid leukemia , *CANCER relapse , *T cells , *FOLLOW-up studies (Medicine) - Abstract
Abstract: Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell–replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. [Copyright &y& Elsevier]
- Published
- 2014
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21. Systematic Mutagenesis of the Murine Gammaherpesvirus 68 M2 Protein Identifies Domains Important for Chronic Infection.
- Author
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Herskowitz, Jeremy H., Siegel, Andrea M., Jacoby, Meagan A., and Speck, Samuel H.
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MUTAGENESIS , *PROTEINS , *HERPESVIRUSES , *INFECTION , *B cells - Abstract
Murine gammaherpesvirus 68 (MHV68) infection of inbred mice represents a genetically tractable small-animal model for assessing the requirements for the establishment of latency, as well as reactivation from latency, within the lymphoid compartment. By day 16 postinfection, MHV68 latency in the spleen is found in B cells, dendritic cells, and macrophages. However, as with Epstein-Barr virus, by 3 months postinfection MHV68 latency is predominantly found in isotype-switched memory B cells. The MHV68 M2 gene product is a latency-associated antigen with no discernible homology to any known cellular or viral proteins. However, depending on experimental conditions, the M2 protein has been shown to play a critical role in both the efficient establishment of latency in splenic B cells and reactivation from latently infected splenic B cells. Inspection of the sequence of the M2 protein reveals several hallmarks of a signaling molecule, including multiple PXXP motifs and two potential tyrosine phosphorylation sites. Here, we report the generation of a panel of recombinant MHV68 viruses harboring mutations in the M2 gene that disrupt putative functional motifs. Subsequent analyses of the panel of M2 mutant viruses revealed a functionally important cluster of PXXP motifs in the C-terminal region of M2, which have previously been implicated in binding Vav proteins (P. A. Madureira, P. Matos, I. Soeiro, L. K. Dixon, J. P. Simas, and E. W. Lam, J. Biol. Chem. 280:37310-37318, 2005; L. Rodrigues, M. Pires de Miranda, M. J. Caloca, X. R. Bustelo, and J. P. Simas, J. Virol. 80:6123-6135, 2006). Further characterization of two adjacent PXXP motifs in the C terminus of the M2 protein revealed differences in the functions of these domains in M2-driven expansion of primary murine B cells in culture. Finally, we show that tyrosine residues 120 and 129 play a critical role in both the establishment of splenic latency and reactivation from latency upon explant of splenocytes into tissue culture. Taken together, these analyses will aide future studies for identifying M2 interacting partners and B-cell signaling pathways that are manipulated by the M2 protein. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
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22. A phase I study of carfilzomib for relapsed or refractory acute myeloid and acute lymphoblastic leukemia.
- Author
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Wartman, Lukas D., Fiala, Mark A., Fletcher, Theresa, Hawkins, Emily R., Cashen, Amanda, DiPersio, John F., Jacoby, Meagan A., Stockerl-Goldstein, Keith E., Pusic, Iskra, Uy, Geoffrey L., Westervelt, Peter, and Vij, Ravi
- Subjects
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DRUG efficacy , *LYMPHOBLASTIC leukemia treatment , *MYELOID leukemia , *LEUKEMIA treatment - Abstract
A letter to the editor is presented on the study regarding the effectiveness of carfilzomib drug for acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) treatment.
- Published
- 2016
- Full Text
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23. 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, Eric, Rettig, Michael P., Campbell, Kirsten, Cashen, Amanda F., DiPersio, John F., Gao, Feng, Jacoby, Meagan A., Pusic, Iskra, Romee, Rizwan, Schroeder, Mark A., Uy, Geoffrey L., Marcus, Stephen, and Westervelt, Peter
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DECITABINE , *AZACITIDINE , *CELL adhesion molecules , *OVERALL survival , *SURVIVAL rate , *ACUTE myeloid leukemia , *SODIUM - Abstract
• Combining DSTAT with azacitidine appears feasible with no increased toxicity seen. • A 20 % response rate was observed in this patient population with HMA refractory MDS. • Mobilization of myeloblasts was not observed during the first cycle of DSTAT and azacitidine. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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24. Murine Gammaherpesvirus 68 Infection Is Associated with Lymphoproliferative Disease and Lymphoma in BALB β2 Microglobulin-Deficient Mice.
- Author
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Tarakanova, Vera L., Suarez, Felipe, Tibbetts, Scott A., Jacoby, Meagan A., Weck, Karen E., Hess, Jay L., Speck, Samuel H., and Virgin IV, Herbert W.
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HERPESVIRUS diseases , *LYMPHOPROLIFERATIVE disorders , *MICE , *HYPERPLASIA , *PLASMA cells , *IN situ hybridization , *EPSTEIN-Barr virus diseases , *VIROLOGY - Abstract
Human gammaherpesvirus infections are associated with development of lymphoproliferative disease. Understanding of the mechanisms of gammaherpesvirus lymphomagenesis during chronic infection in a natural host has been limited by the exquisite species specificity of human gammaherpesviruses and the expense of primates. Murine gammaherpesvirus γHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818–826, 1994). We report the development of an animal model of γHV68 lymphomagenesis in BALB/c β2 microglobulin-deficient mice (BALB β2m-/-). γHV68 infection induced two lymphoproliferative lesions: B-cell lymphoma and atypical lymphoid hyperplasia (ALHL ALH lesion histology resembled lesions of Epstein-Barr virus-associated post-transplant lymphoproliferative disease and was characterized by the abnormal infiltration of the white pulp with cells expressing the plasma cell marker CD138. Lymphomas observed in γHV68-infected animals were B220+/CD3- large-cell lymphomas. γHV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in γHV68-infected spleens with normal histology. Unlike ALH lesions, γHV68 vtRNA-positive cells were rare in lymphomas. γHV68 infection of BALB β2m-/- mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies. Our findings suggest that γHV68 induces lymphomas via hit-and-run oncogenesis, paracrine effects, or stimulation of chronic inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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25. Establishment and Maintenance of Gammaherpesvirus Latency Are Independent of Infective Dose and Route of Infection.
- Author
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Tibbetts, Scott A., Loh, Joy, van Berkel, Victor, McClellan, James S., Jacoby, Meagan A., Kapadia, Sharookh B., Speck, Samuel H., and Virgin IV, Herbert W.
- Subjects
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HERPESVIRUSES , *INFECTION , *VIRAL replication - Abstract
Examines the link of the establishment and maintenance of gammaherpesvirus latency with infective dose and route of infection. Implications for the prevention and treatment of gammaherpesvirus-related disease; Frequencies of ex vivo reactivation; Stability of levels of acute-phase replication and latent infection.
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- 2003
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26. 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
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OVERALL survival , *MYELODYSPLASTIC syndromes , *AZACITIDINE , *CLINICAL trials , *LEUKEMIA - Published
- 2021
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- View/download PDF
27. 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, 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
- *
MYELODYSPLASTIC syndromes , *AZACITIDINE , *CLINICAL trials , *PROGRESSION-free survival - Abstract
• Survival rates reported among HR-MDS patients are inconsistent across clinical studies. • Real-world OS with azacitidine is consistently shorter compared to that observed in the large pivotal trial AZA-001. • We investigated surrogate endpoints for patients with HR-MDS treated with azacitidine. • This systematic review determined clinical benchmarks for future studies of HMA-based combinations. • Benchmarks of response from 237 clinical studies included complete remission (CR) rate, marrow CR, and overall survival. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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28. 3. Use of a targeted gene panel to inform treatment decisions for patients with AML.
- Author
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Barnell, Erica K., Newcomer, Kenneth F., Skidmore, Zachary L., Krysiak, Kilannin, Anderson, Sydney R., Spencer, David H., Duncavage, Eric J., Griffith, Malachi, Jacoby, Meagan A., and Griffith, Obi
- Subjects
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ACUTE myeloid leukemia , *PHARMACOGENOMICS , *GENES - Published
- 2020
- Full Text
- View/download PDF
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