21 results on '"Westervelt, Peter"'
Search Results
2. Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia.
- Author
-
Barnell, Erica K., Newcomer, Kenneth F., Skidmore, Zachary L., Krysiak, Kilannin, Anderson, Sydney R., Wartman, Lukas D., Oh, Stephen T., Welch, John S., Stockerl-Goldstein, Keith E., Vij, Ravi, Cashen, Amanda F., Pusic, Iskra, Westervelt, Peter, Abboud, Camille N., Ghobadi, Armin, Uy, Geoffrey L., Schroeder, Mark A., Dipersio, John F., Politi, Mary C., and Spencer, David H.
- Subjects
ACUTE myeloid leukemia ,PATIENT decision making ,PHYSICIANS ,GENETIC variation ,HEMATOLOGIC malignancies - Abstract
PURPOSE: Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood. METHODS: Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50). RESULTS: In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration–approved drugs. CONCLUSION: This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. The effect of donor type on outcomes in adults with acute myeloid leukemia after reduced‐intensity hematopoietic peripheral blood cell transplant – a retrospective study.
- Author
-
Rashid, Nahid, Slade, Michael, Abboud, Ramzi, Gao, Feng, DiPersio, John F., Westervelt, Peter, Uy, Geoffrey, Stockerl‐Goldstein, Keith, Romee, Rizwan, and Schroeder, Mark A.
- Subjects
ACUTE myeloid leukemia ,BLOOD cells ,HEMATOPOIETIC stem cells ,STEM cell transplantation ,TRANSPLANTATION of organs, tissues, etc. - Abstract
Summary: We retrospectively analyzed outcomes in patients with acute myeloid leukemia (AML) receiving reduced‐intensity conditioning (RIC) hematopoietic stem cell transplants (HCT) from a peripheral blood (PB) source. We identified 46 haploidentical HCT (haplo), 59 matched unrelated donor HCT (MUD), and 40 matched related donor HCT (SIB) patients at a single institution. Haplo had improved overall survival (OS) when compared to MUD, HR 2.03 (P = 0.01) but not SIB, HR 1.17 (P = 0.61). There were no differences in relapse rates or treatment‐related mortality (TRM). Haplo had higher rates of acute graft‐versus‐host disease (GVHD) grade II–IV at day 180 than MUD (44% vs. 25%, P = 0.03) and SIB (44% vs. 13% P < 0.01). Rates of acute GVHD III–IV and chronic GVHD were similar among the groups. Haplo had slower engraftment rates compared to MUD with neutrophil engraftment at 87% vs. 93%, (P < 0.01) and platelet engraftment at 59% vs. 86%, (P < 0.01) at 28 days. Although patients receiving haplo had higher acute GVHD II–IV and slower engraftment, they did not have increased TRM. These data may suggest that patients receiving haplo have improved OS compared to MUD for AML patients receiving RIC transplants. This should be confirmed using a larger cohort. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
4. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
- Author
-
Wong, Terrence N., Ramsingh, Giridharan, Young, Andrew L., Miller, Christopher A., Touma, Waseem, Welch, John S., Lamprecht, Tamara L., Shen, Dong, Hundal, Jasreet, Fulton, Robert S., Heath, Sharon, Baty, Jack D., Klco, Jeffery M., Ding, Li, Mardis, Elaine R., Westervelt, Peter, DiPersio, John F., Walter, Matthew J., Graubert, Timothy A., and Ley, Timothy J.
- Subjects
ACUTE myeloid leukemia ,MYELODYSPLASTIC syndromes ,P53 protein ,GENETIC mutation ,PHYSIOLOGICAL effects of chemotherapy ,GENETICS - Abstract
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53
+/− haematopoietic stem/progenitor cells (HSPCs), the Tp53+/− HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
5. Clonal Architecture of Secondary Acute Myeloid Leukemia Defined by Single-Cell Sequencing.
- Author
-
Hughes, Andrew E. O., Magrini, Vincent, Demeter, Ryan, Miller, Christopher A., Fulton, Robert, Fulton, Lucinda L., Eades, William C., Elliott, Kevin, Heath, Sharon, Westervelt, Peter, Ding, Li, Conrad, Donald F., White, Brian S., Shao, Jin, Link, Daniel C., DiPersio, John F., Mardis, Elaine R., Wilson, Richard K., Ley, Timothy J., and Walter, Matthew J.
- Subjects
ACUTE myeloid leukemia ,VIRUS cloning ,TUMORS ,SINGLE nucleotide polymorphisms ,GENE expression - Abstract
Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions—the population frequency of individual clones, their genetic composition, and their evolutionary relationships—which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
6. Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene.
- Author
-
Welch, John S., Westervelt, Peter, Li Ding, Larson, David E., Klco, Jeffery M., Kulkarni, Shashikant, Wallis, John, Chen, Ken, Payton, Jacqueline E., Fulton, Robert S., Veizer, Joelle, Schmidt, Heather, Vickery, Tammi L., Heath, Sharon, Watson, Mark A., Tomasson, Michael H., Link, Daniel C., Graubert, Timothy A., DiPersio, John F., and Mardis, Elaine R.
- Subjects
- *
DISEASES in older women , *ACUTE myeloid leukemia , *NUCLEOTIDE sequence , *GENETIC mutation , *GENETICS - Abstract
The article describes the case of a 39-year-old woman with acute myeloid leukemia (AML) on whom whole-genome sequencing was conducted to identify cryptic, actionable genetic mutations in a clinically relevant time frame. She was enrolled in an institutional review board-approved protocol that maintained patient anonymity within the research team but which allowed the latter to communicate medically relevant information to the treating physician. A cytogenetically cryptic event was identified through the use of massively parallel paired-end sequencing.
- Published
- 2011
- Full Text
- View/download PDF
7. Acquired copy number alterations in adult acute myeloid leukemia genomes.
- Author
-
Walter, Matthew J., Payton, Jacqueline E., Ries, Rhonda E., Shannon, William D., Deshmukh, Hrishikesh, Yu Zhao, Baty, Jack, Heath, Sharon, Westervelt, Peter, Watson, Mark A., Tomasson, Michael H., Nagarajan, Rakesh, O'Gara, Brian P., Bloomfield, Clara D., Mrózek, Krzysztof, Selzer, Rebecca R., Richmond, Todd A., Kitzman, Jacob, Geoghegan, Joel, and Eis, Peggy S.
- Subjects
GENOMICS ,ACUTE myeloid leukemia ,COMPARATIVE genomic hybridization ,DNA microarrays ,CYTOGENETICS ,GENOMES - Abstract
Cytogenetic analysis of acute myeloid leukemia (AML) cells has accelerated the identification of genes important for AML pathogenesis. To complement cytogenetic studies and to identify genes altered in AML genomes, we performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using 1.85 million feature SNP arrays. Acquired copy number alterations (CNAs) were confirmed using an ultra-dense array comparative genomic hybridization platform. A total of 201 somatic CNAs were found in the 86 AML genomes (mean, 2.34 CNAs per genome). with French-American-British system M6 and M7 genomes containing the most changes (10-29 CNAs per genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, whereas 40% of patients with an abnormal karyotype had additional (NA detected by SNP array. and several (NA regions were recurrent. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls occurred in samples with a normal karyotype. Collectively, 34 of 86 AML genomes (40%) contained alterations not found with cytogenetics, and 98% of these regions contained genes. Of 86 genomes, 43 (50%) had no (NA or UPD at this level of resolution. In this study of 86 adult AML genomes. the use of an unbiased high-resolution genomic screen identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumor suppressor genes. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
8. Role of Transplant Conditioning Regimen Intensity in High-Risk Acute Myelogenous Leukemia.
- Author
-
Westervelt, Peter
- Subjects
- *
ACUTE myeloid leukemia , *ALEMTUZUMAB , *TRANSPLANTATION of organs, tissues, etc. , *COMORBIDITY , *CHRONIC myeloid leukemia - Abstract
In the current issue of Biology of Blood and Marrow Transplantation, Konuma et al. [1] report the results of a retrospective analysis of outcomes for cytogenetically defined, poor-risk acute myelogenous leukemia (AML) patients after allogeneic hematopoietic stem cell (HSC) transplant with myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC). Prognostic tools have been developed and validated to distill complex comorbidities prevalent among older patients into a discrete score predictive of outcome with transplant using both RIC and MAC regimens [7]. For patients with AML deemed suitable for either MAC or RIC transplant, however, the optimal conditioning regimen has until recently been a topic of debate. [Extracted from the article]
- Published
- 2020
- Full Text
- View/download PDF
9. Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide and Peripheral Blood Stem Cell Grafts in Older Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome.
- Author
-
Slade, Michael, DiPersio, John F., Westervelt, Peter, Vij, Ravi, Schroeder, Mark A., and Romee, Rizwan
- Subjects
- *
HEMATOPOIETIC stem cell transplantation , *CYCLOPHOSPHAMIDE , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *DISEASES in older people - Abstract
Many hematologic malignancies are diseases of aging, and the use of hematopoietic cell transplant (HCT) is growing rapidly among older adults. Modern post-transplant cyclophosphamide (PTCy) protocols with haploidentical (haplo) donors have dramatically expanded the donor pool for patients requiring HCT. Initial studies were performed with bone marrow grafts, which require the donor to undergo anesthesia during harvest. However, the use of mobilized peripheral blood stem cells (PBSCs) may be desirable, especially with older donors. However, data on PBSC haplo-HCT in older adults are lacking. To characterize the impact of age on outcomes in haplo-HCT, we identified all adult patients undergoing haplo-HCT with PTCy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at our institution from January 2009 to June 2016. Patients were grouped into 3 cohorts: Age 1 (≤55), Age 2 (55 to 65), and Age 3 (≥65). To characterize the impact of donor type on outcomes in older patients, we identified age- and disease risk index (DRI)-matched patient age ≥ 65 undergoing HLA-matched unrelated donor (MUD) HCT for AML or MDS during the same time frame. Patients were scored for disease risk and underlying comorbidities using the DRI and HCT-specific comorbidity index. Overall survival (OS) was analyzed using 3 different Cox proportional hazards models. We identified 112 haplo-HCT patients, 95 with AML and 17 with MDS. There were 61 patients in Age 1, 29 patients in Age 2, and 22 in Age 3. Median OS was 448, 397, and 147 days in Age 1, Age 2, and Age 3 patients (log-rank, P = .04). After adjusting for other risk factors, age ≥ 65 was associated with significantly worse OS after haplo-HCT (aHR, 2.16; 95% CI, 1.15 to 4.07). There was a trend toward increased relapse among older patients at 2 years (56%; 95% CI, 32% to 79%) versus Age 1 (41%; 95% CI, 28% to 54%) and Age 2 (31%; 95% CI, 12% to 50%) ( P = .08). Among patients age ≥ 65, donor type (MUD versus haplo) did not impact OS (aHR, 1.03; 95% CI, .56 to 1.88) after adjusting for other risk factors. Prior allo-HCT (aHR, 4.95; 95% CI, 1.82 to 13.49) and myeloablative conditioning (aHR, 1.97; 95% CI, 1.04 to 3.73) were associated with inferior survival. Although age ≥ 65 was associated with inferior OS in our haplo-HCT cohort, no difference was seen in survival between MUD and haplo-HCT. Therefore, the use of haploidentical donors in older patients is a reasonable treatment option, especially if there is concern for clinical deterioration. A careful pretransplant evaluation and analysis of risks and benefits is warranted when offering this transplant modality to older adults, especially in patients with previous transplant or poor performance status. Strategies to reduce the risk of relapse and decrease nonrelapse mortality in older adults are areas of ongoing research, and prospective studies are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
10. Peritransplant Serum Albumin Decline Predicts Subsequent Severe Acute Graft-versus-Host Disease after Mucotoxic Myeloablative Conditioning.
- Author
-
Rashidi, Armin, DiPersio, John F., Westervelt, Peter, Abboud, Camille N., Schroeder, Mark A., Cashen, Amanda F., Pusic, Iskra, and Romee, Rizwan
- Subjects
- *
MYELOSUPPRESSION , *SERUM albumin , *DISEASE risk factors , *GRAFT versus host disease , *HEMATOPOIETIC stem cell transplantation , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *PATIENTS - Abstract
Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 ± .5 versus .8 ± .4 g/dL, respectively; P < .001). In multivariate analysis DeltaAlb remained a significant predictor of severe aGVHD (odds ratio, 5.68; 95% CI, 1.65 to 19.64; P = .006; area under the ROC curve, .74; 95% CI, .63 to .86; P < .001). The best cutoff for DeltaAlb to predict severe aGVHD was .9, with a sensitivity, specificity, and overall classification accuracy of 77%, 66%, and 69%, respectively. The model was validated using the bootstrap technique, with no significant change in its performance. These results were not generalizable to a cohort of 30 patients who received less mucotoxic myeloablative or reduced-intensity conditioning. In conclusion, with mucotoxic myeloablative HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for ultimately allowing for individualized GVHD prophylaxis and potential intervention according to the predicted risk. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
11. A Phase 1 Trial of CNDO-109–Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.
- Author
-
Fehniger, Todd A., Miller, Jeffrey S., Stuart, Robert K., Cooley, Sarah, Salhotra, Amandeep, Curtsinger, Julie, Westervelt, Peter, Dipersio, John F., Hillman, Timothy M., Silver, Nova, Szarek, Michael, Gorelik, Leonid, Lowdell, Mark W., and Rowinsky, Eric
- Subjects
- *
KILLER cells , *MYELOID leukemia , *CELL-mediated cytotoxicity , *CELL lines , *CYTOKINES , *PATIENTS , *THERAPEUTICS , *PHYSIOLOGY - Abstract
Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell–resistant cell lines. To translate this finding to the clinic, CNDO-109–activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 10 5 (n = 3), 1 × 10 6 (n = 3), and 3 × 10 6 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 10 5 ), 156 (1 × 10 6 ), and 337 (3 × 10 6 ) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
12. T Cell–Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.
- Author
-
How, Joan, Slade, Michael, Vu, Khoan, DiPersio, John F., Westervelt, Peter, Uy, Geoffrey L., Abboud, Camille N., Vij, Ravi, Schroeder, Mark A., Fehniger, Todd A., and Romee, Rizwan
- Subjects
- *
ACUTE myeloid leukemia treatment , *STEM cell transplantation , *CYCLOPHOSPHAMIDE , *DISEASE incidence , *HOMOGRAFTS - Abstract
Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
13. Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy.
- Author
-
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.
- Subjects
- *
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.
- Published
- 2017
- Full Text
- View/download PDF
14. Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation.
- Author
-
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
- Subjects
- *
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]
- Published
- 2016
- Full Text
- View/download PDF
15. Chemotherapy versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome after Allogeneic Stem Cell Transplant.
- Author
-
Motabi, Ibraheem H., Ghobadi, Armin, Liu, Jingxia, Schroeder, Mark, Abboud, Camille N., Cashen, Amanda F., Stockler-Goldstein, Keith E., Uy, Geoffrey L., Vij, Ravi, Westervelt, Peter, and DiPersio, John F.
- Subjects
- *
CANCER chemotherapy , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *GRAFT versus host disease , *STEM cell transplantation - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
16. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.
- Author
-
Churpek, Jane E., Pyrtel, Khateriaa, Kanchi, Krishna-Latha, Jin Shao, Koboldt, Daniel, Miller, Christopher A., Dong Shen, Fulton, Robert, O'Laughlin, Michelle, Fronick, Catrina, Pusic, Iskra, Uy, Geoffrey L., Braunstein, Evan M., Levis, Mark, Ross, Julie, Elliott, Kevin, Heath, Sharon, Jiang, Allan, Westervelt, Peter, and DiPersio, John F.
- Subjects
- *
GENOMICS , *SOMATIC cells , *MYELODYSPLASTIC syndromes , *ACUTE myeloid leukemia , *DISEASE susceptibility , *FAMILY history (Medicine) - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
17. Hematologic Recovery after Pretransplant Chemotherapy Does Not Influence Survival after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients.
- Author
-
Vu, Khoan, Manjappa, Shivaprasad, DiPersio, John F., Gao, Feng, Westervelt, Peter, Vij, Ravi, Stockerl-Goldstein, Keith E., Uy, Geoffrey L., Abboud, Camille N., Schroeder, Mark A., Fehniger, Todd A., Cashen, Amanda F., and Romee, Rizwan
- Subjects
- *
CELL transplantation , *HEMATOPOIESIS , *ACUTE myeloid leukemia , *CANCER chemotherapy , *HEMATOLOGY , *PATIENTS - Abstract
Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
18. Protective Effect of Cytomegalovirus Reactivation on Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients Is Influenced by Conditioning Regimen.
- Author
-
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
- Subjects
- *
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
- Full Text
- View/download PDF
19. Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
- Author
-
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
- Subjects
- *
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
- View/download PDF
20. CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression.
- Author
-
Spencer, David H., Russler-Germain, David A., Ketkar, Shamika, Helton, Nichole M., Lamprecht, Tamara L., Fulton, Robert S., Fronick, Catrina C., O’Laughlin, Michelle, Heath, Sharon E., Shinawi, Marwan, Westervelt, Peter, Payton, Jacqueline E., Wartman, Lukas D., Welch, John S., Wilson, Richard K., Walter, Matthew J., Link, Daniel C., DiPersio, John F., and Ley, Timothy J.
- Subjects
- *
ACUTE myeloid leukemia , *GENETIC mutation , *DNA methylation , *DISEASE progression , *PATIENTS , *GENETICS - Abstract
Summary DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A R882H , has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A R882 mutations. Non-leukemic hematopoietic cells with DNMT3A R882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A R882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3A R882 , while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
21. Comparable Survival with HLA Haploidentical and Mismatched Unrelated Donor Transplants in Patients with AML and MDS.
- Author
-
Bansal, Dhruv, Slade, Michael, Manjappa, Shivaprasad, Goldsmith, Scott R., DiPersio, John F., Westervelt, Peter, Uy, Geoffrey L., Vij, Ravi, Abboud, Camille, Stockerl-Goldstein, Keith, Trinkaus, Kathryn, and Romee, Rizwan
- Subjects
- *
HLA histocompatibility antigens , *ORGAN donors , *ORGAN donation , *ACUTE myeloid leukemia , *CLINICAL trials - Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.