80 results on '"Raja Luthra"'
Search Results
2. Clinical Testing for Mismatch Repair in Neoplasms Using Multiple Laboratory Methods
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Richard K. Yang, Hui Chen, Sinchita Roy-Chowdhuri, Asif Rashid, Hector Alvarez, Mark Routbort, Keyur P. Patel, Raja Luthra, L. Jeffrey Medeiros, and Gokce A. Toruner
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mismatched repair deficiency ,microsatellite instability ,solid tumors ,next-generation sequencing ,immunohistochemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: A deficiency in DNA mismatch repair function in neoplasms can be assessed by an immunohistochemical (IHC) analysis of the deficiency/loss of the mismatch repair proteins (dMMR) or by PCR-based methods to assess high microsatellite instability (MSI-H). In some cases, however, there is a discrepancy between the IHC and MSI analyses. Several studies have addressed the issue of discrepancy between IHC and MSI deficiency assessment, but there are limited studies that also incorporate genetic/epigenetic alterations. Methods: In this single-institution retrospective chart-review study, we reviewed 706 neoplasms assessed between 2015 and 2021. All eligible neoplasms were assessed by IHC testing, MSI analysis by PCR-based assay, and tumor-normal paired next-generation sequencing (NGS) analysis. Eighty percent of neoplasms with MLH1 protein loss had a concurrent MLH1 promoter methylation analysis. Mutation data for MMR genes, IHC, MSI analysis, and tumor histology were correlated with each other. Results: Fifty-eight (8.2%) of 706 neoplasms had MSI-H by PCR and/or dMMR by IHC. Of the 706 analyzed neoplasms, 688 neoplasms (98%) had concordant results: MSI-H/dMMR (n = 44), microsatellite-stable (MSS)/proficient MMR (pMMR) (n = 625), and MSI-Low (L)/pMMR (n = 19). Of the remaining 18 neoplasms, 9 had a major discordance: MSS/loss of MSH2 and MSH6 (n = 3), MSS/loss of MSH6 (n = 2), MSS/Loss of MLH1 and PMS2 (n = 1), and MSI-High/pMMR (n = 3). In total, 57% of cases with dMMR and 61% of cases with MSI-H had a null mutation of an MMR gene mutation (or methylation of the MLH1 promoter), whereas this figure was 1% for neoplasms with a normal IHC or MSI pattern (p < 0.001). Among 9 cases with major discordance between MSI and IHC, only 3 cases (33%) had an underlying genetic/epigenetic etiology, whereas 37 (76%) of 49 cases with MSI-H and/or dMMR and without major discordance had an underlying genetic abnormality (p = 0.02). Discussion: For most neoplasms, IHC and PCR-based MSI testing results are concordant. In addition, an underlying genetic abnormality (a null mutation of an MMR gene or MLH1 promoter methylation) was attributable to dMMR and/or MSI-H findings. For neoplasms with major discordance in IHC and MSI testing, the addition and integration of NGS results and MLH1 promoter methylation analyses can be beneficial for resolving borderline cases, thereby facilitating patient management.
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- 2022
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3. Immunohistochemical and Molecular Features of Melanomas Exhibiting Intratumor and Intertumor Histomorphologic Heterogeneity
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Haider A. Mejbel, Sri Krishna C. Arudra, Dinesh Pradhan, Carlos A. Torres-Cabala, Priyadharsini Nagarajan, Michael T. Tetzlaff, Jonathan L. Curry, Doina Ivan, Dzifa Y. Duose, Raja Luthra, Victor G. Prieto, Leomar Y. Ballester, and Phyu P. Aung
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melanoma ,histophenotypic heterogeneity ,tumor heterogeneity ,next-generation sequencing ,driver mutations ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor (n = 5, 100%; intratumor: n = 2, 40%; intertumor: n = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions (n = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy.
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- 2019
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4. Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era.
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Santiago Montes-Moreno, Mark J Routbort, Elijah J Lohman, Bedia A Barkoh, Rashmi Kanagal-Shamanna, Carlos E Bueso-Ramos, Rajesh R Singh, L Jeffrey Medeiros, Raja Luthra, and Keyur P Patel
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Medicine ,Science - Abstract
ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease.
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- 2018
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5. Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer.
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Amir Mehrvarz Sarshekeh, Shailesh Advani, Michael J Overman, Ganiraju Manyam, Bryan K Kee, David R Fogelman, Arvind Dasari, Kanwal Raghav, Eduardo Vilar, Shanequa Manuel, Imad Shureiqi, Robert A Wolff, Keyur P Patel, Raja Luthra, Kenna Shaw, Cathy Eng, Dipen M Maru, Mark J Routbort, Funda Meric-Bernstam, and Scott Kopetz
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Medicine ,Science - Abstract
SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p
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- 2017
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6. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.
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Evan N Cohen, Hui Gao, Simone Anfossi, Michal Mego, Neelima G Reddy, Bisrat Debeb, Antonio Giordano, Sanda Tin, Qiong Wu, Raul J Garza, Massimo Cristofanilli, Sendurai A Mani, Denise A Croix, Naoto T Ueno, Wendy A Woodward, Raja Luthra, Savitri Krishnamurthy, and James M Reuben
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Medicine ,Science - Abstract
Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.
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- 2015
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7. Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months
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Aziz Nazha, Hagop Kantarjian, Preetesh Jain, Carlos Romo, Elias Jabbour, Alfonso Quintas-Cardama, Raja Luthra, Lynne Abruzzo, Gautam Borthakur, Farhad Ravandi, Sherry Pierce, Susan O’Brien, and Jorge Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Response to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.
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- 2013
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8. Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia
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Aziz Nazha, Jorge Cortes, Stefan Faderl, Sherry Pierce, Naval Daver, Tapan Kadia, Gautam Borthakur, Raja Luthra, Hagop Kantarjian, and Farhad Ravandi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are among the most frequent molecular aberrations in patients with acute myeloid leukemia. We retrospectively analyzed 324 patients with acute myeloid leukemia treated with front-line induction chemotherapy between October 2004 and March 2010. Fifty-six patients had FLT3-ITD mutation at diagnosis. Fifty-one (91%) patients with FLT3-ITD achieved complete remission. Thirteen patients had FLT3 analysis at complete remission. None had FLT3-ITD. Twenty-five (49%) patients with FLT3-ITD relapsed. Of these, 13 (52%) had FLT3-ITD at relapse (3 negative and 9 not done). Among the 201 patients without FLT3-ITD at diagnosis who achieved complete remission, 77 (38%) relapsed among whom 8 (10%) patients acquired FLT3-ITD clone. We conclude that FLT3-ITD mutations are unstable at follow up and may occur for the first time at relapse. Therefore, FLT3-ITD is not a reliable marker for minimal residual disease in acute myeloid leukemia.
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- 2012
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9. Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer
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Van K. Morris, Michael J. Overman, Michael Lam, Christine M. Parseghian, Benny Johnson, Arvind Dasari, Kanwal Raghav, Bryan K. Kee, Ryan Huey, Robert A. Wolff, John Paul Shen, June Li, Isabel Zorrilla, Ching-Wei D. Tzeng, Hop S. Tran Cao, Yun Shin Chun, Timothy E. Newhook, Nicolas Vauthey, Dzifa Duose, Raja Luthra, Cara Haymaker, and Scott Kopetz
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Article - Abstract
Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1,200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGFβ and PD-L1 inhibition. Significance: Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.
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- 2022
10. Figure SF2 from Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer
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Scott Kopetz, Cara Haymaker, Raja Luthra, Dzifa Duose, Nicolas Vauthey, Timothy E. Newhook, Yun Shin Chun, Hop S. Tran Cao, Ching-Wei D. Tzeng, Isabel Zorrilla, June Li, John Paul Shen, Robert A. Wolff, Ryan Huey, Bryan K. Kee, Kanwal Raghav, Arvind Dasari, Benny Johnson, Christine M. Parseghian, Michael Lam, Michael J. Overman, and Van K. Morris
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Supplemental Figure S2
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- 2023
11. Table S3 from Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer
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Scott Kopetz, Cara Haymaker, Raja Luthra, Dzifa Duose, Nicolas Vauthey, Timothy E. Newhook, Yun Shin Chun, Hop S. Tran Cao, Ching-Wei D. Tzeng, Isabel Zorrilla, June Li, John Paul Shen, Robert A. Wolff, Ryan Huey, Bryan K. Kee, Kanwal Raghav, Arvind Dasari, Benny Johnson, Christine M. Parseghian, Michael Lam, Michael J. Overman, and Van K. Morris
- Abstract
Supplemental Table S3
- Published
- 2023
12. Data from Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer
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Scott Kopetz, Cara Haymaker, Raja Luthra, Dzifa Duose, Nicolas Vauthey, Timothy E. Newhook, Yun Shin Chun, Hop S. Tran Cao, Ching-Wei D. Tzeng, Isabel Zorrilla, June Li, John Paul Shen, Robert A. Wolff, Ryan Huey, Bryan K. Kee, Kanwal Raghav, Arvind Dasari, Benny Johnson, Christine M. Parseghian, Michael Lam, Michael J. Overman, and Van K. Morris
- Abstract
Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1,200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGFβ and PD-L1 inhibition.Significance:Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.
- Published
- 2023
13. Abstract P4-08-19: Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer
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Lim, Bora, primary, Alexander, Angela, additional, Willey, Jie S., additional, Sun, Huiming, additional, Liu, Suyu, additional, Patel, Anisha B., additional, Parra, Edwin Roger, additional, Haymaker, Cara, additional, Soto, Luisa Solis, additional, Serrano, Alejandra, additional, Sun, Baohua, additional, Lima, Cibelle Freitas Pinto, additional, Tamegnon, Auriole, additional, Pandurengan, Renganayaki K., additional, Douse, Dzifa, additional, Lan, Jessica, additional, Raja, Luthra, additional, Chu, Randy, additional, Knafl, Mark, additional, Woodman, Scott E., additional, Zhu, Haifeng, additional, Shulze, Katja, additional, Fedenko, Katherine, additional, Darbonne, Walter, additional, Ueno, Naoto T., additional, and Valero, Vicente, additional
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- 2023
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14. Supplementary Tables 1 - 3 from Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic
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David S. Hong, Funda Meric-Bernstam, Razelle Kurzrock, Ravi Salgia, Raja Luthra, Sinchita Roy-Chowdhuri, Marylin M. Li, Vijaykumar Holla, Apostolia M. Tsimberidou, Aung Naing, Ralph G. Zinner, Jennifer J. Wheler, Siqing Fu, Filip Janku, Kenneth Hess, Gerald S. Falchook, Debora De Melo Gagliato, Chad Tang, and Denis L.F. Jardim
- Abstract
Table S1 - Histologies and tumor grade by site according to MET amplification status. Table S2- Type of BRAF mutations by tumor site. Table S3 - List of phase I trials included as best trials for MET amplified patients.
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- 2023
15. Data from Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic
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David S. Hong, Funda Meric-Bernstam, Razelle Kurzrock, Ravi Salgia, Raja Luthra, Sinchita Roy-Chowdhuri, Marylin M. Li, Vijaykumar Holla, Apostolia M. Tsimberidou, Aung Naing, Ralph G. Zinner, Jennifer J. Wheler, Siqing Fu, Filip Janku, Kenneth Hess, Gerald S. Falchook, Debora De Melo Gagliato, Chad Tang, and Denis L.F. Jardim
- Abstract
Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.Conclusion:MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.
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- 2023
16. 128. Clinical testing of mismatch repair in neoplasms using multiple laboratory methods
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Gokce Toruner, Hui Chen, Sinchita Roy-Chowdhuri, Asif Rashid, Keyur Patel, Raja Luthra, L. Jeffrey Medeiros, and Richard Yang
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Cancer Research ,Genetics ,Molecular Biology - Published
- 2022
17. MON-491 TRK-Fusion Thyroid Cancer: A Clinical Overview in a Large Population at a Single Cancer Center
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Steven I. Sherman, Maria E. Cabanillas, Kate Poropatich, Sasan Fazeli, Michelle A. Williams, Keyur P. Patel, Mark J. Routbort, Camilo Jimenez, Steven G. Waguespack, Mouhammed Amir Habra, Naifa L. Busaidy, Ramona Dadu, Lina Altameemi, Mimi I. Hu, and Raja Luthra
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Oncology ,Thyroid ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Thyroid Neoplasia and Cancer ,Large population ,Cancer ,macromolecular substances ,medicine.disease ,Trk receptor ,Internal medicine ,medicine ,Center (algebra and category theory) ,business ,Thyroid cancer ,AcademicSubjects/MED00250 - Abstract
Introduction: Most thyroid cancers (TC) are due to mutually exclusive somatic driver mutations. NTRK fusions are rare oncogenic drivers in papillary TC (PTC), poorly differentiated TC (PDTC) and anaplastic TC (ATC), estimated to be in 2.3% of all TC. However, the clinical presentation and behavior of TRK-fusion TC remains largely unknown. Methods / Case Presentation: Using institutional databases, we identified all TC patients (pts) with an NTRK fusion reported on somatic testing performed by a CLIA-certified laboratory. Data from the medical records were collected. The objective of this study was to investigate the clinical and pathological features of TC pts whose tumors harbored an NTRK fusion. Results / Discussion: We identified 36 TC pts with somatic NTRK fusions. Fusion testing was generally done in pts with advanced or radioactive iodine refractory (RAI-R) disease. Median age at diagnosis was 27.4 years (range 4–75 years), 21 (58%) were female and 16 (44%) were pediatric. 28/36 (78%) pts had PTC, 2/36 (5%) PDTC and 6/36 (17%) ATC. There were a total of 12 (33%) NTRK1, 24 (67%) NTRK3, and no NTRK2 fusions. In ATC and PDTC pts NTRK3 was the most common NTRK fusion 7/8 (87%). In PTC pts, 11 (39%) had NTRK1 and 17 (61%) had NTRK3. In the adult pts NTRK3 was more common 17/20 (85%) (Odds Ratio 7.2, P=0.013), however, in pediatric pts rate of NTRK1 and NTRK3 were similar. One pt had additional mutations along with the NTRK fusion, an ATC pt with multiple mutations including BRAF V600E. Of the 30 PTC/PDTC pts, 23 (77%) had distant metastases (mets). 14 (38%) pts had distant mets at diagnosis and 11 (69%) pediatric pts had distant mets. Lung 21 (70%) and bone 9 (30%) were the most common distant mets sites. In the PTC pts with distant mets, 9 (41%) had RAI-avid and 11 (50%) had RAI-R disease. In the entire cohort of 36 pts, 17 (53%) were on a systemic therapy of whom 11 pts were PTC. NTRK directed was the most common systemic therapy 16 (94%). All PTC pts were alive with a median time from diagnosis of 46 months (Interquartile 1–3: 25–118 months). Four ATC and one PDTC pts had died at the time of the analysis. Conclusions: In this study we confirmed that NTRK fusions occur primarily in PTC but also in less differentiated tumors. Most were young pts but NTRK fusions were identified in tumors from adults as old as 75 years. NTRK1 and NTRK3 were the most common NTRK fusions with NTRK3 being more common in adults. In thyrocyte-derived TC pts, NTRK fusions are mutually exclusive genetic events that occur in pts of all ages and varying histologies. Given the availability of NTRK targeted therapy, consideration should be given to testing for NTRK fusions in advanced thyroid cancer pts, especially those in whom prior genetic testing did not identify an oncogenic driver.
- Published
- 2020
18. Immunohistochemical and Molecular Features of Melanomas Exhibiting Intratumor and Intertumor Histomorphologic Heterogeneity
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Phyu P. Aung, Jonathan L. Curry, Dzifa Y. Duose, Sri Krishna C. Arudra, Leomar Y. Ballester, Doina Ivan, Haider A. Mejbel, Carlos A. Torres-Cabala, Victor G. Prieto, Dinesh Pradhan, Michael T. Tetzlaff, Raja Luthra, and Priyadharsini Nagarajan
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,driver mutations ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,DNA sequencing ,Article ,03 medical and health sciences ,0302 clinical medicine ,tumor heterogeneity ,medicine ,melanoma ,Neoplasm ,Gene ,Mutation ,histophenotypic heterogeneity ,Genetic heterogeneity ,Melanoma ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,Tumor morphology ,030220 oncology & carcinogenesis ,Immunohistochemistry ,next-generation sequencing - Abstract
Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor (n = 5, 100%, intratumor: n = 2, 40%, intertumor: n = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions (n = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy.
- Published
- 2019
19. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment
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William G. Wierda, Mary Beth Rios, Guilin Tang, Tapan M. Kadia, Gautam Borthakur, Raja Luthra, Graciela M. Nogueras González, Ghayas C. Issa, Keyur P. Patel, Farhad Ravandi, Elias Jabbour, Nicholas J. Short, Guillermo Garcia-Manero, Hagop M. Kantarjian, Koji Sasaki, Jorge E. Cortes, Alessandra Ferrajoli, and Sara Dellasala
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Immunology ,Philadelphia chromosome ,Trisomy 8 ,Biochemistry ,Gastroenterology ,Disease-Free Survival ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Chromosomes, Human ,Humans ,Prospective Studies ,Survival rate ,Metaphase ,Chromosome Aberrations ,business.industry ,Ponatinib ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Survival Rate ,Dasatinib ,chemistry ,Nilotinib ,030220 oncology & carcinogenesis ,Chromosome abnormality ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were -Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which -Y was the only clonal abnormality, and all others. We found that patients with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = .02), EFS (68% vs 86%, P = .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P = .03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P = .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL
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- 2017
20. Clinical outcomes based on multigene profiling in metastatic breast cancer patients
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Caimiao Wei, Aysegul A. Sahin, Vincent Valero, Reva K. Basho, Debu Tripathy, Mariana Chavez-MacGregor, Funda Meric-Bernstam, Naoto T. Ueno, Sinchita Roy-Chowdhuri, Huiqin Chen, Jia Zeng, Stacy L. Moulder, Chetna Wathoo, Kenna R. Shaw, Debora de Melo Gagliato, Ricardo H. Alvarez, John Mendelsohn, Gordon B. Mills, Maryam Shariati, Raja Luthra, and Jennifer K. Litton
- Subjects
0301 basic medicine ,Gerontology ,Oncology ,medicine.medical_specialty ,Genotype ,Cancer therapy ,Breast Neoplasms ,Tp53 mutation ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Gene Frequency ,Cancer Medicine ,Surgical oncology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Genomic medicine ,Genetic Predisposition to Disease ,TP53 ,Neoplasm Metastasis ,neoplasms ,Alleles ,Neoplasm Staging ,business.industry ,Gene Expression Profiling ,Genomics ,PIK3CA ,Prognosis ,medicine.disease ,Metastatic breast cancer ,3. Good health ,030104 developmental biology ,Multigene Family ,030220 oncology & carcinogenesis ,Mutation ,Cohort ,Female ,metastatic breast cancer ,business ,Priority Research Paper - Abstract
// Reva K. Basho 1,* , Debora de Melo Gagliato 2,* , Naoto T. Ueno 2 , Chetna Wathoo 3 , Huiqin Chen 4 , Maryam Shariati 5 , Caimiao Wei 4,6 , Ricardo H. Alvarez 2,7 , Stacy L. Moulder 2 , Aysegul A. Sahin 8 , Sinchita Roy-Chowdhuri 8 , Mariana Chavez-MacGregor 2,9 , Jennifer K. Litton 2 , Vincent Valero 2 , Raja Luthra 8 , Jia Zeng 3 , Kenna R. Shaw 3 , John Mendelsohn 3,10 , Gordon B. Mills 3,11 , Debu Tripathy 2 and Funda Meric-Bernstam 3,5,12 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Pfizer, Inc, New York, NY, USA 7 The Cancer Treatment Centers of America, Chicago, IL, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Funda Meric-Bernstam, email: // Keywords : metastatic breast cancer, genomics, TP53, PIK3CA Received : April 06, 2016 Accepted : October 13, 2016 Published : October 28, 2016 Abstract BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene ( N = 126) and/or 46 or 50 gene ( N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.
- Published
- 2016
21. Relapsed Refractory BRAF-Negative, IGHV4-34–Positive Variant of Hairy Cell Leukemia: A Distinct Entity?
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Keyur P. Patel, Hagop M. Kantarjian, Sergej Konoplev, Farhad Ravandi, Zeev Estrov, Preetesh Jain, Chi Young Ok, Jeffrey L. Jorgensen, and Raja Luthra
- Subjects
Proto-Oncogene Proteins B-raf ,Leukemia, Hairy Cell ,Cancer Research ,business.industry ,medicine.disease ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Antineoplastic Combined Chemotherapy Protocols ,Relapsed refractory ,Splenectomy ,Cancer research ,Cladribine ,Humans ,Medicine ,Female ,Hairy cell leukemia ,Immunoglobulin Heavy Chains ,Rituximab ,business ,Pentostatin ,Aged ,030215 immunology - Published
- 2016
22. Detectable FLT3-ITD or RAS mutation at the time of transformation from MDS to AML predicts for very poor outcomes
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Koichi Takahashi, Guillermo Garcia-Manero, Tapan M. Kadia, Zach Bohannan, Keyur P. Patel, Monica Cabrero, Elias Jabbour, Farhad Ravandi, Talha Badar, Courtney D. DiNardo, Gautam Borthakur, Raja Luthra, Sherry Pierce, Philip A. Thompson, Hagop M. Kantarjian, Jorge E. Cortes, Marina Konopleva, and Naval Daver
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Kaplan-Meier Estimate ,medicine.disease_cause ,Article ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Codon ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,Mutation ,Proportional hazards model ,business.industry ,Myelodysplastic syndromes ,Hazard ratio ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,body regions ,Leukemia, Myeloid, Acute ,Leukemia ,Cell Transformation, Neoplastic ,Genes, ras ,Treatment Outcome ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Myelodysplastic Syndromes ,Fms-Like Tyrosine Kinase 3 ,Disease Progression ,Mutation testing ,Female ,business ,psychological phenomena and processes - Abstract
Background The molecular events that drive the transformation from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) have yet to be fully characterized. We hypothesized that detection of these mutations at the time of transformation from MDS to AML may lead to poorer outcomes. Methods We analyzed 102 MDS patients who were admitted to our institution between 2004 and 2013, had wild-type (wt) FLT3-ITD and RAS at diagnosis, progressed to AML, and had serial mutation testing at both the MDS and AML stages. Results We detected FLT3-ITD and/or RAS mutations in twenty-seven (26%) patients at the time of transformation to AML. Twenty-two patients (81%) had RAS mutations and five (19%) had FLT3-ITD mutations. The median survival after leukemia transformation in patients who had detectable RAS and/or FLT3-ITD mutations was 2.4 months compared to 7.5 months in patients who retained wt RAS and FLT3-ITD (hazard ratio [HR]: 3.08, 95% confidence interval [CI]: 1.9–5.0, p FLT3-ITD and RAS mutations had independent prognostic significance for poor outcome.
- Published
- 2015
23. Sensitive PCR-based monitoring and early detection of relapsed JAK2 V617F myelofibrosis following transplantation
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Richard E. Champlin, Lohith S. Bachegowda, Rashmi Kanagal-Shamanna, Uday R. Popat, Srdan Verstovsek, Meenakshi Mehrotra, Raja Luthra, Mithun Vinod Shah, and Keyur P. Patel
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Time Factors ,Early detection ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Myelofibrosis ,Aged ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Minimal residual disease ,Transplantation ,030104 developmental biology ,Early Diagnosis ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Female ,business ,JAK2 V617F ,Biomarkers - Published
- 2017
24. Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations
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Keyur P. Patel, William G. Wierda, Sara Dellasala, Gautam Borthakur, Elias Jabbour, Raja Luthra, Tapan M. Kadia, Mary Beth Rios, Kiran Naqvi, Farhad Ravandi, Hagop M. Kantarjian, Guillermo Garcia-Manero, Jorge E. Cortes, Susan O'Brien, and Sherry Pierce
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Survival ,Fusion Proteins, bcr-abl ,medicine.disease_cause ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Aged ,Aged, 80 and over ,Mutation ,Hematology ,ABL ,business.industry ,Incidence (epidemiology) ,Myeloid leukemia ,Middle Aged ,Prognosis ,030104 developmental biology ,Protein kinase domain ,Fusion transcript ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Tyrosine kinase - Abstract
Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR–ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response—CHR-4; complete cytogenetic response—CCyR-1; major molecular response—MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response—PCyR-3). After a median follow-up of 65 months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p = 0.003); median overall survival was 12 months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.
- Published
- 2017
25. Improvement in clinical outcome ofFLT3ITD mutated acute myeloid leukemia patients over the last one and a half decade
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Betul Oran, Michael Andreeff, Tapan M. Kadia, Graciela M. Nogueras-Gonzalez, Guillermo Garcia Manero, William G. Wierda, Talha Badar, Farhad Ravandi, Keyur P. Patel, Gautam Borthakur, Raja Luthra, Richard E. Champlin, Marina Konopleva, Naval Daver, Hagop M. Kantarjian, and Jorge E. Cortes
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Univariate analysis ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Surgery ,Internal medicine ,Fms-Like Tyrosine Kinase 3 ,Medicine ,business ,Survival analysis - Abstract
AML with FLT3 ITD mutations are associated with poor outcome. We reviewed outcomes of patients with FLT3 ITD mutated AML to investigate trends over time. We analyzed 224 AML patients (excluding patients with core binding factor and acute promyelocytic leukemia) referred to our institution between 2000 and 2014. Patients were divided into five cohorts by era: 2000-2002 (Era 1, n = 19), 2003-2005 (Era 2, n = 41), 2006-2008 (Era 3, n = 53), 2009-2011 (Era 4, n = 55), and 2012-2014 (Era 5, n = 56) to analyze differences in outcome. The baseline characteristics were not statistically different across Eras. The response rate (CR/CRp) from Era 1-5 was 68%, 49%, 72%, 73%, and 75%, respectively. The overall response rate (all Eras) with chemotherapy alone versus chemotherapy plus FLT3 inhibitor was 67% and 72.5%, respectively (P = 0.4). The median time to relapse was 6, 3.6, 7.9, 8.1 months and not reached from Eras 1 through 5, respectively (P = 0.001). The median OS has improved: 9.6, 7.6, 14.4, 15.7, and 17.8 month from Eras 1-5, respectively (P =
- Published
- 2015
26. Insights from response to tyrosine kinase inhibitor therapy in a rare myeloproliferative neoplasm with CALR mutation and BCR-ABL1
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Raja Luthra, L. Jeffrey Medeiros, Keyur P. Patel, Hagop M. Kantarjian, Sanam Loghavi, Jorge E. Cortes, Meenakshi Mehrotra, Srdan Verstovsek, Naveen Pemmaraju, Yang Huh, Pei Lin, and Rashmi Kanagal-Shamanna
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Pathology ,medicine.medical_specialty ,biology ,Essential thrombocythemia ,business.industry ,medicine.drug_class ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tyrosine-kinase inhibitor ,Dasatinib ,Bcr abl1 ,medicine ,biology.protein ,Cancer research ,CALR Mutation ,business ,Calreticulin ,Myeloproliferative neoplasm ,medicine.drug - Abstract
To the editor: Calreticulin ( CALR ) mutations have been reported primarily in the context of JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis.[1][1][⇓][2][⇓][3][⇓][4]-[5][5] CALR mutations are exceedingly rare in the setting of t(9;22)/ BCR-ABL1 ,[4][4],[5][5] with
- Published
- 2015
27. Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic
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Jennifer J. Wheler, Sinchita Roy-Chowdhuri, Marylin M. Li, Vijay Kumar Holla, Denis Leonardo Fontes Jardim, Filip Janku, Gerald S. Falchook, Raja Luthra, Siqing Fu, Apostolia Maria Tsimberidou, Razelle Kurzrock, Aung Naing, Funda Meric-Bernstam, Debora de Melo Gagliato, David S. Hong, Kenneth R. Hess, Chad Tang, Ravi Salgia, and Ralph Zinner
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Adolescent ,medicine.medical_treatment ,Population ,Metastasis ,Targeted therapy ,Young Adult ,Neoplasms ,Internal medicine ,medicine ,Humans ,PTEN ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Child ,education ,Aged ,Neoplasm Staging ,Aged, 80 and over ,education.field_of_study ,Clinical Trials, Phase I as Topic ,biology ,business.industry ,Gene Amplification ,Cancer ,Histology ,Middle Aged ,Proto-Oncogene Proteins c-met ,Prognosis ,medicine.disease ,Texas ,Clinical trial ,Treatment Outcome ,Child, Preschool ,Concomitant ,Mutation ,biology.protein ,Female ,Neoplasm Grading ,business - Abstract
Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications. Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status. Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response. Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.
- Published
- 2014
28. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms
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Sa A. Wang, Rashmi Kanagal-Shamanna, Adam Bagg, Eric D. Hsi, Courtney D. DiNardo, Kathryn Foucar, Heesun J. Rogers, Joseph Hatem, Julia T. Geyer, Ramon V. Tiu, Keyur P. Patel, Jesse Jaso, Daniel A. Arber, Patricia S. Fox, Ken H. Young, Srdan Verstovsek, Francesco C. Stingo, Carlos E. Bueso-Ramos, Devon Chabot-Richards, Meenakshi Mehrotra, Raja Luthra, Attilio Orazi, Robert P. Hasserjian, and Elizabeth Weinzierl
- Subjects
Adult ,Blood Platelets ,Male ,Pathology ,medicine.medical_specialty ,Myeloid ,Clinical Trials and Observations ,Leukocytosis ,DNA Mutational Analysis ,Immunology ,Biology ,Biochemistry ,Gastroenterology ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,Myelodysplastic–myeloproliferative diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Granulocyte Precursor Cells ,Myeloproliferative neoplasm ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Hematology ,L-Lactate Dehydrogenase ,Myelodysplastic syndromes ,food and beverages ,Cell Biology ,Middle Aged ,Prognosis ,medicine.disease ,Myelodysplastic-Myeloproliferative Diseases ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Hematologic Neoplasms ,Karyotyping ,Myelodysplastic Syndromes ,Mutation ,Atypical chronic myeloid leukemia ,Female ,medicine.symptom ,Follow-Up Studies - Abstract
Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN-U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters.
- Published
- 2014
29. Abstract 3162: Prognostic value of tumor mutational burden using a 409 gene NGS panel in cancer patients with advanced stage recurrent or treatment refractory disease
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Richard K. Yang, Peng Wang, Fatima Z. Jelloul, Mark J. Routbort, Scott Kopetz, Kenna R. Shaw, Jack J. Lee, Jiexin Zhang, Hui Chen, Keyur P. Patel, Raja Luthra, and Russell R. Broaddus
- Subjects
Cancer Research ,Oncology - Abstract
Tumor Mutational Burden (TMB) is a promising biomarker for prediction of response to immune checkpoint blockade (ICB). It is uncertain whether ICB has prognostic value outside of ICB therapy. The CMS400 next generation sequencing panel (NGS) is a 409 gene, 15,992 amplicon, and 1.745 Mb panel instituted during 2014-2015 and run for 556 cancer patients who had been consented for participation within a prospective molecular pathology biomarker trial (PA14-0099). All patients had advanced or recurrent solid tumor malignancies that were refractory to at least one line of systemic therapy prior to enrollment. Survival time was calculated from time of NGS-tested tissue collection. TMB was calculated by dividing reported mutations (RM) by 1.745Mb, the genetic footprint of the NGS panel. Subtraction of germline single nucleotide polymorphisms was performed for each patient. GraphPad Prism 7.03 software was used to calculate p values and to plot Kaplan-Meier survival curves. One hundred seven patients (19.2%) received ICB. When stratified by reported mutations (RM: 0, 1, 2, 3, 4-5, 6-7, 8-9, 10-18, and >19), a statistically significant decrement of overall survival was seen with increasing TMB in patients not treated with ICB (Table 1, p Median Survival Stratified by Tumor Mutational Burden and ICB Treatment StatusAll PtsAll PtsICB TreatedICB TreatedNo ICBNo ICBReported Mutations# of PtsMedian Survival (Months)# of PtsMedian Survival (Months)# of PtsMedian Survival (Months)p-value (Log-rank)Hazard Ratio of ICB Therapy95% CI of HR of ICB Therapy0 RM7150.71958.85248.50.3190.7050.368 - 1.341 RM8550.91262.07347.40.3390.6840.345 - 1.362 RM9433.91928.07533.90.8650.9510.535 - 1.693 RM8830.51951.26928.90.1890.7040.428 - 1.164-5 RM9330.81141.08230.40.5390.8150.442 - 1.506-7 RM4928.41127.33828.550.6230.8270.401 - 1.718-18 RM5623.95828.84823.10.5491.2520.553 - 2.84>19 RM2041.38102.31224.20.00230.1800.0599 - 0.543Total55635.810747.944933.40.00490.7070.567 - 0.882p-value (Log-rank) Citation Format: Richard K. Yang, Peng Wang, Fatima Z. Jelloul, Mark J. Routbort, Scott Kopetz, Kenna R. Shaw, Jack J. Lee, Jiexin Zhang, Hui Chen, Keyur P. Patel, Raja Luthra, Russell R. Broaddus. Prognostic value of tumor mutational burden using a 409 gene NGS panel in cancer patients with advanced stage recurrent or treatment refractory disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3162.
- Published
- 2019
30. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia
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Farhad Ravandi, Sergej Konoplev, Lynne Abruzzo, Paolo Strati, Elias J. Jabbour, Alfonso Quintás-Cardama, Jeffrey L. Jorgensen, Gautam Borthakur, Susan O'Brien, Raja Luthra, Stefan Faderl, Hagop M. Kantarjian, Jorge E. Cortes, and D. A. Thomas
- Subjects
Cancer Research ,medicine.medical_specialty ,Vincristine ,Cyclophosphamide ,business.industry ,Cancer ,Myeloid leukemia ,Imatinib ,medicine.disease ,Gastroenterology ,Dasatinib ,Regimen ,Oncology ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,medicine ,business ,Dexamethasone ,medicine.drug - Abstract
BACKGROUND Chronic myeloid leukemia (CML) may progress to blast phase (BP) at the rate of 1% to 1.5% per year. With the use of single-agent tyrosine kinase inhibitors, median overall survival ranges between 7 and 11 months. METHODS The outcome was analyzed for 42 patients with lymphoid BP-CML who were treated with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (HCVAD) plus imatinib or dasatinib. RESULTS Complete hematological response was achieved in 90% of patients, complete cytogenetic remission in 58%, and complete molecular remission in 25%. Flow cytometry minimal residual disease negativity was achieved by 42% of evaluable patients after induction. Eighteen patients received allogeneic stem cell transplant (SCT) while in first complete hematological response. Median remission duration was 14 months and was longer among SCT recipients (P = .01) on multivariate analysis. Median overall survival was 17 months (range, 7-27 months) and was longer among SCT recipients (P
- Published
- 2013
31. RAS and TP53, Not NOTCH1, Can Predict Survival in Adults with Acute T-Cell Lymphoblastic Leukemia Treated with Hypercvad
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Mark J. Routbort, Ali Sakhdari, Zhuang Zuo, Sanam Loghavi, C. Cameron Yin, Keyur P. Patel, Raja Luthra, Chi Young Ok, L. Jeffrey Medeiros, and Rashmi Kanagal-Shamanna
- Subjects
Oncology ,Vincristine ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Internal medicine ,Nelarabine ,Medicine ,Doxorubicin ,Bone marrow ,business ,Neoadjuvant therapy ,Dexamethasone ,medicine.drug - Abstract
Context: Adult T-cell lymphoblastic leukemia (T-ALL) is a rare heterogeneous group of acute leukemias which accounts for about one third of all Philadelphia negative ALLs. Risk stratification of T-ALL is based predominantly on measurable residual disease (MRD) at the end of induction therapy. Recently, an oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) was shown to distinguish low and high risk groups in adult T-ALL patients enrolled in GRAALL-2003 and -2005 trials (J Clin Oncol. 2013). However, it is not known if this oncogenetic classifier can stratify adult T-ALL patients treated with a different regimen (hyperCVAD). Design: We searched our institutional database to identify adult T-ALL patients with available mutational analysis. Clinically validated next-generation sequencing gene panel assays were performed in all patients. We retrieved clinicopathologic, cytogenetic and mutational data from medical records. Overall survival (OS), defined from the time of diagnosis to death from any cause, and event-free (EFS) survival, defined as the time from diagnosis to first outcome event (induction failure, induction death, death during remission, second malignant neoplasm, or relapse), were calculated. Results: We identified 28 T-ALL patients with available mutational analyses at the time of diagnosis. All patients received hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with or without nelarabine for the first induction chemotherapy. The study cohort included 23 men and 5 women with a median age of 37 years at diagnosis (range: 18 - 75). The median blast percentage was 79% (range: 6 - 96) and 56.5% (range: 0 - 91) in bone marrow (BM) and peripheral blood (PB), respectively. Conventional cytogenetic analysis was available for 26 patients. These included 11 cases with normal karyotype, 8 patients with simple karyotypic abnormality (less than 3 abnormalities), and 7 patients with complex karyotype (at least 3 abnormalities). Twenty-seven (96%) patients achieved complete remission. With a median follow-up of 16.1 months (range: 0.6 - 46), 21 (71%) patients were alive and the 3-year overall survival rate was 60%. The five most commonly mutated genes were NOTCH1, NRAS, DNMT3A, KRAS and TP53 in 17 (61%), 7 (25%), 6(21%), 4 (14%) and 3 (11%) patients, respectively. Mutations in FBXW7 and PTEN were not detected. TP53 and K/NRAS mutations were mutually exclusive. The oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) and NOTCH1 mutation did not show significant risk stratification (p>0.05, figure - 1) in overall (OS) or event-free (EFS) survival. However, patients with K/NRAS or TP53 mutation had a worse outcome compared to patients without mutations in respective genes. DNMT3A mutation did not show a significant difference in outcome (p>0.05). Designating high-risk when patients had mutations in RAS or TP53 and low-risk when mutations are not detected in those genes, patients with high-risk disease had a significant worse outcome (p=0.01, figure 2). Conclusion: Our data suggest that the oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) might not be applicable to adult T-ALL patients treated with hyperCVAD. Instead, RAS/TP53 mutation status showed significant risk stratification. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
32. FLT3mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia
- Author
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Naval Daver, Hagop M. Kantarjian, Jorge E. Cortes, Sa Wang, Farhad Ravandi, Keyur P. Patel, Raja Luthra, Paolo Strati, Xiao Qin Dong, Elias Jabbour, Tapan M. Kadia, and Guillermo Garcia-Manero
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Adolescent ,DNA Mutational Analysis ,Chronic myelomonocytic leukemia ,Article ,Myelogenous ,fluids and secretions ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Survival rate ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Incidence ,Incidence (epidemiology) ,Myeloid leukemia ,hemic and immune systems ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Protein Structure, Tertiary ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Myelodysplastic Syndromes ,Mutation ,embryonic structures ,Immunology ,Female ,business - Abstract
FMS-like tyrosine kinase III (FLT3) mutations occur in one-third of acute myeloid leukemia (AML) patients and predict poor outcome. The incidence and impact of FLT3 in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is unknown. We conducted a retrospective review to identify WHO MDS and CMML patients with FLT3 mutations at diagnosis. A total of 2,119 patients with MDS and 466 patients with CMML were evaluated at MD Anderson between 1997 and 2010. Of these, FLT3 mutation analysis was performed on 1,232 (58%) MDS and 302 (65%) CMML patients. FLT3 mutations were identified in 12 (0.95%) MDS patients: 9 (75%) had FLT3-ITD mutation and 3 had FLT3-tyrosine kinase domain (TKD) mutation. MDS patients with FLT3 mutations were younger (P = 0.02) and presented as RAEB (P = 0.03) more frequently. Median overall survival (OS) for FLT3-mutated MDS patients was 19.0 months versus 16.4 months for FLT3-nonmutated MDS patients (P = 0.08). FLT3 mutations were identified in 13 (4.3%) CMML patients: 8 had FLT3-ITD mutation and 5 had FLT3-TKD mutation. There were no significant differences in demographic and disease characteristics among CMML patients with and without FLT3 mutations. Median OS for FLT3-mutated CMML patients was 10.8 months versus 21.3 months for FLT3-nonmutated CMML patients (P = 0.12). FLT3 occurs in MDS and CMML at a lower frequency than AML and does not predict poor outcome.
- Published
- 2012
33. Impact of numerical variation in FMS-like tyrosine kinase receptor 3 internal tandem duplications on clinical outcome in normal karyotype acute myelogenous leukemia
- Author
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Gautam Borthakur, Raja Luthra, Sherry Pierce, Stefan Faderl, Farhad Ravandi, Tapan M. Kadia, Keyur P. Patel, Wei Qiao, Hagop M. Kantarjian, and Jorge E. Cortes
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.disease_cause ,Article ,Receptor tyrosine kinase ,Myelogenous ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Mutation ,biology ,business.industry ,Cancer ,Karyotype ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Karyotyping ,Multivariate Analysis ,Fms-Like Tyrosine Kinase 3 ,Cohort ,Immunology ,biology.protein ,business - Abstract
BACKGROUND: The impact of single versus multiple fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD) mutations on the clinical outcome of patients with acute myelogenous leukemia has not been well studied, and particularly has not been investigated while simultaneously accounting for the quantitative mutation burden. METHODS: The authors conducted a multivariate analysis of overall survival, event-free survival, and complete remission duration, including numeric variation (single vs multiple) and quantitative mutant burden of FLT3-ITD as variables among other clinically relevant factors. RESULTS: An analysis of a cohort of 1043 patients with AML demonstrated that, among patients with normal-karyotype acute myelogenous leukemia and FLT3-ITD mutation, overall survival and event-free survival were not affected by the number of FLT3-ITD mutations, but complete remission duration was significantly longer in patients who had multiple FLT3-ITD mutations (median, 86 weeks vs 34 weeks; P = .03). CONCLUSIONS: The current results indicated that time-to-event analyses of patients with normal-karyotype acute myelogenous leukemia and FLT3-ITD mutation should take into account the number of mutations and the mutant burden, among other factors. Cancer 2012. © 2012 American Cancer Society.
- Published
- 2012
34. Clinical and proteomic characterization of acute myeloid leukemia with mutatedRAS
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Guillermo Garcia-Manero, Gautam Borthakur, Raja Luthra, Sherry Pierce, Farhad Ravandi, Hagop M. Kantarjian, Tapan M. Kadia, Jorge E. Cortes, Steven M. Kornblau, Emil J. Freireich, and Stefan Faderl
- Subjects
Adult ,Male ,Proteomics ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Article ,Disease-Free Survival ,Young Adult ,White blood cell ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Remission Induction ,Cytarabine ,Myeloid leukemia ,Cancer ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,Genes, ras ,medicine.anatomical_structure ,Mutation ,Immunology ,ras Proteins ,Female ,Bone marrow ,business ,Signal Transduction ,medicine.drug - Abstract
BACKGROUND: Activating mutations in RAS are frequently present in patients with acute myeloid leukemia (AML), but their overall prognostic impact is not clear. METHODS: A retrospective analysis was performed to establish the clinical characteristics of patients with RAS-mutated (RASmut) AML, to analyze their outcome by therapy, and to describe the proteomic profile of RASmut compared with wild-type RAS (RASWT) AML. RESULTS: Of 609 patients with newly diagnosed AML, 11% had RASmut. Compared with RASWT, patients with RASmut AML were younger (median age, 54 years vs 63 years; P = .001), had a higher white blood cell count (16K mm−3 vs 4K mm−3 ; P < 0.001) and bone marrow blast percentage (56% vs 42%; P = .01) at diagnosis, and were less likely to have an antecedent hematologic disorder (36% vs 50%; P = .03). The inv(16) karyotype was overrepresented in patients with RASmut and the −5 and/or −7 karyotype was underrepresented. RAS mutations were found to have no prognostic impact on overall survival or disease-free survival overall or within cytogenetic subgroups. There was a suggestion that patients with RASmut benefited from cytarabine (AraC)-based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS-Raf-MAP kinase and phosphoinositide 3-kinase (PI3K) signaling pathways in patients with RASmut. CONCLUSIONS: RAS mutations in AML may delineate a subset of patients who benefit from AraC-based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways. Cancer 2012. © 2012 American Cancer Society.
- Published
- 2012
35. Real Time PCR Detects Relapse of JAK2 V617F Myelofibrosis Earlier Than Pyrosequencing after Allogeneic Transplantation
- Author
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Meenakshi Mehrotra, Richard E. Champlin, Keyur P. Patel, Srdan Verstovsek, Rashmi Kanagal Shamanna, Raja Luthra, Mithun Vinod Shah, and Uday R. Popat
- Subjects
0301 basic medicine ,Transplantation ,Allogeneic transplantation ,business.industry ,Hematology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Real-time polymerase chain reaction ,030220 oncology & carcinogenesis ,Immunology ,Medicine ,Pyrosequencing ,business ,Myelofibrosis ,JAK2 V617F - Published
- 2017
36. Refractory Anemia With Ring Sideroblasts Associated With Marked Thrombocytosis
- Author
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Sergej Konoplev, Raja Luthra, C. Cameron Yin, Pei Lin, Inga Gurevich, and L. Jeffrey Medeiros
- Subjects
Pathology ,medicine.medical_specialty ,Thrombocytosis ,business.industry ,Anemia ,Myelodysplastic/Myeloproliferative Neoplasm ,General Medicine ,Refractory anemia with ringed sideroblasts ,medicine.disease ,Refractory anemia with ring sideroblasts ,Medicine ,Platelet ,Leukocytosis ,medicine.symptom ,business ,Myeloproliferative neoplasm - Abstract
Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a provisional entity in the current World Health Organization classification and is thought to be a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We analyzed 18 cases of RARS-T. All patients had thrombocytosis (platelet count, 515–1,100 × 103/μL [515–1,100 × 109/L]) and anemia (hemoglobin level, 7.2–12.6 g/dL [72–126 g/L]). Three patients had mild leukocytosis (WBC count, 3,900–16,300/μL [3.9–16.3 × 109/L]). Ring sideroblasts were 8% to 75% in the bone marrow. Megakaryocytes showed a spectrum of morphologic findings. JAK2V617F was identified in 9 of 15 cases, including 7 of 9 with thrombocytosis (platelet count, >600 × 103/μL [600 × 109/L]) and 1 with 8% ring sideroblasts. The MPLW515L mutation was not detected (n = 9). We conclude that RARS-T is a pathogenetically heterogeneous group of limited diagnostic usefulness. Approximately 60% of cases carry JAK2V617Fand seem to be closer to an MPN in which ring sideroblasts may be a secondary phenomenon. The remaining cases usually lack the JAK2V617Fmutation, have a platelet count less than 600 × 103/μL (600 × 109/L), and may represent an MDS or MPN with thrombocytosis of unknown mechanisms.
- Published
- 2011
37. ETV6–FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant
- Author
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Lindsey M. Lyle, Raja Luthra, Srdan Verstovsek, Kate J. Newberry, Keyur P. Patel, Meenakshi Mehrotra, Lorenzo Falchi, Uday R. Popat, and Gary Lu
- Subjects
Sorafenib ,Cancer Research ,Pathology ,medicine.medical_specialty ,Hematology ,Biology ,medicine.disease ,Article ,Transplantation ,Fusion gene ,ETV6 ,Oncology ,hemic and lymphatic diseases ,Cancer research ,medicine ,Homologous chromosome ,Eosinophilia ,medicine.symptom ,Stem cell ,Myeloproliferative neoplasm ,medicine.drug - Abstract
ETV6–FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant
- Published
- 2014
38. Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era
- Author
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Rajesh R. Singh, Raja Luthra, Elijah J. Lohman, Rashmi Kanagal-Shamanna, Carlos E. Bueso-Ramos, Bedia A. Barkoh, Santiago Montes-Moreno, Mark J. Routbort, Keyur P. Patel, and L. Jeffrey Medeiros
- Subjects
Male ,0301 basic medicine ,Nonsense mutation ,lcsh:Medicine ,Biology ,Somatic evolution in cancer ,Frameshift mutation ,Clonal Evolution ,03 medical and health sciences ,symbols.namesake ,Germline mutation ,Gene Frequency ,Recurrence ,Biomarkers, Tumor ,Humans ,False Positive Reactions ,Gene Regulatory Networks ,lcsh:Science ,Genotyping ,Early Detection of Cancer ,Aged ,Genetics ,Sanger sequencing ,Multidisciplinary ,Point mutation ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,Prognosis ,Repressor Proteins ,030104 developmental biology ,Molecular Diagnostic Techniques ,Hematologic Neoplasms ,Mutation ,Mutation (genetic algorithm) ,symbols ,Female ,lcsh:Q - Abstract
ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease.
- Published
- 2018
39. Improvement in clinical outcome of FLT3 ITD mutated acute myeloid leukemia patients over the last one and a half decade
- Author
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Talha, Badar, Hagop M, Kantarjian, Graciela M, Nogueras-Gonzalez, Gautam, Borthakur, Guillermo, Garcia Manero, Michael, Andreeff, Marina, Konopleva, Tapan M, Kadia, Naval, Daver, William G, Wierda, Raja, Luthra, Keyur, Patel, Betul, Oran, Richard, Champlin, Farhad, Ravandi, and Jorge E, Cortes
- Subjects
Adult ,Male ,Niacinamide ,Adolescent ,Gene Expression ,Antineoplastic Agents ,Article ,Recurrence ,Humans ,Transplantation, Homologous ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Analysis of Variance ,Phenylurea Compounds ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Sorafenib ,Survival Analysis ,Leukemia, Myeloid, Acute ,Treatment Outcome ,fms-Like Tyrosine Kinase 3 ,Mutation ,Female - Abstract
AML with FLT3 ITD mutations are associated with poor outcome. We reviewed outcomes of patients with FLT3 ITD mutated AML to investigate trends over time. We analyzed 224 AML patients (excluding patients with core binding factor and acute promyelocytic leukemia) referred to our institution between 2000 and 2014. Patients were divided into five cohorts by era: 2000-2002 (Era 1, n = 19), 2003-2005 (Era 2, n = 41), 2006-2008 (Era 3, n = 53), 2009-2011 (Era 4, n = 55), and 2012-2014 (Era 5, n = 56) to analyze differences in outcome. The baseline characteristics were not statistically different across Eras. The response rate (CR/CRp) from Era 1-5 was 68%, 49%, 72%, 73%, and 75%, respectively. The overall response rate (all Eras) with chemotherapy alone versus chemotherapy plus FLT3 inhibitor was 67% and 72.5%, respectively (P = 0.4). The median time to relapse was 6, 3.6, 7.9, 8.1 months and not reached from Eras 1 through 5, respectively (P = 0.001). The median OS has improved: 9.6, 7.6, 14.4, 15.7, and 17.8 month from Eras 1-5, respectively (P = 0.001). Stem cell transplant as a time-dependent variable, showed better OS in the univariate analysis (HR: 0.57, 95% CI: 0.39-0.84, P = 0.004) but did not retained its significance in multivariate analysis (HR: 0.75, 95% CI: 0.50-1.13, P = 0.16). Our data suggest improvement in outcome of FLT3 ITD mutated AML patients over the last 15 years. This is probably due to improvement in treatment strategies, including but not limited to integration of FLT3 inhibitors and increased use of SCT.
- Published
- 2015
40. Clinical next generation sequencing to identify actionable aberrations in a phase I program
- Author
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Shelley M. Herbrich, Keyur P. Patel, Aung Naing, Mark J. Routbort, Lauren Brusco, Russell Broaddus, Genevieve M. Boland, David S. Hong, Chacha Horombe, Amber Johnson, Vivek Subbiah, Kenna R. Mills Shaw, Funda Meric-Bernstam, Filip Janku, Siqing Fu, Sarina Anne Piha-Paul, Keith A. Baggerly, John Mendelsohn, Gordon B. Mills, and Raja Luthra
- Subjects
Oncology ,medicine.medical_specialty ,Cancer therapy ,Gynecologic oncology ,Biology ,Bioinformatics ,medicine.disease_cause ,DNA sequencing ,Surgical oncology ,Internal medicine ,Neoplasms ,medicine ,Humans ,General hospital ,Precision Medicine ,Genomic sequencing ,High-Throughput Nucleotide Sequencing ,medicine.disease ,humanities ,Mutation ,genomic sequencing ,actionable genes ,Sarcoma ,KRAS ,Research Paper - Abstract
// Genevieve M. Boland 1,2 , Sarina A. Piha-Paul 3 , Vivek Subbiah 3 , Mark Routbort 4 , Shelley M. Herbrich 5 , Keith Baggerly 6 , Keyur P. Patel 4 , Lauren Brusco 3 , Chacha Horombe 7 , Aung Naing 3 , Siqing Fu 3 , David S. Hong 3 , Filip Janku 3 , Amber Johnson 7 , Russell Broaddus 8 , Raja Luthra 4 , Kenna Shaw 7 , John Mendelsohn 7 , Gordon B. Mills 7,9 and Funda Meric-Bernstam 2,3,7 1 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Funda Meric-Bernstam, email: // Keywords : genomic sequencing, actionable genes Received : November 10, 2014 Accepted : April 23, 2015 Published : May 08, 2015 Abstract Purpose: We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer. Methods: We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA). Results: Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified. Conclusion: Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials .
- Published
- 2014
41. Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months
- Author
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Alfonso Quintás-Cardama, Lynne V. Abruzzo, Raja Luthra, Hagop M. Kantarjian, Elias Jabbour, Jorge E. Cortes, Sherry Pierce, Carlos Guillermo Romo, Farhad Ravandi, Preetesh Jain, Aziz Nazha, Gautam Borthakur, and Susan O'Brien
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Time Factors ,Myeloid ,Adolescent ,Chronic Myeloid Leukemia ,Young Adult ,Internal medicine ,medicine ,Humans ,Young adult ,Protein Kinase Inhibitors ,Survival rate ,Aged ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Cytogenetic Analysis ,Leukemia, Myeloid, Chronic-Phase ,Immunology ,Female ,Major Cytogenetic Response ,business ,Tyrosine kinase ,Follow-Up Studies ,medicine.drug - Abstract
Response to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.
- Published
- 2013
42. Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
- Author
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Mark J. Routbort, Cathy Eng, Bryan K. Kee, Eduardo Vilar, David R. Fogelman, Robert A. Wolff, Amir Mehrvarz Sarshekeh, Keyur P. Patel, Michael J. Overman, Dipen M. Maru, Arvind Dasari, Ganiraju C. Manyam, Shailesh Advani, Imad Shureiqi, Scott Kopetz, Raja Luthra, Kanwal Pratap Singh Raghav, Shanequa Manuel, Kenna R. Mills Shaw, and Funda Meric-Bernstam
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,lcsh:Medicine ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Missense mutation ,lcsh:Science ,neoplasms ,Multidisciplinary ,integumentary system ,business.industry ,lcsh:R ,Hazard ratio ,Retrospective cohort study ,Odds ratio ,medicine.disease ,digestive system diseases ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,lcsh:Q ,KRAS ,business - Abstract
SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p
- Published
- 2017
43. Validation of the 2016 Revision to the World Health Organization (WHO) Classification of Myelodysplastic Syndromes with Diploid Karyotype
- Author
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John Lee, Rashmi Kanagal-Shamanna, Zhuang Zuo, Guillermo Garcia-Manero, Chong Zhao, Carlos E. Bueso-Ramos, Juliana E. Hidalgo Lopez, L. Jeffrey Medeiros, Denái R. Milton, Hye Ryoun Kim, Keyur P. Patel, Michelle Janania Martinez, Raja Luthra, Elias Jabbour, and Francesco C. Stingo
- Subjects
Sanger sequencing ,Pathology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Karyotype ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,symbols.namesake ,medicine.anatomical_structure ,Dysplasia ,hemic and lymphatic diseases ,White blood cell ,Internal medicine ,medicine ,Absolute neutrophil count ,symbols ,Bone marrow ,business ,Survival analysis - Abstract
Introduction: The revised 2016 WHO classification of MDS has highlighted the value of morphologic evaluation and mutation analysis of bone marrow (BM)/ peripheral blood (PB) to further refine prognostication. These highlights include: (1) increased emphasis on lineage dysplasia compared with cytopenias; (2) objective enumeration of blast % for reproducibility; (3) accurate quantification of ring sideroblasts (RS); and (4) mutation analysis for SF3B1 in cases showing RS >5% and TP53 in MDS with isolated del(5q). Most of the proposed changes are within the categories of low-grade MDS. In this study, we evaluated 264 cases of MDS with diploid karyotype using the 2016 WHO system. Methods: We selected consecutive cases of MDS with diploid karyotype with BM morphological evidence of dysplasia and reclassified using the 2016 WHO system. Mutation analysis for SF3B1 (exons 14 and 15), SRSF2 (exon 1) and U2AF1 (exons 2 and 6) was performed using Sanger sequencing. Patient data were collected from the medical record. The Kaplan-Meier method was used to estimate OS and time-to-AML transformation. The associations between outcome and clinical and pathological parameters were determined using univariate and multivariate Cox proportional hazards regression models. Results: The study group included 264 MDS patients: 168 (64%) men and 96 (36%) women with a median age of 66.9 years (range, 28.3 - 89.1). The median hemoglobin, absolute neutrophil count (ANC), platelet count, and white blood cell (WBC) count were 10.0 g/dL, 1.9 x 109/L, 114.5 x 109/L, and 3.5 x 109/L, respectively. The median BM blast percentage was 2.5; 74% of the patients had < 5% BM blasts. MDS sub-classification according to the 2008 WHO classification was: RCUD, n=5 (2%); RA, n=9 (3%); RARS, n=16 (6%); RCMD, n=152 (58%); RAEB-1, n=56 (21%); RAEB-2, n=20 (8%), and MDS-U, n=6 (2%). Reclassification using the 2016 WHO classification: MDS with single lineage dysplasia (MDS-SLD, n=14, 5%), MDS with multi-lineage dysplasia (MDS-MLD, n=112, 42%), MDS with RS (including single lineage and multi-lineage dysplasia, MDS-RS, n=56, 21%); MDS-EB1, n=56 (21%), MDS-EB2, n=20 (8%) and MDS-U, n=6 (2%). Grading of fibrosis using reticulin/ trichrome stains showed absent-minimal fibrosis (grades 0-1) in 56/85 (66%) and moderate-severe fibrosis (2-3) in 29/85 (34%) cases. Mutation analysis for splicing factors was performed on 15 cases. Ten cases with 0-5% RS showed 2 cases each with SRSF2 and U2AF1 mutations. No cases had SF3B1 mutation. 5 cases with >5% RS showed SF3B1 mutations in 4 cases and 1 case each with SRSF2 and U2AF1 mutations. Over a median follow-up duration of 22.4 months (range, 0-156.8), 128 (48%) patients died. The median OS was 46.1 months (95% CI: 32.3, 58.4). Patients categorized as MDS-SLD by 2016 WHO had the best OS (156.8 months), followed by MDS-RS (58.7 months), MDS-MLD (46.3 months) and MDS-EB (21.2 months) (p Conclusions: Morphological evaluation of BM/PB (for dysplasia, % BM blasts and RS) provides additional prognostic value and continues to be a critical component for evaluation of MDS patients. Molecular studies for splicing factor mutations are ongoing on all samples with >1% RS. Figure Figure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
- Published
- 2016
44. Routine Clinical Testing for Actionable Mutations in CLL Using Endcll Assay V1: The Initial MD Anderson Experience
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William G. Wierda, C. Cameron Yin, Sherry Pierce, Michael J. Keating, Rashmi Kanagal Shamanna, Nitin Jain, Mark J. Routbort, Xinyan Lu, L. Jeffrey Medeiros, Hagop M. Kantarjian, Keyur P. Patel, Raja Luthra, and Rajesh R. Singh
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Immunology ,Somatic hypermutation ,Gene mutation ,medicine.disease_cause ,Bioinformatics ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,medicine ,Bruton's tyrosine kinase ,Mutation ,biology ,business.industry ,Cell Biology ,Hematology ,CD79B ,030104 developmental biology ,chemistry ,Ibrutinib ,biology.protein ,IGHV@ ,DDX3X ,business - Abstract
Background: Recent large scale genomic profiling and clinical correlation studies of chronic lymphocytic leukemia (CLL) identified clinically significant gene mutations with important clinical prognostic and potential therapeutic implications. Integration of individual clonal and subclonal gene mutation information with existing prognostic markers such as somatic hypermutation and chromosomal aberrations provide comprehensive risk stratification for CLL patients. In addition, mutations in BTK and PLCG2 are associated with resistance to targeted therapies using BTK inhibitors (ibrutinib). We implemented routine clinical testing for CLL patients. We describe our initial experience with EndCLL Assay V1, a high yield targeted NGS assay for routine clinical testing of clinically significant mutations in CLL and B-cell neoplasms. Materials and Methods: DNA from total of 376 blood or bone marrow samples containing >10% CLL cells were tested during the panel validation and subsequent routine clinical testing. Targeted sequencing was performed on 29 genes reported to be mutated in CLL and other B-cell neoplasms. These include ATM, BIRC3, BTK, CALR, CARD11, CD79A, CD79B, CHD2, CSMD3, CXCR4, DDX3X, EZH2, FAT1, FBXW7, KLHL6, LRP1B, MAPK1, MUC2, MYD88, NOTCH1, PLCG2, PLEKHG5, POT1, SF3B1, SPEN, TGM7, TP53, XPO1 and ZMYM3. Panel design included a combination of hotspots, limited exons and all exon coverage as required to detect known clinically significant mutations in the genes targeted in the panel. A total of 500 ng input DNA was used to prepare sequencing libraries using Agilent Haloplex HS chemistry, which incorporates unique molecular barcodes in each DNA molecule being sequenced. Sequencing was performed on MiSeq sequencers (Illumina) followed by data analysis on Agilent SureCall v3.0. The average per base coverage depth ranged from 1500x to 4000x based on the number of samples per run. The analytical sensitivity of the assay was determined to be at 2% to 5% for reliable and reproducible detection of mutations depending on the sequencing coverage and percentage of mutant reads. Results: For cases with available information, the average age was 63.3 years (range: 22-87, median: 64). The male:female ratio was 2:1 and the ratio of cases with unmutated:mutated IGHV was 1.2:1. Positive FISH results for -11q, +12, -13q and -17p were detected in 18%, 23%, 59% and 15% cases respectively. Out of 376 samples tested, 249 (66.2%) showed at least one mutation. Average number of genes mutated per sample was 1.1 (range: 0-5, median: 1) and the average number of total mutations per sample was 1.4 (range 0-7, median: 1). Top 10 mutated genes included TP53, SF3B1, NOTCH1, ATM, BIRC3, XPO1, MYD88, SPEN, BTK and KLHL6 (Figure 1). Patterns of co-mutations and mutual exclusivity were observed (Figure 1). Top 10 mutations (hotspots) are listed in the table. Mutations in 3'UTR of NOTCH1 were detected in 5/376 (%) cases. Resistance mutations in BTK codon 481 were detected in 10 patients on ibrutinib treatment, including 5 cases with >1 mutations and 2 cases with subclonal mutations indicating early treatment resistant clone. Clinical findings in all 10 cases were consistent with proven or emerging treatment resistance. No mutations were detected in PLCG2 (codons 646-685). One patient initially on ibrutinib and on idelalisib treatment showed acquisition of 17p deletion and a subclonal TP53 mutation at the time of ibrutinib resistance and progression to an aggressive disease course. Use of molecular barcodes allowed efficient detection of low level subclonal mutations. Correlations with a comprehensive set of clinicopathologic parameters as well as treatment outcomes are in progress. Conclusion: The targeted EndCLL Mutation Assay V1 allowed a high yield detection of clinically significant mutations in 66% of the patient samples using a clinically sustainable panel design accommodating up to 24 multiplexed samples in a single sequencing run. Use of molecular barcodes allows removal of PCR duplicates and enables accurate calling of subclonal mutations for prognostication. This was evident in simultaneous detection of subclonal BTK mutations allows early detection of emerging ibrutinib resistant clone while obtaining additional prognostic information. Overall, the EndCLL Assay V1 is a valuable addition for CLL patient care. Figure 1 Figure 1. Disclosures Jain: Incyte: Research Funding; BMS: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria. Wierda:Gilead: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Abbvie: Research Funding.
- Published
- 2016
45. Clinical Implications of TP53 Mutations in Adult Patients with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) Treated with the Hypercvad-Based Regimens
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Keyur P. Patel, Elias Jabbour, Koichi Takahashi, Rashmi Kanagal-Shamanna, Sherry Pierce, Zeev Estrov, Rebecca Garris, Marina Konopleva, Koji Sasaki, Preetesh Jain, Gautam Borthakur, Raja Luthra, Susan O'Brien, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M. Kadia, Hagop M. Kantarjian, Jorge E. Cortes, William G. Wierda, and Nitin Jain
- Subjects
Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,Gene mutation ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Minimal residual disease ,03 medical and health sciences ,0302 clinical medicine ,Chemoimmunotherapy ,030220 oncology & carcinogenesis ,Internal medicine ,Acute lymphocytic leukemia ,Cohort ,Medicine ,KRAS ,business ,030215 immunology - Abstract
Introduction - TP53 is the most extensively studied gene in cancer and is associated with a poor outcome. The clinical implication of TP53 gene mutations in adult ALL has not been evaluated. Methods - We screened for TP53 mutations in 119 newly diagnosed patients with ALL who were treated with HCVAD-based regimens (2012-2016) and evaluated the predictive and prognostic value of TP53mutations. Bone marrow samples underwent targeted amplicon-based next-generation sequencing (NGS) based mutation analysis. Results - Among 119 patients with adult ALL, we identified 23 patients (19%, 22 B-cell; 1 T-cell) with TP53 mutations (TP53mut); 96 had wild type TP53 (TP53wt; 83 B-cell; 13 T-cell). BCR/ABL1 rearrangement was noted in 2/23 TP53mut ALL and 43/96 TP53wt ALL (p=0.001). Of the 23 patients with TP53mut, 20 were missense, 2 were nonsense mutations and 1 was an insertion/ deletion, spanning exons 2-10. The most common pattern of amino acid substitution,in 10 of the 23 patients, was a substitution of arginine to histidine or proline on different codons. The median TP53 mutant allelic frequency was 42.2% (range, 1.4 - 93.8). Seven patients (30%) with TP53muthad concurrent mutations: NRAS in 2, BRAF, NOTCH1, TET2, DNMT3A, and EZH2 - 1 each. Among patients with TP53wt, 40 patients (42%) had mutations in other genes: 9 JAK2, 7 NRAS, 5 KRAS, 5 NOTCH1, 3 IDH2, 2 each with DNMT3A, ASXL1, FLT3, PTPN11, and 1 with TET2. The clinical characteristics, pattern of mutations, response to therapy, and outcomes of patients with TP53mut ALL (n=23) vs. TP53wt ALL(n=96) were compared (Table 1 and Figure-1). Patients with TP53mutALL were significantly older at presentation (median age 60 years [24-81] versus 46 years [18-81]; p=0.01) and had significantly lower platelet counts (29 x 109 /L versus 45 x 109/L; p=0.01) and lower peripheral blood blast percentages (10% versus 43%; p=0.005). Distribution of chromosomal aberrations was significantly different among the two groups: t(9;22) was observed at a much lower rate in TP53mut ALL, while hyper and hypodiploidy were more commonly encountered in TP53mut ALL There was no significant difference in the complete remission (83% in TP53mut ALL versus 91% in TP53wt ALL, p=0.25) and minimal residual disease (66% in TP53mut ALL versus 59% in TP53wt ALL, p=0.23) rates between the 2 groups. Overall, the median follow-up was 11.3 months (range, 0.2 to 41 months). There was no statistically significant difference in outcome between patients with and without TP5mutation. (Figure -1 A-B). The 3-year event-free (EFS) and overall survival (OS) rates were 45% and 42% in patients with TP53mutand 46% and 59% in those with TP53wt. The median EFS was 18 and 26.7 months (p=0.37) respectively. The median OS was 27.5 and 37.2 months (p=0.20), respectively. Furthermore, no significant difference was observed when only patients with Philadelphia-negative B-ALL were assessed. Conclusions - TP53 mutations are seen in about 19% of adult with newly diagnosed ALL. Patients tend to be older with higher incidence of hypodiploidy. TP53 mutations had no significant negative impact on outcome in patients treated with Hyper-CVAD based regimens. Further studies are underway at our institution to expand the cohort and identify the relevance of TP53mutations in adult ALL in the era of novel chemoimmunotherapy. *3 patients in TP53 - Mutated group had 1 patient each with miscellaneous/insufficient metaphases/ not done while 6 patients had miscellaneous aberrations and 4 with insufficient metaphases TP53wild type respectively Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; BMS: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria. Wierda:Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
- Published
- 2016
46. Value of Immunohistochemistry-Based Direct Visualization for Localization, Lineage Determination and Monitoring of IDH1 p.R132H Mutant Clones in AML
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L. Jeffrey Medeiros, Mark J. Routbort, Hagop M. Kantarjian, Habibe Kurt, Keyur P. Patel, Jeffrey L. Jorgensen, Farhad Ravandi, Rashmi Kanagal-Shamanna, Courtney D. DiNardo, Carlos E. Bueso-Ramos, Raja Luthra, and Joseph D. Khoury
- Subjects
education.field_of_study ,Pathology ,medicine.medical_specialty ,IDH1 ,medicine.diagnostic_test ,Immunology ,Population ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Minimal residual disease ,IDH2 ,medicine.anatomical_structure ,Biopsy ,medicine ,Immunohistochemistry ,Bone marrow ,education - Abstract
Background Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are important prognostic biomarkers in acute myeloid leukemia (AML). Although the clinicopathologic correlates of IDH mutations have been extensively studied, the distribution of abnormal myeloid cells carrying these mutations has not been studied. Specific localization of cells carrying IDH mutations will be useful in further understanding the pathophysiology and post-treatment biology of IDH mutant cases of AML. This characterization is becoming particularly relevant for identification of minimal residual disease, especially for patients treated with novel IDHinhibitors. In this study, we characterized IDH1 p.R132H clones in bone marrow specimens involved by AML using a mutation specific antibody. Materials and Methods Bone marrow tissue sections (biopsy or clot specimens) from 32 AML cases with IDH1 p.R132H mutation were stained with IDH1 p.R132H-mutation specific antibody. These cases include 20 de novoAML and 12 cases of AML with myelodysplasia-related changes (AML-MRC). We also included 10 AML cases with wild-type IDH1 as a control. After confirmation of the positive IDH1 immunohistochemical (IHC) signal in the primary specimens, follow up bone marrow specimens (n=67) including (a) persistent disease, (b) minimal residual disease by flow cytometry, (3) complete remission by morphology and flow cytometry, but, positive for mutation by PCR, as well as (4) relapsed cases after complete remission were included in the study (in progress). We also included pre- and post-treatment (unresponsive with increasing blast counts, stable disease, persistent disease with decreasing blast counts, complete remission, and relapse) bone marrow specimens (n=72) from 16 patients treated with IDH inhibitors (in progress). Results All the IDH1 wild type AML cases were negative for IDH1 IHC stain showing 100% specificity. Positive signal was detected in all de novo AML and AML-MRC (allelic frequency ranges from 1.8% to 47% by PCR) except one AML case with 8.9% allele burden which was a limited sample; overall sensitivity was 96%. The IHC signal was detected in the cytoplasm of myelomonocytic cells, their precursors, and megakaryocytes. Erythroid precursors, lymphoid cells, endothelial cells, and osteoblasts were consistently negative. The signal intensity ranged from weak (n=10) to moderate (n=9), to strong (n=13). The positive cells predominantly showed an interstitial distribution in the bone marrow. In the de novo AML group, only the immature cells were positive in 100% of pre-treatment AML cases. However, both mature and immature cells were positive in 7/13 (54%) post-treatment AML cases (6 cases treated with hypomethylating agents). One case was transformed from MPN which also showed positivity in mature and immature cells. In two cases with complete morphologic remission and one case with minimal residual disease detected by flow cytometry, IHC signal was detected in both mature and immature cells; both patients relapsed in 8 and 11 months. In the AML-MRC group, both immature and mature cells were positive in 11/12 (92%) cases of which 2 were not previously treated indicating the possibility that IDH1 mutation is an early event. Since the remaining 9 patients were treated with hypomethylating agents, the positivity of both mature and immature cells as a result of maturation effect versus an early event cannot be assessed. Additional studies for follow-up AML cases, including cases on an IDH inhibitor clinical trial are in progress. Conclusions Our preliminary data indicate that IDH1 IHC is a highly specific and sensitive tool to detect IDH1 R132H mutated cases and can be used as a primary method to localize the population of mutation-bearing cells in the bone marrow. IHC also allows determination of whether the IDH1 mutation in the post-treatment setting is arising from immature or mature cells. IHC provides an opportunity to understand the difference between these two populations and, based on characterization of cell type and distribution, may be helpful to predict whether the risk of relapse is high. Disclosures DiNardo: Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding.
- Published
- 2016
47. Tyrosine Kinase Inhibitors as Initial Therapy for Patients with Chronic Myeloid Leukemia in Accelerated Phase
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Hagop M. Kantarjian, Farhad Ravandi, Jorge E. Cortes, Guillermo Garcia-Manero, Richard E. Champlin, Long Xuan Trinh, Lynne V. Abruzzo, Tapan M. Kadia, Sherry Pierce, Srdan Verstovsek, Maro Ohanian, Elias Jabbour, Susan O'Brien, Alessandra Ferrajoli, Alfonso Quintás-Cardama, Gautam Borthakur, Raja Luthra, and Mona Lisa Alattar
- Subjects
Oncology ,Myeloid ,Male ,Cancer Research ,Time Factors ,bcr-abl ,Dasatinib ,Fusion Proteins, bcr-abl ,Somatic evolution in cancer ,Accelerated phase CML ,Major molecular response ,Piperazines ,hemic and lymphatic diseases ,80 and over ,Cancer ,Aged, 80 and over ,ABL ,Leukemia ,breakpoint cluster region ,Myeloid leukemia ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Treatment Outcome ,6.1 Pharmaceuticals ,Benzamides ,Imatinib Mesylate ,Female ,Tyrosine kinase ,medicine.drug ,Adult ,medicine.medical_specialty ,Clinical Sciences ,Oncology and Carcinogenesis ,Leukemia, Myeloid, Accelerated Phase ,Accelerated Phase ,Article ,Disease-Free Survival ,Young Adult ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Aged ,Complete cytogenetic response ,Tyrosine kinase inhibitors ,business.industry ,Fusion Proteins ,Evaluation of treatments and therapeutic interventions ,Imatinib ,Thiazoles ,Second generation TKI ,Orphan Drug ,Pyrimidines ,Nilotinib ,Immunology ,business ,Follow-Up Studies - Abstract
Background Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy. Patients and Methods We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets 9 /L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16). Results The rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs. Conclusion TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.
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- 2013
48. Correlation between peripheral blood and bone marrow samples for detection of PML-RARA fusion transcripts by quantitative PCR in patients with acute promyelocytic leukemia
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Keyur P. Patel, G. Garcia-Manero, Eli Estey, Zeev Estrov, Koji Sasaki, Alessandra Ferrajoli, Tapan M. Kadia, Srdan Verstovsek, Sherry Pierce, Hagop M. Kantarjian, Jorge E. Cortes, Gautam Borthakur, Raja Luthra, Mark Brandt, and Farhad Ravandi
- Subjects
Acute promyelocytic leukemia ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Peripheral blood ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Oncology ,Medicine ,In patient ,Bone marrow ,business - Published
- 2015
49. Mutated NPM1 in patients with acute myeloid leukemia in remission and relapse
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Aziz Nazha, Sherry Pierce, Guillermo Garcia-Manero, Preetesh Jain, Naval Daver, Farhad Ravandi, Naveen Pemmaraju, Ohad Benjamini, Hagop M. Kantarjian, Stefan Faderl, Jorge E. Cortes, Keyur P. Patel, Gautam Borthakur, Raja Luthra, and Tapan M. Kadia
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,NPM1 ,DNA Mutational Analysis ,Karyotype ,Clone (cell biology) ,Biology ,Gastroenterology ,Article ,Young Adult ,Internal medicine ,medicine ,Humans ,In patient ,Young adult ,Aged ,Retrospective Studies ,Aged, 80 and over ,Remission Induction ,Wild type ,Myeloid leukemia ,Nuclear Proteins ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,Minimal residual disease ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,Immunology ,Mutation ,Female ,Neoplasm Recurrence, Local ,Nucleophosmin - Abstract
Patients with newly diagnosed AML (n = 360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients, including 46 of the 137 (33.5%) NK patients, had NPM1 mutation at baseline. Thirty-nine patients (30 NK) had available NPM1 status at the time of complete remission (CR) and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for eight patients (six with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD.
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- 2013
50. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia
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Paolo, Strati, Hagop, Kantarjian, Deborah, Thomas, Susan, O'Brien, Sergej, Konoplev, Jeffrey L, Jorgensen, Raja, Luthra, Lynne, Abruzzo, Elias, Jabbour, Alfonso, Quintas-Cardama, Gautam, Borthakur, Stefan, Faderl, Farhad, Ravandi, and Jorge, Cortes
- Subjects
Adult ,Male ,Cytarabine ,Dasatinib ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Dexamethasone ,Piperazines ,Article ,Thiazoles ,Methotrexate ,Pyrimidines ,Doxorubicin ,Vincristine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Benzamides ,Imatinib Mesylate ,Humans ,Female ,Blast Crisis ,Cyclophosphamide ,Aged - Abstract
Chronic myeloid leukemia (CML) may progress to blast phase (BP) at the rate of 1% to 1.5% per year. With the use of single-agent tyrosine kinase inhibitors, median overall survival ranges between 7 and 11 months.The outcome was analyzed for 42 patients with lymphoid BP-CML who were treated with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (HCVAD) plus imatinib or dasatinib.Complete hematological response was achieved in 90% of patients, complete cytogenetic remission in 58%, and complete molecular remission in 25%. Flow cytometry minimal residual disease negativity was achieved by 42% of evaluable patients after induction. Eighteen patients received allogeneic stem cell transplant (SCT) while in first complete hematological response. Median remission duration was 14 months and was longer among SCT recipients (P = .01) on multivariate analysis. Median overall survival was 17 months (range, 7-27 months) and was longer among SCT recipients (P .001) and patients treated with dasatinib (P = .07) on multivariate analysis. Although a high rate of hematologic toxicity (100%) and infectious complications (59%) were observed, the related rate of treatment discontinuation was low (7% and 9%, respectively).HCVAD combined with tyrosine kinase inhibitors is an effective regimen for the management of BP-CML, particularly when followed by allogeneic SCT.
- Published
- 2013
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