790 results on '"Mrinal M. Patnaik"'
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2. FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience
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Clifford M. Csizmar, Antoine N. Saliba, Patricia T. Greipp, Hassan Alkhateeb, Kebede H. Begna, James M. Foran, Naseema Gangat, William J. Hogan, C. Christopher Hook, Mark R. Litzow, Abhishek A. Mangaonkar, Jeanne M. Palmer, Animesh Pardanani, Mithun V. Shah, Ayalew Tefferi, Mehrdad Hefazi Torghabeh, Alexandra P. Wolanskyj-Spinner, Mrinal M. Patnaik, Scott H Kaufmann, and Aref Al-Kali
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Not available.
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- 2024
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3. Prognostic impact of ‘multi-hit’ versus ‘single hit’ TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases
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Talha Badar, Ahmad Nanaa, Ehab Atallah, Rory M. Shallis, Emily C. Craver, Zhuo Li, Aaron D. Goldberg, Antoine N. Saliba, Anand Patel, Jan P. Bewersdorf, Adam Duvall, Madelyn Burkart, Danielle Bradshaw, Yasmin Abaza, Maximilian Stahl, Neil Palmisiano, Guru Subramanian Guru Murthy, Amer M. Zeidan, Vamsi Kota, Mrinal M. Patnaik, and Mark R. Litzow
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p
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- 2024
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4. Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent
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Nickolas Steinauer, Kristen McCullough, Aref Al-Kali, Hassan B. Alkhateeb, Kebede H. Begna, Abhishek A. Mangaonkar, Antoine N. Saliba, Mehrdad Torghabeh, Mark R. Litzow, William J. Hogan, Mithun Shah, Mrinal M. Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Cecilia Arana Yi, Ayalew Tefferi, and Naseema Gangat
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Not available.
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- 2024
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5. Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms
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Anmol Baranwal, Mark Gurney, Rami Basmaci, Bahga Katamesh, Rong He, David S. Viswanatha, Patricia Greipp, James Foran, Talha Badar, Hemant Murthy, Cecilia Arana Yi, Jeanne Palmer, Abhishek A. Mangaonkar, Mrinal M. Patnaik, Mark R. Litzow, William J. Hogan, Kebede Begna, Naseema Gangat, Ayalew Tefferi, Aref Al-Kali, Mithun V. Shah, and Hassan B. Alkhateeb
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P
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- 2024
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6. U2AF1 pathogenic variants in myeloid neoplasms and precursor states: distribution of co-mutations and prognostic heterogeneity
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Talha Badar, Yenny A. Moreno Vanegas, Ahmad Nanaa, James M. Foran, Aref Al-Kali, Abhishek Mangaonkar, Hemant Murthy, Hassan B. Alkhateeb, David Viswanatha, Rong He, Mithun Shah, Cecilia Arana Yi, Mark R. Litzow, Naseema Gangat, Ayalew Tefferi, and Mrinal M. Patnaik
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.
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- 2023
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7. TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms
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Mithun Vinod Shah, Elizabeth Ngoc Hoa Tran, Syed Shah, Rakchha Chhetri, Anmol Baranwal, Dariusz Ladon, Carl Shultz, Aref Al-Kali, Anna L. Brown, Dong Chen, Hamish S. Scott, Patricia Greipp, Daniel Thomas, Hassan B. Alkhateeb, Deepak Singhal, Naseema Gangat, Sharad Kumar, Mrinal M. Patnaik, Christopher N. Hahn, Chung Hoow Kok, Ayalew Tefferi, and Devendra K. Hiwase
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53 mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53 mut. We analyzed 488 t-MN patients for TP53 mut. At least one TP53 mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53 mut t-MN had a VAF ≥10%. TP53 mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53 mut VAF 10% blasts had inferior survival compared to
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- 2023
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8. Abnormal karyotype is an independent predictor of inferior survival in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
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Mostafa Abdallah, Kristen McCullough, Rimal Ilyas, Kebede H. Begna, Aref Al-Kali, Mark R. Litzow, William J. Hogan, Abhishek Mangaonkar, Hassan Alkhateeb, Mithun V. Shah, Michelle A. Elliott, James M. Foran, Talha Badar, Jeanne M. Palmer, Cecilia Arana Yi, Lisa Sproat, Animesh Pardanani, Mrinal M. Patnaik, Horatiu Olteanu, Rhett P. Ketterling, Ayalew Tefferi, and Naseema Gangat
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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9. Prognostic relevance of clonal hematopoiesis in myeloid neoplastic transformation in patients with follicular lymphoma treated with radioimmunotherapy
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Zhuoer Xie, Terra Lasho, Arushi Khurana, Alejandro Ferrer, Christy Finke, Abhishek A. Mangaonkar, Stephen Ansell, Jenna Fernandez, Mithun Vinod Shah, Aref Al-Kali, Naseema Gangat, Jithma Abeykoon, Thomas E. Witzig, and Mrinal M. Patnaik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
While novel radioisotope therapies continue to advance cancer care, reports of therapy-related myeloid neoplasms (t-MN) have generated concern. The prevalence and role of clonal hematopoiesis (CH) in this process remain to be defined. We hypothesized that: (i) CH is prevalent in relapsed follicular lymphoma and is associated with t-MN transformation, and (ii) radiation in the form of radioimmunotherapy (RIT) plays a role in clonal progression. In this retrospective cohort study, we evaluated the prevalence and prognostic impact of CH on clinical outcomes in 58 heavily pre-treated follicular lymphoma patients who received RIT. Patients had been given a median of four lines of therapy before RIT. The prevalence of CH prior to RIT was 46%, while it was 67% (P=0.15) during the course of RIT and subsequent therapies in the paired samples. Fourteen (24%) patients developed t-MN. Patients with t-MN had a higher variant allele fraction (38% vs. 15%; P=0.02) and clonal complexity (P=0.03) than those without. The spectrum of CH differed from that in age-related CH, with a high prevalence of DNA damage repair and response pathway mutations, absence of spliceosome mutations, and a paucity of signaling mutations. While there were no clear clinical associations between RIT and t-MN, or overall survival, patients with t-MN had a higher mutant clonal burden, along with extensive chromosomal abnormalities (median survival, afer t-MN diagnosis, 0.9 months). The baseline prevalence of CH was high, with an increase in prevalence on exposure to RIT and subsequent therapies. The high rates of t-MN with marked clonal complexities and extensive chromosomal damage underscore the importance of better identifying and studying genotoxic stressors accentuated by therapeutic modalities.
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- 2023
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10. CPX-351 (Vyxeos™) treatment in blast-phase myeloproliferative neoplasm (MPN-BP): real-world experience in 12 consecutive cases
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Rimal Ilyas, Kristen McCullough, Talha Badar, Mrinal M. Patnaik, Hassan Alkhateeb, Abhishek Mangaonkar, Animesh Pardanani, Ayalew Tefferi, and Naseema Gangat
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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11. The ABNL-MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes
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Tamara K. Moyo, Jason H. Mendler, Raphael Itzykson, Ashwin Kishtagari, Eric Solary, Adam C. Seegmiller, Aaron T. Gerds, Gregory D. Ayers, Amy E. Dezern, Aziz Nazha, Peter Valent, Arjan A. van de Loosdrecht, Francesco Onida, Lisa Pleyer, Blanca Xicoy Cirici, Raoul Tibes, Klaus Geissler, Rami S. Komrokji, Jing Zhang, Ulrich Germing, David P. Steensma, Daniel H. Wiseman, Michael Pfeilstöecker, Chiara Elena, Nicholas C. P. Cross, Jean-Jacques Kiladjian, Michael Luebbert, Ruben A. Mesa, Guillermo Montalban-Bravo, Guillermo F. Sanz, Uwe Platzbecker, Mrinal M. Patnaik, Eric Padron, Valeria Santini, Pierre Fenaux, Michael R. Savona, and On Behalf of the MDS/MPN International Working Group
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ABNL MARRO ,MDS/MPN ,ASTX727 ,Itacitinib ,Phase 1b/2 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. Methods ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. Discussion Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. Trial registration This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
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- 2022
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12. Therapy-related myeloid neoplasms following chimeric antigen receptor T-cell therapy for Non-Hodgkin Lymphoma
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Hassan B. Alkhateeb, Razan Mohty, Patricia Greipp, Radhika Bansal, Matthew Hathcock, Allison Rosenthal, Hemant Murthy, Mohamed Kharfan-Dabaja, Jose C. Bisneto Villasboas, Nora Bennani, Stephen M. Ansell, Mrinal M. Patnaik, Mark R. Litzow, Rong He, Dong Chen, Aref Al-Kali, Saad S. Kenderian, Yi Lin, and Mithun Vinod Shah
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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13. Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms
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Mithun Vinod Shah, Abhishek A. Mangaonkar, Kebede H. Begna, Hassan B. Alkhateeb, Patricia Greipp, Ahmad Nanaa, Michelle A. Elliott, William J. Hogan, Mark R. Litzow, Kristen McCullough, Ayalew Tefferi, Naseema Gangat, Mrinal M. Patnaik, Aref Al-Kali, Rong He, and Dong Chen
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with
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- 2022
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14. Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms
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Talha Badar, Ahmad Nanaa, James M. Foran, David Viswanatha, Aref Al-Kali, Terra Lasho, Christy Finke, Hassan B Alkhateeb, Rong He, Naseema Gangat, Mithun Shah, Ayalew Tefferi, Abhishek A Mangaonkar, Mark R Litzow, Laura J. Ongie, Timothy Chlon, Alejandro Ferrer, and Mrinal M. Patnaik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41path and DDX41VUS (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.
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- 2023
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15. Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
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Moritz Binder, Ryan M. Carr, Terra L. Lasho, Christy M. Finke, Abhishek A. Mangaonkar, Christopher L. Pin, Kurt R. Berger, Amelia Mazzone, Sandeep Potluri, Tamas Ordog, Keith D. Robertson, David L. Marks, Martin E. Fernandez-Zapico, Alexandre Gaspar-Maia, and Mrinal M. Patnaik
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Science - Abstract
‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
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- 2022
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16. Myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): Mayo-Moffitt collaborative study of 158 patients
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Abhishek A. Mangaonkar, Terra L. Lasho, Rhett P. Ketterling, Kaaren K. Reichard, Naseema Gangat, Aref Al-Kali, Kebede H. Begna, Animesh Pardanani, Najla H. Al Ali, Chetasi Talati, David Sallman, Eric Padron, Mrinal M. Patnaik, Ayalew Tefferi, and Rami Komrokji
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The current World Health Organization (WHO) classification of myeloid malignancies includes myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) as a distinct entity. Previous literature on predictors of survival was based on the provisional category of refractory anemia with ring sideroblast and thrombocytosis (RARS-T), which was not subject to MDS/MPN-RS-T exclusionary criteria such as PB blast% ≥1, BM blast% ≥5 or cytogenetic abnormalities such as t(3;3)(q21.2;q26.2), inv(3)(q21.23q26.2) or isolated del(5q). We examined overall (OS) and leukemia-free (LFS) survival and its predictors, among 158 patients with WHO-defined MDS/MPN-RS-T. In univariate analysis, age ≥70 years (P = 0.006), hemoglobin (Hb) ≤10 g/dL (P = 0.03) and abnormal karyotype (excluding -Y, P = 0.008) were associated with shortened OS, which was otherwise not affected by either ASXL1 (P = 0.7), SF3B1 (P = 0.4) or JAK2 V617F (P = 0.7) mutations; in multivariable analysis, Hb ≤ 10 g/dL (P = 0.03) and abnormal karyotype (P = 0.001) remained significant, and thus allowed the development of an operational survival model with low (0 risk factors, median OS 10.5 years), intermediate (1 risk factor, median OS 4.8 years) and high risk (2 risk factors, median OS 1.4 years) categories (P = 0.0009). Comparison of MDS/MPN-RS-T (n = 158) and MDS/MPN-U with BM RS ≥ 15% (MDS/MPN-U-RS; n = 25) did not reveal significant differences in frequency of thrombosis, OS, or LFS, although SF3B1 mutation frequency was higher in the former (93% versus 59%; P = 0.0005). These data suggest limited survival impact for molecular abnormalities and the morphological distinction between MDS/MPN-RS-T and MDS/MPN-U-RS.
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- 2022
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17. Molecular markers demonstrate diagnostic and prognostic value in the evaluation of myelodysplastic syndromes in cytopenia patients
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Rong He, Jonathan Chiou, Allison Chiou, Dong Chen, Constance P. Chen, Caroline Spethman, Kurt R. Bessonen, Jennifer L. Oliveira, Phuong L. Nguyen, Kaaren K. Reichard, James D. Hoyer, Simon D. Althoff, Dana J. Roh, Mechelle A. Miller, Ji Yuan, Horatiu Olteanu, Kebede Begna, Ayalew Tefferi, Hassan Alkhateeb, Mrinal M. Patnaik, Mark R. Litzow, Aref Al-Kali, and David S. Viswanatha
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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18. Clinical and molecular correlates from a predominantly adult cohort of patients with short telomere lengths
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Abhishek A. Mangaonkar, Alejandro Ferrer, Filippo Pinto E. Vairo, Caleb W. Hammel, Carri Prochnow, Naseema Gangat, William J. Hogan, Mark R. Litzow, Steve G. Peters, J. P. Scott, James P. Utz, Misbah Baqir, Eva M. Carmona-Porquera, Sanjay Kalra, Hiroshi Sekiguchi, Shakila P. Khan, Douglas A. Simonetto, Eric W. Klee, Patrick S. Kamath, Anja C. Roden, Avni Y. Joshi, Cassie C. Kennedy, Mark E. Wylam, and Mrinal M. Patnaik
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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19. Predictors of response to venetoclax plus hypomethylating agent therapy and survival in blastphase myeloproliferative neoplasm
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Naseema Gangat, Rimal Ilyas, Kristen McCullough, Kebede H. Begna, Aref Al-Kali, Mrinal M. Patnaik, Mark R. Litzow, William J. Hogan, Abhishek Mangaonkar, Hassan Alkhateeb, Mithun V. Shah, Michelle A. Elliott, James M. Foran, Talha Badar, Jeanne M. Palmer, Curtis A. Hanson, Animesh Pardanani, and Ayalew Tefferi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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20. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
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Ryan M. Carr, Denis Vorobyev, Terra Lasho, David L. Marks, Ezequiel J. Tolosa, Alexis Vedder, Luciana L. Almada, Andrey Yurcheko, Ismael Padioleau, Bonnie Alver, Giacomo Coltro, Moritz Binder, Stephanie L. Safgren, Isaac Horn, Xiaona You, Eric Solary, Maria E. Balasis, Kurt Berger, James Hiebert, Thomas Witzig, Ajinkya Buradkar, Temeida Graf, Peter Valent, Abhishek A. Mangaonkar, Keith D. Robertson, Matthew T. Howard, Scott H. Kaufmann, Christopher Pin, Martin E. Fernandez-Zapico, Klaus Geissler, Nathalie Droin, Eric Padron, Jing Zhang, Sergey Nikolaev, and Mrinal M. Patnaik
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Science - Abstract
Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.
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- 2021
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21. Mayo Clinic experience with 1123 adults with acute myeloid leukemia
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Kebede H. Begna, Walid Ali, Naseema Gangat, Michelle A. Elliott, Aref Al-Kali, Mark R. Litzow, C. Christopher Hook, Alexandra P. Wolanskyj-Spinner, William J. Hogan, Mrinal M. Patnaik, Animesh Pardanani, Darci L. Zblewski, Dong Chen, Rong He, David Viswanatha, Curtis A. Hanson, Rhett P. Ketterling, and Ayalew Tefferi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive (n = 766) or lower intensity (n = 144) chemotherapy or supportive care (n = 213), with respective median survivals of 22, 9, and 2 months (p 60 years (HR 2.2, 1.9–2.6), adverse karyotype (HR 2.9, 1.9–4.9), intermediate-risk karyotype (HR 1.6, 1.02–2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5–2.4), and other secondary AML (HR 1.3 (1.1–1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3+NPM1− (HR 2.8, 1.4–5.6), FLT3+/NPM+ (HR 2.6 (1.3–5.2), and FLT3−NPM1− (HR 1.8, 1.0–3.0).
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- 2021
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22. CSF3R T618I mutant chronic myelomonocytic leukemia (CMML) defines a proliferative CMML subtype enriched in ASXL1 mutations with adverse outcomes
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Evandro D. Bezerra, Terra L. Lasho, Christy M. Finke, Antoine N. Saliba, Michelle A. Elliott, Animesh D. Pardanani, Naseema Gangat, Abhishek A. Mangaonkar, Rhett P. Ketterling, Ayalew Tefferi, Eric Solary, and Mrinal M. Patnaik
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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23. How I diagnose and treat chronic myelomonocytic leukemia
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Mrinal M. Patnaik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia (15-30% over 3-5 years). While CMML is morphologically classified into CMML-0, 1 and 2 based on peripheral blood and bone marrow promonocyte/blast counts, a more clinically relevant classification into dysplastic and proliferative subtypes, based on the presenting white blood cell count, is helpful in prognostication and therapeutics. CMML is a neoplasm associated with aging, occurring on the background of clonal hematopoiesis, with TET2 and SRSF2 mutations being early initiating events. The subsequent acquisitions of ASXL1, RUNX1, SF3B1 and DNMT3A mutations usually give rise to dysplastic CMML, while ASXL1, JAK2V617F and RAS pathway mutations give rise to proliferative CMML. Patients with proliferative CMML have a more aggressive course with higher rates of transformation to acute myeloid leukemia. Allogeneic stem cell transplant remains the only potential cure for CMML; however, given the advanced median age at presentation (73 years) and comorbidities, it is an option for only a few affected patients (10%). While DNA methyltransferase inhibitors are approved for the management of CMML, the overall response rates are 40-50%, with true complete remission rates of
- Published
- 2022
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24. SF3B1-mutant myelodysplastic syndrome/myeloproliferative neoplasms: a unique molecular and prognostic entity
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Abhishek A. Mangaonkar, Terra L. Lasho, Christy Finke, Rhett P. Ketterling, Kaaren K. Reichard, Kristen McCullough, Naseema Gangat, Aref Al-Kali, Kebede H. Begna, William H. Hogan, Mark R. Litzow, Hassan Alkhateeb, Mithun Shah, Animesh Pardanani, Ayalew Tefferi, Najla H. Al Ali, Chetasi Talati, David Sallman, Eric Padron, Rami Komrokji, and Mrinal M. Patnaik
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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25. Erythrocytosis associated with EPAS1(HIF2A), EGLN1(PHD2), VHL, EPOR or BPGM mutations: The Mayo Clinic experience
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Naseema Gangat, Jennifer L. Oliveira, Tavanna R Porter, James D. Hoyer, Aref Al-Kali, Mrinal M. Patnaik, Animesh Pardanani, and Ayalew Tefferi
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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26. Metagenomic shotgun sequencing of blood to identify bacteria and viruses in leukemic febrile neutropenia
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Prakhar Vijayvargiya, Adeline Feri, Mathilde Mairey, Cécile Rouillon, Patricio R. Jeraldo, Zerelda Esquer Garrigos, Matthew J. Thoendel, Kerryl E. Greenwood-Quaintance, M. Rizwan Sohail, Priya Sampathkumar, Megan T. Spychalla, A. K. Stewart, Mrinal M. Patnaik, Aaron J. Tande, Stéphane Cruveiller, Irene Hannet, Pascale Beurdeley, and Robin Patel
- Subjects
Medicine ,Science - Abstract
Despite diagnostic advances in microbiology, the etiology of neutropenic fever remains elusive in most cases. In this study, we evaluated the utility of a metagenomic shotgun sequencing based assay for detection of bacteria and viruses in blood samples of patients with febrile neutropenia. We prospectively enrolled 20 acute leukemia patients and obtained blood from these patients at three time points: 1) anytime from onset of neutropenia until before development of neutropenic fever, 2) within 24 hours of onset of neutropenic fever, 3) 5–7 days after onset of neutropenic fever. Blood samples underwent sample preparation, sequencing and analysis using the iDTECT® Dx Blood v1® platform (PathoQuest, Paris, France). Clinically relevant viruses or bacteria were detected in three cases each by metagenomic shotgun sequencing and blood cultures, albeit with no concordance between the two. Further optimization of sample preparation methods and sequencing platforms is needed before widespread adoption of this technology into clinical practice.
- Published
- 2022
27. A homozygous missense variant in UBE2T is associated with a mild Fanconi anemia phenotype
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Laura Schultz-Rogers, Francis P. Lach, Kimberly A. Rickman, Alejandro Ferrer, Abhishek A. Mangaonkar, Tanya L. Schwab, Christopher T. Schmitz, Karl J. Clark, Nikita R. Dsouza, Michael T. Zimmermann, Mark Litzow, Nicole Jacobi, Eric W. Klee, Agata Smogorzewska, and Mrinal M. Patnaik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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28. Bone marrow findings in Erdheim-Chester disease: increased prevalence of chronic myeloid neoplasms
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Gaurav Goyal, Aishwarya Ravindran, Yuanhang Liu, Rong He, Mithun V. Shah, N. Nora Bennani, Mrinal M. Patnaik, Karen L. Rech, and Ronald S. Go
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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29. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease
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Gaurav Goyal, Aishwarya Ravindran, Jason R. Young, Mithun V. Shah, N. Nora Bennani, Mrinal M. Patnaik, Grzegorz S. Nowakowski, Gita Thanarajasingam, Thomas M. Habermann, Robert Vassallo, Taimur Sher, Sameer A. Parikh, Karen L. Rech, and Ronald S. Go
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.
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- 2020
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30. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions
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Peter Valent, Attilio Orazi, Michael R. Savona, Mrinal M. Patnaik, Francesco Onida, Arjan A. van de Loosdrecht, Detlef Haase, Torsten Haferlach, Chiara Elena, Lisa Pleyer, Wolfgang Kern, Tea Pemovska, Gregory I. Vladimer, Julie Schanz, Alexandra Keller, Michael Lübbert, Thomas Lion, Karl Sotlar, Andreas Reiter, Theo De Witte, Michael Pfeilstöcker, Klaus Geissler, Eric Padron, Michael Deininger, Alberto Orfao, Hans-Peter Horny, Peter L. Greenberg, Daniel A. Arber, Luca Malcovati, and John M. Bennett
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between ‘normal’, pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
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- 2019
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31. Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia Patients Treated With Hypomethylating Agents
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Matthieu Duchmann, Fevzi F. Yalniz, Alessandro Sanna, David Sallman, Catherine C. Coombs, Aline Renneville, Olivier Kosmider, Thorsten Braun, Uwe Platzbecker, Lise Willems, Lionel Adès, Michaela Fontenay, Raajit Rampal, Eric Padron, Nathalie Droin, Claude Preudhomme, Valeria Santini, Mrinal M. Patnaik, Pierre Fenaux, Eric Solary, and Raphael Itzykson
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR] = 0.85, p = 0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1mut (Hazard Ratio [HR] = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations. Keywords: Chronic myelomonocytic leukemia, Hypomethylating agents, Somatic mutations, Prognosis
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- 2018
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32. Targeted next-generation sequencing in blast phase myeloproliferative neoplasms
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Terra L. Lasho, Mythri Mudireddy, Christy M. Finke, Curtis A. Hanson, Rhett P. Ketterling, Natasha Szuber, Kebede H. Begna, Mrinal M. Patnaik, Naseema Gangat, Animesh Pardanani, and Ayalew Tefferi
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm–relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of RUNX1 mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of RUNX1 mutations.
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- 2018
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33. Classification of Monocytes, Promonocytes and Monoblasts Using Deep Neural Network Models: An Area of Unmet Need in Diagnostic Hematopathology
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Mazen Osman, Zeynettin Akkus, Dragan Jevremovic, Phuong L. Nguyen, Dana Roh, Aref Al-Kali, Mrinal M. Patnaik, Ahmad Nanaa, Samia Rizk, and Mohamed E. Salama
- Subjects
digital imaging ,artificial intelligence ,improving diagnosis accuracy ,monocytes ,promonocytes and monoblasts ,chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) for acute monoblastic leukemia and acute monocytic leukemia ,Medicine - Abstract
The accurate diagnosis of chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) subtypes with monocytic differentiation relies on the proper identification and quantitation of blast cells and blast-equivalent cells, including promonocytes. This distinction can be quite challenging given the cytomorphologic and immunophenotypic similarities among the monocytic cell precursors. The aim of this study was to assess the performance of convolutional neural networks (CNN) in separating monocytes from their precursors (i.e., promonocytes and monoblasts). We collected digital images of 935 monocytic cells that were blindly reviewed by five experienced morphologists and assigned into three subtypes: monocyte, promonocyte, and blast. The consensus between reviewers was considered as a ground truth reference label for each cell. In order to assess the performance of CNN models, we divided our data into training (70%), validation (10%), and test (20%) datasets, as well as applied fivefold cross validation. The CNN models did not perform well for predicting three monocytic subtypes, but their performance was significantly improved for two subtypes (monocyte vs. promonocytes + blasts). Our findings (1) support the concept that morphologic distinction between monocytic cells of various differentiation level is difficult; (2) suggest that combining blasts and promonocytes into a single category is desirable for improved accuracy; and (3) show that CNN models can reach accuracy comparable to human reviewers (0.78 ± 0.10 vs. 0.86 ± 0.05). As far as we know, this is the first study to separate monocytes from their precursors using CNN.
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- 2021
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34. Clinical correlates, prognostic impact and survival outcomes in chronic myelomonocytic leukemia patients with the JAK2V617F mutation
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Mrinal M. Patnaik, Prateek A. Pophali, Terra L. Lasho, Christy M. Finke, Pedro Horna, Rhett P. Ketterling, Naseema Gangat, Abhishek A. Mangaonkar, Animesh Pardanani, and Ayalew Tefferi
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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35. A Systematic Review on Predisposition to Lymphoid (B and T cell) Neoplasias in Patients With Primary Immunodeficiencies and Immune Dysregulatory Disorders (Inborn Errors of Immunity)
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Irbaz Bin Riaz, Warda Faridi, Mrinal M. Patnaik, and Roshini S. Abraham
- Subjects
primary immunodeficiencies ,B cell lymphoma ,T cell lymphoma ,systematic (literature) reviews ,immunodeficiency ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Primary immunodeficiencies and immune dysregulatory disorders (PIDDs; now referred to as inborn errors in immunity) are rare disorders with a prevalence of 41. 4 or 50.5 per 100,000 persons (1). The incidence of malignancy in PIDD patents is the second-highest cause of death in children as well as adults, after infection, and is higher in certain PIDDs compared to others. We performed a systematic review of the literature to identify reports of B cell and T cell neoplasias in PIDDs and clustered them based on their classification in the IUIS schema. As would be expected, higher susceptibility to malignancies are typically reported in patients with Common Variable Immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity, in particular, DNA repair defects, or in the context of impaired immune regulatory control. There is not much evidence of increased risk for cancer in patients with innate immune defects, indicating that not all types of infection or genetic susceptibility predispose equally to cancer risk. Viral infections, in particular EBV, HHV and HPV, have been shown to increase susceptibility to developing cancer, but also patients with defects in immune regulation, such as Autoimmune Lymphoproliferative Syndrome (ALPS), activated p110delta syndrome (APDS type 1) and IL-10 receptor deficiency among others have a higher incidence of neoplastic disease, particularly lymphomas. In fact, lymphomas account for two-thirds of all malignancies reported in PIDD patients (2), with either a combined immunodeficiency or DNA repair defect predominating as the underlying immune defect in one registry, or antibody deficiencies in another (3). The vast majority of lymphomas reported in the context of PIDDs are B cell lymphomas, though T cell lymphomas have been reported in a few studies, and tend to largely be associated with chromosomal breakage disorders (4) or Cartilage Hair Hypoplasia (5). There appears to be a much higher prevalence of T cell lymphomas in patients with secondary immunodeficiencies (6), though this could reflect treatment bias. We reviewed the literature and summarized the reports of B and T cell lymphoma in PIDD patients to survey the current state of knowledge in this area.
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- 2019
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36. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets
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Pashtoon M. Kasi, Mark R. Litzow, Mrinal M. Patnaik, Shahrukh K. Hashmi, and Naseema Gangat
- Subjects
Acute Leukemia ,FMS-like tyrosine kinase-3 (FLT3) inhibitors ,ASP2215 ,Clonal evolution ,Philadelphia chromosome (BCR-ABL) ,Ponatinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
For acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215) to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉)
- Published
- 2016
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37. MYST3/CREBBP Rearranged Acute Myeloid Leukemia after Adjuvant Chemotherapy for Breast Cancer
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Arjun Gupta, Mrinal M. Patnaik, and Harris V. Naina
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Although rare, clinicians and patients must be aware that therapy related malignancies, specifically acute myeloid leukemia (AML), can occur as a complication of adjuvant chemotherapy for breast cancer. Vigilance for signs and symptoms is appropriate. AML with t (8;16) is a specific translocation leading to formation of a fusion protein (MYST3/CREBBP). The MYST3/CREBBP AML tends to develop within 2 years of adjuvant chemotherapy, especially for breast cancer, without preceding myelodysplasia. It usually presents with disseminated intravascular coagulation and osteolytic lesions and has a poor prognosis despite aggressive resuscitation and therapy. With the increasing use of adjuvant chemotherapy for breast cancer, we are seeing a definite increase in the incidence of therapy related myelodysplastic syndromes and AML. One must keep this complication in mind while counseling and following up breast cancer patients who have received adjuvant chemotherapy. New osteolytic bone lesions in a patient with history of breast cancer do not necessarily mean metastatic disease and should be fully evaluated.
- Published
- 2014
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38. Safety of Pegfilgrastim (Neulasta) in Patients with Sickle Cell Trait/Anemia
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Pashtoon Murtaza Kasi, Mrinal M. Patnaik, and Prema P. Peethambaram
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.
- Published
- 2013
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39. Clonal Hematopoiesis of Indeterminate Potential Is Associated With Coronary Microvascular Dysfunction In Early Nonobstructive Coronary Artery Disease
- Author
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Nadia Akhiyat, Terra Lasho, Morsaleh Ganji, Takumi Toya, Chang-Xin Shi, Xianfeng Chen, Esteban Braggio, Ali Ahmad, Michel T. Corban, Keith Stewart, Jenna Fernandez, Zhuoer Xie, Christy Finke, Lilach O. Lerman, Mrinal M. Patnaik, and Amir Lerman
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Background: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is a risk factor for cardiovascular disease. The relationship between CHIP and coronary microvascular dysfunction (CMD) is unknown. The current study examines the association between CHIP and CH with CMD and the potential relationships in risk for adverse cardiovascular outcomes. Methods: In this retrospective observational study, targeted next-generation sequencing was performed for 177 participants with no coronary artery disease who presented with chest pain and underwent routine coronary functional angiogram. Patients with somatic mutations in leukemia-associated driver genes in hematopoietic stem and progenitor cells were examined; CHIP was considered at a variant allele fraction ≥2%; CH was considered at a variant allele fraction ≥1%. CMD was defined as coronary flow reserve to intracoronary adenosine of ≤2. Major adverse cardiovascular events considered were myocardial infarction, coronary revascularization, or stroke. Results: A total of 177 participants were examined. Mean follow-up was 12±7 years. A total of 17 patients had CHIP and 28 had CH. Cases with CMD (n=19) were compared with controls with no CMD (n=158). Cases were 56±9 years, were 68% women, and had more CHIP (27%; P =0.028) and CH (42%; P =0.001) than controls. CMD was associated with independent risk for major adverse cardiovascular events (hazard ratio, 3.89 [95% CI, 1.21–12.56]; P =0.023), and 32% of this risk was mediated by CH. The risk mediated by CH was ≈0.5× as large as the direct effect of CMD on major adverse cardiovascular events. Conclusions: In humans, we observe patients with CMD are more likely to have CHIP, and nearly one-third of major adverse cardiovascular events in CMD are mediated by CH.
- Published
- 2023
40. Molecular characterization stratifies VQ myeloma cells into two clusters with distinct risk signatures and drug responses
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Evan Flietner, Mei Yu, Govinda Poudel, Anthony J. Veltri, Yun Zhou, Adhithi Rajagopalan, Yubin Feng, Terra Lasho, Zhi Wen, Yuqian Sun, Mrinal M. Patnaik, Natalie S. Callander, Fotis Asimakopoulos, Demin Wang, and Jing Zhang
- Subjects
Cancer Research ,Genetics ,Molecular Biology - Published
- 2023
41. Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations
- Author
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Abhishek A. Mangaonkar and Mrinal M. Patnaik
- Subjects
Hematology - Published
- 2023
42. A three‐gene leukaemic stem cell signature score is robustly prognostic in chronic myelomonocytic leukaemia
- Author
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Yu‐Hung Wang, Chi‐Yuan Yao, Chien‐Chin Lin, Kristian Gurashi, Fabio M. R. Amaral, Hasse Bossenbroek, Andres Jerez, Tim C. P. Somervaille, Moritz Binder, Mrinal M. Patnaik, Hsin‐An Hou, Wen‐Chien Chou, Kiran Batta, Daniel H. Wiseman, and Hwei‐Fang Tien
- Subjects
Hematology - Published
- 2023
43. Role of ASXL1 in hematopoiesis and myeloid diseases
- Author
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Xin Gao, Xiaona You, Nathalie Droin, Lauren G. Banaszak, Jane Churpek, Eric Padron, Klaus Geissler, Eric Solary, Mrinal M. Patnaik, and Jing Zhang
- Subjects
Repressor Proteins ,Cancer Research ,Myeloproliferative Disorders ,Leukemia ,Mutation ,Genetics ,Humans ,Cell Biology ,Hematology ,Molecular Biology ,Hematopoiesis - Abstract
Next-generation sequencing technology, including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and are associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for the future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.
- Published
- 2022
44. Finding consistency in classifications of myeloid neoplasms: a perspective on behalf of the International Workshop for Myelodysplastic Syndromes
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Amer M. Zeidan, Jan Philipp Bewersdorf, Rena Buckstein, Mikkael A. Sekeres, David P. Steensma, Uwe Platzbecker, Sanam Loghavi, Jacqueline Boultwood, Rafael Bejar, John M. Bennett, Uma Borate, Andrew M. Brunner, Hetty Carraway, Jane E. Churpek, Naval G. Daver, Matteo Della Porta, Amy E. DeZern, Fabio Efficace, Pierre Fenaux, Maria E. Figueroa, Peter Greenberg, Elizabeth A. Griffiths, Stephanie Halene, Robert P. Hasserjian, Christopher S. Hourigan, Nina Kim, Tae Kon Kim, Rami S. Komrokji, Vijay Kutchroo, Alan F. List, Richard F. Little, Ravi Majeti, Aziz Nazha, Stephen D. Nimer, Olatoyosi Odenike, Eric Padron, Mrinal M. Patnaik, Gail J. Roboz, David A. Sallman, Guillermo Sanz, Maximilian Stahl, Daniel T. Starczynowski, Justin Taylor, Zhuoer Xie, Mina Xu, Michael R. Savona, Andrew H. Wei, Omar Abdel-Wahab, and Valeria Santini
- Subjects
Leukemia, Myeloid, Acute ,Cancer Research ,Myeloproliferative Disorders ,Oncology ,Neoplasms ,Myelodysplastic Syndromes ,Humans ,Hematology - Published
- 2022
45. Juvenile myelomonocytic leukemia; moving forward
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M. Tarek Elghetany, Hélène Cavé, Rita De Vito, Mrinal M. Patnaik, Eric Solary, and Joseph D. Khoury
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Cancer Research ,Oncology ,Hematology - Published
- 2023
46. Development of a multiomics model for identification of predictive biomarkers for COVID-19 severity: a retrospective cohort study
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Seul Kee Byeon, Anil K Madugundu, Kishore Garapati, Madan Gopal Ramarajan, Mayank Saraswat, Praveen Kumar-M, Travis Hughes, Rameen Shah, Mrinal M Patnaik, Nicholas Chia, Susan Ashrafzadeh-Kian, Joseph D Yao, Bobbi S Pritt, Roberto Cattaneo, Mohamed E Salama, Roman M Zenka, Benjamin R Kipp, Stefan K G Grebe, Ravinder J Singh, Amir A Sadighi Akha, Alicia Algeciras-Schimnich, Surendra Dasari, Janet E Olson, Jesse R Walsh, A J Venkatakrishnan, Garrett Jenkinson, John C O'Horo, Andrew D Badley, and Akhilesh Pandey
- Subjects
Proteomics ,SARS-CoV-2 ,COVID-19 ,Medicine (miscellaneous) ,Health Informatics ,Prognosis ,Lipids ,Cohort Studies ,Health Information Management ,Lipidomics ,Cytokines ,Humans ,Metabolomics ,Decision Sciences (miscellaneous) ,Pandemics ,Biomarkers ,Retrospective Studies - Abstract
COVID-19 is a multi-system disorder with high variability in clinical outcomes among patients who are admitted to hospital. Although some cytokines such as interleukin (IL)-6 are believed to be associated with severity, there are no early biomarkers that can reliably predict patients who are more likely to have adverse outcomes. Thus, it is crucial to discover predictive markers of serious complications.In this retrospective cohort study, we analysed samples from 455 participants with COVID-19 who had had a positive SARS-CoV-2 RT-PCR result between April 14, 2020, and Dec 1, 2020 and who had visited one of three Mayo Clinic sites in the USA (Minnesota, Arizona, or Florida) in the same period. These participants were assigned to three subgroups depending on disease severity as defined by the WHO ordinal scale of clinical improvement (outpatient, severe, or critical). Our control cohort comprised of 182 anonymised age-matched and sex-matched plasma samples that were available from the Mayo Clinic Biorepository and banked before the COVID-19 pandemic. We did a deep profiling of circulatory cytokines and other proteins, lipids, and metabolites from both cohorts. Most patient samples were collected before, or around the time of, hospital admission, representing ideal samples for predictive biomarker discovery. We used proximity extension assays to quantify cytokines and circulatory proteins and tandem mass spectrometry to measure lipids and metabolites. Biomarker discovery was done by applying an AutoGluon-tabular classifier to a multiomics dataset, producing a stacked ensemble of cutting-edge machine learning algorithms. Global proteomics and glycoproteomics on a subset of patient samples with matched pre-COVID-19 plasma samples was also done.We quantified 1463 cytokines and circulatory proteins, along with 902 lipids and 1018 metabolites. By developing a machine-learning-based prediction model, a set of 102 biomarkers, which predicted severe and clinical COVID-19 outcomes better than the traditional set of cytokines, were discovered. These predictive biomarkers included several novel cytokines and other proteins, lipids, and metabolites. For example, altered amounts of C-type lectin domain family 6 member A (CLEC6A), ether phosphatidylethanolamine (P-18:1/18:1), and 2-hydroxydecanoate, as reported here, have not previously been associated with severity in COVID-19. Patient samples with matched pre-COVID-19 plasma samples showed similar trends in muti-omics signatures along with differences in glycoproteomics profile.A multiomic molecular signature in the plasma of patients with COVID-19 before being admitted to hospital can be exploited to predict a more severe course of disease. Machine learning approaches can be applied to highly complex and multidimensional profiling data to reveal novel signatures of clinical use. The absence of validation in an independent cohort remains a major limitation of the study.Eric and Wendy Schmidt.
- Published
- 2022
47. Targeted testing of bone marrow specimens with cytoplasmic vacuolization to identify previously undiagnosed cases of VEXAS syndrome
- Author
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Alexander S Hines, Matthew J Koster, Allison R Bock, Ronald S Go, Kenneth J Warrington, Horatiu Olteanu, Terra L Lasho, Mrinal M Patnaik, and Kaaren K Reichard
- Subjects
Rheumatology ,Pharmacology (medical) - Abstract
Objective To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically applicable, targeted-screening approach. Methods Bone marrow reports from 1 May 2014 through 18 Feb 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumor, amyloidosis, or POEMS were excluded as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features, and treatment response. Patients with available DNA material and moderate (3 pts) or high (4–5 pts) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome. Results 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome for which 21 patients met moderate to high suspicion. Available DNA was present in 8 patients of which 7 (87.5%) had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7), and myeloid precursors only (0/7). Conclusion In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.
- Published
- 2023
48. Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML
- Author
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Christopher T. Letson, Maria E. Balasis, Hannah Newman, Moritz Binder, Alexis Vedder, Fumi Kinose, Markus Ball, Traci Kruer, Ariel Quintana, Terra L. Lasho, Christy M. Finke, Luciana L. Almada, Jennifer M. Grants, Guolin Zhang, Martin E. Fernandez-Zapico, Alexandre Gaspar-Maia, Jeffrey Lancet, Rami Komrokji, Eric Haura, David A. Sallman, Gary W. Reuther, Aly Karsan, Uwe Rix, Mrinal M. Patnaik, and Eric Padron
- Subjects
Cancer Research ,Oncology - Abstract
Background: Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and PDX models of disease. We utilized standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusion: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination.
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- 2023
49. Antineutrophil cytoplasmic antibody–associated vasculitis and <scp>VEXAS</scp> syndrome: comment on the article by Muratore et al
- Author
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Matthew J. Koster, Umar Ghaffar, Tanaz A. Kermani, Mrinal M. Patnaik, Ronald S. Go, Abhishek A. Mangaonkar, Kaaren K. Reichard, Horatiu Olteanu, and Kenneth J. Warrington
- Subjects
Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2023
50. Characterization and Optimization of Multiomic Single-Cell Epigenomic Profiling
- Author
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Leticia Sandoval, Wazim Mohammed Ismail, Amelia Mazzone, Mihai Dumbrava, Jenna Fernandez, Amik Munankarmy, Terra Lasho, Mortiz Binder, Vernadette Simon, Kwan Hyun Kim, Nicholas Chia, Jeong Heon Lee, S. John Weroha, Mrinal M. Patnaik, and Alexandre Gaspar-Maia
- Abstract
The snATAC + snRNA platform allows epigenomic profiling of open chromatin and gene expression with single-cell resolution. The most critical assay step is to isolate high-quality nuclei to proceed with droplet-base single nuclei isolation and barcoding. With the increasing popularity of multiomic profiling in various fields, there is a need for optimized and reliable nuclei isolation methods, mainly for human tissue samples. Herein we compared different nuclei isolation methods for cell suspensions, such as peripheral blood mononuclear cells (PBMC, n=18) and a solid tumor type, ovarian cancer (OC) (n=18), derived from debulking surgery. Nuclei morphology and sequencing output parameters were used to evaluate the quality of preparation. Our results show that NP-40 detergent-based nuclei isolation yields better sequencing results than collagenase tissue dissociation for OC, significantly impacting cell identification and analysis. Given the utility of applying such techniques to frozen samples, we also tested frozen preparation and digestion (n=6). A paired comparison between frozen and fresh samples validated the quality of both specimens. Finally, we demonstrate the reproducibility of scRNA and snATAC + snRNA platform, by comparing the gene expression profiling of PBMC. Our results highlight how the choice of nuclei isolation methods is critical for obtaining quality data in multiomic assays. It also shows that the measurement of expression between scRNA and snRNA is comparable and effective for cell type identification.
- Published
- 2023
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