256 results on '"Jorge E. Cortes"'
Search Results
2. Sotatercept for anemia of myelofibrosis: a phase II investigator-initiated study
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Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Sharon D. Bledsoe, Naval G. Daver, Elias J. Jabbour, Tapan M. Kadia, Zeev Estrov, Steven M. Kornblau, Michael Andreeff, Nitin Jain, Jorge E. Cortes, Gautam Borthakur, Yesid Alvarado, Mary Ann Richie, Mackenzie H. Dobbins, Selene A. McCrackin, Lingsha Zhou, Sherry A. Pierce, Xuemei Wang, Allison M. Pike, Guillermo Garcia-Manero, Hagop M. Kantarjian, and Srdan Verstovsek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2024
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3. Population modeling of bosutinib exposure‐response in patients with newly diagnosed chronic phase chronic myeloid leukemia
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May Garrett, Beverly Knight, Jorge E. Cortes, and Michael W. Deininger
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bosutinib ,chronic myeloid leukemia ,efficacy ,PK/PD ,safety ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The BELA and BFORE trials compared bosutinib starting doses of 500 mg once daily (QD) and 400 mg QD, respectively, with imatinib in adults with newly diagnosed chronic phase chronic myeloid leukemia (CP‐CML). The B1871048 trial evaluated bosutinib 400 mg QD in Japanese patients with newly diagnosed CP‐CML. Aim This analysis assessed the impact of a lower bosutinib starting dose on key efficacy and safety outcomes. Materials & Methods A pharmacokinetic model was used to estimate metrics of bosutinib exposure, and logistic regression was used to investigate relationships with efficacy (cumulative major molecular response [MMR] and cumulative complete cytogenetic response [CCyR]) and safety outcomes (eight prespecified adverse events). Results Totals of 573 and 574 patients were included in the efficacy and safety endpoint analyses, respectively. Cumulative MMR and CCyR were similar across studies. Log(Ctrough) and log(Cavg) were significant predictors of MMR and CCyR, and the probability of achieving MMR or CCyR increased 1.3‐fold or 2.7‐fold for every 1 unit increase in log(Ctrough) or log(Cavg), respectively. An exposure–response relationship was identified between time‐to‐event and risk of diarrhea, nausea, and vomiting. Significant relationships were also observed between time‐to‐event and log(Cavg), Ctrough, and Cavg with diarrhea, nausea, and vomiting, respectively. Discussion A bosutinib exposure‐response relationship with safety and efficacy was observed. Conclusion Compared with 500 mg QD, a bosutinib starting dose of 400 mg QD improved tolerability in some patients with newly diagnosed CP‐CML without compromising efficacy. ClinicalTrials.gov identifiers: NCT00574873; NCT02130557; NCT03128411.
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- 2023
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4. Teledermatology for skin cancer screening in rural Georgia utilizing teledermoscopy and distance learning: An ongoing report
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McKenzie E. Maloney, BS, Marisol Miranda-Galvis, DDS, MS, PhD, Brenda Santellano Juarez, MD, Kenza Mamouni, MBA, PhD, Lorriane Odhiambo, PhD, MPH, Samah Ibrahim, MBBS, K.M. Monirul Islam, PhD, Rhea-Beth Markowitz, PhD, Koosh Desai, MD, Harold Rabinovitz, MD, Kendall Buchanan, MD, Douglas Patten, MD, Loretta S. Davis, MD, and Jorge E. Cortes, MD
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dermatology ,distance learning ,oncology ,skin cancer ,teledermoscopy ,teledermatology ,Dermatology ,RL1-803 - Published
- 2023
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5. Cross-intolerance with bosutinib after prior tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia: long-term analysis of a phase I/II study
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Jorge E. Cortes, Jeff H. Lipton, Vamsi Kota, Fausto Castagnetti, Sarit Assouline, Tim H. Brümmendorf, Eric Leip, Andrea Viqueira, and Carlo Gambacorti-Passerini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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6. Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial
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Jorge E. Cortes, Tara L. Lin, Kobby Asubonteng, Stefan Faderl, Jeffrey E. Lancet, and Thomas Prebet
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Acute myeloid leukemia ,Chemotherapy ,CPX-351 ,European LeukemiaNet 2017 risk subgroup ,Post hoc ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract CPX-351 (Europe: Vyxeos® liposomal; United States: Vyxeos®) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 improved the remission frequency, overall survival, and post-transplant survival versus 7 + 3. This post hoc analysis evaluated the final 5-year follow-up outcomes according to the European LeukemiaNet 2017 risk classification. CPX-351–treated patients had a higher remission frequency (adverse risk: 41% vs 26%; intermediate risk: 58% vs 39%) and longer median overall survival (adverse risk: 7.59 vs 5.52 months; intermediate risk: 11.86 vs 7.75 months) and post-transplant survival (adverse risk: 43.14 vs 7.08 months; intermediate risk: not reached vs 13.57 months) versus 7 + 3, with outcomes generally poorer among patients with adverse-risk AML. The safety profile of CPX-351 among patients with adverse-risk or intermediate-risk AML was consistent with that of the overall study population. Early mortality was lower, and hospitalization length of stay per patient-year was shorter with CPX-351 versus 7 + 3 within the adverse-risk and intermediate-risk subgroups. The favorable outcomes observed with CPX-351 in this post hoc analysis are consistent with results for the overall study population and further support the use of CPX-351 in these patients. ClinicalTrials.gov Identifier: NCT01696084.
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- 2022
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7. A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase
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Valentin García-Gutiérrez, Massimo Breccia, Elias Jabbour, Michael Mauro, and Jorge E. Cortes
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Chronic myeloid leukemia ,Tyrosine kinase inhibitors ,First-line treatment ,Treatment switching ,Treatment-free remission ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians’ international and personal experiences, may give insight into alternative approaches not previously considered.
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- 2022
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8. Update on the role of gemtuzumab-ozogamicin in the treatment of acute myeloid leukemia
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Mahesh Swaminathan and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Gemtuzumab-ozogamicin (GO) is an antibody-drug conjugate (ADC) in which a monoclonal antibody targeting CD33 is covalently linked to the toxin calicheamicin. GO was initially approved by the United States Food and Drug Administration (FDA) for the treatment of adult patients with CD33 + acute myeloid leukemia (AML) in 2000. However, GO was recalled from the US market due to the lack of efficacy, and higher incidence of hepatotoxicities, including hepatic veno-occlusive disease (VOD), observed in phase 3 SWOG-0106 study. Since then, several other phase 3 studies have evaluated the efficacy of GO in the frontline treatment of adult patients with AML using different GO doses and schedules. The pivotal study that led to the reconsideration of GO was the French ALFA-0701 study, which used a lower and fractionated dose of GO in combination with standard chemotherapy (SC). Patients treated with the GO combination had a significantly longer survival outcome. The modified schedule also improved the toxicity profile. A systematic review and meta-analysis of over 3000 patients treated in five phase 3 studies showed that adding GO to SC improved relapse-free and overall survival. Most importantly, 6 mg/m 2 dose of GO was associated with higher grade ⩾3 hepatoxicities and VOD than 3 mg/m 2 . The survival benefit was significant in the favorable and intermediate cytogenetic risk groups. This led to the reapproval of GO in 2017 for the treatment of patients with CD33 + AML. Currently, several clinical trials are exploring the role of GO with various combinations and in eliminating the measurable residual disease in patients with CD33 + AML.
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- 2023
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9. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML
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Jorge E. Cortes, Tara L. Lin, Geoffrey L. Uy, Robert J. Ryan, Stefan Faderl, and Jeffrey E. Lancet
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Acute myeloid leukemia ,Chemotherapy ,Relapse ,Survival ,Toxicity ,Quality-of-life ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.
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- 2021
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10. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers
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Nikhil Shri Sahajpal, Ashis K. Mondal, Harmanpreet Singh, Ashutosh Vashisht, Sudha Ananth, Daniel Saul, Alex R. Hastie, Benjamin Hilton, Barbara R. DuPont, Natasha M. Savage, Vamsi Kota, Alka Chaubey, Jorge E. Cortes, and Ravindra Kolhe
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optical genome mapping ,523-gene NGS panel ,myeloid cancers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel had an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Importantly, the IPSS-R cytogenetic risk group changed from very good/good to very poor in 22% of MDS (2/9) cases based on comprehensive profiling (karyotyping, FISH, and 54-gene panel vs. OGM and 523-gene panel), while additionally identifying six compound heterozygous events of potential clinical relevance in six cases (6/30, 20%). This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers demonstrated increased yield of actionable targets that can potentially result in improved clinical outcomes.
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- 2023
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11. Health care access and utilization among adult cancer survivors: Results from the National Institutes of Health 'All of Us' Research Program
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Steven S. Coughlin, Jie Chen, and Jorge E. Cortes
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cancer ,cancer survivors ,health care access ,health care utilization ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Many cancer survivors face financial difficulties that prevent them from receiving appropriate health care. Racial/ethnic disparities in receipt of health care have been reported among cancer survivors, but recent data for important racial/ethnic subgroups of the US population are lacking. Methods To learn more about barriers to healthcare access faced by cancer survivors, we analyzed data from the NIH “All of Us” Research Program. Data were analyzed about demographic factors and other personal characteristics, personal medical history of cancer, healthcare utilization, and access to care. Results As of November 2020, a total of 5426 participants had a history of cancer (excluding skin cancer). About 88.2% were non‐Hispanic White; 3.9% were Black, African American, or African; 1.3% were Asian; 4.1% were Hispanic, Latino, or Spanish; and 1.2% reported more than one race. Just over one‐half had an annual income of $75,000 or greater. The majority of the participants (71.7%) were college graduates or had an advanced degree. About 47.0%% had private health insurance, 41.0% had Medicare, 6.0% had Medicaid, and the remainder had military, Veterans Affairs, other insurance, or no health insurance. Frequently cited reasons for delayed care in the past 12 months were “had to pay out of pocket for some or all of the procedures,” “deductible was too high/or could not afford the deductible,” “couldn't afford the copay,” “couldn't get time off work,” and “were nervous about seeing a health care provider.” Discussion A minority of cancer survivors who participated in the NIH “All of Us” Program had difficulty paying for health care in the past 12 months. Of particular concern are minorities such as African American and Hispanic cancer survivors along with those who are low income.
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- 2021
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12. Impact of frontline treatment approach on outcomes of myeloid blast phase CML
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Kapil Saxena, Elias Jabbour, Ghayas Issa, Koji Sasaki, Farhad Ravandi, Abhishek Maiti, Naval Daver, Tapan Kadia, Courtney D. DiNardo, Marina Konopleva, Jorge E. Cortes, Musa Yilmaz, Kelly Chien, Sherry Pierce, Hagop Kantarjian, and Nicholas J. Short
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CML ,Blast phase ,Chemotherapy ,Hypomethylating agent ,TKI ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach. Methods We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes. Results Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p
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- 2021
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13. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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Musa Yilmaz, Mansour Alfayez, Courtney D. DiNardo, Gautam Borthakur, Tapan M. Kadia, Marina Y. Konopleva, Sanam Loghavi, Rashmi Kanagal-Shamanna, Keyur P. Patel, Elias J. Jabbour, Guillermo Garcia-Manero, Naveen Pemmaraju, Sherry A. Pierce, Issa Ghayas, Nicholas J. Short, Guillermo Montalban-Bravo, Koichi Takahashi, Rita Assi, Ahmad S. Alotaibi, Maro Ohanian, Michael Andreeff, Jorge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi, and Naval G. Daver
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FLT3 mutations ,Sequential FLT3 inhibitors ,Midostaurin ,Sorafenib ,Quizartinib ,Gilteritinib ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45–55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. Results In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion CRc rates drop progressively with sequential exposure to FLT3i’s in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.
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- 2020
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14. Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia
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Jorge E. Cortes, Marcos de Lima, Hervé Dombret, Elihu H. Estey, Sergio A. Giralt, Pau Montesinos, Christoph Röllig, Adriano Venditti, and Eunice S. Wang
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Acute myeloid leukemia ,Adverse events ,Gemtuzumab ozogamicin ,Treatment management ,VOD/SOS ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians’ recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.
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- 2020
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15. Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Jorge E. Cortes, Florian H. Heidel, Walter Fiedler, B. Douglas Smith, Tadeusz Robak, Pau Montesinos, Anna Candoni, Brian Leber, Mikkael A. Sekeres, Daniel A. Pollyea, Roxanne Ferdinand, Weidong Wendy Ma, Thomas O’Brien, Ashleigh O’Connell, Geoffrey Chan, and Michael Heuser
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Glasdegib ,Acute myeloid leukemia ,Clinical trial ,Disease response ,Efficacy ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015). Methods This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR. Results In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41–0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively. Conclusions Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR. Trial registration ClinicalTrials.gov NCT01546038 (March 7, 2012)
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- 2020
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16. Management of adverse events associated with bosutinib treatment of chronic-phase chronic myeloid leukemia: expert panel review
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Jorge E. Cortes, Jane F. Apperley, Daniel J. DeAngelo, Michael W. Deininger, Vamsi K. Kota, Philippe Rousselot, and Carlo Gambacorti-Passerini
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Tyrosine kinase inhibitor ,Bosutinib ,Chronic myeloid leukemia ,Dosing strategies ,Adverse events ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.
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- 2018
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17. A prospective analysis of symptom burden for patients with chronic myeloid leukemia in chronic phase treated with frontline second‐ and third‐generation tyrosine kinase inhibitors
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Alejandro Zulbaran‐Rojas, Huei‐Kan Lin, Qiuling Shi, Loretta A. Williams, Binsah George, Guillermo Garcia‐Manero, Elias Jabbour, Susan O’Brien, Farhad Ravandi, William Wierda, Zeev Estrov, Gautam Borthakur, Tapan Kadia, Charles Cleeland, Jorge E. Cortes, and Hagop Kantarjian
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BCR‐ABL ,chronic myeloid leukemia ,symptom burden ,tyrosine kinase inhibitors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Treatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) is effective but needs to continue for several years, possibly indefinitely. Although generally safe, TKI may have hitherto poorly recognized effects in the quality of life (QoL) of such patients. Methods We prospectively measured the symptom burden of patients with chronic phase CML enrolled on frontline TKI trials with dasatinib, nilotinib, or ponatinib. A total of 219 patients were enrolled and filled out the MD Anderson Symptom Inventory (MDASI)‐CML questionnaire before the start of therapy and during follow‐up at defined time points of 3, 6, 9, 12, 18, and 24 months. Results The median age was 50 years. Longitudinal analysis showed relatively stable symptom severity scores over time. Fatigue was the most common symptom in all three cohorts, both prior to the start of therapy and during therapy, including after achievement of deep molecular remission. Work was the most affected component of daily living. Overall patients tolerated therapy well with improvement of their symptoms from baseline, with few dose reductions related to toxicity or symptomatology. Although 31% of the patients who completed MDASI‐CML achieved complete molecular remission by 24 months of treatment, nearly 90% experienced persistent mild symptoms. Conclusion Side effects related to TKIs may impact the quality of life in patients with CML‐CP. Further studies should investigate factors (comorbidities, concomitant medications, dose and schedule, etc) associated with these symptoms and interventions that may improve the patients’ QoL, including treatment discontinuation when safely feasible.
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- 2018
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18. Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia
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Iman Abou Dalle, Ronald Paranal, Jabra Zarka, Shilpa Paul, Koji Sasaki, Wen Li, Jing Ning, Nicholas J. Short, Maro Ohanian, Jorge E. Cortes, Elias J. Jabbour, and Ghayas C. Issa
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P
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- 2020
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19. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens
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Abhishek Maiti, Caitlin R. Rausch, Jorge E. Cortes, Naveen Pemmaraju, Naval G. Daver, Farhad Ravandi, Guillermo Garcia-Manero, Gautam Borthakur, Kiran Naqvi, Maro Ohanian, Nicholas J. Short, Yesid Alvarado, Tapan M. Kadia, Koichi Takahashi, Musa Yilmaz, Nitin Jain, Steven Kornblau, Guillermo Montalban Bravo, Koji Sasaki, Michael Andreeff, Prithiviraj Bose, Alessandra Ferrajoli, Ghayas C. Issa, Elias J. Jabbour, Lucia Masarova, Philip A. Thompson, Sa Wang, Sergej Konoplev, Sherry A. Pierce, Jing Ning, Wei Qiao, John S. Welch, Hagop M. Kantarjian, Courtney D. DiNardo, and Marina Y. Konopleva
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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20. Establishing geothermometric constraints on the local geothermal gradients: Case study of the Eastern Cordillera Basin, Colombia
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Carlos A. Barrera, Carlos A. Vargas, and Jorge E. Cortes
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Geodesy ,QB275-343 ,Geophysics. Cosmic physics ,QC801-809 - Abstract
Geochemical analyses were performed on 170 coal bed-trapped groundwater samples from 97 underground mines located in the Eastern Cordillera Basin, Colombia. The waters analyzed in this paper are from exploited coal beds, located up to 0.73 km deep, which emerge along with the local fault systems. The hydrochemical facies were classified based on the concentration of major ions by inferring the equilibrium state and rock water source. The main hydrochemical facies presented in the groundwater study are SO4CaMg, HCO3Ca, HCO3CaMg, and SO4HCO3 mixed waters. We used geothermometric equations to estimate the most probable temperature under in-situ conditions and the propagation of errors theory to test the results. The geothermal gradient in the study area is close to 30 °C/km, which is consistent with measurements from oil wells within the study area. Principal Component Analysis was used to explain factors affecting formation water composition and hydrogeochemical evolution of aquifers. Keywords: Geothermometers, Hydrochemistry, Coal bed, Formation waters, Eastern Cordillera Basin
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- 2018
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21. Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes
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Koichi Takahashi, Feng Wang, Kiyomi Morita, Yuanqing Yan, Peter Hu, Pei Zhao, Abdallah Abou Zhar, Chang Jiun Wu, Curtis Gumbs, Latasha Little, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Marisela Mendoza, Erika Thompson, Jianhua Zhang, Courtney D. DiNardo, Nitin Jain, Farhad Ravandi, Jorge E. Cortes, Guillermo Garcia-Manero, Steven Kornblau, Michael Andreeff, Elias Jabbour, Carlos Bueso-Ramos, Akifumi Takaori-Kondo, Marina Konopleva, Keyur Patel, Hagop Kantarjian, and P. Andrew Futreal
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Science - Abstract
Mixed phenotype acute leukemia (MPAL) is a rare leukemia that presents both myeloid and lymphoid markers on blasts. Here the authors perform genomic analysis to show MPAL involves genetic and epigenetic heterogeneity and is genetically distinct from AML, B-ALL, and T-ALL.
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- 2018
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22. Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy
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Zimu Gong, L. Jeffrey Medeiros, Jorge E. Cortes, Zi Chen, Lan Zheng, Yan Li, Shi Bai, Pei Lin, Roberto N. Miranda, Jeffrey L. Jorgensen, Timothy J. McDonnell, Wei Wang, Hagop M. Kantarjian, and Shimin Hu
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: The high fatality of patients with blast phase (BP) chronic myeloid leukemia (CML) necessitates identification of high-risk (HR) patients to prevent onset of BP. Here, we investigated the risk of BP based on additional chromosomal abnormality (ACA) profiles in a cohort of 2326 CML patients treated with tyrosine kinase inhibitors (TKIs). We examined the time intervals from initial diagnosis to ACA emergence (interval 1), from ACA emergence to onset of BP (interval 2), and survival after onset of BP (interval 3). Based on BP risk associated with each ACA, patients were stratified into intermediate-1, intermediate-2, and HR groups, with a median duration of interval 2 of unreached, 19.2 months, and 1.9 months, respectively. There was no difference in durations of intervals 1 or 3 among 3 groups. Including patients without ACAs who formed the standard-risk group, the overall 5-year cumulative probability of BP was 9.8%, 28.0%, 41.7%, and 67.4% for these 4 groups, respectively. The pre-BP disease course in those who developed BP was similar regardless of cytogenetic alterations, and 84.4% of BP patients developed BP within the first 5 years of diagnosis. In summary, interval 2 is the predominant determinant of BP risk and patient outcome. By prolonging the duration of interval 2, TKI therapy mitigates BP risk associated with low-risk ACAs or no ACAs but does not alter the natural course of CML with HR ACAs. Thus, we have identified a group of patients who have HR of BP and may benefit from timely alternative treatment to prevent onset of BP.
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- 2017
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23. Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV)
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Lucia Masarova, C. Cameron Yin, Jorge E. Cortes, Marina Konopleva, Gautam Borthakur, Kate J. Newberry, Hagop M. Kantarjian, Carlos E. Bueso-Ramos, and Srdan Verstovsek
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Essential thrombocythemia ,Polycythemia vera ,Pegylated interferon alfa-2a ,Histomorphological response ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Pegylated interferon alfa-2a (PEG-IFN-α-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG-IFN-α-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients. Methods Among 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6–24 months while on therapy in all patients, and after therapy discontinuation in some patients. Results The median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous. Conclusions Our results show the ability of PEG-IFN-α-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients.
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- 2017
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24. Correction to: Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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Musa Yilmaz, Mansour Alfayez, Courtney D. DiNardo, Gautam Borthakur, Tapan M. Kadia, Marina Y. Konopleva, Sanam Loghavi, Rashmi Kanagal-Shamanna, Keyur P. Patel, Elias J. Jabbour, Guillermo Garcia‑Manero, Naveen Pemmaraju, Sherry A. Pierce, Issa Ghayas, Nicholas J. Short, Guillermo Montalban-Bravo, Koichi Takahashi, Rita Assi, Ahmad S. Alotaibi, Maro Ohanian, Michael Andreeff, Jorge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi, and Naval G. Daver
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Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
An amendment to this paper has been published and can be accessed via the original article.
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- 2021
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25. Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis
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Prajwal Boddu, Hagop M. Kantarjian, Guillermo Garcia-Manero, Farhad Ravandi, Srdan Verstovsek, Elias Jabbour, Gautam Borthakur, Marina Konopleva, Kapil N. Bhalla, Naval Daver, Courtney D. DiNardo, Christopher B. Benton, Koichi Takahashi, Zeev Estrov, Sherry R. Pierce, Michael Andreeff, Jorge E. Cortes, and Tapan M. Kadia
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Secondary acute myeloid leukemia (s-AML) includes therapy-related AML and AML evolving from antecedent hematological disorder (AHD). s-AML arising after treating AHD likely represents a prognostically distinct, high-risk disease category. In this study, treated s-AML (ts-AML) was defined by: (1) prior diagnosis of myelodysplasia, myeloproliferative neoplasm, or aplastic anemia and (2) at least 1 therapy for that diagnosis. ts-AML was categorized by age (< or ≥60 years), and each cohort assessed for response rates and overall survival (OS) on various treatment regimens. Survival outcomes were compared against other high-risk prognostic subsets. Results showed that complete response and 8-week mortality rates were 32% and 27% in the younger, and 24% and 19% in the older age groups, respectively. There was a significant OS difference within s-AML based on prior treatment of AHD (ie, ts-AML vs s-AML with untreated AHD, 4.2 vs 9.2 months; P < .001). Survival in ts-AML was poor across both cohorts (younger and older, 5 and 4.7 months, respectively). In younger AML, survival was significantly inferior in ts-AML when compared with deletion 5/7, TP53, 3q abnormality, and therapy-related AML groups (median, 5 vs 7.9, 7.8, 7.9, and 11.2 months, respectively; P < .01). Additional adverse karyotype within ts-AML was associated with even worse outcomes (OS range, 1.6-2.8 months). ts-AML represents a very high-risk category, even in younger AML patients. s-AML should be further classified to describe ts-AML, an entity less responsive to currently applied treatment approaches. Future AML trial designs should accommodate ts-AML as a distinct subgroup.
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- 2017
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26. Therapy-related myelofibrosis does not appear to exist
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Lucia Masarova, Gabriele Todisco, Taghi Manshouri, Kate J. Newberry, Jorge E. Cortes, Hagop M. Kantarjian, Zeev Estrov, and Srdan Verstovsek
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Specialties of internal medicine ,RC581-951 - Published
- 2017
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27. Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia
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Timothy P. Hughes, Pierre Laneuville, Philippe Rousselot, David S. Snyder, Delphine Rea, Neil P. Shah, David Paar, Elisabetta Abruzzese, Andreas Hochhaus, Jeffrey H. Lipton, and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034/Dose-optimization. With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not. clinicaltrials.gov identifier 00481247; 00123474.
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- 2019
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28. Phase 3 results for vosaroxin/cytarabine in the subset of patients ≥60 years old with refractory/early relapsed acute myeloid leukemia
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Farhad Ravandi, Ellen K. Ritchie, Hamid Sayar, Jeffrey E. Lancet, Michael D. Craig, Norbert Vey, Stephen A. Strickland, Gary J. Schiller, Elias Jabbour, Arnaud Pigneux, Heinz-August Horst, Christian Récher, Virginia M. Klimek, Jorge E. Cortes, Angelo-Michele Carella, Miklos Egyed, Utz Krug, Judith A. Fox, Adam R. Craig, Renee Ward, Jennifer A. Smith, Gary Acton, Hagop M. Kantarjian, and Robert K. Stuart
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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29. Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia
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Prajwal Boddu, Gautam Borthakur, Mythili Koneru, Xuelin Huang, Kiran Naqvi, William Wierda, Prithviraj Bose, Elias Jabbour, Zeev Estrov, Jan Burger, Yesid Alvarado, April Deshmukh, Ami Patel, Antonio Cavazos, Lina Han, Jorge E. Cortes, Hagop Kantarjian, Michael Andreeff, and Marina Konopleva
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LY2510924 ,idarubicin ,cytarabine ,relapsed refractory ,acute myeloid leukemia ,CXC4 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model.Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18–70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/μL was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion.Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19–70). Median number of prior therapies was 1 (1–3). Six and five patients were treated at dose-levels “0” (10 mg) and “1” (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels “0” and “1,” respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ≥ 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy.Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level.
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- 2018
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30. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study
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Carlo Gambacorti-Passerini, Jorge E. Cortes, Jeff H. Lipton, Hagop M. Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Rocco Crescenzo, Nathalie Bardy-Bouxin, Mark Shapiro, Kay Noonan, Eric Leip, Liza DeAnnuntis, Tim H. Brümmendorf, and H. Jean Khoury
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6–96.3) and 25.6 (0.2–96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3–5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
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- 2018
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31. Frontline therapy with high-dose imatinib versus second generation tyrosine kinase inhibitor in patients with chronic-phase chronic myeloid leukemia – a propensity score analysis
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Koji Sasaki, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi, Koichi Takahashi, Marina Konopleva, Gautam Borthakur, Guillermo Garcia-Manero, William Wierda, Naval Daver, Preetesh Jain, Toshihisa Satta, Sherry Pierce, May Beth Rios, and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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32. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy
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Gautam Borthakur, Herve Dombret, Philippe Schafhausen, Tim Henrik Brummendorf, Nicolas Boissel, Elias Jabbour, Mariangela Mariani, Laura Capolongo, Patrizia Carpinelli, Cristina Davite, Hagop Kantarjian, and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Two dosing schedules were studied: schedule A, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1–7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1–14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m2. Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18).
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- 2015
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33. Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies
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Gautam Borthakur, Michael G. Rosenblum, Moshe Talpaz, Naval Daver, Farhad Ravandi, Stefan Faderl, Emil J. Freireich, Tapan Kadia, Guillermo Garcia-Manero, Hagop Kantarjian, and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We conducted a phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with relapsed, refractory myeloid leukemias. Twenty-eight patients received the construct intravenously at four dose levels (12, 18, 28 and 40 mg/m2 per course) in a “3+3” study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m2 total dose was considered the maximally tolerated dose. Four patients developed a reduction in peripheral blood blasts of at least 50%. Three patients treated with the 10, 12 and 28 mg/m2 doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m2. Pharmacokinetic analysis demonstrated that the highest blood levels achieved were 200-300 ng/mL which cleared with a half-life of ∼20 hours. Antigenicity was low with one patient at the 12 mg/m2 dose and one patient at the 18 mg/m2 dose (2/23,
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- 2013
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34. Hypocellular acute myeloid leukemia in adults: analysis of the clinical outcome of 123 patients
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Aref Al-Kali, Sergej Konoplev, Erpei Lin, Tapan Kadia, Stefan Faderl, Farhad Ravandi, Mohamad Ayoubi, Mark Brandt, Jorge E. Cortes, Hagop Kantarjian, and Gautam Borthakur
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The hypocellular variant of acute myeloid leukemia accounts for less than 10% of all cases of adult acute myeloid leukemia. It is defined by having less than 20 percent of cellular bone marrow in a biopsy at presentation. It is unclear in the literature whether the outcome of hypocellular acute myeloid leukemia differs from that of non-hypocellular acute myeloid leukemia.Design and Methods We retrospectively analyzed all the cases reported to be hypocellular acute myeloid leukemia between 2000 and 2009. A second pathology review was conducted and the diagnosis was confirmed in all cases.Results One hundred twenty-three (9%) patients were identified: patients with hypocellular acute myeloid leukemia were older than those with non-hypocellular acute myeloid leukemia (P=0.009) and more frequently presented with cytopenias (P
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- 2012
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35. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias
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Gautam Borthakur, Hagop Kantarjian, Farhad Ravandi, Weiguo Zhang, Marina Konopleva, John J. Wright, Stefan Faderl, Srdan Verstovsek, Sheela Mathews, Michael Andreeff, and Jorge E. Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.Design and Methods Fifty patients received one of two different schedules; Schedule “A”: once or twice daily, five days per week, every week for a 21 day cycle, and Schedule “B”: once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules.Results Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation.Conclusions Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations. (ClinicalTrials.gov Identifier: NCT00217646)
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- 2011
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36. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers
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Kolhe, Nikhil Shri Sahajpal, Ashis K. Mondal, Harmanpreet Singh, Ashutosh Vashisht, Sudha Ananth, Daniel Saul, Alex R. Hastie, Benjamin Hilton, Barbara R. DuPont, Natasha M. Savage, Vamsi Kota, Alka Chaubey, Jorge E. Cortes, and Ravindra
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optical genome mapping ,523-gene NGS panel ,myeloid cancers - Abstract
The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel had an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Importantly, the IPSS-R cytogenetic risk group changed from very good/good to very poor in 22% of MDS (2/9) cases based on comprehensive profiling (karyotyping, FISH, and 54-gene panel vs. OGM and 523-gene panel), while additionally identifying six compound heterozygous events of potential clinical relevance in six cases (6/30, 20%). This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers demonstrated increased yield of actionable targets that can potentially result in improved clinical outcomes.
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- 2023
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37. Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results
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Michael J. Mauro, Timothy P. Hughes, Dong-Wook Kim, Delphine Rea, Jorge E. Cortes, Andreas Hochhaus, Koji Sasaki, Massimo Breccia, Moshe Talpaz, Oliver Ottmann, Hironobu Minami, Yeow Tee Goh, Daniel J. DeAngelo, Michael C. Heinrich, Valle Gómez-García de Soria, Philipp le Coutre, Francois-Xavier Mahon, Jeroen J. W. M. Janssen, Michael Deininger, Naranie Shanmuganathan, Mark B. Geyer, Silvia Cacciatore, Fotis Polydoros, Nithya Agrawal, Matthias Hoch, Fabian Lang, Hematology, CCA - Cancer biology and immunology, and CCA - Imaging and biomarkers
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Cancer Research ,Oncology ,Hematology - Abstract
Asciminib is approved for patients with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10–200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.
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- 2023
38. Within patient genetic diversity of bla KPC harboring Klebsiella pneumoniae in a Colombian hospital and identification of a new NTEKPC platform
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Johana Madroñero, Ricaurte Alejandro Marquez-Ortiz, Erika Vergara, Carlos A. Nieto, Javier Escobar-Perez, Zayda Lorena Corredor Rozo, Deisy Abril, Jorge E. Cortes, Aura Lucía Leal, Diana Palacios, Natasha Vanegas, and Zandra De La Rosa
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Whole genome sequencing ,Genetics ,Genetic diversity ,Multidisciplinary ,biology ,Klebsiella pneumoniae ,Science ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,bacterial infections and mycoses ,Genome ,Plasmid ,Pulsed-field gel electrophoresis ,polycyclic compounds ,Multilocus sequence typing ,Medicine ,Gene - Abstract
Resistance to carbapenems in Klebsiellapneumoniae has been mostly related with the worldwide dissemination of KPC, largely due to the pandemic clones belonging to the complex clonal (CC) 258. To unravel blaKPC post-endemic clinical impact, here we describe clinical characteristics of 68 patients from a high complexity hospital, and the molecular and genetic characteristics of their 139 blaKPC—K.pneumoniae (KPC-Kp) isolates. Of the 26 patients that presented relapses or reinfections, 16 had changes in the resistance profiles of the isolates recovered from the recurrent episodes. In respect to the genetic diversity of KPC-Kp isolates, PFGE revealed 45 different clonal complexes (CC). MLST for 12 representative clones showed ST258 was present in the most frequent CC (23.0%), however, remaining 11 representative clones belonged to non-CC258 STs (77.0%). Interestingly, 16 patients presented within-patient genetic diversity of KPC-Kp clones. In one of these, three unrelated KPC-Kp clones (ST258, ST504, and ST846) and a blaKPC—K.variicola isolate (ST182) were identified. For this patient, complete genome sequence of one representative isolate of each clone was determined. In K.pneumoniae isolates blaKPC was mobilized by two Tn3-like unrelated platforms: Tn4401b (ST258) and Tn6454 (ST504 and ST846), a new NTEKPC-IIe transposon for first time characterized also determined in the K.variicola isolate of this study. Genome analysis showed these transposons were harbored in different unrelated but previously reported plasmids and in the chromosome of a K.pneumoniae (for Tn4401b). In conclusion, in the blaKPC post-endemic dissemination in Colombia, different KPC-Kp clones (mostly non-CC258) have emerged due to integration of the single blaKPC gene in new genetic platforms. This work also shows the intra-patient resistant and genetic diversity of KPC-Kp isolates. This circulation dynamic could impact the effectiveness of long-term treatments.
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- 2021
39. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data
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Daniel A. Arber, Attilio Orazi, Robert P. Hasserjian, Michael J. Borowitz, Katherine R. Calvo, Hans-Michael Kvasnicka, Sa A. Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E. Bueso-Ramos, Jorge E. Cortes, Paola Dal Cin, Courtney D. DiNardo, Hervé Dombret, Eric J. Duncavage, Benjamin L. Ebert, Elihu H. Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A. Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S. Hobbs, Ronald Hoffman, Elias J. Jabbour, Jean-Jacques Kiladjian, Richard A. Larson, Michelle M. Le Beau, Mignon L.-C. Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G. Mullighan, Charlotte Niemeyer, Olatoyosi M. Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P. Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R. Savona, Charles A. Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A. Stock, Richard M. Stone, Martin S. Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M. Vannucchi, Paresh Vyas, Andrew H. Wei, Olga K. Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi, Arber, Daniel A, Orazi, Attilio, Hasserjian, Robert P, Borowitz, Michael J, Branford, Susan, Tefferi, Ayalew, and Hematology
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Consensus ,Leukemia ,Myeloproliferative Disorders ,Immunology ,Genomics ,Cell Biology ,Hematology ,Settore MED/08 - Anatomia Patologica ,World Health Organization ,Biochemistry ,Hematologic Neoplasms ,Acute Disease ,Humans ,myeloid neoplasia ,lymphoid neoplasia - Abstract
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
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- 2022
40. Citywide preparedness for a pandemic: A cross-sectional survey of knowledge, attitudes, and practices about respiratory infection prevention in Bogotá, Colombia
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Yuliet Liliana Rosero-Lasso, Jorge E. Cortes, and Pilar Espitia
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Health Knowledge, Attitudes, Practice ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Health Personnel ,030106 microbiology ,infecciones por coronavirus ,lcsh:Medicine ,Disaster Planning ,Coronavirus infections ,Colombia ,Brief Communication ,General Biochemistry, Genetics and Molecular Biology ,respiratory tract infections/prevention and control ,03 medical and health sciences ,0302 clinical medicine ,profesionales para control de infecciones ,Surveys and Questionnaires ,Health care ,Absenteeism ,medicine ,Infection control ,Humans ,030212 general & internal medicine ,infection control practitioners ,Pandemics ,Respiratory Tract Infections ,Infection Control ,business.industry ,lcsh:R ,personal de salud ,Respiratory infection ,infecciones del sistema respiratorio/prevención y control ,conocimientos, actitudes y práctica en salud ,Middle Aged ,Organizational Policy ,Cross-Sectional Studies ,Family medicine ,Preparedness ,Sick leave ,Respiratory virus ,Female ,Sick Leave ,business ,Infection Control Practitioners - Abstract
Healthcare personnel plays an important role in the prevention of acute respiratory infections in hospital settings.Our aim was to establish the level of knowledge about respiratory virus infections and the attitudes and practices among healthcare workers, leaders of infection control committees in hospitals of Bogotá, Colombia.We used a self-administered questionnaire of 28 items during the monthly meeting sponsored by the local health authority. "Yes or no" and "true or false" questions were applied to measure knowledge. Attitudes and practices were measured with a Likert-type scale according to the agreement degree.We surveyed 70 healthcare workers. Respondents demonstrated a good level of knowledge as 80% of them answered correctly more than five questions. A total of 54.4% showed a low degree of agreement when asked if their institutions have the policy to stay home when they are sick with respiratory symptoms and 67.1% never or rarely remain at home under such conditions.Healthcare worker leaders of infection control committees in Bogotá's ospitals have adequate knowledge about the prevention of seasonal respiratory viruses. There is a need for implementing urgent sick leave policies as a measure to prevent the spread of potential coronavirus infections in hospitals.Introducción. El personal de salud juega un papel importante en la prevención de la diseminación de los virus respiratorios en los hospitales. Objetivo. Establecer el nivel de conocimiento y determinar las actitudes y prácticas en relación con los virus respiratorios entre los encargados de los comités de infecciones de los hospitales de Bogotá. Materiales y métodos. Los participantes respondieron una encuesta de 28 ítems durante una de las sesiones mensuales del comité de infecciones de la ciudad. Se midió el conocimiento y se formularon preguntas sobre las actitudes y las prácticas utilizando una escala de tipo Likert para evaluar la conformidad. Resultados. Se encuestaron 70 trabajadores de salud. Los participantes tenían un buen nivel de conocimiento, ya que el 80 % de los respondientes tuvieron cinco o más respuestas correctas. El 54,4 % mostró un bajo nivel de conformidad en cuanto a si susinstituciones tenían una política de quedarse en casa en caso de síntomas respiratorios y 64,1 % nunca o casi nunca se queda en casa cuando presenta dichos síntomas. Conclusión. Los trabajadores de la salud que encabezan los comités de infecciones de los hospitales de Bogotá tienen un adecuado conocimiento de la prevención de los virus respiratorios. Deben implementarse políticas de quedarse en casa para el personal con síntomas gripales, con el fin de prevenir la potencial diseminación de virus en los hospitales.
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- 2020
41. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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Guillermo Garcia-Manero, Nicholas J. Short, Keyur P. Patel, Elias Jabbour, Mansour Alfayez, Tapan M. Kadia, Naval Daver, Koichi Takahashi, Ahmad S. Alotaibi, Hagop M. Kantarjian, Sherry Pierce, Musa Yilmaz, Jorge E. Cortes, Farhad Ravandi, Courtney D. DiNardo, Issa Ghayas, Guillermo Montalban-Bravo, Rita Assi, Marina Konopleva, Sanam Loghavi, Naveen Pemmaraju, Michael Andreeff, Rashmi Kanagal-Shamanna, Maro Ohanian, and Gautam Borthakur
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Adult ,Male ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,Gilteritinib ,lcsh:RC254-282 ,Young Adult ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Overall survival ,Humans ,In patient ,Midostaurin ,Protein Kinase Inhibitors ,Molecular Biology ,Aged ,Retrospective Studies ,Aged, 80 and over ,Hematology ,business.industry ,lcsh:RC633-647.5 ,Research ,FLT3 mutations ,Correction ,lcsh:Diseases of the blood and blood-forming organs ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Low-intensity therapy ,Leukemia, Myeloid, Acute ,Treatment Outcome ,fms-Like Tyrosine Kinase 3 ,Oncology ,chemistry ,Sequential FLT3 inhibitors ,Mutation ,Flt3 mutation ,Cohort ,FLT3-PCR ,Female ,business ,Quizartinib ,medicine.drug - Abstract
Background Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45–55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. Results In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion CRc rates drop progressively with sequential exposure to FLT3i’s in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.
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- 2020
42. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
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Guillermo Garcia-Manero, Michael Andreeff, Ken Furudate, Keyur P. Patel, Jianhua Zhang, Nicholas Navin, Elias Jabbour, Farhad Ravandi, Feng Wang, Niko Beerenwinkel, P. Andrew Futreal, Erika Thompson, Curtis Gumbs, Latasha Little, Koichi Takahashi, Kiyomi Morita, Jack Kuipers, Tianyuan Hu, Sanam Loghavi, Sa A. Wang, Jairo Matthews, Kapil N. Bhalla, Courtney D. DiNardo, Daisuke Nakada, Tomoyuki Tanaka, Yuya Sasaki, Marina Konopleva, Katharina Jahn, Hagop M. Kantarjian, Jorge E. Cortes, Carlos E. Bueso-Ramos, Yuanqing Yan, and Xingzhi Song
- Subjects
0301 basic medicine ,Male ,General Physics and Astronomy ,medicine.disease_cause ,Somatic evolution in cancer ,Cohort Studies ,Mice ,0302 clinical medicine ,Single-cell analysis ,Mice, Inbred NOD ,Convergent evolution ,hemic and lymphatic diseases ,Cancer genomics ,lcsh:Science ,Mutation ,Multidisciplinary ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,Genomics ,Middle Aged ,Leukemia ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Single-Cell Analysis ,Tumour heterogeneity ,Science ,Computational biology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Article ,Acute myeloid leukaemia ,Clonal Evolution ,03 medical and health sciences ,medicine ,Animals ,Humans ,Genetic Association Studies ,Aged ,Models, Genetic ,General Chemistry ,Sequence Analysis, DNA ,medicine.disease ,030104 developmental biology ,lcsh:Q - Abstract
Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine., Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.
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- 2020
43. The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis
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Srdan Verstovsek, Lucia Masarova, Tapan M. Kadia, Farhad Ravandi, Guillermo Garcia-Manero, Jairo Matthews, Jorge E. Cortes, Mahran Shoukier, Koji Sasaki, Gautam Borthakur, Kiran Naqvi, and Elias Jabbour
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Ruxolitinib ,medicine.medical_specialty ,Eltrombopag ,Gastroenterology ,Benzoates ,Article ,chemistry.chemical_compound ,Internal medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Myocardial infarction ,Myelofibrosis ,Protein Kinase Inhibitors ,Thrombocytosis ,business.industry ,Myeloid leukemia ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Thrombocytopenia ,Venous thrombosis ,Hydrazines ,Treatment Outcome ,chemistry ,Primary Myelofibrosis ,Elevated transaminases ,Pyrazoles ,business ,medicine.drug - Abstract
Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKI) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); with a median age of 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12 of 15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients five could re-escalate the TKI dose and nine improved their response. None of the six patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1,000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted (clinicaltrials gov. Identifier: NCT01428635).
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- 2020
44. Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia
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Jeanne Mendell, Ophelia Yin, Mark J. Levis, Dongwoo Kang, Youngsook Choi, Siddhartha Ganguly, Malaz Abutarif, Giovanni Martinelli, Elizabeth Ludwig, Hannah Huang, Samer K. Khaled, David Jaworowicz, Jorge E. Cortes, Nigel H. Russell, Alwin Krämer, Alexander E. Perl, and Jill Fiedler-Kelly
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Adult ,Male ,Adolescent ,Body Surface Area ,Population ,Cmax ,Administration, Oral ,AC886 ,Pharmacology ,acute myeloid leukemia ,030226 pharmacology & pharmacy ,relapsed/refractory ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Pharmacometrics ,population pharmacokinetics ,Medicine ,Humans ,Pharmacology (medical) ,Drug Interactions ,Benzothiazoles ,education ,Protein Kinase Inhibitors ,Active metabolite ,Quizartinib ,Aged ,Body surface area ,Aged, 80 and over ,education.field_of_study ,Clinical Trials as Topic ,business.industry ,Phenylurea Compounds ,Area under the curve ,Myeloid leukemia ,Middle Aged ,Healthy Volunteers ,quizartinib ,Leukemia, Myeloid, Acute ,chemistry ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Concomitant ,Area Under Curve ,Cytochrome P-450 CYP3A Inhibitors ,Female ,business - Abstract
Quizartinib is an FMS‐like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3‐internal tandem duplication–mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM‐R study. Quizartinib was given as a single dose or multiple once‐daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed‐effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were
- Published
- 2020
45. Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia
- Author
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Naval Daver, Courtney D. DiNardo, Ahmad Ghorab, Farhad Ravandi, Allyson Price, Tapan M. Kadia, Naveen Pemmaraju, Gautam Borthakur, Xuemei Wang, Dai Chihara, Fevzi Firat Yalniz, Koji Sasaki, Hagop M. Kantarjian, Keyur P. Patel, Ghayas C. Issa, Jorge E. Cortes, Hyunsoo Hwang, and Iman Abou Dalle
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Oncology ,Adult ,Male ,NPM1 ,medicine.medical_specialty ,Myeloid ,Adolescent ,medicine.medical_treatment ,lcsh:RC254-282 ,Article ,Acute myeloid leukaemia ,Cytogenetics ,Young Adult ,Medical research ,fluids and secretions ,Internal medicine ,hemic and lymphatic diseases ,Medicine ,Humans ,Young adult ,Protein Kinase Inhibitors ,Survival analysis ,Alleles ,Aged ,Aged, 80 and over ,Chemotherapy ,business.industry ,Myeloid leukemia ,hemic and immune systems ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Survival Analysis ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,fms-Like Tyrosine Kinase 3 ,Mutation ,embryonic structures ,Female ,business ,Nucleophosmin - Abstract
FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24–0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7–1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25–0.66, p p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35–0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19–0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.
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- 2020
46. Candidemia en Colombia
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José Franklin Ruiz, Lizeth Natalia Melgarejo-Moreno, Jorge E. Cortes, and Elkin V Lemos
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Pediatrics ,micosis ,Latin Americans ,Antifungal Agents ,unidad de cuidados intensivos ,intensive care units ,candidiasis, invasive ,Revisión De Tema ,lcsh:Medicine ,Disease ,Comorbidity ,Infant, Premature, Diseases ,Postoperative Complications ,Risk Factors ,Neoplasms ,colombia ,APACHE ,Candida ,Incidence (epidemiology) ,Candidiasis ,Prognosis ,High incidence ,Developed country ,Infant, Premature ,medicine.drug ,medicine.medical_specialty ,Neutropenia ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Opportunistic Infections ,Colombia ,candidiasis invasiva ,General Biochemistry, Genetics and Molecular Biology ,Immunocompromised Host ,Disease severity ,Species Specificity ,Drug Resistance, Fungal ,Renal Dialysis ,Intensive care ,medicine ,Humans ,mycoses ,invasive fungal infections ,business.industry ,candidemia ,lcsh:R ,Respiration, Artificial ,candidiasis ,Catheter-Related Infections ,business ,Fluconazole ,infecciones fúngicas invasivas - Abstract
Resumen En Colombia, especialmente en las unidades de cuidados intensivos, la candidemia es una causa frecuente de infección del torrente sanguíneo y representa el 88 % de las infecciones fúngicas en pacientes hospitalizados, con una mortalidad entre 36 y 78 %. Su incidencia en Colombia es mayor a la reportada en los países desarrollados e, incluso, en otros países de Latinoamérica. Para su manejo deben considerarse los factores de riesgo del paciente, luego valorar las características clínicas y, finalmente, hacer los estudios microbiológicos y, si es necesario, pruebas moleculares. En general, las guías estadounidenses, latinoamericanas y europeas recomiendan las equinocandinas como el tratamiento de primera línea de la candidemia y difieren en el uso de fluconazol dependiendo de la 'evidencia', la gravedad de la enfermedad, la exposición previa a los azoles y la prevalencia de Candida no albicans. Dada su gran incidencia en nuestro país, asociada con una elevada mortalidad, esta infección debe buscarse sistemáticamente en pacientes con factores de riesgo, con el fin de iniciar oportunamente el tratamiento antifúngico. Abstract In Colombia, especially in intensive care units, candidemia is a frequent cause of infection, accounting for 88% of fungal infections in hospitalized patients, with mortality ranging from 36% to 78%. Its incidence in Colombia is higher than that reported in developed countries and even higher than in other Latin American countries. First, the patient's risk factors should be considered, and then clinical characteristics should be assessed. Finally, microbiological studies are recommended and if the evidence supports its use, molecular testing. In general, American, Latin American, and European guides place the echinocandins as the first-line treatment for candidemia and differ in the use of fluconazole based on evidence, disease severity, previous exposure to azoles, and prevalence of Candida non-albicans. Taking into account the high incidence of this disease in our setting, it should be looked for in patients with risk factors to start a prompt empirical anti-fungal treatment.
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- 2020
47. Safety-Critical Event Triggered Control via Input-to-State Safe Barrier Functions
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Pio Ong, Andrew J. Taylor, Aaron D. Ames, and Jorge E. Cortes
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0209 industrial biotechnology ,Control and Optimization ,Computer science ,Critical event ,Distributed computing ,020208 electrical & electronic engineering ,Control (management) ,Context (language use) ,02 engineering and technology ,Electrical Engineering and Systems Science - Systems and Control ,020901 industrial engineering & automation ,Control and Systems Engineering ,Bounded function ,0202 electrical engineering, electronic engineering, information engineering ,State (computer science) ,Transcription (software) ,Mathematics - Optimization and Control - Abstract
The efficient utilization of available resources while simultaneously achieving control objectives is a primary motivation in the event-triggered control paradigm. In many modern control applications, one such objective is enforcing the safety of a system. The goal of this paper is to carry out this vision by combining event-triggered and safety-critical control design. We discuss how a direct transcription, in the context of safety, of event-triggered methods for stabilization may result in designs that are not implementable on real hardware due to the lack of a minimum interevent time. We provide a counterexample showing this phenomena and, building on the insight gained, propose an event-triggered control approach via Input to State Safe Barrier Functions that achieves safety while ensuring that interevent times are uniformly lower bounded. We illustrate our results in simulation., Comment: 6 pages, 2 figures, submitted to L-CSS + CDC 2020
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- 2021
48. Inotuzumab Ozogamicin with Bosutinib for Relapsed or Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia or Lymphoid Blast Phase of Chronic Myeloid Leukemia
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Farhad Ravandi, Partow Kebriaei, Naval Daver, Nitin Jain, Abhishek Maiti, Elias Jabbour, Naveen Pemmaraju, Jing Ning, Nicholas J. Short, Marina Konopleva, Tapan M. Kadia, Hagop M. Kantarjian, and Jorge E. Cortes
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Adult ,Male ,medicine.medical_specialty ,Neutropenia ,Philadelphia chromosome ,Gastroenterology ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,medicine ,Humans ,Inotuzumab Ozogamicin ,Philadelphia Chromosome ,Aged ,Inotuzumab ozogamicin ,Aniline Compounds ,business.industry ,Myeloid leukemia ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Rash ,Leukemia ,030220 oncology & carcinogenesis ,Quinolines ,Female ,medicine.symptom ,business ,Blast Crisis ,Bosutinib ,030215 immunology ,medicine.drug - Abstract
Relapsed/refractory (R/R) Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes. We designed a phase 1/2 study combining inotuzumab ozogamicin with bosutinib for this patient population. Patients with T315I mutation were excluded. Bosutinib was administered daily at three dose levels (300 mg/d, 400 mg/d, 500 mg/d) in a 3 + 3 design. Inotuzumab ozogamicin was dosed weekly during cycle one, and once every 4 weeks subsequently for a total of six cycles. The primary objective was to determine the safety and the maximum tolerated dose (MTD) of bosutinib in combination with inotuzumab ozogamicin. Eighteen patients were enrolled (Ph-positive ALL, n = 16; LBP-CML, n = 2). The median age was 62 years (range, 19-74) and the median number of prior therapies was one (range, 1-5). Dose limiting toxicities included grade 3 skin rash and bosutinib 400 mg daily was determined as the MTD. The most frequent grade 3/4 treatment-emergent adverse events were thrombocytopenia (60%) and neutropenia (38%). A complete response (CR) / CR with incomplete count recovery (CRi) was achieved in 15/18 (83%) patients; 11/18 (61%) patients achieved negative measurable residual disease by flow cytometry. Complete molecular response was noted in 10/18 (56%) patients. The 30-day mortality was 0%. After a median follow-up of 44 months, the median duration of response and overall survival were 7.7 months and 13.5 months, respectively. Six patients had a subsequent allogeneic stem cell transplant. No patient developed veno-occlusive disease. Inotuzumab ozogamicin with bosutinib was well tolerated in R/R Ph-positive ALL and LBP-CML.
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- 2021
49. SARS-CoV2/COVID-19 Infection in Transplant Recipients and in Patients on the Organ Transplant Waiting List in Colombia
- Author
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Carlos A. Benavides-V, Karime Osorio-Arango, Yazmín Rocío Arias-Murillo, Carolina Plazas-Sierra, María A. Salinas-N, and Jorge E. Cortes
- Subjects
Adult ,Male ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Waiting Lists ,MEDLINE ,030230 surgery ,Colombia ,Organ transplantation ,Article ,03 medical and health sciences ,0302 clinical medicine ,Public health surveillance ,Pandemic ,medicine ,Humans ,Hospital Mortality ,Registries ,Pandemics ,Aged ,Transplantation ,business.industry ,SARS-CoV-2 ,SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus type 2 ,Mortality rate ,Risk of infection ,COVID-19 ,Organ Transplantation ,Middle Aged ,ICU, Intensive care unite ,Donation ,Emergency medicine ,030211 gastroenterology & hepatology ,Female ,Surgery ,business - Abstract
In an effort to assess our determination to continue transplant activity in Colombia during the Covid-19/pandemic, this study seeks to describe the risk of infection and mortality of transplanted patients versus those on waiting list. Therefore, a descriptive study of SARS-CoV-2/COVID-19 infection in transplant recipients and patients on waiting list was conducted. The data sources were the information systems of the Instituto Nacional de Salud of Colombia: National Donation and Transplant Information System, the National Public Health Surveillance System and the National COVID-19 Data Repository. Characteristics of the patients who tested positive were analyzed and the mortality rate was determined. An RT-PCR test for SARS-CoV-2/COVID-19 was performed in 7% of the transplant recipients included in this study, and 14.8% of them tested positive. Among patients on the waiting list, 15.2% were tested and 16.7% showed positive results. Overall, 1% (84/8,108) of the transplant recipients and 2.5% (74/2,926) of patients on waiting list were infected with SARS-CoV-2/COVID-19. There were no differences in mortality between these groups (p=0.8748). In conclusion, with the data obtained so far, the hospital availability, and the adoption of safety protocols in the institutions, our findings can support the continuity of the transplant activities in this country., HIGHLIGHTS • As on July 31, 2020, a total of 1,011 patients including transplant recipients and those on the organ transplant waiting list were tested for SARS-CoV-2. Confirmed infection was seen in 158 cases • The results as on July 31, 2020 in Colombia indicate a statistically lower incidence of infection in transplant recipients (1.03%) compared to that in patients on the waiting list (2.52%) who were mostly (94.6%) on dialysis, and probably could not adhere to the strict quarantine due to this condition. • The case mortality rate in the study population (transplant recipients and patients on the organ transplant waiting list) was 3 times higher than that in the general population (13.3% and 3.9%, respectively). • There were no statistically significant differences in mortality among transplant recipients and those on the waiting list for transplant (p=0.8980).
- Published
- 2021
- Full Text
- View/download PDF
50. Pharmacokinetics and Pharmacodynamics of Cefepime in Adults with Hematological Malignancies and Febrile Neutropenia after Chemotherapy
- Author
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Julio César Gómez, Ricardo Sánchez, Daniel S Parra, Edelberto Silva, Sonia Isabel Cuervo, Jorge E. Cortes, Jose Camilo Álvarez, Lorena L Jiménez, and Jorge Aurelio Díaz
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Cefepime ,030106 microbiology ,Antibiotics ,RM1-950 ,Neutropenia ,Biochemistry ,Microbiology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,cefepime ,Pharmacology (medical) ,hematologic neoplasms ,030212 general & internal medicine ,Dosing ,General Pharmacology, Toxicology and Pharmaceutics ,chemotherapy-induced febrile neutropenia ,Chemotherapy ,Creatinine ,business.industry ,medicine.disease ,Infectious Diseases ,chemistry ,cephalosporins ,Therapeutics. Pharmacology ,business ,pharmacokinetics ,Febrile neutropenia ,medicine.drug - Abstract
Patients with chemotherapy-induced febrile neutropenia (CIFN) may have changes in the pharmacokinetics (PK) compared to patients without malignancies or neutropenia. Those changes in antibiotic PK could lead to negative outcomes for patients if the therapy is not adequately adjusted to this. In this, open-label, non-randomized, prospective, observational, and descriptive study, a PK model of cefepime was developed for patients with hematological neoplasms and post-chemotherapy febrile neutropenia. This study was conducted at a cancer referral center, and study participants were receiving 2 g IV doses of cefepime every 8 h as 30-min infusions. Cefepime PK was well described by a two compartment model with a clearance dependent on a serum creatinine level. Using Monte Carlo simulations, it was shown that continuous infusions of 6g q24h could have a good achievement of PK/PD targets for MIC levels below the resistance cut-off point of Enterobacteriaceae. According to the simulations, it is unnecessary to increase the daily dose of cefepime (above 6 g daily) to increase the probability of target attainment (PTA). Cumulative fraction of response (CFR) using interment dosing was suboptimal for empirical therapy regimens against K. pneumoniae and P. aeruginosa, and continuous infusions could be used in this setting to maximize exposure. Patients with high serum creatinine levels were more likely to achieve predefined PK/PD targets than patients with low levels.
- Published
- 2021
- Full Text
- View/download PDF
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