18 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. 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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4. 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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5. 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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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. Phase II trial of ponatinib in patients with chronic myeloid leukemia resistant to one previous tyrosine kinase inhibitor
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Hagop M. Kantarjian, Jorge E. Cortes, Jeffrey Skinner, Elias Jabbour, and David Sanford
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Relative risk reduction ,medicine.medical_specialty ,business.industry ,Ponatinib ,Phases of clinical research ,Common Terminology Criteria for Adverse Events ,Hematology ,Clinical trial ,Dasatinib ,chemistry.chemical_compound ,Nilotinib ,chemistry ,Internal medicine ,Immunology ,medicine ,Adverse effect ,business ,Online Only Articles ,medicine.drug - Abstract
Ponatinib is a tyrosine kinase inhibitor (TKI) designed to overcome resistance-inducing mutations, including the T315I mutation, in the ABL kinase domain. Initial clinical trials of ponatinib reported major cytogenetic response (MCyR) rates over 60% in heavily treated patients with chronic myeloid leukemia in chronic phase (CML-CP) and approval for patients who had received prior treatment with a TKI was granted by regulatory authorities in 2012.1–3 Due to concerns of thrombotic vascular events, ponatinib was transiently withdrawn from the US market in October 2013 on the recommendation of the FDA and later re-introduced in January 2014. Ponatinib is currently indicated for: 1) CML patients with the T315I mutation or in cases where no other TKI is indicated (US label); or 2) those resistant or intolerant to dasatinib or nilotinib, or for those in whom imatinib therapy is not clinically appropriate or who have the T315I mutation (European label). Over 90% of patients enrolled in earlier clinical trials of ponatinib had received at least 2 prior TKI. Among patients who have received just one TKI, data are only available for imatinib failure. Less than 50% of patients achieve a MCyR with dasatinib, nilotinib or bosutinib after imatinib failure, and deeper (i.e. molecular) responses are even less common. There are no prospective data on the use of ponatinib after failure of a 2nd generation TKI, making this sequence of therapy empirical. We designed a single center phase II clinical trial (clinicaltrials.gov identifier: 01746836) of ponatinib in patients with CML-CP and resistance or intolerance to only one FDA-approved TKI (imatinib, nilotinib or dasatinib). Failure of previous TKI therapy was defined according of European LeukemiaNet (ELN) recommendations.4 Exclusion criteria included: exposure to other non-FDA approved TKI, New York Heart Association (NYHA) cardiac class 3–4 heart disease, history of acute coronary syndrome, history of stroke or transient ischemic attack, history of peripheral arterial occlusive disease, history or venous thromboembolism, history of clinically significant ventricular arrhythmia, uncontrolled hypertension, history of pancreatitis, pregnancy or breastfeeding, and previous use of more than one FDA-approved TKI. The primary objective of the study was to estimate the rate of MCyR (CCyR + PCyR) at six months. Secondary outcomes included cytogenetic response at other time points, molecular response and toxicity profile. Hematologic, cytogenetic and molecular responses were determined according to ELN 2009 guidelines.4 The severity of adverse events (AEs) were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).5 Patients were initially treated at a starting dose of 45 mg/day; in October 2013 the starting dose was amended to 30 mg/day. Recruitment onto the trial took place between March 2013 and September 2013. Five patients were enrolled before the study was closed to new patient enrollment at the recommendation of the FDA due to safety concerns. All patients enrolled onto the trial continued ponatinib upon closure of the study, and the dose was reduced to 15–30 mg/day to minimize the risk of thrombotic vascular events. All patients were eligible for the trial due to failure of previous TKI therapy with specific reasons including: loss of CCyR (n=1), no CCyR after 18 months (n=1), no CCyR after 18 months + T315I mutant (n=1), T315I mutant (n=1) and no PCyR after 12 months (n=1). No other resistance mutations were identified at the time of enrollment. Median age was 50 years (range 42–74 years) and the previous TKI exposure included imatinib (n=3) and dasatinib (n=2). Only one patient had significant base-line cardiovascular (CV) risk factors (hypertension). Four patients (80%) achieved a CCyR at both the 3-month and 6-month assessment. Molecular responses at 12 months were: 1 patient MR4.5, 2 patients MMR, one patient with a significant reduction in transcript (0.11%), and one patient with no significant molecular response. After a median follow up of 22 months (range 18–26 months), cumulative best response for all patients was PCyR in one (previously treated with dasatinib) and MR4.5 in 4 patients. Responses were durable with all 4 patients who achieved a CCyR at six months maintaining an MR4.0 (n=1) or MR4.5 (n=3) at last follow up. The base-line disease status and response data are summarized in Table 1. Table 1. Base-line characteristics and responses. Grade 3–4 AEs included: hypertension (n=2), development of a neoplasm (superficially invasive skin squamous cell carcinoma) (n=1), increased lipase (n=2), increased amylase (n=1), increased ALT (n=2), increased AST (n=2), thrombocytopenia (n=1), and neutropenia (n=1). Four patients developed hypertension (Grade 2–3), one of them with base-line hypertension. Three of these 4 patients with hypertension were successfully treated with antihypertensive medication, while the other was monitored and was normotensive at subsequent visits without intervention. No venous or arterial thrombotic events were observed in any of the patients. Neither of the 2 patients who had increased lipase/amylase developed clinical pancreatitis. In both patients, a rise in pancreatic enzymes was observed within two months of starting ponatinib. In both instances, ponatinib was held for 1–2 weeks and re-started without significant rise in lipase or amylase. Similarly, neither patient experiencing grade 3 increases in AST/ALT had clinical symptoms of liver dysfunction or abnormal liver function testing. These patients were managed with dose interruption and ponatinib was successfully re-introduced at a reduced dose in both patients (15 mg/day). Recurrent grade 3–4 neutropenia and thrombocytopenia occurred in the patient who did not achieve a CCyR. These episodes were managed with treatment interruption and dose reduction with improvement in blood counts. All patients had a dose reduction; 2 patients continue on 30 mg/day and 3 patients on 15 mg/day. The median time to first dose reduction was three months (range 1–8 months) and this occurred either empirically to reduce CV risk in 3 patients or due to an AE in 2 patients. In summary, 80% of patients with exposure to one prior TKI achieved a CCyR and MR4.0 or better, with sustained responses over a relatively long follow-up period. Although interpretation of the findings of our trial is limited by the small number of patients, our results reinforce the efficacy of ponatinib in patients failing only one TKI. Our findings are consistent with the results of the phase I and phase II trials of ponatinib in CML-CP patients with TKI-resistance/intolerance, in which the rate of CCyR was 63% and 46%, respectively.2,3 Response rates in the phase II clinical trial were highest in CML-CP patients treated with only one previous TKI with CCyR and MMR rates of 74% and 47%, respectively.3 However, only 19 such patients were treated. The rate of venous and arterial thrombotic events with ponatinib in earlier studies was 37% and 24% in the phase I and II clinical trials, respectively, reported over longer follow-up periods.6,7 No patients in our trial experienced a thrombotic event, which could be explained by a random null rate due to the small number of patients and/or by the relative absence of significant CV risk factors in these patients. Most patients experiencing thrombotic events in previous clinical trials had pre-existing risk factors for CV events.8,9 In our series, the only CV event observed was hypertension, which was manageable with therapy in all patients concerned. It is also possible that, as patients in our trial received ponatinib at lower doses for most of the time they were on treatment due to early dose reductions, the risk of vascular thrombotic events might have been reduced. Currently, the approved starting dose of ponatinib is 45 mg/day, although it is acknowledged that the optimal starting dose of ponatinib is not known.1 In the phase I clinical trial, a peak serum concentration of 40 nM was achieved with a dose of 15 mg/day, which is the concentration required to suppress the development of resistance mutations in vitro.2 Furthermore, a post hoc study of previous clinical trials using ponatinib projected that dose reductions of 15 mg/day were associated with a 40% relative risk reduction of arterial thrombosis.10 Importantly, it is apparent from our results that patients can have sustained responses on lower doses of ponatinib, and the toxicity profile of ponatinib was manageable at these doses in our group. The results in this small cohort of patients suggest that ponatinib can be of clinical benefit for patients with CML-CP who have received only one prior TKI. Despite the availability of multiple TKIs, the results in this patient population could be improved, as the rate of CCyR in previous trials does not reach 50%, and EFS at 4–5 years is only approximately 50%.11–13 Further studies are required to help define the efficacy, safety and optimal dosing of ponatinib in this patient population.
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- 2015
15. 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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Farhad Ravandi, Naval Daver, Tapan M. Kadia, Michael G. Rosenblum, Moshe Talpaz, Hagop M. Kantarjian, Guillermo Garcia-Manero, Jorge E. Cortes, Stefan Faderl, Emil J. Freireich, and Gautam Borthakur
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Adult ,Male ,Myeloid ,medicine.drug_class ,Antineoplastic Agents ,Pharmacology ,Monoclonal antibody ,Immunotoxin ,medicine ,Humans ,Gelonin ,Aged ,Aged, 80 and over ,biology ,business.industry ,Immunotoxins ,Antibodies, Monoclonal ,Hematology ,Articles ,Middle Aged ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Treatment Outcome ,Leukemia, Myeloid ,Immunoglobulin G ,biology.protein ,Ribosome Inactivating Proteins, Type 1 ,Anti-CD33 Immunotoxin ,Female ,Bone marrow ,Antibody ,business - 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/m(2) per course) in a "3+3" study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m(2) 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/m(2) doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m(2). 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/m(2) dose and one patient at the 18 mg/m(2) dose (2/23,10%) developing antibodies to the recombinant gelonin component after 28 days. We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.
- Published
- 2013
16. Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia
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Gautam Borthakur, Raja Luthra, Sherry Pierce, Hagop M. Kantarjian, Jorge E. Cortes, Aziz Nazha, Tapan M. Kadia, Naval Daver, Stefan Faderl, and Farhad Ravandi
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Oncology ,Adult ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Karyotype ,Clone (cell biology) ,medicine.disease_cause ,Young Adult ,Recurrence ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Young adult ,Aged ,Retrospective Studies ,Mutation ,business.industry ,Remission Induction ,Induction chemotherapy ,Myeloid leukemia ,Retrospective cohort study ,hemic and immune systems ,Hematology ,Middle Aged ,Prognosis ,Minimal residual disease ,body regions ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Fms-Like Tyrosine Kinase 3 ,Immunology ,embryonic structures ,Original Articles and Brief Reports ,business ,psychological phenomena and processes - Abstract
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are among the most frequent molecular aberrations in patients with acute myeloid leukemia. We retrospectively analyzed 324 patients with acute myeloid leukemia treated with front-line induction chemotherapy between October 2004 and March 2010. Fifty-six patients had FLT3-ITD mutation at diagnosis. Fifty-one (91%) patients with FLT3-ITD achieved complete remission. Thirteen patients had FLT3 analysis at complete remission. None had FLT3-ITD. Twenty-five (49%) patients with FLT3-ITD relapsed. Of these, 13 (52%) had FLT3-ITD at relapse (3 negative and 9 not done). Among the 201 patients without FLT3-ITD at diagnosis who achieved complete remission, 77 (38%) relapsed among whom 8 (10%) patients acquired FLT3-ITD clone. We conclude that FLT3-ITD mutations are unstable at follow up and may occur for the first time at relapse. Therefore, FLT3-ITD is not a reliable marker for minimal residual disease in acute myeloid leukemia.
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- 2012
17. A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome
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Mahesh Swaminathan, Hagop M Kantarjian, Mark Levis, Veronica Guerra, Gautam Borthakur, Yesid Alvarado, Courtney D DiNardo, Tapan Kadia, Guillermo Garcia-Manero, Maro Ohanian, Naval Daver, Marina Konopleva, Naveen Pemmaraju, Alessandra Ferrajoli, Michael Andreeff, Nitin Jain, Zeev Estrov, Elias J Jabbour, William G Wierda, Sherry Pierce, Maria Rhona Pinsoy, Lianchun Xiao, Farhad Ravandi, and Jorge E Cortes
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
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- 2021
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18. Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring
- Author
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Rajyalakshmi Luthra, Keyur P. Patel, Neelima G. Reddy, Varan Haghshenas, Mark J. Routbort, Michael A. Harmon, Bedia A. Barkoh, Rashmi Kanagal-Shamanna, Farhad Ravandi, Jorge E Cortes, Hagop M Kantarjian, L. Jeffrey Medeiros, and Rajesh R. Singh
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Routine molecular testing in acute myeloid leukemia involves screening several genes of therapeutic and prognostic significance for mutations. A comprehensive analysis using single-gene assays requires large amounts of DNA, is cumbersome and timely consolidation of results for clinical reporting is challenging. High throughput, next-generation sequencing platforms widely used in research have not been tested vigorously for clinical application. Here we describe the clinical application of MiSeq, a next-generation sequencing platform to screen mutational hotspots in 54 cancer-related genes including genes relevant in acute myeloid leukemia (NRAS, KRAS, FLT3, NPM1, DNMT3A, IDH1/2, JAK2, KIT and EZH2). We sequenced 63 samples from patients with acute myeloid leukemia/myelodysplastic syndrome using MiSeq and compared the results with those obtained using another next-generation sequencing platform, Ion-Torrent Personal Genome Machine and other conventional testing platforms. MiSeq detected a total of 100 single nucleotide variants and 23 NPM1 insertions that were confirmed by Ion Torrent or conventional platforms, indicating complete concordance. FLT3-internal tandem duplications (n=10) were not detected; however, re-analysis of the MiSeq output by Pindel, an indel detection algorithm, did detect them. Dilution studies of cancer cell-line DNA showed that the quantitative accuracy of mutation detection was up to an allelic frequency of 1.5% with a high level of inter- and intra-run assay reproducibility, suggesting potential utility for monitoring response to therapy, clonal heterogeneity and evolution. Examples demonstrating the advantages of MiSeq over conventional platforms for disease monitoring are provided. Easy work-flow, high throughput multiplexing capability, 4-day turnaround time and simultaneous assessment of routinely tested and emerging markers make MiSeq highly applicable for clinical molecular testing in acute myeloid leukemia.
- Published
- 2014
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