96 results on '"Cortes, Jorge E."'
Search Results
2. Social needs and health-related quality of life among hematologic cancer survivors.
- Author
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Coughlin SS, Ayyala DN, Stewart JL, and Cortes JE
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- Humans, Middle Aged, Quality of Life, Food Supply, Survivors, Cancer Survivors, Multiple Myeloma, Hematologic Neoplasms, Leukemia
- Abstract
Objectives: Recent studies have examined social needs (social determinants of health) among cancer survivors, but studies have not specifically focused on patients with leukemia or lymphoma. We examined food insecurity and other social needs among hematologic cancer survivors, including individuals who had completed primary therapy for leukemia, lymphoma, or multiple myeloma. A particular focus of the study was on the relationship between social needs and health-related quality of life., Methods: We conducted a postal survey of a multiethnic cohort of hematologic cancer survivors who reside in Augusta, GA, or the surrounding area and who had been treated at the Georgia Cancer Center., Results: A total of 53 patients with a history of hematologic cancer (leukemia, lymphoma, or multiple myeloma) completed the survey (10.6% response rate). The mean age was 62.6 years. The participants were diverse according to annual household income and employment status. About two-thirds were white and almost one-third were African American. Five of 52 participants (9.6%) experienced food insecurity. Patients with food insecurity had poorer HRQOL compared with those who were food secure (63.3 vs. 87.33, p = 0.0308). A similar pattern was seen for those who had difficulty paying utility bills, those who had housing insecurity, and those who had to go without health care because of a lack of transportation. Overall, there was a statistically significant inverse association between HRQOL and number of social needs (p = 0.004)., Conclusion: When caring for cancer survivors, social needs such as food insecurity and housing insecurity are important considerations for oncologists and primary care providers, especially when caring for patients with lower socioeconomic status and racial/ethnic minorities., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2022
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3. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.
- Author
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Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Döhner H, and Tefferi A
- Subjects
- Acute Disease, Consensus, Genomics, Humans, World Health Organization, Hematologic Neoplasms pathology, Leukemia diagnosis, Leukemia genetics, Leukemia pathology, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology
- 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.
- Published
- 2022
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4. Optimizing management of acute leukemia in community centers and when to refer.
- Author
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Jillella AP, Cortes JE, and Kota VK
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- Acute Disease, Humans, Referral and Consultation, Community Mental Health Centers, Leukemia therapy
- Abstract
Treatment of acute leukemia has been delivered predominantly in academic and larger leukemia treatment centers with the infrastructure and staff needed to manage patients receiving complex therapeutic regimens and supportive care. However, in recent years, several oral agents and less-myelosuppressive regimens were approved, making it possible for these patients to receive therapy in smaller community hospitals and oncology office practices. In this review, we discuss the optimum community setting, type of patient who can be treated, agents that can be applied, and an appropriate clinical circumstance in which a referral to a tertiary center should be made., Competing Interests: Conflict-of-interest disclosure: A.P.J. declares no conflicts of interest. J.E.C. consults with or has an advisory role with Amphivena Therapeutics, Astellas Pharma, Bio-Path Holdings Inc., BiolineRx, Bristol-Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer,Takeda, and received research funding from Astellas Pharma (Inst), Bristol-Myers Squibb (Inst), Daiichi Sankyo (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst), Merus (Inst), Novartis (Inst), Pfizer (Inst), Sun Pharma (Inst), Takeda (Inst), Tolero Pharmaceuticals (Inst), and Trovagene (Inst). V.K.K. has provided consultancy or in an advisory board role for Novartis and Pfizer., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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5. Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias.
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Cortes JE, Gambacorti-Passerini C, Kim DW, Kantarjian HM, Lipton JH, Lahoti A, Talpaz M, Matczak E, Barry E, Leip E, Brümmendorf TH, and Khoury HJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Aniline Compounds administration & dosage, Aniline Compounds therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Creatinine blood, Female, Glomerular Filtration Rate drug effects, Humans, Kidney Function Tests, Leukemia diagnosis, Leukemia drug therapy, Male, Middle Aged, Neoplasm Staging, Nitriles administration & dosage, Nitriles therapeutic use, Patient Outcome Assessment, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors therapeutic use, Quinolines administration & dosage, Quinolines therapeutic use, Retrospective Studies, Young Adult, Aniline Compounds adverse effects, Antineoplastic Agents adverse effects, Kidney Diseases diagnosis, Kidney Diseases etiology, Leukemia complications, Leukemia genetics, Nitriles adverse effects, Philadelphia Chromosome, Protein Kinase Inhibitors adverse effects, Quinolines adverse effects
- Abstract
Background: The purpose of the study was to assess renal function in patients with Philadelphia chromosome-positive leukemias receiving bosutinib or imatinib., Patients and Methods: Patients received first-line bosutinib (n = 248) or imatinib (n = 251; phase III trial), or second-line or later bosutinib (phase I/II trial; n = 570). Adverse events (AEs) and changes from baseline in estimated glomerular filtration rate (eGFR) and serum creatinine were assessed., Results: Time from the last patient's first dose to data cutoff was ≥ 48 months. Renal AEs were reported in 73/570 patients (13%) receiving second-line or later bosutinib, and in 22/248 (9%) and 16/251 (6%) receiving first-line bosutinib and imatinib, respectively. eGFR in patients receiving bosutinib declined over time with more patients developing Grade ≥ 3b eGFR (< 45 mL/min/1.73 m
2 according to the Modification of Diet in Renal Disease method) with second-line or later bosutinib (139/570, 24%) compared with first-line bosutinib (26/248, 10%) and imatinib (25/251, 10%); time to Grade ≥ 3b eGFR was shortest with second-line or later bosutinib. Similar proportions of patients receiving second-line or later bosutinib (74/139, 53%), first-line bosutinib (15/26, 58%), and first-line imatinib (15/25, 60%) improved to ≥ 45 mL/min/1.73 m2 eGFR as of the last follow-up. In a regression analysis, first-line treatment with bosutinib versus imatinib was not a significant predictor of Grade ≥ 3b eGFR., Conclusion: Long-term bosutinib treatment is associated with an apparently reversible decline in renal function with frequency and characteristics similar to renal decline observed with long-term imatinib treatment. Patients with risk factors for Grade ≥ 3b eGFR should be monitored closely., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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6. Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia.
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Badar T, Handisides DR, Benito JM, Richie MA, Borthakur G, Jabbour E, Harutyunyan K, Konoplev S, Faderl S, Kroll S, Andreeff M, Pearce T, Kantarjian HM, Cortes JE, Thomas DA, and Konopleva M
- Subjects
- Adult, Aged, Bone Marrow drug effects, Bone Marrow pathology, Esophagitis chemically induced, Female, Humans, Hyperbilirubinemia chemically induced, Leukemia complications, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute drug therapy, Male, Maximum Tolerated Dose, Middle Aged, Nitroimidazoles adverse effects, Phosphoramide Mustards adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Prodrugs administration & dosage, Salvage Therapy, Stomatitis chemically induced, Young Adult, Hypoxia, Leukemia drug therapy, Nitroimidazoles administration & dosage, Phosphoramide Mustards administration & dosage
- Abstract
Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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7. Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.
- Author
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Benito J, Ramirez MS, Millward NZ, Velez J, Harutyunyan KG, Lu H, Shi YX, Matre P, Jacamo R, Ma H, Konoplev S, McQueen T, Volgin A, Protopopova M, Mu H, Lee J, Bhattacharya PK, Marszalek JR, Davis RE, Bankson JA, Cortes JE, Hart CP, Andreeff M, and Konopleva M
- Subjects
- Animals, Bone Marrow pathology, Cell Line, Tumor, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, Leukemia drug therapy, Leukemia genetics, Magnetic Resonance Imaging, Mice, Treatment Outcome, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Bone Marrow metabolism, Hypoxia metabolism, Leukemia metabolism, Leukemia pathology, Nitroimidazoles pharmacology, Phosphoramide Mustards pharmacology, Prodrugs pharmacology, Tumor Microenvironment drug effects
- Abstract
Purpose: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models., Experimental Design: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models., Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells., Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins., (©2015 American Association for Cancer Research.)
- Published
- 2016
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8. Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens.
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Karjalainen K, Jaalouk DE, Bueso-Ramos C, Bover L, Sun Y, Kuniyasu A, Driessen WH, Cardó-Vila M, Rietz C, Zurita AJ, O'Brien S, Kantarjian HM, Cortes JE, Calin GA, Koivunen E, Arap W, and Pasqualini R
- Subjects
- Amino Acid Sequence, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Ligands, Molecular Sequence Data, Antineoplastic Agents pharmacology, Leukemia drug therapy, Lymphoma drug therapy, Peptides pharmacology, Receptors, Interleukin-11 antagonists & inhibitors
- Abstract
Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma., Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile., Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases., (©2015 American Association for Cancer Research.)
- Published
- 2015
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9. Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.
- Author
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Badar T, Cortes JE, Ravandi F, O'Brien S, Verstovsek S, Garcia-Manero G, Kantarjian H, and Borthakur G
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Farnesol administration & dosage, Farnesol therapeutic use, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Salicylates administration & dosage, Signal Transduction drug effects, Transcriptional Activation drug effects, Treatment Outcome, Antineoplastic Agents therapeutic use, Farnesol analogs & derivatives, Genes, ras drug effects, Leukemia drug therapy, Salicylates therapeutic use, raf Kinases antagonists & inhibitors
- Abstract
Background: Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme., Patients and Methods: We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design., Results: Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints., Conclusion: Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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10. Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia.
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Karjalainen K, Pasqualini R, Cortes JE, Kornblau SM, Lichtiger B, O'Brien S, Kantarjian HM, Sidman RL, Arap W, and Koivunen E
- Subjects
- High-Throughput Screening Assays, Humans, Leukemia metabolism, Leukemia pathology, Drug Screening Assays, Antitumor, Leukemia drug therapy, Oxygen metabolism, Small Molecule Libraries
- Abstract
Background: The authors developed an ex vivo methodology to perform drug library screening against human leukemia., Methods: The strategy for this screening relied on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. Several advantages were observed: 1) partial recapitulation of the leukemia microenvironment, 2) use of native hemoglobin oxygenation as a real-time sensor/reporter, 3) cost-effectiveness, 4) species specificity, and 5) a format that enables high-throughput screening., Results: For a proof of concept, a chemical library (size, approximately 20,000 compounds) was screened against human leukemia cells. Seventy compounds were identified ("hit" rate, 0.35%; Z-factor = 0.71) that had activity, and 20 compounds were examined to identify 18 true-positive compounds (90%). Finally, the results demonstrated that carbonohydraxonic diamide group-containing compounds are potent antileukemia agents that induce cell death in leukemia cells and in patient-derived samples., Conclusions: The current results indicated that this unique functional assay can identify novel drug candidates and can help with the development of future applications in personalized drug selection for patients with leukemia., (© 2013 American Cancer Society.)
- Published
- 2014
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11. Pneumonia during remission induction chemotherapy in patients with acute leukemia.
- Author
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Garcia JB, Lei X, Wierda W, Cortes JE, Dickey BF, Evans SE, and Ost DE
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- Acute Disease, Adult, Age Factors, Aged, Cohort Studies, Female, Humans, Hypoalbuminemia, Leukemia drug therapy, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes drug therapy, Neutropenia, Opportunistic Infections mortality, Pneumonia mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proportional Hazards Models, Remission Induction, Retrospective Studies, Risk Factors, Thrombocytopenia, Induction Chemotherapy, Leukemia complications, Opportunistic Infections complications, Pneumonia complications
- Abstract
Background: Pneumonia is a major cause of death during induction chemotherapy for acute leukemia. The purpose of this study was to quantify the incidence, risk factors, and outcomes of pneumonia in patients with acute leukemia., Methods: We conducted a retrospective cohort study of 801 patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphocytic leukemia (ALL) who underwent induction chemotherapy., Measurements and Main Results: Pneumonia was present at induction start in 85 patients (11%). Of the 716 remaining patients, 148 (21%) developed pneumonia. The incidence rate of pneumonia was higher in MDS and AML than in ALL (0.013 vs. 0.008 vs. 0.003 pneumonias per day, respectively; P < 0.001). In multivariate analysis, age greater than or equal to 60 years, AML, low platelet count, low albumin level, neutropenia, and neutrophil count greater than 7,300 were risk factors. The case fatality rate of pneumonia was 17% (40 of 233). Competing risk analysis demonstrated that in the absence of pneumonia, death was rare: 28-day mortality was 6.2% for all patients but only 1.26% in those without pneumonia. Compared with patients without pneumonia, patients with pneumonia had more intensive care unit days, longer hospital stays, and 49% higher costs (P < 0.001)., Conclusions: Pneumonia after induction chemotherapy for acute leukemia continues to be common, and it is the most important determinant of early mortality after induction chemotherapy. Given the high incidence, morbidity, mortality, and cost of pneumonia, interventions aimed at prevention are warranted in patients with acute leukemia.
- Published
- 2013
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12. A journey searching for a cure for leukemia. Interviewed by Natasha Galukande.
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Cortes JE
- Subjects
- Clinical Trials as Topic, Humans, Leukemia genetics, Leukemia pathology, Leukemia therapy
- Published
- 2013
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13. Targeting neuropilin-1 in human leukemia and lymphoma.
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Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, O'Brien S, Kantarjian HM, Cortes JE, Koivunen E, Arap W, and Pasqualini R
- Subjects
- Acute Disease, Amino Acid Sequence, Apoptosis drug effects, Binding Sites genetics, Bone Marrow Cells metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Immunohistochemistry, K562 Cells, Leukemia genetics, Leukemia pathology, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Lymphoma genetics, Lymphoma pathology, Molecular Sequence Data, Neuropilin-1 genetics, Oligopeptides genetics, Oligopeptides metabolism, Peptide Library, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Binding, RNA Interference, U937 Cells, Leukemia metabolism, Lymphoma metabolism, Neuropilin-1 metabolism, Oligopeptides pharmacology
- Abstract
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (F(F)/(Y)XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence (D)(KLAKLAK)₂. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-(D)(KLAKLAK)₂ is a promising drug candidate in this setting.
- Published
- 2011
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14. Phase II study of alemtuzumab in chronic lymphoproliferative disorders.
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Ferrajoli A, O'Brien SM, Cortes JE, Giles FJ, Thomas DA, Faderl S, Kurzrock R, Lerner S, Kontoyiannis DP, and Keating MJ
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- Adult, Aged, Aged, 80 and over, Alemtuzumab, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm adverse effects, Antineoplastic Agents adverse effects, Humans, Immunocompromised Host, Infections immunology, Leukemia immunology, Leukemia mortality, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Prolymphocytic drug therapy, Lymphoma immunology, Lymphoma mortality, Middle Aged, Survival Rate, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antineoplastic Agents therapeutic use, Leukemia drug therapy, Lymphoma drug therapy
- Abstract
Background: Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders., Methods: Seventy-eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T-cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4-12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir., Results: The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty-six patients (46%) experienced at least one episode of fever or infection., Conclusions: Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11551)
- Published
- 2003
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15. Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with refractory leukemia.
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Giles FJ, Garcia-Manero G, Cortes JE, Baker SD, Miller CB, O'Brien SM, Thomas DA, Andreeff M, Bivins C, Jolivet J, and Kantarjian HM
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Cytosine administration & dosage, Cytosine adverse effects, Dioxolanes administration & dosage, Dioxolanes adverse effects, Female, Humans, Leukemia, Lymphoid drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid drug therapy, Male, Middle Aged, Myelodysplastic Syndromes drug therapy, Remission Induction, Antineoplastic Agents therapeutic use, Cytosine analogs & derivatives, Cytosine therapeutic use, Dioxolanes therapeutic use, Leukemia drug therapy
- Abstract
Purpose: To investigate the activity of a novel dioxolane L-nucleoside analog, troxacitabine (L-(-)-OddC, BCH-4556), in patients with refractory leukemia., Patients and Methods: Study participants were patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was provided as an intravenous infusion for more than 30 minutes daily for 5 days at a dose of 8.0 mg/m(2)/d (40 mg/m(2) per course). Courses were given every 3 to 4 weeks according to antileukemic efficacy., Results: Forty-two patients (AML, 18 patients; MDS, one patient; ALL, six patients; CML-BP, 17 patients) were treated. Median age was 51 years (range, 23 to 80 years); 22 patients were male. Stomatitis was the most significant adverse event, with three patients (7%) and two patients (5%), respectively, experiencing grade 3 or 4 toxicity. Ten patients (24%) had grade 3 hand-foot syndrome, and two patients (5%) had grade 3 skin rash. One patient (2%) had grade 3 fatigue and anorexia. Marrow hypoplasia occurred between days 14 and 28 in 12 (75%) of 16 assessable patients with AML. Two complete remissions and one partial remission (18%) were observed in 16 assessable patients with AML. None of six patients with ALL responded. Six (37%) of 16 assessable patients with CML-BP experienced a return to chronic-phase disease., Conclusion: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.
- Published
- 2002
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16. Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies
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Mughal, Tariq I, Pemmaraju, Naveen, Psaila, Bethan, Radich, Jerald, Bose, Prithviraj, Lion, Thomas, Kiladjian, Jean‐Jacques, Rampal, Raajit, Jain, Tania, Verstovsek, Srdnan, Yacoub, Abdulraheem, Cortes, Jorge E, Mesa, Ruben, Saglio, Giuseppe, and Etten, Richard A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Rare Diseases ,Orphan Drug ,Cancer ,Anemia ,Biomarkers ,Biomarkers ,Tumor ,Combined Modality Therapy ,Disease Management ,Disease Susceptibility ,Drug Development ,Humans ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Molecular Diagnostic Techniques ,Molecular Targeted Therapy ,Myeloproliferative Disorders ,Prognosis ,Single-Cell Analysis ,Translational Research ,Biomedical ,Treatment Outcome ,BCR-ABL1 mutants ,genomic risk scores ,interferon-alpha ,luspatercept ,non-JAK-STAT therapies ,single-cell genomics ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.
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- 2020
17. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs
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Jain, Preetesh, Kantarjian, Hagop, Boddu, Prajwal C, Nogueras-González, Graciela M, Verstovsek, Srdan, Garcia-Manero, Guillermo, Borthakur, Gautam, Sasaki, Koji, Kadia, Tapan M, Sam, Princy, Ahaneku, Hycienth, O'Brien, Susan, Estrov, Zeev, Ravandi, Farhad, Jabbour, Elias, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Clinical Sciences ,Cardiovascular ,Hematology ,Rare Diseases ,Adult ,Antineoplastic Agents ,Cardiovascular Diseases ,Dasatinib ,Female ,Humans ,Imatinib Mesylate ,Imidazoles ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Protein Kinase Inhibitors ,Pyridazines ,Pyrimidines ,Thrombosis ,Treatment Outcome ,Cardiovascular medicine and haematology - Abstract
Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.
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- 2019
18. Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia
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Hughes, Timothy P, Laneuville, Pierre, Rousselot, Philippe, Snyder, David S, Rea, Delphine, Shah, Neil P, Paar, David, Abruzzese, Elisabetta, Hochhaus, Andreas, Lipton, Jeffrey H, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Orphan Drug ,Pediatric Research Initiative ,Pediatric ,Clinical Trials and Supportive Activities ,Hematology ,Childhood Leukemia ,Pediatric Cancer ,Rare Diseases ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Dasatinib ,Disease-Free Survival ,Female ,Humans ,Incidence ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Pleural Effusion ,Malignant ,Risk Factors ,Survival Rate ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - 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
19. 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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Zulbaran‐Rojas, Alejandro, Lin, Huei‐Kan, Shi, Qiuling, Williams, Loretta A, George, Binsah, Garcia‐Manero, Guillermo, Jabbour, Elias, O’Brien, Susan, Ravandi, Farhad, Wierda, William, Estrov, Zeev, Borthakur, Gautam, Kadia, Tapan, Cleeland, Charles, Cortes, Jorge E, and Kantarjian, Hagop
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Biomedical and Clinical Sciences ,Clinical Sciences ,Hematology ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Dasatinib ,Female ,Humans ,Imidazoles ,Leukemia ,Myeloid ,Chronic-Phase ,Male ,Middle Aged ,Protein Kinase Inhibitors ,Pyridazines ,Pyrimidines ,Quality of Life ,Symptom Assessment ,Young Adult ,BCR-ABL ,chronic myeloid leukemia ,symptom burden ,tyrosine kinase inhibitors ,Biochemistry and Cell Biology ,Oncology and Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundTreatment 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.MethodsWe 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.ResultsThe 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.ConclusionSide 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
20. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia
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Lancet, Jeffrey E, Uy, Geoffrey L, Cortes, Jorge E, Newell, Laura F, Lin, Tara L, Ritchie, Ellen K, Stuart, Robert K, Strickland, Stephen A, Hogge, Donna, Solomon, Scott R, Stone, Richard M, Bixby, Dale L, Kolitz, Jonathan E, Schiller, Gary J, Wieduwilt, Matthew J, Ryan, Daniel H, Hoering, Antje, Banerjee, Kamalika, Chiarella, Michael, Louie, Arthur C, and Medeiros, Bruno C
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Orphan Drug ,Clinical Trials and Supportive Activities ,Hematology ,Pediatric ,Cancer ,Rare Diseases ,Clinical Research ,Pediatric Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Daunorubicin ,Female ,Humans ,Leukemia ,Myeloid ,Acute ,Male ,Middle Aged ,Neoplasms ,Second Primary ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.
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- 2018
21. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML.
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Cortes, Jorge E, Tallman, Martin S, Schiller, Gary J, Trone, Denise, Gammon, Guy, Goldberg, Stuart L, Perl, Alexander E, Marie, Jean-Pierre, Martinelli, Giovanni, Kantarjian, Hagop M, and Levis, Mark J
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Clinical Research ,Rare Diseases ,Hematology ,Childhood Leukemia ,Pediatric Research Initiative ,Clinical Trials and Supportive Activities ,Cancer ,Pediatric ,Pediatric Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Antineoplastic Agents ,Benzothiazoles ,Dose-Response Relationship ,Drug ,Female ,Gastrointestinal Diseases ,Gene Duplication ,Heart Diseases ,Hematologic Diseases ,Humans ,Kaplan-Meier Estimate ,Leukemia ,Myeloid ,Acute ,Male ,Middle Aged ,Oncogene Proteins ,Fusion ,Phenylurea Compounds ,Protein Kinase Inhibitors ,Salvage Therapy ,Tandem Repeat Sequences ,Young Adult ,fms-Like Tyrosine Kinase 3 ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Immunology - Abstract
This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
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- 2018
22. A phase I/II randomized trial of clofarabine or fludarabine added to idarubicin and cytarabine for adults with relapsed or refractory acute myeloid leukemia
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Short, Nicholas J, Kantarjian, Hagop, Ravandi, Farhad, Huang, Xuelin, Xiao, Lianchun, Garcia-Manero, Guillermo, Plunkett, William, Gandhi, Varsha, Sasaki, Koji, Pemmaraju, Naveen, Daver, Naval G, Borthakur, Gautam, Jain, Nitin, Konopleva, Marina, Estrov, Zeev, Kadia, Tapan M, Wierda, William G, DiNardo, Courtney D, Brandt, Mark, O’Brien, Susan M, Cortes, Jorge E, and Jabbour, Elias
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Hematology ,Pediatric ,Pediatric Cancer ,Childhood Leukemia ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Bone Marrow ,Clofarabine ,Cytarabine ,Drug Resistance ,Neoplasm ,Humans ,Idarubicin ,Leukemia ,Myeloid ,Acute ,Middle Aged ,Neoplasm Recurrence ,Local ,Progression-Free Survival ,Remission Induction ,Survival Rate ,Treatment Outcome ,Vidarabine ,Young Adult ,Acute myeloid leukemia ,relapsed ,refractory ,purine nucleoside analogues ,clofarabine ,fludarabine ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology - Abstract
The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = .50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p = .48), and the median overall survival was 6.3 and 4.7 months, respectively (p = .28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML.
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- 2018
23. Prediction for sustained deep molecular response of BCR‐ABL1 levels in patients with chronic myeloid leukemia in chronic phase
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Sasaki, Koji, Kantarjian, Hagop, O'Brien, Susan, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Garcia‐Manero, Guillermo, Wierda, William, Daver, Naval, Ferrajoli, Alessandra, Takahashi, Koichi, Jain, Preetesh, Rios, Mary Beth, Pierce, Sherry, Jabbour, Elias, and Cortes, Jorge E
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Hematology ,Rare Diseases ,Cancer ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Female ,Follow-Up Studies ,Fusion Proteins ,bcr-abl ,Humans ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Models ,Biological ,Prognosis ,Prospective Studies ,Protein Kinase Inhibitors ,Randomized Controlled Trials as Topic ,Treatment Outcome ,Young Adult ,best fit average ,chronic myeloid leukemia ,minimum acceptable ,molecular response with BCR-ABL1 level < 0.0032% on the international scale ,tyrosine kinase inhibitor ,molecular response with BCR-ABL1 level ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BACKGROUND:The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level
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- 2018
24. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients
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Jain, Preetesh, Kantarjian, Hagop M, Ghorab, Ahmad, Sasaki, Koji, Jabbour, Elias J, Nogueras Gonzalez, Graciela, Kanagal-Shamanna, Rashmi, Issa, Ghayas C, Garcia-Manero, Guillermo, Kc, Devendra, Dellasala, Sara, Pierce, Sherry, Konopleva, Marina, Wierda, William G, Verstovsek, Srdan, Daver, Naval G, Kadia, Tapan M, Borthakur, Gautam, O'Brien, Susan, Estrov, Zeev, Ravandi, Farhad, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Hematology ,Rare Diseases ,Cancer ,Clinical Research ,Stem Cell Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Blast Crisis ,Cohort Studies ,Female ,Humans ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Prognosis ,Protein Kinase Inhibitors ,Protein-Tyrosine Kinases ,Risk Factors ,Survival Analysis ,Young Adult ,blast phase ,bosutinib ,chronic myeloid leukemia ,dasatinib ,imatinib ,nilotinib ,ponatinib ,tyrosine kinase inhibitors ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundOutcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.MethodsA total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.ResultsThe median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count
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- 2017
25. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia
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Jabbour, Elias, Short, Nicholas J, Ravandi, Farhad, Huang, Xuelin, Xiao, Lianchun, Garcia‐Manero, Guillermo, Plunkett, William, Gandhi, Varsha, Sasaki, Koji, Pemmaraju, Naveen, Daver, Naval G, Borthakur, Gautam, Jain, Nitin, Konopleva, Marina, Estrov, Zeev, Kadia, Tapan M, Wierda, William G, DiNardo, Courtney D, Brandt, Mark, O'Brien, Susan M, Cortes, Jorge E, and Kantarjian, Hagop
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Pediatric ,Rare Diseases ,Hematology ,Cancer ,Clinical Trials and Supportive Activities ,Childhood Leukemia ,Pediatric Cancer ,Patient Safety ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Adenine Nucleotides ,Adolescent ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Arabinonucleosides ,Clofarabine ,Cytarabine ,Humans ,Idarubicin ,Leukemia ,Myeloid ,Acute ,Middle Aged ,Neoadjuvant Therapy ,Treatment Outcome ,Vidarabine ,Young Adult ,acute myeloid leukemia ,clofarabine ,fludarabine ,induction ,nucleoside analog ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundFludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML).MethodsHerein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine.ResultsThe complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged
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- 2017
26. Outcomes of adults with relapsed or refractory Burkitt and high‐grade B‐cell leukemia/lymphoma
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Short, Nicholas J, Kantarjian, Hagop M, Ko, Heidi, Khoury, Joseph D, Ravandi, Farhad, Thomas, Deborah A, Garcia‐Manero, Guillermo, Khouri, Maria, Cortes, Jorge E, Wierda, William G, Verstovsek, Srdan, Estrov, Zeev, Ferrajoli, Alessandra, Thompson, Philip A, Pierce, Sherry, O'Brien, Susan M, and Jabbour, Elias
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Adult ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Asparaginase ,Burkitt Lymphoma ,Cyclophosphamide ,Dexamethasone ,Disease-Free Survival ,Doxorubicin ,Drug Resistance ,Neoplasm ,Etoposide ,Follow-Up Studies ,Humans ,Kaplan-Meier Estimate ,Leukemia ,B-Cell ,Lymphoma ,B-Cell ,Lymphoma ,Non-Hodgkin ,Methotrexate ,Polyethylene Glycols ,Prednisone ,Recurrence ,Remission Induction ,Retrospective Studies ,Rituximab ,Salvage Therapy ,Treatment Outcome ,Vincristine ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Published
- 2017
27. A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL
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Jain, Nitin, Balakrishnan, Kumudha, Ferrajoli, Alessandra, O’Brien, Susan M, Burger, Jan A, Kadia, Tapan M, Cortes, Jorge E, Ayres, Mary L, Tambaro, Francesco Paolo, Keating, Michael J, Gandhi, Varsha, and Wierda, William G
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Cancer ,Hematology ,Lymphoma ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Bendamustine Hydrochloride ,Female ,Follow-Up Studies ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Neoplasm Staging ,Prognosis ,Rituximab ,Survival Rate ,Vidarabine ,CLL ,bendamustine ,chemoimmunotherapy ,fludarabine ,rituximab ,Oncology and carcinogenesis - Abstract
Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (
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- 2017
28. Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship
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Koller, Paul B, Kantarjian, Hagop M, Nogueras‐Gonzalez, Graciela M, Jabbour, Elias, Verstovsek, Srdan, Borthakur, Gautam, Estrov, Zeev, Wierda, William G, Garcia‐Manero, Guillermo, Ferrajoli, Alessandra, Ravandi, Farhad, O'Brien, Susan M, and Cortes, Jorge E
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Aging ,Clinical Trials and Supportive Activities ,Rare Diseases ,Cancer ,Hematology ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Clinical Trials as Topic ,Disease-Free Survival ,Female ,Humans ,Imatinib Mesylate ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Protein Kinase Inhibitors ,Skin Neoplasms ,chronic myeloid leukemia ,second cancer ,survivor ,tyrosine kinase inhibitor ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundSome patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies.MethodsThe current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014.ResultsOf the 630 patients with CML who were treated with frontline tyrosine kinase inhibitors, 626 had a known prior malignancy status. Of these, 45 patients (7%) had a prior malignancy other than nonmelanoma skin cancer whereas 17 patients (3%) had a history of nonmelanoma skin cancers alone. Characteristics of CML were similar between the patients with no prior malignancy, those with a prior malignancy, and those with nonmelanoma skin cancer. Patients with a prior malignancy were found to have an older median age compared with the other 2 groups. The most common prior malignancies were nonmelanoma skin cancer in 20 patients, breast cancer in 11 patients, melanoma in 7 patients, prostate cancer in 6 patients, and colorectal cancer in 5 patients. With regard to CML, the event-free survival, transformation-free survival, and failure-free survival rates were found to be similar between the groups. There was a statistically significantly decreased survival in the group with a prior malignancy versus the group with no prior malignancy versus the group with nonmelanoma skin cancer. In a multivariate analysis, advanced age and an elevated creatinine level were found to be associated with worse survival after a diagnosis of CML.ConclusionsPatients with CML with a history of prior malignancies appear to have the same excellent outcome as patients with no prior malignancies. In the few instances in which concomitant therapy for other malignancies was required during therapy with tyrosine kinase inhibitors, this was able to be accomplished without significant toxicity. Cancer 2017;123:609-616. © 2016 American Cancer Society.
- Published
- 2017
29. Prognostic impact of pretreatment cytogenetics in adult Philadelphia chromosome–negative acute lymphoblastic leukemia in the era of minimal residual disease
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Issa, Ghayas C, Kantarjian, Hagop M, Yin, C Cameron, Qiao, Wei, Ravandi, Farhad, Thomas, Deborah, Short, Nicholas J, Sasaki, Koji, Garcia‐Manero, Guillermo, Kadia, Tapan M, Cortes, Jorge E, Daver, Naval, Borthakur, Gautam, Jain, Nitin, Konopleva, Marina, Khouri, Issa, Kebriaei, Partow, Champlin, Richard E, Pierce, Sherry, O’Brien, Susan M, and Jabbour, Elias
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Hematology ,Childhood Leukemia ,Cancer ,Pediatric ,Rare Diseases ,Pediatric Cancer ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Cytarabine ,Cytodiagnosis ,Disease-Free Survival ,Doxorubicin ,Female ,Humans ,Leukemia ,Myeloid ,Chronic ,Atypical ,BCR-ABL Negative ,Male ,Middle Aged ,Neoplasm ,Residual ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Remission Induction ,Treatment Outcome ,Vincristine ,acute lymphoblastic leukemia ,complex ,cytogenetics ,hypodiploidy ,minimal residual disease ,prognosis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundThe introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL).MethodsThis study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen.ResultsThe median age was 40 years (range, 13-86 years). One hundred eighty-six patients (43%) had diploid cytogenetics, 32 (7%) had complex cytogenetics (defined as ≥ 5 chromosomal abnormalities), 27 (6%) had low hypodiploidy/near-triploidy (Ho-Tr), 24 (6%) had high hyperdiploidy, and 24 (6%) had a mixed-lineage leukemia (MLL) rearrangement. Patients with an MLL rearrangement, Ho-Tr, or a complex karyotype had significantly worse relapse-free survival (RFS) and overall survival (OS) than the diploid group. According to a multivariate analysis including all the baseline characteristics and MRD status, Ho-Tr and a complex karyotype were independent predictive factors for worse RFS and OS. Furthermore, survival among all cytogenetic groups was similar, regardless of the treatment received.ConclusionsA complex karyotype and Ho-Tr are adverse prognostic factors for adults with ALL independently of the MRD status. These findings suggest that pretreatment cytogenetics remain a valuable prognostic tool in this population. Cancer 2017;123:459-467. © 2016 American Cancer Society.
- Published
- 2017
30. Dasatinib in imatinib‐resistant or ‐intolerant chronic‐phase, chronic myeloid leukemia patients: 7‐year follow‐up of study CA180‐034
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Shah, Neil P, Rousselot, Philippe, Schiffer, Charles, Rea, Delphine, Cortes, Jorge E, Milone, Jorge, Mohamed, Hesham, Healey, Diane, Kantarjian, Hagop, Hochhaus, Andreas, and Saglio, Giuseppe
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Clinical Research ,Cancer ,Hematology ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Antineoplastic Agents ,Dasatinib ,Disease-Free Survival ,Drug Resistance ,Neoplasm ,Follow-Up Studies ,Humans ,Imatinib Mesylate ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Leukemia ,Myeloid ,Chronic-Phase ,Pancytopenia ,Patient Safety ,Pleural Effusion ,Protein Kinase Inhibitors ,Treatment Outcome ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Dasatinib was approved at 100 mg once daily for imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180-034 (NCT00123474) study. Here we present the final 7-year analysis of this pivotal study, the longest follow-up to date of any second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib-resistant or -intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven-year rates for major molecular response (MMR), progression-free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR-ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug-related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long-term efficacy and well-established safety profile of dasatinib for patients with imatinib-resistant or -intolerant CML in chronic phase. Am. J. Hematol. 91:869-874, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
31. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial
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Cortes, Jorge E, Saglio, Giuseppe, Kantarjian, Hagop M, Baccarani, Michele, Mayer, Jiří, Boqué, Concepción, Shah, Neil P, Chuah, Charles, Casanova, Luis, Bradley-Garelik, Brigid, Manos, George, and Hochhaus, Andreas
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Clinical Research ,Orphan Drug ,Rare Diseases ,Hematology ,Pediatric ,Cancer ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Dasatinib ,Fusion Proteins ,bcr-abl ,Humans ,Imatinib Mesylate ,Leukemia ,Myeloid ,Chronic-Phase ,Middle Aged ,Mutation ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeWe report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.Patients and methodsPatients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).ResultsAt the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms.ConclusionThese final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
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- 2016
32. Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: Effects on response and toxicity
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Schiffer, Charles A, Cortes, Jorge E, Hochhaus, Andreas, Saglio, Giuseppe, le Coutre, Philipp, Porkka, Kimmo, Mustjoki, Satu, Mohamed, Hesham, and Shah, Neil P
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Cancer ,Hematology ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Antineoplastic Agents ,Clinical Trials ,Phase III as Topic ,Dasatinib ,Disease-Free Survival ,Female ,Humans ,Imatinib Mesylate ,Incidence ,Killer Cells ,Natural ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Leukemia ,Myeloid ,Accelerated Phase ,Leukemia ,Myeloid ,Chronic-Phase ,Lymphocytosis ,Male ,Middle Aged ,Pleural Effusion ,Protein Kinase Inhibitors ,Randomized Controlled Trials as Topic ,Retrospective Studies ,T-Lymphocytes ,Cytotoxic ,dasatinib ,leukemia ,chronic myeloid ,killer cells ,natural ,lymphocytosis ,T-lymphocytes ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundThe proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML).MethodsThe incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed.ResultsLymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis.ConclusionsOverall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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- 2016
33. Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors
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Sasaki, Koji, Kantarjian, Hagop M, Jain, Preetesh, Jabbour, Elias J, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Takahashi, Koichi, Pemmaraju, Naveen, Daver, Naval, Pierce, Sherry A, O'Brien, Susan M, and Cortes, Jorge E
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Hematology ,Clinical Trials and Supportive Activities ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Adolescent ,Adult ,Age Factors ,Aged ,Aged ,80 and over ,Analysis of Variance ,Dasatinib ,Disease-Free Survival ,Dose-Response Relationship ,Drug ,Drug Administration Schedule ,Female ,Humans ,Imatinib Mesylate ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Leukemia ,Myeloid ,Chronic-Phase ,Male ,Middle Aged ,Multivariate Analysis ,Predictive Value of Tests ,Prospective Studies ,Protein Kinase Inhibitors ,Randomized Controlled Trials as Topic ,Severity of Illness Index ,Sex Factors ,Survival Analysis ,Treatment Outcome ,Young Adult ,chronic myeloid leukemia ,conditional survival ,response ,tyrosine kinase inhibitors ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundTyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment.MethodsCumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction.ResultsA total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period.ConclusionsIn the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society.
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- 2016
34. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors
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Yilmaz, Musa, Lahoti, Amit, O'Brien, Susan, Nogueras-González, Graciela M, Burger, Jan, Ferrajoli, Alessandra, Borthakur, Gautam, Ravandi, Farhad, Pierce, Sherry, Jabbour, Elias, Kantarjian, Hagop, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Clinical Sciences ,Cancer ,Hematology ,Rare Diseases ,Clinical Research ,Kidney Disease ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Renal and urogenital ,Acute Kidney Injury ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Creatinine ,Dasatinib ,Dose-Response Relationship ,Drug ,Female ,Follow-Up Studies ,Glomerular Filtration Rate ,Humans ,Imatinib Mesylate ,Incidence ,Kidney ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Protein Kinase Inhibitors ,Protein-Tyrosine Kinases ,Pyrimidines ,Renal Insufficiency ,Chronic ,Retrospective Studies ,Treatment Outcome ,Young Adult ,chronic myeloid leukemia ,dasatinib ,glomerular filtration rate changes ,imatinib ,kidney injury ,nilotinib ,outcome ,tyrosine kinase inhibitor ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundChronic use of tyrosine kinase inhibitors (TKIs) may lead to previously unrecognized adverse events. This study evaluated the incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) in chronic-phase (CP) chronic myeloid leukemia (CML) patients treated with imatinib, dasatinib, and nilotinib.MethodsFour hundred sixty-eight newly diagnosed CP CML patients treated with TKIs were analyzed. The molecular and cytogenetic response data, creatinine, and glomerular filtration rate (GFR) were followed from the start of therapy to the last follow-up (median, 52 months). GFR was estimated with the Modification of Diet in Renal Disease equation.ResultsNineteen patients (4%) had TKI-associated AKI. Imatinib was associated with a higher incidence of AKI in comparison with dasatinib and nilotinib (P = .014). Fifty-eight patients (14%) developed CKD while they were receiving a TKI; 49 of these patients (84%) did so while they were being treated with imatinib (P
- Published
- 2015
35. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials
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Sasaki, Koji, Strom, Sara S, O'Brien, Susan, Jabbour, Elias, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Pemmaraju, Naveen, Daver, Naval, Jain, Preetesh, Pierce, Sherry, Kantarjian, Hagop, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Hematology ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Clinical Trials as Topic ,Female ,Humans ,Leukemia ,Myeloid ,Chronic-Phase ,Male ,Middle Aged ,Prospective Studies ,Protein Kinase Inhibitors ,Survival Rate ,Young Adult ,Cardiorespiratory Medicine and Haematology ,Cardiovascular medicine and haematology - Abstract
BackgroundTyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population.MethodsIn this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability.FindingsOur analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population.InterpretationIn the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy.FundingMD Anderson Cancer Center, National Cancer Institute.
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- 2015
36. Phase II, multicenter, randomized trial of CPX‐351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML
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Cortes, Jorge E, Goldberg, Stuart L, Feldman, Eric J, Rizzeri, David A, Hogge, Donna E, Larson, Melissa, Pigneux, Arnaud, Recher, Christian, Schiller, Gary, Warzocha, Krzysztof, Kantarjian, Hagop, Louie, Arthur C, and Kolitz, Jonathan E
- Subjects
Childhood Leukemia ,Pediatric ,Clinical Trials and Supportive Activities ,Clinical Research ,Hematology ,Pediatric Cancer ,Cancer ,Rare Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aminoglycosides ,Amsacrine ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Cladribine ,Cytarabine ,Daunorubicin ,Disease-Free Survival ,Etoposide ,Female ,Gemtuzumab ,Humans ,Injections ,Kaplan-Meier Estimate ,Leukemia ,Myeloid ,Acute ,Liposomes ,Male ,Middle Aged ,Mitoxantrone ,Recurrence ,Remission Induction ,Risk Assessment ,Salvage Therapy ,Treatment Outcome ,Vidarabine ,Acute Myeloid Leukemia ,Phase II ,First Relapse ,Chemotherapy Intervention ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundCPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy.MethodsThis phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point.ResultsPatient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%).ConclusionsTaken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.
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- 2015
37. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG‐GO) as front‐line regimen in patients with core binding factor acute myelogenous leukemia
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Borthakur, Gautam, Cortes, Jorge E, Estey, Elihu E, Jabbour, Elias, Faderl, Stefan, O'Brien, Susan, Garcia‐Manero, Guillermo, Kadia, Tapan Mahendra, Wang, Xuemei, Patel, Keyur, Luthra, Rajyalakshmi, Koller, Charles, Brandt, Mark, Ravandi, Farhad, and Kantarjian, Hagop
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Hematology ,Cancer ,Pediatric Cancer ,Pediatric Research Initiative ,Childhood Leukemia ,Clinical Research ,Rare Diseases ,Pediatric ,Adult ,Aged ,Aminoglycosides ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Core Binding Factors ,Cytarabine ,Disease-Free Survival ,Female ,Gemtuzumab ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Leukemia ,Myeloid ,Acute ,Male ,Middle Aged ,Survival Rate ,Vidarabine ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML.
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- 2014
38. Tyrosine Kinase Inhibitors as Initial Therapy for Patients With Chronic Myeloid Leukemia in Accelerated Phase
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Ohanian, Maro, Kantarjian, Hagop M, Quintas-Cardama, Alfonso, Jabbour, Elias, Abruzzo, Lynne, Verstovsek, Srdan, Borthakur, Gautam, Ravandi, Farhad, Garcia-Manero, Guillermo, Champlin, Richard, Pierce, Sherry, Alattar, Mona Lisa, Trinh, Long Xuan, Luthra, Raja, Ferrajoli, Alessandra, Kadia, Tapan, O'Brien, Susan, and Cortes, Jorge E
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Cancer ,Orphan Drug ,Rare Diseases ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Benzamides ,Dasatinib ,Disease-Free Survival ,Female ,Follow-Up Studies ,Fusion Proteins ,bcr-abl ,Humans ,Imatinib Mesylate ,Leukemia ,Myeloid ,Accelerated Phase ,Male ,Middle Aged ,Piperazines ,Protein Kinase Inhibitors ,Protein-Tyrosine Kinases ,Pyrimidines ,Thiazoles ,Time Factors ,Treatment Outcome ,Young Adult ,Accelerated phase CML ,Complete cytogenetic response ,Major molecular response ,Second generation TKI ,Tyrosine kinase inhibitors ,Clinical Sciences ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
BackgroundAccelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy.Patients and methodsWe analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets < 100 × 10(9)/L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16).ResultsThe rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs.ConclusionTKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.
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- 2014
39. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors
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Falchi, Lorenzo, Kantarjian, Hagop M, Wang, Xuemei, Verma, Dushyant, Quintás‐Cardama, Alfonso, O'Brien, Susan, Jabbour, Elias J, Ravandi‐Kashani, Farhad, Borthakur, Gautam, Garcia‐Manero, Guillermo, Verstovsek, Srdan, Burger, Jan A, Luthra, Raja, and Cortes, Jorge E
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Hematology ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Benzamides ,Biomarkers ,Tumor ,Dasatinib ,Disease-Free Survival ,Female ,Fusion Proteins ,bcr-abl ,Humans ,Imatinib Mesylate ,Leukemia ,Myeloid ,Chronic-Phase ,Male ,Middle Aged ,Neoplasm Proteins ,Piperazines ,Protein Kinase Inhibitors ,Pyrimidines ,RNA ,Messenger ,RNA ,Neoplasm ,Real-Time Polymerase Chain Reaction ,Survival Analysis ,Thiazoles ,Treatment Outcome ,Young Adult ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.
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- 2013
40. Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias
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Cortes, Jorge E, Kantarjian, Hagop, Shah, Neil P, Bixby, Dale, Mauro, Michael J, Flinn, Ian, O'Hare, Thomas, Hu, Simin, Narasimhan, Narayana I, Rivera, Victor M, Clackson, Tim, Turner, Christopher D, Haluska, Frank G, Druker, Brian J, Deininger, Michael WN, and Talpaz, Moshe
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Pediatric ,Hematology ,Cancer ,Rare Diseases ,Clinical Research ,Pediatric Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Amylases ,Antineoplastic Agents ,Dose-Response Relationship ,Drug ,Drug Resistance ,Neoplasm ,Female ,Follow-Up Studies ,Fusion Proteins ,bcr-abl ,Humans ,Imidazoles ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Lipase ,Male ,Middle Aged ,Mutation ,Pancreatitis ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Protein-Tyrosine Kinases ,Pyridazines ,Structure-Activity Relationship ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundResistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.MethodsIn this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).ResultsDose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.ConclusionsPonatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
- Published
- 2012
41. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high‐risk myelodysplastic syndrome
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Lahoti, Amit, Kantarjian, Hagop, Salahudeen, Abdulla K, Ravandi, Farhad, Cortes, Jorge E, Faderl, Stefan, O'Brien, Susan, Wierda, William, and Mattiuzzi, Gloria N
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Rare Diseases ,Pediatric ,Hematology ,Cancer ,Childhood Leukemia ,Pediatric Cancer ,Kidney Disease ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Renal and urogenital ,Good Health and Well Being ,Acute Kidney Injury ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Female ,Humans ,Kidney Function Tests ,Leukemia ,Myeloid ,Acute ,Male ,Middle Aged ,Myelodysplastic Syndromes ,Prognosis ,Risk Factors ,acute kidney failure ,acute myeloid leukemia ,myelodysplastic syndrome ,dialysis ,logistic models ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
Background: Acute kidney injury (AKIis a common complication in the treatment of patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS), but, to the authors' knowledge, its clinical relevance has not been detailed to date. The objective of the current study was to identify the incidence, predictors, and outcome for AKI in patients with AML and HR-MDS.Methods: Data were analyzed from 537 patients with AML or HR-MDS undergoing induction chemotherapy from 1999 to 2007. Predictors for AKI were identified by logistic regression. Eight-week mortality of patients was estimated by the Kaplan-Meier method stratified by the RIFLE criteria, a novel multilevel classification system for AKI based on the percent rise in serum creatinine from baseline (Risk, >50%; Injury, >100%; and Failure, >200% or requiring dialysis).Results: A total of 187 patients (36%) developed AKI. Significant independent risk factors for AKI included the following: age >/=55 years (odds ratio [OR], 1.8), mechanical ventilation (OR, 16), use of vancomycin (OR, 2.3), diuretics (OR, 3.0), amphotericin B lipid formulation (OR, 2.7), vasopressors (OR, 4.9), leukopenia (OR, 1.9), hypoalbuminemia (OR, 1.4), and use of non-fludarabine-based chemotherapy (OR, 2.7). The 8-week mortality rates were 3.8%, 13.6%, 19.6%, and 61.7% for the non-RIFLE, Risk, Injury, and Failure categories, respectively. Patients requiring dialysis (8%) had a median survival of 33 days. Survival of patients who achieved complete remission was favorable, regardless of degree of AKI.Conclusions: The RIFLE classification for AKI appears to have prognostic utility in predicting mortality in patients with AML or HR-MDS. Relatively mild elevations in creatinine are associated with higher mortality. Strategies to avoid nephrotoxic drugs or fluid overload may be of benefit. Cancer 2010. (c) 2010 American Cancer Society.
- Published
- 2010
42. Long‐term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome–positive leukemia resistant or intolerant to prior therapy.
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Cortes, Jorge E., Kantarjian, Hagop M., Mauro, Michael J., An, Fiona, Nick, Sonja, Leip, Eric, Gambacorti‐Passerini, Carlo, and Brümmendorf, Tim H.
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OTITIS media with effusion , *CHRONIC myeloid leukemia , *PATIENT safety , *EXUDATES & transudates , *LEUKEMIA , *LYMPHOBLASTIC leukemia - Abstract
Introduction: Long‐term follow‐up (≥4 years) demonstrated a low incidence of cardiac and vascular treatment‐emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after ≥ 7 years of follow‐up in patients with Philadelphia chromosome–positive (Ph+) leukemia. Methods: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV). Results: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1 months (range: 0.03‐133.1). The incidence of cardiac, vascular, hypertension, and effusion‐related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3‐4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5‐7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure‐adjusted TEAE rates (patients with TEAEs/total patient‐year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation. Conclusions: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+ CML resistant or intolerant to prior therapy who were treated with bosutinib. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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43. A Phase I Study of Evofosfamide, an Investigational Hypoxia-Activated Prodrug, in Patients with Advanced Leukemia
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Badar, Talha, Handisides, Damian R., Benito, Juliana M., Richie, Mary Ann, Borthakur, Gautam, Jabbour, Elias, Harutyunyan, Karine, Konoplev, Sergej, Faderl, Stefan, Kroll, Stew, Andreeff, Michael, Pearce, Tillman, Kantarjian, Hagop M., Cortes, Jorge E., Thomas, Deborah A., and Konopleva, Marina
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Adult ,Male ,Salvage Therapy ,Stomatitis ,Leukemia ,Maximum Tolerated Dose ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Article ,Leukemia, Myeloid, Acute ,Young Adult ,Bone Marrow ,Nitroimidazoles ,Esophagitis ,Humans ,Female ,Phosphoramide Mustards ,Prodrugs ,Hypoxia ,Aged ,Hyperbilirubinemia - Abstract
Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
44. Conditional Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase in the Era of Tyrosine Kinase Inhibitors
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Sasaki, Koji, Kantarjian, Hagop M, Jain, Preetesh, Jabbour, Elias J, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Takahashi, Koichi, Pemmaraju, Naveen, Daver, Naval, Pierce, Sherry A, O'Brien, Susan M, and Cortes, Jorge E
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Myeloid ,Male ,Dasatinib ,Severity of Illness Index ,tyrosine kinase inhibitors ,80 and over ,Prospective Studies ,Chronic ,Cancer ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,Leukemia ,conditional survival ,response ,Age Factors ,Hematology ,Middle Aged ,Treatment Outcome ,6.1 Pharmaceuticals ,Leukemia, Myeloid, Chronic-Phase ,Public Health and Health Services ,Imatinib Mesylate ,Female ,Drug ,Adult ,Adolescent ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Article ,Disease-Free Survival ,Drug Administration Schedule ,Dose-Response Relationship ,Young Adult ,Sex Factors ,chronic myeloid leukemia ,Clinical Research ,Predictive Value of Tests ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,Aged ,Analysis of Variance ,Dose-Response Relationship, Drug ,Evaluation of treatments and therapeutic interventions ,Survival Analysis ,Good Health and Well Being ,Multivariate Analysis ,Chronic-Phase ,BCR-ABL Positive ,Myelogenous - Abstract
BackgroundTyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment.MethodsCumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction.ResultsA total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period.ConclusionsIn the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society.
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- 2015
45. Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Karjalainen, Katja, Jaalouk, Diana E, Bueso-Ramos, Carlos, Bover, Laura, Sun, Yan, Kuniyasu, Akihiko, Driessen, Wouter HP, Cardó-Vila, Marina, Rietz, Cecilia, Zurita, Amado J, O'Brien, Susan, Kantarjian, Hagop M, Cortes, Jorge E, Calin, George A, Koivunen, Erkki, Arap, Wadih, and Pasqualini, Renata
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Urologic Diseases ,Lymphoma ,Cell Survival ,Pediatric Cancer ,Molecular Sequence Data ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Ligands ,Drug Screening Assays ,Cell Line ,Inhibitory Concentration 50 ,Rare Diseases ,Clinical Research ,Receptors ,Humans ,Amino Acid Sequence ,Oncology & Carcinogenesis ,Cancer ,Pediatric ,Tumor ,Leukemia ,Prostate Cancer ,Antitumor ,Hematology ,Interleukin-11 ,Orphan Drug ,Peptides - Abstract
PurposeThe IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental design and resultsFirst, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.ConclusionsThese results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.
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- 2015
46. Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia
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Karjalainen, Katja, Pasqualini, Renata, Cortes, Jorge E., Kornblau, Steven M., Lichtiger, Benjamin, O'Brien, Susan, Kantarjian, Hagop M., Sidman, Richard L., Arap, Wadih, and Koivunen, Erkki
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bone marrow ,Oncology and Carcinogenesis ,Drug Screening Assays ,chemical library ,Article ,Small Molecule Libraries ,Rare Diseases ,blood ,Humans ,tumor microenvironment ,drug screening ,Oncology & Carcinogenesis ,Cancer ,screening and diagnosis ,Leukemia ,leukemia targeting ,hypoxia ,Antitumor ,Hematology ,High-Throughput Screening Assays ,4.1 Discovery and preclinical testing of markers and technologies ,Oxygen ,Detection ,Orphan Drug ,Good Health and Well Being ,5.1 Pharmaceuticals ,Public Health and Health Services ,Drug Screening Assays, Antitumor ,Development of treatments and therapeutic interventions ,Biotechnology - Abstract
BackgroundThe authors developed an ex vivo methodology to perform drug library screening against human leukemia.MethodsThe strategy for this screening relied on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. Several advantages were observed: 1) partial recapitulation of the leukemia microenvironment, 2) use of native hemoglobin oxygenation as a real-time sensor/reporter, 3) cost-effectiveness, 4) species specificity, and 5) a format that enables high-throughput screening.ResultsFor a proof of concept, a chemical library (size, approximately 20,000 compounds) was screened against human leukemia cells. Seventy compounds were identified ("hit" rate, 0.35%; Z-factor = 0.71) that had activity, and 20 compounds were examined to identify 18 true-positive compounds (90%). Finally, the results demonstrated that carbonohydraxonic diamide group-containing compounds are potent antileukemia agents that induce cell death in leukemia cells and in patient-derived samples.ConclusionsThe current results indicated that this unique functional assay can identify novel drug candidates and can help with the development of future applications in personalized drug selection for patients with leukemia.
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- 2014
47. Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation.
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Nicolini, Franck E., Basak, Grzegorz W., Kim, Dong‐Wook, Olavarria, Eduardo, Pinilla‐Ibarz, Javier, Apperley, Jane F., Hughes, Timothy, Niederwieser, Dietger, Mauro, Michael J., Chuah, Charles, Hochhaus, Andreas, Martinelli, Giovanni, DerSarkissian, Maral, Duh, Mei Sheng, McGarry, Lisa J., Kantarjian, Hagop M., and Cortes, Jorge E.
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STEM cell transplantation ,LEUKEMIA ,ISOLEUCINE ,CANCER treatment ,DISEASE progression ,ANTINEOPLASTIC agents ,LYMPHOBLASTIC leukemia treatment ,HETEROCYCLIC compounds ,TREATMENT of chronic myeloid leukemia ,IMIDAZOLES ,CHROMOSOME abnormalities ,COMPARATIVE studies ,HOMOGRAFTS ,LYMPHOBLASTIC leukemia ,RESEARCH methodology ,MEDICAL cooperation ,MULTIVARIATE analysis ,GENETIC mutation ,RESEARCH ,RESEARCH funding ,SURVIVAL ,EVALUATION research ,CHRONIC myeloid leukemia ,TREATMENT effectiveness ,PROPORTIONAL hazards models ,RETROSPECTIVE studies ,KAPLAN-Meier estimator ,THERAPEUTICS - Abstract
Background: Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo-SCT).Methods: A post hoc, retrospective, indirect comparison of OS among patients who received single-agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo-SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted. Kaplan-Meier survival curves and multivariate Cox proportional-hazards models were used to compare OS between intervention groups, adjusting for time from diagnosis to intervention, age, sex, and geographic region; 24-month and 48-month OS rates and median OS were reported.Results: After adjustment for potential confounders, 24-month and 48-month OS rates were significantly higher in patients with chronic-phase CML (CP-CML) who received ponatinib compared with those who underwent allo-SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013), with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.16-0.84; P = .017). In patients who had accelerated-phase CML, OS rates were not significantly different between the groups (HR, 0.90; 95% CI, 0.20-4.10; P = .889). In patients who had blast-crisis CML and those with Ph+ ALL, ponatinib was associated with shorter OS compared with allo-SCT (blast-crisis CML: HR, 2.29 [95% CI, 1.08-4.82; P = .030]; Ph+ ALL: HR, 2.77 [95% CI, 0.73-10.56; P = .146]).Conclusions: Although allo-SCT remains an important treatment option for patients with T315I-positive advanced CML and Ph+ ALL, ponatinib represents a valuable alternative for patients with T315I-positive CP-CML. Cancer 2017;123:2875-80. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2017
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48. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all- trans retinoic acid and arsenic trioxide.
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Sanford, David, Lo‐Coco, Francesco, Sanz, Miguel A., Di Bona, Eros, Coutre, Steven, Altman, Jessica K., Wetzler, Meir, Allen, Steven L., Ravandi, Farhad, Kantarjian, Hagop, and Cortes, Jorge E.
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TRETINOIN ,ARSENIC trioxide ,ARSENIC oxides ,DERMATOLOGIC agents ,LEUKEMIA - Abstract
Treatment of acute promyelocytic leukaemia ( APL) with arsenic trioxide ( ATO) and all- trans retinoic acid ( ATRA) is highly effective first-line therapy, although approximately 5-10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO ( n = 14). Participants were treated with tamibarotene (6 mg/m
2 /d) during induction and for up to six cycles of consolidation. The overall response rate was 64% ( n = 9), the rate of complete cytogenetic response was 43% ( n = 6) and the rate of complete molecular response was 21% ( n = 3). Relapse was frequent with 7 of 9 responders relapsing after a median of 4·6 months (range 1·6-26·8 months). The median event-free survival ( EFS) was 3·5 months [95% confidence interval (CI) 0-8·6 months] and the median overall survival ( OS) was 9·5 months (95% CI 5·9-13·1 months). These results demonstrate that tamibarotene has activity in relapsed APL after treatment with ATO and ATRA and further studies using tamibarotene as initial therapy and in combination with ATO are warranted. [ABSTRACT FROM AUTHOR]- Published
- 2015
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49. Phase II evaluation of IPI-926, an oral Hedgehog inhibitor, in patients with myelofibrosis.
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Sasaki, Koji, Gotlib, Jason R., Mesa, Ruben A., Newberry, Kate J., Ravandi, Farhad, Cortes, Jorge E., Kelly, Patrick, Kutok, Jeffery L., Kantarjian, Hagop M., and Verstovsek, Srdan
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MYELOFIBROSIS ,PROTEINS ,MYELOPROLIFERATIVE neoplasms ,LEUKEMIA ,ANEMIA - Abstract
The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160 mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis. [ABSTRACT FROM AUTHOR]
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- 2015
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50. Rapid and Reliable Confirmation of Acute Promyelocytic Leukemia by Immunofluorescence Staining With an Antipromyelocytic Leukemia Antibody.
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Dirnov, Nikolay D., Medeiros, L. Jeffrey, Kantarjian, Hagop M., Cortes, Jorge E., Kun-Sang Chang, Bueso-Ramos, Carlos E., and Ravandi, Farhad
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LEUKEMIA ,IMMUNOFLUORESCENCE ,DIAGNOSIS of blood diseases ,BONE marrow ,PATIENTS ,THERAPEUTICS - Abstract
The article presents a study which determines the use of promyelocytic leukemia (PML) immunoflourescence staining in a large group of patients with acute promyelocytic leukemia (APL). The study assessed 349 cases where 199 of them patients are positive with APL and 159 with other conditions. It shows that the anti-PML antibody was positive in 182 of 184 bone marrow (BM) while 32 of 33 peripheral blood (PB) smears showing the reliability of immunoflourescence as diagnostic approach to APL.
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- 2010
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