3,511 results on '"Cortes, Jorge E."'
Search Results
2. Disparities in survival of hematologic malignancies in the context of social determinants of health: a systematic review
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Miranda-Galvis, Marisol, Tjioe, Kellen C., Balas, E. Andrew, Agrawal, Gagan, and Cortes, Jorge E.
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- 2023
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3. 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
4. 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
5. 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
6. 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
7. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data
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Arber, Daniel A., Orazi, Attilio, Hasserjian, Robert P., Borowitz, Michael J., Calvo, Katherine R., Kvasnicka, Hans-Michael, Wang, Sa A., Bagg, Adam, Barbui, Tiziano, Branford, Susan, Bueso-Ramos, Carlos E., Cortes, Jorge E., Dal Cin, Paola, DiNardo, Courtney D., Dombret, Hervé, Duncavage, Eric J., Ebert, Benjamin L., Estey, Elihu H., Facchetti, Fabio, Foucar, Kathryn, Gangat, Naseema, Gianelli, Umberto, Godley, Lucy A., Gökbuget, Nicola, Gotlib, Jason, Hellström-Lindberg, Eva, Hobbs, Gabriela S., Hoffman, Ronald, Jabbour, Elias J., Kiladjian, Jean-Jacques, Larson, Richard A., Le Beau, Michelle M., Loh, Mignon L.-C., Löwenberg, Bob, Macintyre, Elizabeth, Malcovati, Luca, Mullighan, Charles G., Niemeyer, Charlotte, Odenike, Olatoyosi M., Ogawa, Seishi, Orfao, Alberto, Papaemmanuil, Elli, Passamonti, Francesco, Porkka, Kimmo, Pui, Ching-Hon, Radich, Jerald P., Reiter, Andreas, Rozman, Maria, Rudelius, Martina, Savona, Michael R., Schiffer, Charles A., Schmitt-Graeff, Annette, Shimamura, Akiko, Sierra, Jorge, Stock, Wendy A., Stone, Richard M., Tallman, Martin S., Thiele, Jürgen, Tien, Hwei-Fang, Tzankov, Alexandar, Vannucchi, Alessandro M., Vyas, Paresh, Wei, Andrew H., Weinberg, Olga K., Wierzbowska, Agnieszka, Cazzola, Mario, Döhner, Hartmut, and Tefferi, Ayalew
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- 2022
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8. Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial
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Cortes, Jorge E., Lin, Tara L., Asubonteng, Kobby, Faderl, Stefan, Lancet, Jeffrey E., and Prebet, Thomas
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- 2022
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9. A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase
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García-Gutiérrez, Valentin, Breccia, Massimo, Jabbour, Elias, Mauro, Michael, and Cortes, Jorge E.
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- 2022
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10. 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
11. 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
12. 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
13. Recent advances in the genomics and therapy of BCR/ABL1-positive and -negative chronic myeloproliferative neoplasms
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Mughal, Tariq I, Gotlib, Jason, Mesa, Ruben, Koschmieder, Steffen, Khoury, H Jean, Cortes, Jorge E, Barbui, Tiziano, Hehlmann, Rüdiger, Mauro, Michael, Saussele, Susanne, Radich, Jerald P, Van Etten, Richard A, Saglio, Giuseppe, Verstovek, Srdnan, Gale, Robert Peter, and Abdel-Wahab, Omar
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Hematology ,Good Health and Well Being ,Antineoplastic Agents ,Calreticulin ,Cardiovascular Diseases ,Cell Transformation ,Neoplastic ,Chronic Disease ,Congresses as Topic ,Epigenesis ,Genetic ,Fusion Proteins ,bcr-abl ,Humans ,Janus Kinase 2 ,Mastocytosis ,Systemic ,Mutation ,Myeloproliferative Disorders ,Protein Kinase Inhibitors ,Remission Induction ,Staurosporine ,Translational Research ,Biomedical ,CML ,MPN ,TFR ,Mastocytosis ,CALR ,Cardiotoxicity ,JAK2 inhibitors ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology - Abstract
This review is based on the presentations and deliberations at the 7th John Goldman Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN) Colloquium which took place in Estoril, Portugal on the 15th October 2017, and the 11th post-ASH International Workshop on CML and MPN which took place on the 6th-7th December 2016, immediately after the 58th American Society of Hematology Annual Meeting. Rather than present a resume of the proceedings, we have elected to address some of the topical translational research and clinically relevant topics in greater detail. We address recent updates in the genetics and epigenetics of MPN, the mechanisms of transformation by mutant calreticulin, advances in the biology and therapy of systemic mastocytosis, clinical updates on JAK2 inhibitors and other therapeutic approaches for patients with MPNs, cardiovascular toxicity related to tyrosine kinase inhibitors and the concept of treatment-free remission for patients with CML.
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- 2018
14. 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
15. 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
16. 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
17. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses
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Lin, Tara L., Rizzieri, David A., Ryan, Daniel H., Schiller, Gary J., Kolitz, Jonathan E., Uy, Geoffrey L., Hogge, Donna E., Solomon, Scott R., Wieduwilt, Matthew J., Ryan, Robert J., Faderl, Stefan, Cortes, Jorge E., and Lancet, Jeffrey E.
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- 2021
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18. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
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Ganguly, Siddhartha, Cortes, Jorge E., Krämer, Alwin, Levis, Mark J., Martinelli, Giovanni, Perl, Alexander E., Russell, Nigel H., Arunachalam, Meena, Santos, Cedric Dos, Gammon, Guy, Lesegretain, Arnaud, Mires, Derek E., Pham, Hoang, Wang, Yibin, and Khaled, Samer K.
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- 2021
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19. 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
20. 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
21. Poor outcomes associated with +der(22)t(9;22) and −9/9p in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor
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Short, Nicholas J, Kantarjian, Hagop M, Sasaki, Koji, Ravandi, Farhad, Ko, Heidi, Yin, C Cameron, Garcia‐Manero, Guillermo, Cortes, Jorge E, Garris, Rebecca, O'Brien, Susan M, Patel, Keyur, Khouri, Maria, Thomas, Deborah, Jain, Nitin, Kadia, Tapan M, Daver, Naval G, Benton, Christopher B, Issa, Ghayas C, Konopleva, Marina, and Jabbour, Elias
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric Cancer ,Cancer ,Hematology ,Clinical Research ,Childhood Leukemia ,Rare Diseases ,Pediatric ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Chromosome Aberrations ,Chromosomes ,Human ,Pair 22 ,Chromosomes ,Human ,Pair 9 ,Dasatinib ,Disease-Free Survival ,Female ,Gene Deletion ,Humans ,Imatinib Mesylate ,Imidazoles ,Male ,Middle Aged ,Philadelphia Chromosome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Protein Kinase Inhibitors ,Pyridazines ,Survival Rate ,Translocation ,Genetic ,Treatment Outcome ,Young Adult ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.
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- 2017
22. Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor.
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Short, Nicholas J, Kantarjian, Hagop M, Sasaki, Koji, Ravandi, Farhad, Ko, Heidi, Cameron Yin, C, Garcia-Manero, Guillermo, Cortes, Jorge E, Garris, Rebecca, O'Brien, Susan M, Patel, Keyur, Khouri, Maria, Thomas, Deborah, Jain, Nitin, Kadia, Tapan M, Daver, Naval G, Benton, Christopher B, Issa, Ghayas C, Konopleva, Marina, and Jabbour, Elias
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Chromosomes ,Human ,Pair 9 ,Philadelphia Chromosome ,Chromosomes ,Human ,Pair 22 ,Humans ,Chromosome Aberrations ,Translocation ,Genetic ,Imidazoles ,Pyridazines ,Antineoplastic Combined Chemotherapy Protocols ,Protein Kinase Inhibitors ,Prognosis ,Disease-Free Survival ,Treatment Outcome ,Survival Rate ,Gene Deletion ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Young Adult ,Imatinib Mesylate ,Dasatinib ,Rare Diseases ,Pediatric Cancer ,Pediatric ,Hematology ,Clinical Research ,Cancer ,Childhood Leukemia ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Cardiorespiratory Medicine and Haematology ,Immunology - Abstract
In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.
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- 2017
23. 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
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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.
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- 2017
24. 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.
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- 2017
25. Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B‐cell acute lymphoblastic leukemia
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Jabbour, Elias, Short, Nicholas J, Jorgensen, Jeffrey L, Yilmaz, Musa, Ravandi, Farhad, Wang, Sa A, Thomas, Deborah A, Khoury, Joseph, Champlin, Richard E, Khouri, Issa, Kebriaei, Partow, O'Brien, Susan M, Garcia-Manero, Guillermo, Cortes, Jorge E, Sasaki, Koji, Dinardo, Courtney D, Kadia, Tapan M, Jain, Nitin, Konopleva, Marina, Garris, Rebecca, and Kantarjian, Hagop M
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Childhood Leukemia ,Cancer ,Rare Diseases ,Pediatric Research Initiative ,Pediatric ,Hematology ,Pediatric Cancer ,Clinical Research ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,B-Lymphocytes ,Disease-Free Survival ,Hematopoietic Stem Cell Transplantation ,Humans ,Middle Aged ,Neoplasm Recurrence ,Local ,Neoplasm ,Residual ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Salvage Therapy ,Stem Cell Transplantation ,Young Adult ,acute lymphoblastic leukemia ,blinatumomab ,inotuzumab ,minimal residual disease ,refractory ,relapsed ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundMinimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear.MethodsThis study identified 78 patients with relapsed/refractory B-cell ALL who achieved a morphologic response with inotuzumab ozogamicin (n = 41), blinatumomab (n = 11), or mini-hyperfractionated cyclophosphamide, vincristine, and doxorubicin plus inotuzumab (n = 26) during either salvage 1 (S1; n = 46) or salvage 2 (S2; n = 32) and had undergone an MRD assessment by multiparameter flow cytometry at the time of remission.ResultsMRD negativity was achieved in 41 patients overall (53%). The MRD negativity rate was 57% in S1 and 47% in S2. Among patients in S1, achieving MRD negativity was associated with longer event-free survival (EFS; median, 18 vs 7 months; 2-year EFS rate, 46% vs 17%; P = .06) and overall survival (OS; median, 27 vs 9 months; 2-year OS, 52% vs 36%; P = .15). EFS and OS were similar in S2, regardless of the MRD response. Among MRD-negative patients who underwent allogeneic stem cell transplantation (SCT), EFS and OS were superior for those who underwent SCT in S1 rather than S2 (P = .003 and P = .04, respectively). Patients in S1 who achieved MRD negativity and subsequently underwent SCT had the best outcomes with a 2-year OS rate of 65%.ConclusionsPatients with relapsed/refractory ALL who achieve MRD negativity in S1 can have long-term survival. Patients in S2 generally have poor outcomes, regardless of their MRD status. Cancer 2017;123:294-302. © 2016 American Cancer Society.
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- 2017
26. Prognostic significance of day 14 bone marrow evaluation in adults with Philadelphia chromosome–negative acute lymphoblastic leukemia
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Short, Nicholas J, Kantarjian, Hagop M, Sasaki, Koji, Cortes, Jorge E, Ravandi, Farhad, Thomas, Deborah A, Garcia‐Manero, Guillermo, Khouri, Issa, Kebriaei, Partow, Champlin, Richard E, Pierce, Sherry, Issa, Ghayas C, Konopleva, Marina, Kadia, Tapan M, Bueso‐Ramos, Carlos, Khoury, Joseph D, Jain, Nitin, O'Brien, Susan M, and Jabbour, Elias
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Rare Diseases ,Cancer ,Hematology ,Pediatric ,Pediatric Research Initiative ,Childhood Leukemia ,Clinical Research ,Genetics ,Pediatric Cancer ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Bone Marrow ,Bone Marrow Examination ,Disease-Free Survival ,Female ,Humans ,Induction Chemotherapy ,Male ,Middle Aged ,Multivariate Analysis ,Neoplasm ,Residual ,Philadelphia Chromosome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Proportional Hazards Models ,Remission Induction ,Young Adult ,acute lymphoblastic leukemia ,blasts ,day 14 ,minimal residual disease ,prognosis ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundThe role of day 14 (D14) bone marrow (BM) assessment in detecting increased blasts in patients undergoing induction for acute lymphoblastic leukemia (ALL) is not well defined.MethodsThis study evaluated 389 adolescent and adult patients with previously untreated Philadelphia chromosome-negative ALL who received frontline induction chemotherapy and for whom a D14 BM assessment was performed.ResultsA D14 BM blast proportion
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- 2016
27. Hyper‐CVAD plus ponatinib versus hyper‐CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia: A propensity score analysis
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Sasaki, Koji, Jabbour, Elias J, Ravandi, Farhad, Short, Nicholas J, Thomas, Deborah A, Garcia‐Manero, Guillermo, Daver, Naval G, Kadia, Tapan M, Konopleva, Marina Y, Jain, Nitin, Issa, Ghayas C, Jeanis, Vicki, Moore, Haim G, Garris, Rebecca S, Pemmaraju, Naveen, Cortes, Jorge E, O'Brien, Susan M, and Kantarjian, Hagop M
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Hematology ,Pediatric Research Initiative ,Pediatric Cancer ,Cancer ,Pediatric ,Clinical Research ,Rare Diseases ,Childhood Leukemia ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Cyclophosphamide ,Dasatinib ,Dexamethasone ,Disease-Free Survival ,Doxorubicin ,Female ,Humans ,Imidazoles ,Male ,Middle Aged ,Philadelphia Chromosome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Propensity Score ,Prospective Studies ,Pyridazines ,Survival Rate ,Vincristine ,Young Adult ,acute lymphoblastic leukemia ,dasatinib ,hyperfractionated cyclophosphamide ,vincristine ,doxorubicin and dexamethasone ,Philadelphia chromosome ,ponatinib ,dexamethasone ,doxorubicin ,hyperfractionated cyclophosphamide ,vincristine ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundThe clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial.MethodsThe authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts.ResultsPropensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib.ConclusionsThe clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society.
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- 2016
28. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome
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Lee, Je-Hwan, Faderl, Stefan, Pagel, John M., Jung, Chul Won, Yoon, Sung-Soo, Pardanani, Animesh D., Becker, Pamela S., Lee, Howard, Choi, Jeongeun, Lee, Kyoungjune, Kim, Minkyoung, and Cortes, Jorge E.
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- 2020
- Full Text
- View/download PDF
29. 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
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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
30. Final results of a single institution experience with a pediatric‐based regimen, the augmented Berlin–Frankfurt–Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper‐CVAD regimen
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Rytting, Michael E, Jabbour, Elias J, Jorgensen, Jeffrey L, Ravandi, Farhad, Franklin, Anna R, Kadia, Tapan M, Pemmaraju, Naveen, Daver, Naval G, Ferrajoli, Alessandra, Garcia-Manero, Guillermo, Konopleva, Marina Y, Borthakur, Gautam, Garris, Rebecca, Wang, Sa, Pierce, Sherry, Schroeder, Kurt, Kornblau, Steven M, Thomas, Deborah A, Cortes, Jorge E, O'Brien, Susan M, and Kantarjian, Hagop M
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Hematology ,Rare Diseases ,Clinical Research ,Pediatric ,Pediatric Research Initiative ,Pediatric Cancer ,Cancer ,Childhood Leukemia ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Antineoplastic Combined Chemotherapy Protocols ,Asparaginase ,Child ,Cyclophosphamide ,Dexamethasone ,Doxorubicin ,Female ,Humans ,Male ,Myeloid Cells ,Neoplasm ,Residual ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prospective Studies ,Remission Induction ,Survival Rate ,Vincristine ,Young Adult ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
Several studies reported improved outcomes of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric-based ALL regimens. This prompted the prospective investigation of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen, and its comparison with hyper-fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone (hyper-CVAD) in AYA patients. One hundred and six AYA patients (median age 22 years) with Philadelphia chromosome- (Ph) negative ALL received ABFM from October 2006 through March 2014. Their outcome was compared to 102 AYA patients (median age 27 years), treated with hyper-CVAD at our institution. The complete remission (CR) rate was 93% with ABFM and 98% with hyper-CVAD. The 5-year complete remission duration (CRD) were 53 and 55%, respectively (P = 0.98). The 5-year overall survival (OS) rates were 60 and 60%, respectively. The MRD status on Day 29 and Day 84 of therapy was predictive of long-term outcomes on both ABFM and hyper-CVAD. Severe regimen toxicities with ABFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD. In summary, ABFM and hyper-CVAD resulted in similar efficacy outcomes, but were associated with different toxicity profiles, asparaginase-related with ABFM and myelosuppression-related with hyper-CVAD. Am. J. Hematol. 91:819-823, 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. Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia
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Short, Nicholas J, Kantarjian, Hagop M, Jabbour, Elias J, O'Brien, Susan M, Faderl, Stefan, Burger, Jan A, Garris, Rebecca, Qiao, Wei, Huang, Xuelin, Jain, Nitin, Konopleva, Marina, Kadia, Tapan M, Daver, Naval, Borthakur, Gautam, Cortes, Jorge E, and Ravandi, Farhad
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Pediatric ,Pediatric Research Initiative ,Hematology ,Clinical Research ,Pediatric Cancer ,Cancer ,Rare Diseases ,Childhood Leukemia ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Chromosome Aberrations ,Combined Modality Therapy ,Female ,Flow Cytometry ,Follow-Up Studies ,Humans ,Immunophenotyping ,Male ,Middle Aged ,Neoplasm ,Residual ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Remission Induction ,Survival Analysis ,Treatment Outcome ,Young Adult ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse-free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30-125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi-parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known.
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- 2016
33. 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
34. Minimal residual disease assessed by multi‐parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia
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Ravandi, Farhad, Jorgensen, Jeffrey L, O'Brien, Susan M, Jabbour, Elias, Thomas, Deborah A, Borthakur, Gautam, Garris, Rebecca, Huang, Xuelin, Garcia-Manero, Guillermo, Burger, Jan A, Ferrajoli, Alessandra, Wierda, William, Kadia, Tapan, Jain, Nitin, Wang, Sa A, Konoplev, Sergei, Kebriaei, Partow, Champlin, Richard E, McCue, Deborah, Estrov, Zeev, Cortes, Jorge E, and Kantarjian, Hagop M
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Clinical Research ,Rare Diseases ,Hematology ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Cancer ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Female ,Flow Cytometry ,Humans ,Leukocyte Count ,Male ,Middle Aged ,Neoplasm ,Residual ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Prospective Studies ,Remission Induction ,Treatment Outcome ,Young Adult ,acute leukaemia ,flow cytometry ,minimal residual disease ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9·35 × 10(9) /l (range, 0·4-658·1 ×1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P
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- 2016
35. 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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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
36. Long‐term follow‐up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia
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Ravandi, Farhad, O'Brien, Susan M, Cortes, Jorge E, Thomas, Deborah M, Garris, Rebecca, Faderl, Stefan, Burger, Jan A, Rytting, Michael E, Ferrajoli, Alessandra, Wierda, William G, Verstovsek, Srdan, Champlin, Richard, Kebriaei, Partow, McCue, Deborah A, Huang, Xuelin, Jabbour, Elias, Garcia-Manero, Guillermo, Estrov, Zeev, and Kantarjian, Hagop M
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Hematology ,Rare Diseases ,Pediatric Research Initiative ,Genetics ,Pediatric Cancer ,Pediatric ,Clinical Research ,Cancer ,Childhood Leukemia ,Stem Cell Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Cyclophosphamide ,Cytarabine ,Dasatinib ,Dexamethasone ,Doxorubicin ,Female ,Follow-Up Studies ,Humans ,Male ,Methotrexate ,Middle Aged ,Neoplasm ,Residual ,Philadelphia Chromosome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Survival Analysis ,Treatment Outcome ,Vincristine ,Young Adult ,Philadelphia chromosome ,acute lymphoblastic leukemia ,chemotherapy ,combination ,dasatinib ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundThe long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established.MethodsPatients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR.ResultsSeventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I.ConclusionsA combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL.
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- 2015
37. 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
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- 2015
38. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML
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Cortes, Jorge E., Lin, Tara L., Uy, Geoffrey L., Ryan, Robert J., Faderl, Stefan, and Lancet, Jeffrey E.
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- 2021
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39. Impact of frontline treatment approach on outcomes of myeloid blast phase CML
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Saxena, Kapil, Jabbour, Elias, Issa, Ghayas, Sasaki, Koji, Ravandi, Farhad, Maiti, Abhishek, Daver, Naval, Kadia, Tapan, DiNardo, Courtney D., Konopleva, Marina, Cortes, Jorge E., Yilmaz, Musa, Chien, Kelly, Pierce, Sherry, Kantarjian, Hagop, and Short, Nicholas J.
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- 2021
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40. Correction to: Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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Yilmaz, Musa, Alfayez, Mansour, DiNardo, Courtney D., Borthakur, Gautam, Kadia, Tapan M., Konopleva, Marina Y., Loghavi, Sanam, Kanagal-Shamanna, Rashmi, Patel, Keyur P., Jabbour, Elias J., Garcia‑Manero, Guillermo, Pemmaraju, Naveen, Pierce, Sherry A., Ghayas, Issa, Short, Nicholas J., Montalban-Bravo, Guillermo, Takahashi, Koichi, Assi, Rita, Alotaibi, Ahmad S., Ohanian, Maro, Andreeff, Michael, Cortes, Jorge E., Kantarjian, Hagop M., Ravandi, Farhad, and Daver, Naval G.
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- 2021
- Full Text
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41. Phase I Study of S-Trans, Trans-Farnesylthiosalicylic Acid (Salirasib), a Novel Oral RAS Inhibitor in Patients With Refractory Hematologic Malignancies
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Badar, Talha, Cortes, Jorge E, Ravandi, Farhad, O'Brien, Susan, Verstovsek, Srdan, Garcia-Manero, Guillermo, Kantarjian, Hagop, and Borthakur, Gautam
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric ,Rare Diseases ,Clinical Research ,Hematology ,Cancer ,Pediatric Cancer ,Orphan Drug ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Farnesol ,Female ,Genes ,ras ,Humans ,Leukemia ,Male ,Middle Aged ,Neoplasm Recurrence ,Local ,Salicylates ,Signal Transduction ,Transcriptional Activation ,Treatment Outcome ,raf Kinases ,Farnesylation ,RAS mutation ,RAS/RAF/MAPK activation ,Targeted therapy ,Clinical Sciences ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
BackgroundRat 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 methodsWe 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.ResultsSeventeen 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.ConclusionSalirasib 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.
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- 2015
42. 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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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Pediatric ,Lymphoma ,Prostate Cancer ,Urologic Diseases ,Clinical Research ,Cancer ,Pediatric Cancer ,Rare Diseases ,Hematology ,Amino Acid Sequence ,Antineoplastic Agents ,Cell Line ,Tumor ,Cell Survival ,Drug Screening Assays ,Antitumor ,Humans ,Inhibitory Concentration 50 ,Leukemia ,Ligands ,Molecular Sequence Data ,Peptides ,Receptors ,Interleukin-11 ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - 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
43. 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
44. 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
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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
45. Augmented Berlin‐Frankfurt‐Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL)
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Rytting, Michael E, Thomas, Deborah A, O'Brien, Susan M, Ravandi‐Kashani, Farhad, Jabbour, Elias J, Franklin, Anna R, Kadia, Tapan M, Pemmaraju, Naveen, Daver, Naval G, Ferrajoli, Alessandra, Garcia‐Manero, Guillermo, Konopleva, Marina Y, Cortes, Jorge E, Borthakur, Gautham, Garris, Rebecca, Cardenas‐Turanzas, Maria, Schroeder, Kurt, Jorgensen, Jeffrey L, Kornblau, Steven M, and Kantarjian, Hagop M
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Childhood Leukemia ,Stem Cell Research ,Pediatric Cancer ,Pediatric Research Initiative ,Pediatric ,Orphan Drug ,Rare Diseases ,Cancer ,Hematology ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Antineoplastic Combined Chemotherapy Protocols ,Asparaginase ,Cohort Studies ,Consolidation Chemotherapy ,Cyclophosphamide ,Cytarabine ,Daunorubicin ,Dexamethasone ,Doxorubicin ,Female ,Humans ,Induction Chemotherapy ,Maintenance Chemotherapy ,Male ,Mercaptopurine ,Methotrexate ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prospective Studies ,Thioguanine ,Treatment Outcome ,Vincristine ,Young Adult ,Philadelphia chromosome-negative ALL ,acute lymphoblastic leukemia ,augmented Berlin-Frankfurt-Münster ,pediatric-based regimens ,pediatric-based therapy ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundVarious trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen.MethodsEighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes.ResultsThe complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively.ConclusionsABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.
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- 2014
46. 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
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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
47. 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
48. A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis
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Masarova, Lucia, Verstovsek, Srdan, Hidalgo-Lopez, Juliana E., Pemmaraju, Naveen, Bose, Prithviraj, Estrov, Zeev, Jabbour, Elias J., Ravandi-Kashani, Farhad, Takahashi, Koichi, Cortes, Jorge E., Ning, Jing, Ohanian, Maro, Alvarado, Yesid, Zhou, Lingsha, Pierce, Sherry, Gergis, Romany, Patel, Keyur P., Luthra, Rajyalakshmi, Kadia, Tapan M., DiNardo, Courtney D., Borthakur, Gautam, Bhalla, Kapil, Garcia-Manero, Guillermo, Bueso-Ramos, Carlos E., Kantarjian, Hagop M., and Daver, Naval
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- 2018
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49. 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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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Cancer ,Rare Diseases ,Hematology ,Biotechnology ,Development of treatments and therapeutic interventions ,4.1 Discovery and preclinical testing of markers and technologies ,5.1 Pharmaceuticals ,Detection ,screening and diagnosis ,Good Health and Well Being ,Drug Screening Assays ,Antitumor ,High-Throughput Screening Assays ,Humans ,Leukemia ,Oxygen ,Small Molecule Libraries ,blood ,bone marrow ,chemical library ,drug screening ,hypoxia ,leukemia targeting ,tumor microenvironment ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - 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
50. Imatinib-induced postoperative periorbital purpura: GASP (Gleevec-Associated Surgical Purpura) in a woman with imatinib-treated chronic myelogenous leukemia
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Anzalone, C Lane, Cohen, Philip R, Kurzrock, Razelle, and Cortes, Jorge E
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edema ,Gleevec ,imatinib ,periorbital ,postoperative ,purpura - Abstract
Background: Imatinib mesylate is a selective tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia. Ocular side effects of imatinib include periorbital edema, which may become so severe as to obstruct the visual field.Purpose: The purpose of this case study is to describe the clinical characteristics of imatinib- induced postoperative periorbital purpura.Materials and methods: We retrospectively reviewed the medical literature using PubMed, searching the terms edema, Gleevec, imatinib, periorbital, postoperative and purpura. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented.Results: Three patients have undergone surgery to reduce the imatinib-induced periorbital edema; two of these individuals have developed imatinib-induced postoperative periorbital purpura.Conclusion: We recommend discontinuing imatinib usage one week prior to periorbital surgery and not resuming therapy until the eighth postoperative day.
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- 2014
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