132 results on '"Chronic phase chronic myelogenous leukemia"'
Search Results
2. How I treat chronic-phase chronic myelogenous leukemia
- Author
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Ellin Berman
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Oncology ,medicine.medical_specialty ,medicine.drug_class ,Immunology ,Dasatinib ,Antineoplastic Agents ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Protein Kinase Inhibitors ,business.industry ,Ponatinib ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Nilotinib ,chemistry ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,business ,Bosutinib ,medicine.drug ,Chronic myelogenous leukemia - Abstract
When imatinib, the first tyrosine kinase inhibitor (TKI) developed for use in chronic myelogenous leukemia (CML), was approved in 2001, the treatment of this disease was forever changed. Significant reductions in the molecular burden of disease were seen with the first-generation TKI imatinib and, with the addition of dasatinib (2006), nilotinib (2007), bosutinib (2012), and ponatinib (2013), deeper and more rapid reductions were noted. Physicians could begin to tailor TKI therapy to individual patients, and patients who did not respond to or could not tolerate first-line therapy now had options. Importantly, the number of patients who developed accelerated or blast phase disease decreased dramatically. Research in CML continues to evolve; by presenting illustrative cases, this article reviews some of the newer aspects of clinical care in this disease. Updated information regarding bosutinib and asciminib, the latter currently in clinical trials, will be presented; bosutinib is of particular interest as the drug’s transit through the United States Food and Drug Administration highlights the question of what is considered optimal response to TKI therapy. The challenge of understanding the cardiac safety data of ponatinib and the unique dosing schedule based on individual response will be discussed. Lastly, two cases will focus on features of TKI treatment that, remarkably, have become part of the treatment algorithm: family planning for women with CML and stopping therapy after meeting a specific treatment milestone.
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- 2021
3. Dasatinib-induced pulmonary arterial hypertension – A rare late complication
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Vidhya Dhar, Amina Saqib, Uroosa Ibrahim, and Marcel Odaimi
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medicine.drug_class ,Hypertension, Pulmonary ,Dasatinib ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Humans ,Medicine ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Second line treatment ,business.industry ,Late complication ,ABL Tyrosine Kinase ,Middle Aged ,Oncology ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Cancer research ,Female ,business ,030215 immunology ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
Dasatinib is a dual Src/Abl tyrosine kinase inhibitor approved for frontline and second line treatment of chronic phase chronic myelogenous leukemia. Pulmonary arterial hypertension is defined by an increase in mean pulmonary arterial pressure >25 mmHg at rest. Dasatinib-induced pulmonary hypertension has been reported in less than 1% of patients on chronic dasatinib treatment for chronic myelogenous leukemia. The pulmonary arterial hypertension from dasatinib may be categorized as either group 1 (drug-induced) or group 5 based on various mechanisms that may be involved including the pathogenesis of the disease process of chronic myelogenous leukemia. There have been reports of dasatinib-induced pulmonary arterial hypertension being reversible. We report a case of pulmonary arterial hypertension in a 46-year-old female patient with chronic phase chronic myelogenous leukemia on dasatinib treatment for over 10 years. She had significant improvement in symptoms after discontinuation of dasatinib and initiation of vasodilators. Several clinical questions arise once patients experience significant adverse effects as discussed in our case.
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- 2018
4. Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance
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Sucha Nand, Hanh P. Mai, and Daulath Singh
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Pediatrics ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,Imatinib mesylate ,Cohort ,medicine ,Chronic phase CML ,business ,Adverse effect ,Myeloproliferative neoplasm ,Chronic myelogenous leukemia - Abstract
Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
5. Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors
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Jeffrey H. Lipton, Lisa J. McGarry, Peter Bryden, Stuart Mealing, Beth Woods, Stephanie Lustgarten, J. Whelan, Hui Huang, Neil Hawkins, and Manpreet K Sidhu
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Cancer Research ,medicine.drug_class ,Pharmacology ,Chronic phase chronic myelogenous leukemia ,Disease-Free Survival ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Protein Kinase Inhibitors ,business.industry ,Ponatinib ,Hematology ,medicine.disease ,respiratory tract diseases ,Survival Rate ,Dasatinib ,Oncology ,chemistry ,Nilotinib ,business ,Bosutinib ,Tyrosine kinase ,Chronic myelogenous leukemia ,medicine.drug - Abstract
We compared the efficacy of ponatinib and second-generation tyrosine kinase inhibitors (2G-TKIs: bosutinib, dasatinib, and nilotinib) in chronic phase CML resistant/intolerant to ≥1 prior 2G-TKI. Estimated probabilities of CCyR with 2G-TKI ranged from 22% to 26%, compared with 60% (95% CrI 52-68%) with ponatinib. The estimated probability of ponatinib providing higher response rate than all other included treatments was 99% (CCyR) and 97% (MCyR). Use of further 2G-TKI may provide limited benefit in CP-CML patients resistant/intolerant to prior 2G-TKI treatment. Compared with 2G-TKIs, ponatinib is estimated to provide substantially higher probability of achieving CCyR and MCyR; safety was not compared.
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- 2015
6. NK cell dynamics and association with molecular response in early chronic phase chronic myelogenous leukemia (CML-CP) patients treated with nilotinib
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Satu Mustjoki, Dominik Wolf, Bjørn Tore Gjertsen, Sieghart Sopper, Andreas Hochhaus, Jeroen Janssen, Kimmo Porkka, Francis J. Giles, Hematology, and CCA - Cancer biology and immunology
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0301 basic medicine ,Cancer Research ,Antineoplastic Agents ,Biology ,Philadelphia chromosome ,Chronic phase chronic myelogenous leukemia ,Cell Line ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Lymphocytes ,Imatinib ,Hematology ,medicine.disease ,3. Good health ,Killer Cells, Natural ,Dasatinib ,Leukemia ,Pyrimidines ,030104 developmental biology ,Oncology ,Nilotinib ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Immunology ,Leukocytes, Mononuclear ,K562 Cells ,medicine.drug ,K562 cells - Abstract
NK cell dynamics and association with molecular response in early chronic phase chronic myelogenous leukemia (CML-CP) patients treated with nilotinib
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- 2017
7. Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia
- Author
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Deborah L. White, Zlatko Trajanoski, Jeroen Janssen, Kimmo Porkka, Andreas Hochhaus, Matthias Baldauf, Gert J. Ossenkoppele, Guenther Gastl, Dominik Wolf, Bjørn Tore Gjertsen, Sieghart Sopper, Frank Giles, Timothy P. Hughes, Andreas Burchert, Peter Valent, Thomas Ernst, Thomas Schenk, Satu Mustjoki, Hematology, and CCA - Cancer biology and immunology
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,T-Lymphocytes ,Antineoplastic Agents ,ADAM17 Protein ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Immunologic Factors ,Prospective Studies ,L-Selectin ,Immunologic Surveillance ,Protein Kinase Inhibitors ,business.industry ,Imatinib ,Flow Cytometry ,Prognosis ,medicine.disease ,Minimal residual disease ,3. Good health ,Leukemia ,Pyrimidines ,030104 developmental biology ,Oncology ,Nilotinib ,Immunology ,Sokal Score ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
- Published
- 2017
8. Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease
- Author
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Francois-Xavier Mahon, Philippe Rousselot, Ali G. Turhan, Franck E. Nicolini, Delphine Rea, François Guilhot, Jean-Claude Chomel, Marc Spentchian, Josy Reiffers, Michel Tulliez, Philippe Agape, Agnès Guerci-Bresler, Martine Gardembas, Lydia Roy, Stéphane Prost, Jean Michel Cayuela, Gabriel Etienne, Aude Charbonnier, Joelle Guilhot, Pascale Cony-Makhoul, Martine Escoffre-Barbe, and Bruno Varet
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Disease-Free Survival ,Drug Administration Schedule ,Piperazines ,Tyrosine-kinase inhibitor ,Young Adult ,Recurrence ,Risk Factors ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,business.industry ,Remission Induction ,Imatinib ,Middle Aged ,medicine.disease ,Surgery ,Discontinuation ,Leukemia ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,Oncology ,Benzamides ,Imatinib Mesylate ,Female ,France ,business ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.
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- 2014
9. Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group
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Daisuke Imanishi, Shimeru Kamihira, Reishi Yamasaki, Makiko Horai, Katsunori Yanagihara, Hisashi Soda, Daisuke Sasaki, Kensuke Horio, Tatsuro Joh, Yasuhisa Kawaguchi, Daisuke Ogawa, Masatoshi Matsuo, Emi Matsuo, Koji Ando, Takuya Fukushima, Jun Nakashima, Jun Taguchi, Tomoko Hata, Yasushi Miyazaki, Hideki Tsushima, Junnya Makiyama, Shinichiro Yoshida, Yoshitaka Imaizumi, Yuji Moriwaki, Hiroaki Taniguchi, Hiroaki Nonaka, Yumi Takasaki, Masao Tomonaga, Hidehiro Itonaga, Yukiyoshi Moriuchi, Hiroo Hasegawa, Sayaka Mori, Yuko Doi, Masataka Taguchi, Yasushi Sawayama, Kazuhiro Nagai, Takeharu Kato, and Shinya Sato
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Male ,Cancer Research ,DNA Mutational Analysis ,Resistance ,Fusion Proteins, bcr-abl ,medicine.disease_cause ,Piperazines ,Tyrosine-kinase inhibitor ,Fusion gene ,Japan ,Risk Factors ,hemic and lymphatic diseases ,Prospective Studies ,Aged, 80 and over ,Mutation ,Gene Expression Regulation, Leukemic ,Reverse Transcriptase Polymerase Chain Reaction ,Hematology ,Middle Aged ,Treatment Outcome ,Oncology ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,Tyrosine kinase ,Chronic myelogenous leukemia ,medicine.drug ,Adult ,Adolescent ,medicine.drug_class ,Chronic phase chronic myelogenous leukemia ,Young Adult ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Analysis of Variance ,Dose-Response Relationship, Drug ,business.industry ,Imatinib ,medicine.disease ,BCR-ABL1 ,respiratory tract diseases ,Pyrimidines ,Protein kinase domain ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,business ,Alternative splicing - Abstract
An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment., Leukemia Research, 38(1), pp.76-83; 2014
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- 2014
10. Relative increase in lymphocytes from as early as 1 month predicts improved response to dasatinib in chronic-phase chronic myelogenous leukemia
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Osamu Iwase, Takashi Kumagai, Koji Oba, Kazuteru Ohashi, Hisashi Wakita, Junichi Sakamoto, Yasuji Kozai, Atsushi Shinagawa, Shinichiro Okamoto, Yukari Shirasugi, Koiti Inokuchi, Chikashi Yoshida, Jin Takeuchi, Shin Fujisawa, Shingo Yano, Kaichi Nishiwaki, Hisashi Sakamaki, and Eri Matsuki
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Myeloid ,Adolescent ,Lymphocytosis ,Lymphocyte ,Dasatinib ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,Immunophenotyping ,Young Adult ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Lymphocyte Count ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,Aged, 80 and over ,business.industry ,Imatinib ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Lymphocyte Subsets ,Thiazoles ,Leukemia ,Phenotype ,Pyrimidines ,Treatment Outcome ,medicine.anatomical_structure ,Leukemia, Myeloid, Chronic-Phase ,Immunology ,Female ,medicine.symptom ,business ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts150 % at 1 month or200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.
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- 2013
11. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis
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Véronique Maguer-Satta, Sandrine Hayette, Martin C. Müller, Wei Zhou, Eric Lippert, Jane F. Apperley, Gabriel Etienne, Charles Chuah, Catherine Roche-Lestienne, Jorge E. Cortes, Michael J. Mauro, Mauricette Michallet, Dong-Wook Kim, Franç ois X. Mahon, Simona Soverini, Franck E. Nicolini, Stephane Morisset, John M. Goldman, Andreas Hochhaus, Inge Høgh Dufva, Amr R. Ibrahim, David Marin, Senaka Peter, Giovanni Martinelli, Hélène Labussière, Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Müller MC, Hochhaus A, Dufva IH, Kim DW, Cortes J, Mauro MJ, Chuah C, Labussière H, Morisset S, Roche-Lestienne C, Lippert E, Hayette S, Peter S, Zhou W, Maguer-Satta V, Michallet M, Goldman J, Apperley JF, Mahon FX, Marin D, and Etienne G.
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Fusion Proteins, bcr-abl ,Genes, abl ,Chronic phase chronic myelogenous leukemia ,Cohort Studies ,Young Adult ,hemic and lymphatic diseases ,Internal medicine ,TYROSINE KINASE INHIBITORS ,Humans ,Medicine ,Prospective Studies ,BCR-ABL ,Protein Kinase Inhibitors ,Survival rate ,Aged ,Retrospective Studies ,ABL ,business.industry ,Imatinib ,Articles ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia ,Imatinib mesylate ,Drug Resistance, Neoplasm ,Leukemia, Myeloid, Chronic-Phase ,Mutation ,Immunology ,ABL MUTATIONS ,Female ,business ,Tyrosine kinase ,medicine.drug ,Chronic myelogenous leukemia - Abstract
The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I(+) patients versus not reached for T315I(-) ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I(+) patients versus not reached for T315I(-) patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.
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- 2013
12. Digital image analysis as a tool to assess the effects of imatinib on trabecular bone in patients with chronic myelogenous leukemia
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Daniela Hoehn, Carlos E. Bueso-Ramos, Xuemei Wang, L. Jeffrey Medeiros, Hagop M. Kantarjian, and Jorge E. Cortes
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Adult ,Male ,Pathology ,medicine.medical_specialty ,medicine.drug_class ,Biopsy ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Bone and Bones ,Piperazines ,Tyrosine-kinase inhibitor ,Pathology and Forensic Medicine ,Bone Marrow ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Image Processing, Computer-Assisted ,medicine ,Homeostasis ,Humans ,Receptor ,Aged ,medicine.diagnostic_test ,business.industry ,Imatinib ,Middle Aged ,medicine.disease ,Pyrimidines ,Treatment Outcome ,medicine.anatomical_structure ,Benzamides ,Imatinib Mesylate ,Female ,Bone marrow ,business ,Tyrosine kinase ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Skeletal integrity is sustained by osteoblast-osteoclast interactions, controlled by several signaling pathways that include tyrosine kinases. Imatinib is a tyrosine kinase inhibitor with an extended therapeutic range based on its ability to differentially bind to receptor and nonreceptor tyrosine kinases. In this study, we used digital image analysis to assess changes in trabecular bone surface area within bone marrow biopsy specimens of 34 patients with chronic phase chronic myelogenous leukemia treated with single-agent imatinib. These patients were 25 men and 9 women with a median age of 59 years. We selected representative areas of paired bone marrow biopsy specimens obtained at baseline and within the subsequent 48 months. Computer-assisted analysis was performed to calculate trabecular bone area (TBA) within the sample by using the equation TBA% = sum of trabecular area/total biopsy specimen area. Percentage changes were defined as ΔTBA% and were arbitrarily subdivided into marked (50%), moderate (10%-50%), and mild (10%). During the study interval, TBA% increased in 24 patients (71%) and decreased in 10 patients (29%). Overall, there was a significant increase in TBA% (P = .02). No correlation was found between changes in trabecular bone area and either clinical or cytogenetic response (P = .25). The results show that imatinib therapy can alter trabecular bone in bone marrow biopsy specimens of chronic myelogenous leukemia patients, most often resulting in an increase in TBA%.
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- 2012
13. Stability Analysis of a Model of Interaction Between the Immune System and Cancer Cells in Chronic Myelogenous Leukemia
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Apollos Besse, Franck E. Nicolini, Doron Levy, Geoffrey D. Clapp, Thomas Lepoutre, Samuel Bernard, Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Modélisation mathématique, calcul scientifique (MMCS), Institut Camille Jordan (ICJ), Department of Mathematics [Maryland], University of Maryland [College Park], University of Maryland System-University of Maryland System, Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Center for Scientific Computation and Mathematical Modeling (CSCAMM), Institut Camille Jordan [Villeurbanne] (ICJ), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,General Mathematics ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,Autoimmunity ,Chronic phase chronic myelogenous leukemia ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Bifurcation analysis ,medicine ,Humans ,Immune response ,[MATH]Mathematics [math] ,Protein Kinase Inhibitors ,General Environmental Science ,Pharmacology ,Chemistry ,General Neuroscience ,Models, Immunological ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Mathematical Concepts ,Protein-Tyrosine Kinases ,medicine.disease ,3. Good health ,030104 developmental biology ,Computational Theory and Mathematics ,030220 oncology & carcinogenesis ,Cancer cell ,Leukemia, Myeloid, Chronic-Phase ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Linear stability ,Steady state (chemistry) ,Stem cell ,General Agricultural and Biological Sciences ,Tyrosine kinase ,Chronic myelogenous leukemia - Abstract
International audience; We describe here a simple model for the interaction between leukemic cells and the autologous immune response in chronic phase chronic myelogenous leukemia (CML). This model is a simplified version of the model we proposed in [Clapp et al., Cancer Research, 75:4053-4062, 2015]. Our simplification is based on the observation that certain key characteristics of the dynamics of CML can be captured with a three compartments model: two for the leukemic cells (stem cells and mature cells) and one for the immune response. We characterize the existence of steady states and their stability for generic forms of immunosuppres-sive effects of leukemic cells. We provide a complete co-dimension one bifurcation analysis. Our results show how clinical response to tyrosine kinase inhibitors treatment is compatible with the existence of a stable low-disease, treatment-free steady state.
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- 2016
14. Clinical Safety and Efficacy of Nilotinib or Dasatinib in Patients with Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia and Pre-existing Liver and/or Renal Dysfunction
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Naval Daver, Amit Lahoti, Susan O'Brien, Tapan M. Kadia, Gautam Borthakur, Koji Sasaki, Preetesh Jain, Sherry Pierce, Alessandra Ferrajoli, Elias Jabbour, Naveen Pemmaraju, Hagop M. Kantarjian, and Jorge E. Cortes
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Dasatinib ,Renal function ,Antineoplastic Agents ,Kidney Function Tests ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Liver Function Tests ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Kidney ,medicine.diagnostic_test ,business.industry ,Liver Diseases ,Organ dysfunction ,Acute kidney injury ,Hematology ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Pyrimidines ,Treatment Outcome ,Oncology ,Nilotinib ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Female ,Kidney Diseases ,medicine.symptom ,Liver function tests ,business ,medicine.drug ,Follow-Up Studies - Abstract
The safety and efficacy of front-line nilotinib and dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML-CP) with pre-existing liver and/or renal dysfunction are unknown.We analyzed the adverse event rates, response rates, and survival rates of 215 patients with CML-CP with or without renal and/or liver dysfunction who had been treated with front-line nilotinib (n = 108) or dasatinib (n = 107).The overall median follow-up period was 49 months. At baseline, 6 dasatinib-treated patients (6%) had mild renal dysfunction and 13 (12%) had mild liver dysfunction. Also, 8 nilotinib-treated patients (7%) had mild renal dysfunction, 1 (1%) moderate renal dysfunction, and 9 (8%) mild liver dysfunction. No significant differences were found in the rate of complete cytogenetic response, major molecular response, or molecular response by a 4.5 log reduction on the international scale between the organ function cohorts. Dasatinib- or nilotinib-treated patients with baseline renal dysfunction had a greater incidence of transient reversible acute kidney injury (P = .011 and P.001), and nilotinib-treated patients with renal dysfunction had a greater incidence of bleeding (P.001).Patients with CML-CP and mild to moderate renal or liver dysfunction can be safely treated with front-line dasatinib or nilotinib and can achieve response rates similar to those of patients with CML-CP without organ dysfunction.
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- 2015
15. Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase Chronic Myelogenous Leukemia patients
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Franck E. Nicolini, Mohamad Sobh, Arthur Bert, Hélène Labussière-Wallet, Emilie Blond, Jocelyne Drai, Marie Balsat, Isabelle Redonnet-vernhet, Maël Heiblig, Madeleine Etienne, Gaelle Fossard, Stephane Morisset, Francois-Xavier Mahon, Gabriel Etienne, Stéphane Giraudier, Jean-Christophe Lega, Martine Escoffre-Barbe, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Départment de Biochimie, Hospices Civils de Lyon (HCL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)
- Subjects
Male ,Myeloid ,Homocysteine ,[SDV]Life Sciences [q-bio] ,Coronary Artery Disease ,Pharmacology ,Gastroenterology ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,0302 clinical medicine ,infection chronique ,hemic and lymphatic diseases ,Prospective Studies ,BCR-ABL ,ComputingMilieux_MISCELLANEOUS ,Age Factors ,Hematology ,Middle Aged ,erythroleucémie ,chronic phase CML ,nilotinib ,homocysteine ,cardiovascular events ,3. Good health ,Leukemia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,patient ,medicine.drug ,Adult ,Hyperhomocysteinemia ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Drug Administration Schedule ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Online Only Articles ,Triglycerides ,Aged ,Retrospective Studies ,business.industry ,Cholesterol, HDL ,medicine.disease ,Imatinib mesylate ,Pyrimidines ,chemistry ,Nilotinib ,cardiovasculaire ,business ,Hématologie ,thérapie ,030215 immunology - Abstract
Fossard, Gaelle Blond, Emilie Balsat, Marie Morisset, Stephane Giraudier, Stephane Escoffre-Barbe, Martine Labussiere-Wallet, Helene Heiblig, Mael Bert, Arthur Etienne, Madeleine Drai, Jocelyne Sobh, Mohamad Redonnet-Vernhet, Isabelle Lega, Jean-Christophe Mahon, Francois-Xavier Etienne, Gabriel Nicolini, Franck Emmanuel; International audience
- Published
- 2015
16. Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity
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John T. Harty, Catherine Matte-Martone, Douglas R. Green, Jinling Liu, Maria Chikina, Warren D. Shlomchik, and Meng Zhou
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,T cell ,Graft vs Leukemia Effect ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,Major histocompatibility complex ,Chronic phase chronic myelogenous leukemia ,03 medical and health sciences ,Interferon-gamma ,Mice ,Downregulation and upregulation ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,neoplasms ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,Chemistry ,Myeloid leukemia ,General Medicine ,Neoplasms, Experimental ,medicine.disease ,3. Good health ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,surgical procedures, operative ,Leukemia, Myeloid ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Stem cell ,Research Article - Abstract
The graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation (alloSCT) is potent against chronic phase chronic myelogenous leukemia (CP-CML), but blast crisis CML (BC-CML) and acute myeloid leukemias (AML) are GVL resistant. To understand GVL resistance, we studied GVL against mouse models of CP-CML, BC-CML, and AML generated by the transduction of mouse BM with fusion cDNAs derived from human leukemias. Prior work has shown that CD4+ T cell-mediated GVL against CP-CML and BC-CML required intact leukemia MHCII; however, stem cells from both leukemias were MHCII negative. Here, we show that CP-CML, BC-CML, and AML stem cells upregulate MHCII in alloSCT recipients. Using gene-deficient leukemias, we determined that BC-CML and AML MHC upregulation required IFN-γ stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-γ receptor (IFN-γR) and the IFN-α/β receptor IFNAR1. Importantly, IFN-γR-deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-γR/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-γ stimulation, suggesting that IFN-γ sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-γ stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-γ renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.
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- 2015
17. Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: A report from the Children's Oncology Group
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Helen Chen, Charlotte Wood, Vivian G. Oehler, Franklin O. Smith, Linda D. Cooley, Mary Ellen French, Robert B. Gerbing, Todd A. Alonzo, Robert J. Arceci, Myron Chang, Mark L. Bernstein, Martin A. Champagne, Nyla A. Heerema, and Cecilia Fu
- Subjects
medicine.medical_specialty ,business.industry ,Imatinib ,Hematology ,Imatinib therapy ,Pharmacology ,medicine.disease ,Chronic phase chronic myelogenous leukemia ,Clinical trial ,Oncology ,hemic and lymphatic diseases ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Toxicity ,medicine ,Complete Molecular Response ,business ,Complete Hematologic Response ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Purpose To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML). Methods This was an open label, multi-center phase II clinical trial. Courses were defined as consecutive 28-day intervals. Oral imatinib was administered daily at 340 mg/m2 without interruption in the absence of toxicity. Results Fifty-one children received 978 28-day courses of imatinib. The most common toxicities encountered were hematologic. Forty-one patients (80%) achieved a complete hematologic response by the end of course 2. Nineteen children (38%) obtained a complete cytogenetic response (CCyR) at the end of course 3. Overall, 72% achieved CCyR at a median time of 5.6 months. The rate of complete molecular response (>3 log reduction) was 27%. Progression-free and overall survival at 3 years were 72% ± 6.4% and 92% ± 3.9%, respectively. Conclusions Daily oral imatinib at a dose of 340 mg/m2 is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. (This study was registered at ClinicalTrials.gov under identifier NCT00030394.). Pediatr Blood Cancer 2011;57:56–62. © 2011 Wiley-Liss, Inc.
- Published
- 2011
18. The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge
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Laurence Legros, Franck E. Nicolini, François Guilhot, Emmanuelle Nicolas-Virelizier, Jean-Claude Chomel, Jean-Pierre Magaud, Ali G. Turhan, Sandrine Hayette, Isabelle Tigaud, Mauricette Michallet, Sophie Ducastelle, Lydia Roy, and Kaddour Chabane
- Subjects
Adult ,Male ,Harringtonines ,Cancer Research ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Omacetaxine mepesuccinate ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,business.industry ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Oncology ,chemistry ,Nilotinib ,Drug Resistance, Neoplasm ,Homoharringtonine ,Immunology ,Cancer research ,Female ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Purpose The onset of a BCR-ABL T315I mutation during the course of chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs) usually results in poor survival, and therapeutic options remain few in the absence of any allogeneic donor. Patients and Methods We have investigated the affect of subcutaneous omacetaxine (OMA, or homo-harringtonine) cycles on unmutated and T315I-mutated BCR-ABL transcripts in a series of 8 TKI-resistant chronic-phase CML patients and we have addressed the question of whether the administration of OMA could resensitize patients to TKIs. Patients were regularly monitored for total disease burden and for BCR-ABL T315I transcripts using a new quantitative sensitive technique (sensitivity threshold, 0.05%), for up to 27 cycles of OMA. Results Overall, patients demonstrated hematologic, cytogenetic, or molecular improvement. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of patients, after a median of 10.5 cycles (range, 3–27 cycles) of OMA. As the unmutated leukemic burden reduction was modest, 2 patients were submitted to nilotinib after 9 months of sustained BCR-ABL T315I transcripts negativity on OMA and mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge. Conclusion We suggest that OMA (ie, a non-targeted therapy) might provide a better disease control allowing the disappearance of the mutated clone probably elicited by the clone deselection after TKI release, and/or a preferential activity of OMA on the T315I-mutated cells through unknown mechanisms. These observations suggest that OMA could allow a safe TKI rechallenge in patients with resistant chronic-phase CML.
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- 2010
19. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia
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Farhad Ravandi, Jody Hiteshew, Guillermo Garcia-Manero, Srdan Verstovsek, Dan Jones, Jenny Shan, Hagop M. Kantarjian, Jorge E. Cortes, Charles Koller, Alfonso Quintás-Cardama, and Susan O'Brien
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Patient Dropouts ,medicine.drug_class ,Alpha interferon ,Interferon alpha-2 ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,Drug Administration Schedule ,Piperazines ,Article ,Tyrosine-kinase inhibitor ,Polyethylene Glycols ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,business.industry ,Granulocyte-Macrophage Colony-Stimulating Factor ,Interferon-alpha ,Imatinib ,Middle Aged ,medicine.disease ,Minimal residual disease ,Recombinant Proteins ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Oncology ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Immunology ,Imatinib Mesylate ,Female ,business ,medicine.drug ,Chronic myelogenous leukemia - Abstract
BACKGROUND: Most patients with chronic myelogenous leukemia (CML) harbor residual disease, as evidenced by molecular techniques even after treatment with high-dose imatinib (ie, 800 mg/d). Interferon alpha (IFN α) is efficacious in CML likely due to its immunomodulatory properties, and is synergistic in vitro with imatinib and granulocyte macrophage-colony stimulating factor (GM-CSF). METHODS: A study was undertaken to determine whether adding pegylated (PEG) IFN α-2b and GM-CSF to high-dose imatinib may improve the complete molecular response rate in patients with CML in chronic phase. Ninety-four patients were treated with imatinib 800 mg/d for the first 6 months, then randomly assigned to continue high-dose imatinib alone (n = 49) or in combination with PEG IFN α-2b 0.5 μg/kg/wk and GM-CSF 125 mg/m2 3× weekly (n = 45). RESULTS: The median follow-up for all patients was 54 months (range, 7-70 months). There were no differences in the rates of complete cytogenetic response (87% vs 90%; P = 1.0), or of major (77% vs 77%; P = 1.0) or complete (11% vs 13%; P = 1.0) molecular response (on the international scale) at 12 months between the 2 arms, or at any time during the study. Adverse events led to PEG IFN α-2b discontinuation in all patients. CONCLUSIONS: The addition of PEG IFN α-2b and GM-CSF to high-dose imatinib therapy does not improve significantly the cytogenetic or molecular response rates compared with high-dose imatinib alone. The high dropout rate in the PEG IFN α-2b arm may have compromised its potential immunomodulatory benefit. Cancer 2011. © 2010 American Cancer Society.
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- 2010
20. Long-term follow-up of de novo chronic phase chronic myelogenous leukemia patients on front-line imatinib
- Author
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Sandrine Hayette, Anna Schmitt, Franck E. Nicolini, Audrey Bidet, Stephane Morisset, Maël Heiblig, Mohamad Sobh, Pascale Cony-Makhoul, Francois-Xavier Mahon, Gabriel Etienne, Stéphanie Dulucq, Gaëlle Fossard, and Vincent Alcazer
- Subjects
Male ,Cancer Research ,Kaplan-Meier Estimate ,Tyrosine-kinase inhibitor ,0302 clinical medicine ,Cause of Death ,Child ,Aged, 80 and over ,Univariate analysis ,Hematology ,Middle Aged ,Prognosis ,Survival Rate ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,France ,Sokal Score ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Antineoplastic Agents ,Leukemia, Myeloid, Accelerated Phase ,Chronic phase chronic myelogenous leukemia ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Humans ,Protein Kinase Inhibitors ,Molecular Biology ,Survival rate ,Aged ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,Imatinib ,Cell Biology ,medicine.disease ,Imatinib mesylate ,Blast Crisis ,business ,Follow-Up Studies ,030215 immunology ,Chronic myelogenous leukemia - Abstract
For the last 15years, imatinib mesylate (IM) has represented the gold standard treatment for chronic-phase chronic myelogenous leukemia (CP-CML); however, outcomes in the very long term remain unknown. We retrospectively analyzed the outcome of 418 IM first-line treated CP-CML patients followed in three reference centers over 15years in and outside of clinical trials, which is believed to represent the "real-life" care of such patients. Molecular analyses were standardized over the years. In case of intolerance or resistance or IM cessation and progression, all clinical data were collected and analyzed. After a median follow-up of 83 months (range 1-194), the overall survival (OS) rates were 91% and 82%, the progression-free survival (PFS) rates were 88.5% and 81%, and the event-free survival rates, including switching to another tyrosine kinase inhibitor, were 65% and 51%, respectively, at 5 and 10years. Thirteen patients (3%) entered blast crisis (BC) with a median survival of 2.2years after BC onset. Forty-nine percent of patients were in major molecular response at 1 year. Univariate analysis failed to detect any impact on survival of molecular response at 3 and 6 months. Sokal score had a significant impact on OS and PFS in a Cox model. Age had a significant impact on OS and PFS, mainly due to deaths in elderly patients unrelated to CML. Overall, 21% of patients reached a stable (≥1 year) molecular response 4 (MR4) and 6.5% reached MR4.5. At last follow-up, 63% of patients were still on IM and 19% were in treatment-free remission. We conclude that IM is an excellent therapeutic option providing impressive long-term OS rates.
- Published
- 2018
21. Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
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Zhixiang Shen, Jiri Mayer, Sandip Shah, M. Brigid Bradley-Garelik, Charles Chuah, Andreas Hochhaus, Neil P. Shah, Eric Bleickardt, Michele Baccarani, Concepción Boqué, Ricardo Pasquini, Hagop M. Kantarjian, Ted Szatrowski, Jorge E. Cortes, David Shapiro, Hirohisa Nakamae, Beatriz Moiraghi, Manuel Ayala, Chao Zhu, and Françoise Huguet
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Ponatinib ,Myeloid leukemia ,Imatinib ,General Medicine ,Blastic Phase ,Chronic phase chronic myelogenous leukemia ,3. Good health ,Dasatinib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Nilotinib ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Immunology ,Omacetaxine mepesuccinate ,medicine ,business ,030215 immunology ,medicine.drug - Abstract
Background Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. Methods In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. Results After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P = 0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P = 0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P
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- 2010
22. Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia
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Saglio, G, Kim, Dw, Issaragrisil, S, le Coutre, P, Etienne, G, Lobo, C, Pasquini, R, Clark, Re, Hochhaus, A, Hughes, Tp, Gallagher, N, Hoenekopp, A, Dong, M, Haque, A, Alimena, Giuliana, Larson, Ra, Kantarjian, Hm, and Enestnd, Investigators
- Subjects
Myeloid ,Male ,bcr-abl ,Fusion Proteins, bcr-abl ,Kaplan-Meier Estimate ,Pharmacology ,PHASE CML-CP ,Gastroenterology ,Piperazines ,chemistry.chemical_compound ,hemic and lymphatic diseases ,80 and over ,Medicine ,Aged, 80 and over ,Leukemia ,PATIENTS RECEIVING IMATINIB ,Medicine (all) ,HARMONIZING CURRENT METHODOLOGY ,CHRONIC MYELOGENOUS LEUKEMIA ,Ponatinib ,General Medicine ,Middle Aged ,BCR-ABL TRANSCRIPTS ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Antagonists & inhibitors ,Adolescent ,PHASE CML-CP, HARMONIZING CURRENT METHODOLOGY, CHRONIC MYELOGENOUS LEUKEMIA, PATIENTS RECEIVING IMATINIB, UP SUSTAINED SURVIVAL, BCR-ABL TRANSCRIPTS, FOLLOW-UP, PATIENTS PTS, 800 MG, MOLECULAR RESPONSES ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Young Adult ,PATIENTS PTS ,Internal medicine ,Omacetaxine mepesuccinate ,Humans ,Protein Kinase Inhibitors ,MOLECULAR RESPONSES ,Aged ,business.industry ,Blast Crisis ,Pyrimidines ,Fusion Proteins ,Imatinib ,800 MG ,medicine.disease ,Imatinib mesylate ,UP SUSTAINED SURVIVAL ,chemistry ,Nilotinib ,Chronic-Phase ,FOLLOW-UP ,business ,Chronic myelogenous leukemia - Abstract
Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P
- Published
- 2010
23. Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial
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Françoise Huguet, Laurence Legros, Gabriel Etienne, Vérane Schwiertz, Franck E. Nicolini, Delphine Rea, Martine Gardembas, Stephane Morisset, Jean-Christophe Ianotto, Lydia Roy, Shanti Ame, Martine Escoffre-Barbe, Pascal Turlure, Fabrice Larosa, Eric Hermet, Viviane Dubruille, Simona Lapusan, Pascale Cony-Makhoul, Agnès Guerci-Bresler, Stéphanie Dulucq, Denis Caillot, Philippe Rousselot, Francois-Xavier Mahon, Aude Charbonnier, Pascal Lenain, Hyacinthe Johnson-Ansah, Philippe Quittet, Valérie Coiteux, Stéphane Courby, Madeleine Etienne, and Denis Guyotat
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Intention-to-treat analysis ,Anemia ,business.industry ,Incidence (epidemiology) ,030106 microbiology ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Interim analysis ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Pulmonary embolism ,03 medical and health sciences ,Nilotinib ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015). Aims Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82). Methods Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Results Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1. Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid). Conclusion The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting. Disclosures Nicolini: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne: Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux: Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul: BMS: Speakers Bureau. Rousselot: Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat: BMS: Speakers Bureau. Ianotto: Novartis: Other: Grant. Rea: BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon: Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.
- Published
- 2017
24. Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia
- Author
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Timothy Tyler
- Subjects
Oncology ,medicine.medical_specialty ,Dasatinib ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Drug Administration Schedule ,Piperazines ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Drug Interactions ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Clinical Trials as Topic ,business.industry ,Myeloid leukemia ,Imatinib ,medicine.disease ,Thiazoles ,Pyrimidines ,Imatinib mesylate ,Nilotinib ,Drug Resistance, Neoplasm ,Benzamides ,Immunology ,Imatinib Mesylate ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
ObjectiveTo discuss the new dasatinib dosing regimen for the treatment of chronic phase chronic myelogenous leukemia (CP CML) in patients who failed or were intolerant to imatinib therapy.Data SourcesLiterature published between July 2008 and December 2008 was accessed via MEDLINE, the Proceedings of the American Society of Hematology, and the Proceedings of the American Society of Clinical Oncology using the key words chronic myelogenous leukemia, chronic myeloid leukemia, dasatinib, imatinib, nilotinib, pharmacokinetics, and regimen.Study Selection And Data ExtractionMeeting abstracts and reports of major Phase 1–3 studies published in English are included.Data SynthesisImatinib is the standard first-line therapy for CML; however, some patients develop resistance or are intolerant to the drug. Dasatinib was approved for the treatment of imatinib-resistant/intolerant patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia at the dosage of 70 mg twice daily. A Phase 3 dose-optimization study was performed to compare this regimen with others, including dasatinib 100 mg once daily, in patients with CP CML. Results of this study showed that there was no significant difference in efficacy between these 2 regimens. The safety profile was improved in the 100-mg once-daily dasatinib arm with significantly reduced frequencies of grade 3–4 thrombocytopenia and all-grade pleural effusions. The number of patients who had to discontinue, reduce, or interrupt their dosage was also less among patients taking dasatinib 100 mg once daily.ConclusionsDasatinib 100 mg once daily has a more favorable risk to benefit assessment compared with the previous 70 mg twice-daily regimen and is now the recommended schedule for patients with CP CML.
- Published
- 2009
25. Somatic genetics and targeted therapies for cutaneous melanoma
- Author
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Keiran S.M. Smalley and Keith T. Flaherty
- Subjects
Cancer Research ,business.industry ,Somatic cell ,Melanoma ,medicine.medical_treatment ,medicine.disease ,Chronic phase chronic myelogenous leukemia ,Targeted therapy ,Clinical trial ,Oncology ,Interferon ,Immunology ,Cutaneous melanoma ,Cancer research ,Medicine ,Signal transduction ,business ,medicine.drug - Abstract
The standard treatments for metastatic melanoma have not evolved in the past 30 years. It has been a decade since the emergence of high-dose interferon in the adjuvant setting: a therapy with significant limitations in both efficacy and tolerability. The conventional therapies that have proven useful for other cancers have been exhausted with regard to their exploration in melanoma and novel approaches are required. The identification of somatic genetic alterations that activate the MAP kinase and PI3 kinase pathways has provided a foothold for the investigation of signal transduction inhibitors that counter them. Melanoma is more complex than some of the cancers with early success in the application of signal transduction inhibitors, such as chronic phase chronic myelogenous leukemia or gastrointestinal stromal tumors, with regard to the number of genetic aberrations found within any one cell. While reductive laboratory studies have supported the potential therapeutic value of inhibitors of these and other signaling pathways in melanoma, even those experiments do not suggest that every cell in a given tumor will be eradicated with agents that target a single pathway. The current generation of clinical trials, which seek to develop novel signal transduction inhibitors, will ultimately provide the building blocks for regimens that take into account the greater complexity of melanoma at the level of aberrant signal transduction.
- Published
- 2008
26. Phase II, randomized, multicenter, comparative study of peginterferon–α–2a (40 kD) (Pegasys®)versusinterferon α-2a (Roferon®-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia
- Author
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Kudrat Abdulkadyrov, Tim H. Brümmendorf, D Raghunadharao, Anatoly Golenkov, Bengt Bergström, Krishnan Nair, Jeffrey H. Lipton, Nina Khoroshko, and Kisook Yoo
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Phases of clinical research ,Interferon alpha-2 ,Antiviral Agents ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Polyethylene Glycols ,law.invention ,Myelogenous ,Randomized controlled trial ,Pegylated interferon ,law ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Drug Carriers ,business.industry ,Interferon-alpha ,Hematology ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Surgery ,Clinical trial ,Leukemia ,Oncology ,Female ,business ,medicine.drug - Abstract
The efficacy and safety of peginterferon-alpha-2a (40 kD) (PEG-IFNalpha-2a), 450 microg once weekly, versus IFNalpha-2a, 9 MIU once daily, for 12 months, was evaluated in a Phase II study in IFN-naïve patients with chronic-phase, Philadelphia-chromosome-positive CML. At the end of the treatment, complete hematological response was observed in 66.2% (47/71) and 45.2% (33/73) of the PEG-IFNalpha-2a group and IFNalpha-2a groups, respectively (p = 0.009), and major cytogenetic response occurred in 35.2% and 17.8%, respectively (p = 0.016). PEG-IFNalpha-2a was at least as effective as IFNalpha-2a overall, including progression-free survival at the end of treatment, and overall survival after 30 months of follow-up. Adverse events necessitated fewer withdrawals but more dose adjustments in the PEG-IFNalpha-2a group compared with the IFNalpha-2a group (11%versus 23%, and 84.5%versus 65.8%, respectively). In conclusion, PEG-IFNalpha-2a (40 kD), 450 microg once weekly, compared with IFNalpha-2a, 9 MIU once daily, resulted in higher rates of hematologic and cytogenetic response and greater overall survival.
- Published
- 2007
27. Which tyrosine-kinase inhibitor to use first in chronic phase chronic myelogenous leukemia?
- Author
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Morgan Mace, Elias Jabbour, and Jenny Dahl
- Subjects
medicine.drug_class ,Dasatinib ,Chromosomal translocation ,Antineoplastic Agents ,Genes, abl ,Philadelphia chromosome ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,Piperazines ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology (medical) ,neoplasms ,Protein Kinase Inhibitors ,Pharmacology ,business.industry ,Imatinib ,General Medicine ,medicine.disease ,Thiazoles ,Pyrimidines ,Nilotinib ,Clinical Trials, Phase III as Topic ,Drug Resistance, Neoplasm ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Cancer research ,Imatinib Mesylate ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder distinctly characterized by the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. The resulting translocation leads to the development of the BCR-ABL1 oncogene, a constitutively active fusion protein, which leads to uncontrolled cell proliferation and reduced apoptosis and has a clear association with driving the malignant activity of CML cells.Given that the BCR-ABL1 oncogene is a known key cause of CML, it has led to the development of numerous small molecule tyrosine-kinase inhibitors (TKIs), which target the specific oncogene mutation in CML. Presently, there are three FDA-approved TKI agents, imatinib, dasatinib and nilotinib, for the treatment of frontline CML. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents.Imatinib, dasatinib and nilotinib are all effective at yielding hematological, molecular and cytogenetic responses in patients with newly diagnosed CML. Frontline therapy may depend on physician experience, patient age and ability to tolerate therapy, and with the lack of data comparing all three agents alongside each other, imatinib, dasatinib, or nilotinib may all be suitable frontline choices.
- Published
- 2015
28. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia
- Author
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François Guilhot, Laurie Letvak, Richard A. Larson, Bayard L. Powell, Hermine Agis, Norbert Gattermann, Francisco Cervantes, Andreas Hochhaus, Brian J. Druker, Richard T. Silver, Hagop M. Kantarjian, Charlene So, Bengt Simonsson, Thea Kolsen Fischer, Jerald P. Radich, John D. Shepherd, Johan Lanng Nielsen, Alois Gratwohl, Jan J. Cornelissen, Insa Gathmann, Stephen G. O'Brien, Janice Gabrilove, Josy Reiffers, Michael W. Deininger, Kerry Taylor, Richard Stone, Michele Baccarani, Philippe Rousselot, Gregor Verhoef, John M. Goldman, Giuseppe Saglio, Timothy P. Hughes, Medical Oncology, Hematology, Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, and Larson RA
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Chronic phase chronic myelogenous leukemia ,Disease-Free Survival ,Piperazines ,chemistry.chemical_compound ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Omacetaxine mepesuccinate ,medicine ,Humans ,neoplasms ,business.industry ,Ponatinib ,Cytarabine ,Interferon-alpha ,Myeloid leukemia ,Imatinib ,General Medicine ,Protein-Tyrosine Kinases ,Survival Analysis ,Survival Rate ,Dasatinib ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,chemistry ,Nilotinib ,Benzamides ,Immunology ,Imatinib Mesylate ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy.We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events.The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events.After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)
- Published
- 2006
29. Survival advantage from imatinib compared with the combination interferon-α plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials
- Author
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Richard A. Larson, Giorgio Massimini, Lydia Roy, Agnès Guerci-Bresler, Stephen G. O'Brien, Charlene So, Brian J. Druker, Tillmann Krahnke, François Guilhot, and Joelle Guilhot
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Immunology ,Antineoplastic Agents ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Piperazines ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Treatment Failure ,Survival rate ,Survival analysis ,Aged ,Bone Marrow Transplantation ,Retrospective Studies ,business.industry ,Cytarabine ,Interferon-alpha ,Imatinib ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Leukemia ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,Clinical Trials, Phase III as Topic ,Benzamides ,Splenomegaly ,Disease Progression ,Imatinib Mesylate ,Female ,business ,Chronic myelogenous leukemia ,medicine.drug - Abstract
In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.
- Published
- 2006
30. Significance of myelofibrosis in early chronic-phase, chronic myelogenous leukemia on imatinib mesylate therapy
- Author
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Stefan Faderl, Moshe Talpaz, William Wierda, Carlos E. Bueso-Ramos, Mary Beth Rios, Francis Giles, Jorge Cortes, Hagop Kantarjian, Jianqin Shan, and Susan O'Brien
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,Philadelphia chromosome ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Piperazines ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Myelofibrosis ,Survival rate ,Aged ,Aged, 80 and over ,business.industry ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Surgery ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Oncology ,Primary Myelofibrosis ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,business ,Chronic myelogenous leukemia - Abstract
BACKGROUND Myelofibrosis is associated historically with a poor prognosis in patients with chronic myelogenous leukemia (CML). Its significance in the recent era of effective therapy with imatinib mesylate is unknown. METHODS The current study evaluated the significance of the degree of pretreatment myelofibrosis on response and survival with imatinib therapy in patients with newly diagnosed CML. The study group comprised 198 patients with newly diagnosed Philadelphia chromosome-positive, chronic-phase CML treated with imatinib mesylate therapy. They were analyzed for the prognostic significance of bone marrow reticulin fibrosis. RESULTS Severe reticulin (Grade 3–4) fibrosis was observed in 75 patients (38%): Grade 3 in 46 (23%) patients and Grade 4 in 29 (15%) patients. There was a trend towards a lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis (76% vs. 89%; P = 0.07), and a significantly worse survival (estimated 3-year survival rate of 87% vs. 97%; P = 0.04). CONCLUSIONS Although the prognostic significance of severe reticulin fibrosis in patients with newly diagnosed CML receiving imatinib therapy was better, 15% of patients with Grade 4 reticulin fibrosis still had a worse outcome. Cancer 2005. © 2005 American Cancer Society.
- Published
- 2005
31. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia
- Author
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Srdan Verstovsek, Deborah A. Thomas, Hagop M. Kantarjian, Susan O'Brien, Jorge E. Cortes, Allessandra Ferrajoli, Jianqin Shan, Guillermo Garcia-Manero, Mary Beth Rios, Stefan Faderl, Francis J. Giles, Moshe Talpaz, and Laurie Letvak
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Immunology ,Antineoplastic Agents ,Genes, abl ,Blastic Phase ,Philadelphia chromosome ,Biochemistry ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,Piperazines ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Philadelphia Chromosome ,neoplasms ,Survival rate ,Aged ,Aged, 80 and over ,ABL ,business.industry ,Therapies, Investigational ,Imatinib ,Drugs, Investigational ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Benzamides ,Imatinib Mesylate ,Female ,business ,medicine.drug - Abstract
Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC < 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)
- Published
- 2004
32. Case of chronic-phase chronic myelogenous leukemia with an abdominal hematopoietic tumor of leukemic clone origin
- Author
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Naoyuki Katayama, Miho Sakakura, Kohshi Ohishi, Kazunori Nakase, Hiroshi Shiku, Kenichi Nomura, Masahiro Masuya, and Kazuhiro Nishii
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Myeloid ,Fusion Proteins, bcr-abl ,Chronic phase chronic myelogenous leukemia ,Piperazines ,hemic and lymphatic diseases ,medicine ,Humans ,Retroperitoneal Neoplasms ,ABL ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Hematology ,Middle Aged ,medicine.disease ,Extramedullary hematopoiesis ,Leukemia ,Pyrimidines ,medicine.anatomical_structure ,Imatinib mesylate ,Hematopoiesis, Extramedullary ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Lymph Nodes ,Blast Crisis ,business ,Fluorescence in situ hybridization ,Chronic myelogenous leukemia - Abstract
We report a 59-year-old man with chronic myelogenous leukemia (CML) in chronic phase who presented with a large abdominal tumor. Biopsy revealed proliferation of granulocytic-, erythroid-, and megakaryocytic-lineage cells in a retroperitoneal lymph node. The BCR/ABL fusion gene was detected on a paraffin-embedded tissue section of the lymph node by double-color fluorescence in situ hybridization, indicating an extramedullary hematopoietic tumor of CML origin. This patient has achieved a complete cytogenetic response for 19 months with imatinib mesylate (STI571; Gleevec), in association with the regression of the tumor. However, the development of an extramedullary tumor in chronic-phase CML generally indicates a poor prognosis, because it commonly consists of blast proliferation and is followed by blast crisis in the marrow within a few months. This case, therefore, points to the importance of histological examination of extramedullary tumors in CML for evaluation of disease status and for therapeutic decisions.
- Published
- 2004
33. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia
- Author
-
Alfonso Quintás-Cardama, Susan O'Brien, Mary Beth Rios, Hagop M. Kantarjian, Jorge E. Cortes, Moshe Talpaz, and Guillermo Garcia-Manero
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Filgrastim ,Pilot Projects ,Chronic phase chronic myelogenous leukemia ,Piperazines ,hemic and lymphatic diseases ,Internal medicine ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,neoplasms ,Aged ,business.industry ,Standard treatment ,Imatinib ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Surgery ,Granulocyte colony-stimulating factor ,Pyrimidines ,Imatinib mesylate ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Absolute neutrophil count ,business ,medicine.drug - Abstract
BACKGROUND Imatinib mesylate administration has become standard treatment for patients with chronic myelogenous leukemia (CML). Although the safety profile of imatinib is favorable, Grade ≥ 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria) occurs in 35–45% of patients with CML in chronic phase who receive standard-dose imatinib. Myelosuppression results in treatment interruptions, which may compromise responses to imatinib. The authors investigated the ability of granulocyte–colony-stimulating factor (filgrastim) to reverse imatinib-associated neutropenia, thereby allowing for more continuous imatinib administration. METHODS Thirteen patients with chronic-phase CML and Grade ≥ 3, imatinib-induced neutropenia were treated with filgrastim. Treatment with filgrastim was initiated after a median of 22 months from the start of imatinib. Eleven patients received filgrastim 5 μg/kg 1–3 times weekly, and 2 patients received filgrastim 5 μg/kg daily; doses were titrated to maintain an absolute neutrophil count (ANC) ≥ 109/L. RESULTS Seven of 11 patients (64%) who began treatment with an ANC < 1.5 × 109/L had responses (i.e., their ANC improved to ≥ 2 × 109/L within 21 days); the other 4 patients experienced slower recovery but were able to continue receiving imatinib uninterrupted. Before filgrastim administration was initiated, patients did not receive imatinib (due to neutropenia-related treatment interruptions) for an average of 21% of the total time since the start of imatinib. This figure decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before filgrastim treatment was initiated, only one patient had achieved a major (partial) cytogenetic response. After the start of filgrastim treatment, five patients had major cytogenetic responses (including two complete responses). CONCLUSIONS The authors concluded that filgrastim may overcome imatinib-associated neutropenia and allow improved delivery of imatinib. Some patients may experience improvements in their responses to therapy as a result. Cancer 2004. © 2004 American Cancer Society.
- Published
- 2004
34. Frequency of Major Molecular Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic Myeloid Leukemia
- Author
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Martee L. Hensley, Insa Gathmann, Timothy P. Hughes, Andreas Hochhaus, John M. Goldman, Susan Branford, Ann E. Bolton, Zbigniew Rudzki, Iris C. van Hoomissen, Jaspal Kaeda, and Jerald P. Radich
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Transcription, Genetic ,medicine.medical_treatment ,Fusion Proteins, bcr-abl ,Alpha interferon ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Disease-Free Survival ,Piperazines ,Actuarial Analysis ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Medicine ,neoplasms ,Interferon alfa ,Aged ,Chemotherapy ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Remission Induction ,Cytarabine ,Interferon-alpha ,Imatinib ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Benzamides ,Immunology ,Imatinib Mesylate ,Female ,business ,medicine.drug - Abstract
background In a randomized trial, 1106 patients with chronic myeloid leukemia (CML) in chronic phase were assigned to imatinib or interferon alfa plus cytarabine as initial therapy. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial who had a complete cytogenetic remission. methods Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerasechain-reaction assay. Results were expressed relative to the median level of BCR-ABL transcripts in the blood of 30 patients with untreated CML in chronic phase. results In patients who had a complete cytogenetic remission, levels of BCR-ABL transcripts after 12 months of treatment had fallen by at least 3 log in 57 percent of those in the imatinib group and 24 percent of those in the group given interferon plus cytarabine (P=0.003). On the basis of the rates of complete cytogenetic remission of 68 percent in the imatinib group and 7 percent in the group given interferon plus cytarabine at 12 months, an estimated 39 percent of all patients treated with imatinib but only 2 percent of all those given interferon plus cytarabine had a reduction in BCR-ABL transcript levels of at least 3 log (P
- Published
- 2003
35. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study
- Author
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Thomas C. Shea, Jose J. Reiffers, Richard Stone, Steven Coutre, Sante Tura, John M. Goldman, Franco Mandelli, Charles L. Sawyers, François Guilhot, Carole B. Miller, Michael W. Deininger, Insa Gathmann, Monique Ben-Am, Moshe Talpaz, Alan Saven, Andreas Hochhaus, Nigel H. Russell, Christian Peschel, Eric J. Feldman, Charles A. Schiffer, Alois Gratwohl, Enrica Morra, Carlo Gambacorti-Passerini, Renaud Capdeville, Thomas M. Fischer, Brian J. Druker, Richard A. Larson, S. O'Brien, Bernard Chapuis, Oliver G. Ottmann, and Ronald Paquette
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Immunology ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Philadelphia chromosome ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Piperazines ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Enzyme Inhibitors ,neoplasms ,Aged ,Cytopenia ,business.industry ,Imatinib ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Blood Cell Count ,Survival Rate ,Kinetics ,Pyrimidines ,Treatment Outcome ,medicine.anatomical_structure ,Imatinib mesylate ,Benzamides ,Cytogenetic Analysis ,Imatinib Mesylate ,Female ,Blast Crisis ,business ,Tyrosine kinase ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.
- Published
- 2002
36. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study
- Author
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Moshe Talpaz, Andreas Hochhaus, Anne L. Lennard, Richard T. Silver, Thomas M. Fischer, Sofia Fernandes-Reese, Insa Gathmann, Charles L. Sawyers, Michael W. Deininger, Hagop M. Kantarjian, Richard Stone, Charles A. Schiffer, John M. Goldman, François Xavier Mahon, Oliver G. Ottmann, S Tura, Francois Guilhot, Renaud Capdeville, Brian J. Druker, Michele Baccarani, A Gratwohl, and Carlo Gambacorti-Passerini
- Subjects
Adult ,Male ,medicine.medical_specialty ,Immunology ,Leukemia, Myeloid, Accelerated Phase ,Biochemistry ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,Disease-Free Survival ,Piperazines ,Bone Marrow ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Survival rate ,Aged ,Aged, 80 and over ,Blood Cells ,Dose-Response Relationship, Drug ,business.industry ,Imatinib ,Cell Biology ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Prognosis ,medicine.disease ,Hematologic Response ,Survival Rate ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,Benzamides ,Cytogenetic Analysis ,Toxicity ,Imatinib Mesylate ,Female ,business ,Progressive disease ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.
- Published
- 2002
37. Long-Term Follow-Up of De Novo Chronic Phase Chronic Myelogenous Leukemia Patients on Imatinib First-Line
- Author
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Stephane Morisset, Mohamad Sobh, Franck-Emmanuel Nicolini, Pierre Sujobert, Stéphanie Dulucq, Francois-Xavier Mahon, Gabriel Etienne, and Vincent Alcazer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Long term follow up ,First line ,Imatinib ,Hematology ,Chronic phase chronic myelogenous leukemia ,Internal medicine ,Medicine ,business ,medicine.drug - Published
- 2017
38. Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
- Author
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Charles L. Sawyers, Sayuri Ohno-Jones, Hagop M. Kantarjian, Elisabeth Buchdunger, John Ford, Bin Peng, Brian J. Druker, Debra Resta, Nicholas B. Lydon, Renaud Capdeville, and Moshe Talpaz
- Subjects
Adult ,Male ,medicine.medical_treatment ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Piperazines ,Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Interferon alfa ,Aged ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Remission Induction ,Interferon-alpha ,Myeloid leukemia ,Imatinib ,General Medicine ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Blood Cell Count ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Benzamides ,Imatinib Mesylate ,Cancer research ,Female ,business ,Tyrosine kinase ,medicine.drug - Abstract
BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML.We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day.Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions.STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
- Published
- 2001
39. Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia
- Author
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Bruce D. Cheson, Terry L. Smith, Hagop M. Kantarjian, Moshe Talpaz, Jorge E. Cortes, James Gajewski, Mary Beth Rios, Susie Mallard, Francis J. Giles, Susan O'Brien, and Anthony J. Murgo
- Subjects
Male ,Harringtonines ,Cancer Research ,medicine.medical_specialty ,Leukemia, Myeloid, Accelerated Phase ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Omacetaxine mepesuccinate ,Humans ,Medicine ,Interferon alfa ,Dose-Response Relationship, Drug ,business.industry ,Cytarabine ,Interferon-alpha ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Surgery ,Regimen ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Homoharringtonine ,Leukemia, Myeloid, Chronic-Phase ,Female ,business ,Complete Hematologic Response ,Follow-Up Studies ,Chronic myelogenous leukemia ,medicine.drug - Abstract
PURPOSE: : To evaluate the efficacy andtoxicity profiles of a combination regimen of homoharringtonine (HHT)and low-dose cytarabine (ara-C) in patients with Philadelphiachromosome (Ph)–positive chronic myelogenous leukemia (CML) whohad experienced treatment failure with interferon alfa (IFNα)therapy. PATIENTS AND METHODS: One hundred five patients were treated: 100 in chronicphase (15 with cytogenetic clonal evolution) and five in acceleratedphase. Their median age was 52 years; all had been treatedunsuccessfully with IFNα; 94% were in late chronic phase; 43% hadbeen exposed to ara-C and 11% had been exposed to HHT. Patientsreceived HHT 2.5 mg/m2 by continuousinfusion daily for 5 days and ara-C 15mg/m2 daily in two subcutaneous injectionsfor 5 days every 4 weeks. The outcome of the 100 patients in chronicphase was compared with a previous study group of 73 patients treatedwith HHT alone. RESULTS: Overall, the complete hematologic response (CHR) rate in chronic phasewas 72%; the cytogenetic response rate was 32% (major response, 15%;complete response, 5%). Toxicities were acceptable, mostly related tomoderate diarrhea (3%), headaches (3%), cardiovascular events (3%),and myelosuppression-associated complications (3% to 14%). With amedian follow-up period of 25 months, the estimated 4-year survivalrate was 55%. Response rates were identical with HHT plus ara-C versusHHT alone, but the survival was significantly longer with thecombination after accounting for differences in the study groups andby multivariate analysis. CONCLUSION: The combination regimen of HHT and ara-C is effective andsafe in patients with CML who have experienced treatment failure withIFNα and needs to be investigated together with IFNα as partof front-line CML therapy. The addition of ara-C did not improve theresponse rates but may have improved survival, perhaps throughsuppression of clones related to diseasetransformation.
- Published
- 2000
40. A Prospective Randomized Study of Alpha-2b Interferon plus Hydroxyurea or Cytarabine for Patients with Early Chronic Phase Chronic Myelogenous Leukemia: The International Oncology Study Group CML1 Study
- Author
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Anne M. Lynott, Goh Yeow Tee, Zahira Fahed, Jianqin Shan, Martin Chasen, Suresh H. Advani, Shanshan Chen, Ismet Aydogdu, Iman Supandiman, Alendry P. Caviles, Tsu Yi Chao, Zeba Aziz, and Francis J. Giles
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Interferon alpha-2 ,Chronic phase chronic myelogenous leukemia ,law.invention ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Hydroxyurea ,Prospective Studies ,Child ,Prospective cohort study ,Survival rate ,Aged ,business.industry ,Cytarabine ,Interferon-alpha ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Survival Rate ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Leukemia, Myeloid, Chronic-Phase ,Female ,business ,medicine.drug - Abstract
A prospective randomized international study of 143 patients showed no apparent early survival advantage conferred by combining cytarabine, rather than hydroxyurea, with INF as first-line CML therapy. Combinations of alpha-interferon (INF) and chemotherapeutic agents are currently first-line therapy for the majority of patients with chronic myeloid leukemia (CML). The International Oncology Study Group conducted a prospective randomized study comparing INF combined with hydroxyurea or cytarabine. The primary study aim was to compare the survival durations in these patient cohorts. Patients with early chronic phase CML were randomized to receive INF 5 million units (Mu) given five times per week subcutaneously plus hydroxyurea or cytarabine as required to achieve a complete hematologic response and to maintain a WBC count between 2x10(9)/L and 10x10(9)/L and a platelet count between 75x10(9)/L and 100x10(9)/L. Therapy continued as tolerated unless progressive or blast phase disease occurred. At 36 months, the actuarial survival rate was equivalent in both groups: HI group (79 patients) survival was 85% (95% CI, 68-100%), as compared to 95% (95% CI, 79-100%) in the CI group (64 patients). In conclusion if seems that there is no apparent early survival advantage conferred by combining cytarabine, rather than hydroxyurea, with INF as first-line CML therapy.
- Published
- 2000
41. The Risk of Residual Molecular and Cytogenetic Disease in Patients With Philadelphia-Chromosome Positive First Chronic Phase Chronic Myelogenous Leukemia Is Reduced After Transplantation of Allogeneic Peripheral Blood Stem Cells Compared With Bone Marrow
- Author
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Siegfried Seeber, Bertram Opalka, Dietrich W. Beelen, Ahmet H. Elmaagacli, and Ulrich W. Schaefer
- Subjects
medicine.medical_specialty ,Pathology ,Allogeneic transplantation ,business.industry ,Immunology ,Cytogenetics ,Cell Biology ,Hematology ,Philadelphia chromosome ,medicine.disease ,Biochemistry ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,Minimal residual disease ,Transplantation ,medicine.anatomical_structure ,Internal medicine ,medicine ,Bone marrow ,Stem cell ,business - Abstract
The detection of residual molecular and cytogenetic disease was prospectively compared in patients with Philadelphia-chromosome (Ph1) positive first chronic phase chronic myelogenous leukemia (CML) who underwent allogeneic transplantation of unmanipulated peripheral blood stem cells (PBSCT) (n = 29) or bone marrow (BM) (n = 62) using genotypically HLA-identical sibling donors or partially HLA-matched extended family donors. A molecular relapse (MR), as defined by two consecutive positive polymerase chain reaction (PCR) assays for the detection of M-bcr-abl transcripts in a 4-week interval, was found in two of 29 (7%) patients after PBSCT compared with 20 of 62 (32%) patients after bone marrow transplantation (BMT). This corresponds to a 4-year molecular relapse estimate (± standard error) of 7% ± 5% after PBSCT and of 44% ± 8% after BMT (P < .009). With identical follow-up periods of survivors in both patient subsets between 6 and 55 months (median, 28 months), 14 of the 20 patients with MR after BMT progressed to an isolated cytogenetic (n = 10) or a hematologic (n = 4) disease recurrence, resulting in a 4-year cytogenetic relapse estimate of 47% ± 11%, while none of the patients after PBSCT has so far relapsed (P < .006). Multivariate analysis including all potential influencial factors of posttransplant disease recurrence identified the source of stem cells (P < .02) as the only independent predictor of molecular relapse. In conclusion, this prospective comparison of molecular and cytogenetic residual disease demonstrates that peripheral blood stem cell transplants have a more pronounced activity against residual CML cells than bone marrow transplants. Prospective randomized trials comparing PBSCT and BMT in patients with first chronic phase Ph1-positive CML are strictly required to further substantiate differences in the antileukemic activity of the two stem cell sources.
- Published
- 1999
42. Sequential Homoharringtonine and Interferon- in the Treatment of Early Chronic Phase Chronic Myelogenous Leukemia
- Author
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Moshe Talpaz, Emil J. Freireich, Susan O'Brien, Charles Koller, Mary Beth Rios, Sergio Giralt, Michael Andreeff, Eric Feldman, Hagop Kantarjian, Michael J. Keating, Miloslav Beran, and Bruce D. Cheson
- Subjects
myalgia ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Alpha interferon ,Biochemistry ,Gastroenterology ,Chronic phase chronic myelogenous leukemia ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,Omacetaxine mepesuccinate ,otorhinolaryngologic diseases ,medicine ,Interferon alfa ,Chemotherapy ,business.industry ,Cell Biology ,Hematology ,Surgery ,chemistry ,Homoharringtonine ,Cytarabine ,medicine.symptom ,business ,medicine.drug - Abstract
Homoharringtonine (HHT) is a novel plant alkaloid that produced a complete hematologic remission (CHR) in 72% of patients with late chronic phase chronic myelogenous leukemia (CML). Cytogenetic (CG) remissions were noted in 31%. In this study, six courses of HHT were administered to 90 patients with early chronic phase CML (< 1 year from diagnosis). Patients then received interferon-alpha (IFN-alpha) with a target dose of 5 MU/m2 daily. Results were compared with those in a prior group of patients treated with IFN-alpha-based therapy between 1982 and 1990. Ninety-two percent of patients achieved CHR with HHT; CG responses were observed in 60% and were major in 27%. Both CHR and CG response rates were significantly higher than those seen in historical control patients after 6 months of IFN-alpha therapy. After receiving HHT, patients required lower doses of IFN-alpha to maintain a CHR. The median dose delivered was 2.4 MU/m2. This reduction in IFN-alpha dose was associated with a lower incidence of myalgia and gastrointestinal (GI) disturbances than that seen in patients treated at the 5 MU/m2 dose. Overall, CG responses were seen in 66% of the patients who received HHT and IFN-alpha compared with 61% of the historical control patients. HHT is a very effective treatment of early chronic phase CML, and ongoing trials are investigating the simultaneous administration of HHT and IFN-alpha, as well as that of HHT and low-dose cytosine arabinoside in patients failing IFN-alpha therapy.
- Published
- 1999
43. The Costs and Cost-Effectiveness of Unrelated Donor Bone Marrow Transplantation for Chronic Phase Chronic Myelogenous Leukemia
- Author
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Claudio Anasetti, Joseph H. Antin, Jane C. Weeks, Jonathan Patten, Karen M. Kuntz, and Stephanie J. Lee
- Subjects
Pediatrics ,medicine.medical_specialty ,Bone marrow transplantation ,business.industry ,Cost effectiveness ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Surgery ,Transplantation ,medicine.anatomical_structure ,Unrelated Donor ,medicine ,Chronic phase CML ,Bone marrow ,business ,health care economics and organizations ,Chronic myelogenous leukemia - Abstract
Unrelated donor transplantation prolongs survival in some patients with chronic myelogenous leukemia (CML) in chronic phase. However, there are growing concerns about the intensive resources required for this procedure given health care budget constraints. To address this issue, we conducted a study of the costs and cost-effectiveness of unrelated donor transplantation for chronic phase CML. The costs of transplantation were derived from 157 patients from the Brigham and Women’s Hospital (BWH) and the Fred Hutchinson Cancer Research Center (FHCRC). Estimates of the effectiveness of transplantation were taken from our previous work using data from the International Bone Marrow Transplant Registry and the National Marrow Donor Program. The median cost of the first 6 months of care including donor identification, marrow collection, patient hospitalization for transplantation and all outpatient medications and readmissions through 6 months postmarrow infusion was $178,500 (range, $85,000 to $462,400) and the mean was $196,200. Mean costs for patients surviving beyond 6 months posttransplant were significantly lower than for patients dying within that period ($189,700 v $211,000, respectively,P = .03). Posttransplant follow-up costs were high for months 6 to 18, then decreased. The incremental cost-effectiveness of transplantation within 1 year of diagnosis versus -interferon therapy without transplant in the base case of a 35-year-old patient was $51,800/quality-adjusted life year (QALY) gained. Sensitivity analysis showed that most ratios were between $50,000 to $100,000/QALY or within the intermediate zone of acceptable cost-effectiveness ratios.
- Published
- 1998
44. Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia
- Author
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Michael J. Keating, Charles Koller, Moshe Talpaz, Sherry Pierce, M. Beran, Susan O'Brien, Stefano Sacchi, Hagop M. Kantarjian, Eli Estey, and Steven M. Kornblau
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Adolescent ,Long term follow up ,medicine.medical_treatment ,Alpha interferon ,Chronic phase chronic myelogenous leukemia ,Interferon-gamma ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Hydroxyurea ,In patient ,Interferon alfa ,Aged ,Chemotherapy ,business.industry ,Cytarabine ,Follow up studies ,Interferon-alpha ,Hematology ,Middle Aged ,Prognosis ,Recombinant Proteins ,Cytokine ,Interferon Type I ,Leukemia, Myeloid, Chronic-Phase ,Immunology ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
The aim of this analysis was to evaluate the efficacy of alpha-interferon (alpha-IFN) regimens in late chronic phase (diagnosis12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The alpha-IFN programs were sequential studies with human leukocyte alpha-IFN (seven patients), recombinant alpha-IFN alone (15 patients) or with IFN-gamma (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that alpha-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.
- Published
- 1997
45. Interferon Alfa-2b Combined with Cytarabine versus Interferon Alone in Chronic Myelogenous Leukemia
- Author
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François Guilhot, Claude Chastang, Mauricette Michallet, Agnès Guerci, Jean-Luc Harousseau, Frédéric Maloisel, Réda Bouabdallah, Denis Guyotat, Nathalie Cheron, Franck Nicolini, Jean-François Abgrall, Joseph Tanzer, Maurice Navarro, Dominique Bordessoule, Patrick Morice, Norbert Ifrah, Henri Rochant, Jean-Pierre Vilque, Martine Delain, Francis Bauters, and Joëlle Guilhot
- Subjects
medicine.medical_specialty ,business.industry ,Alpha interferon ,General Medicine ,medicine.disease ,Chronic phase chronic myelogenous leukemia ,Gastroenterology ,Surgery ,medicine.anatomical_structure ,Interferon ,Internal medicine ,medicine ,Cytarabine ,Bone marrow ,business ,Complete Hematologic Response ,Interferon alfa ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Background Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. Methods Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome–positive cells in the bone marrow) at 12 months. Results The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon–cytarabine group (360 patients) as compared wit...
- Published
- 1997
46. Ponatinib--a step forward in overcoming resistance in chronic myeloid leukemia
- Author
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Olga Frankfurt and Jonathan D. Licht
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Drug resistance ,Pharmacology ,Chronic phase chronic myelogenous leukemia ,Myelogenous ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Protein Kinase Inhibitors ,Survival analysis ,Clinical Trials as Topic ,business.industry ,Ponatinib ,Imidazoles ,Myeloid leukemia ,medicine.disease ,respiratory tract diseases ,Pyridazines ,Leukemia ,Treatment Outcome ,chemistry ,Drug Resistance, Neoplasm ,Mutation ,business ,Tyrosine kinase - Abstract
With the current therapy, the improvement in survival of patient with early chronic phase chronic myelogenous leukemia (CML) is unrivaled by that of any other leukemia. In fact, extrapolation of the survival curves may suggest that life expectancy of patients who achieve and maintain predetermined milestones may not differ from that of the age-matched healthy adults. The main reasons for such success are the presence of a well-defined molecular target, the BCR-ABL oncogene, necessary and sufficient for the initiation and propagation of CML, and the powerful and selective agents that inhibit it. Five U.S. Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKI), each with unique activities and toxicity profiles, allow for individualized patient care. Despite the remarkable responses of most patients, a small but significant fraction of patients develops clinical resistance to the TKIs, some of which is attributed to the BCR-ABL kinase domain mutations affecting TKI binding and activity. The recently approved third-generation TKI ponatinib showed remarkable activity in the patients with multi-TKI–resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. In lieu of the current emphasis on achieving earlier and more profound responses and excellent activity of ponatinib in the refractory setting, its optimal position among the available armamentarium of agents is being established. Clin Cancer Res; 19(21); 5828–34. ©2013 AACR.
- Published
- 2013
47. Imatinib results in better outcomes than HLA-identical sibling transplants in young persons with newly diagnosed chronic-phase chronic myelogenous leukemia
- Author
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Hao Jiang, Ya-Zhen Qin, Zhao Xy, Liu Ky, Bin Jiang, Meng Lv, Qian Jiang, Yu Wang, Xiaoshuai Zhang, Yan-Rong Liu, Xiao-Jun Huang, Wei Han, Yue-Yun Lai, H. S. Chen, Gale Rp, Dai-Hong Liu, Shan-Shan Chen, Chen Yh, Mei-Jie Zhang, and L P Xu
- Subjects
Adult ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Piperazines ,Cohort Studies ,Myelogenous ,Young Adult ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Sibling ,Young adult ,Intensive care medicine ,business.industry ,Siblings ,Imatinib ,Hematology ,medicine.disease ,Combined Modality Therapy ,Leukemia ,Imatinib mesylate ,Pyrimidines ,Treatment Outcome ,Oncology ,Benzamides ,Imatinib Mesylate ,business ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Imatinib results in better outcomes than HLA-identical sibling transplants in young persons with newly diagnosed chronic-phase chronic myelogenous leukemia
- Published
- 2013
48. Tumor lysis syndrome soon after treatment with hydroxyurea followed by nilotinib in two patients with chronic-phase chronic myelogenous leukemia
- Author
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Jian Hua, Masao Hagihara, Morihiro Inoue, and Yasunobu Iwaki
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Chronic phase chronic myelogenous leukemia ,Tyrosine-kinase inhibitor ,Myelogenous ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Hydroxyurea ,Nucleic Acid Synthesis Inhibitors ,business.industry ,Imatinib ,Hematology ,Middle Aged ,medicine.disease ,Tumor lysis syndrome ,Leukemia ,Pyrimidines ,Nilotinib ,Immunology ,business ,Tumor Lysis Syndrome ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Nilotinib, a second-generation tyrosine kinase inhibitor with 20- to 30-fold greater potency than imatinib, was developed to overcome imatinib intolerance or resistance. Recently, nilotinib has been approved as a first-line treatment for chronic myelogenous leukemia in the US and Japan. Tumor lysis syndrome (TLS) is an extremely rare adverse event that can occur during treatment with nilotinib, with only a few reported cases to date. Herein, we report two patients who developed TLS soon after the start of treatment with nilotinib. While in the first case, which co-presented with underlying mild-to-moderate renal insufficiency due to polycystic kidney disease, the TLS resolved on discontinuation of the drug, the second patient, who had an exceedingly high white blood cell count, presented with disseminated intravascular coagulation and severe liver injury triggered by TLS that developed after the start of nilotinib treatment, and died of multiple organ failure. Therefore, caution is necessary when this drug is used in the first-line setting in patients with renal insufficiency or a high tumor burden.
- Published
- 2013
49. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells
- Author
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Shane Fanning, Nicholas B. Lydon, Sayuri Ohno, Elisabeth Buchdunger, Shu Tamura, Jürg Zimmermann, Brian J. Druker, and Gerald M. Segal
- Subjects
Fusion Proteins, bcr-abl ,Chronic phase chronic myelogenous leukemia ,Piperazines ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Bone Marrow ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Proto-Oncogene Proteins c-abl ,neoplasms ,Blood Cells ,ABL ,Dose-Response Relationship, Drug ,Chemistry ,Stem Cells ,General Medicine ,Protein-Tyrosine Kinases ,medicine.disease ,Fusion protein ,Pyrimidines ,medicine.anatomical_structure ,Imatinib mesylate ,Evaluation Studies as Topic ,Benzamides ,Imatinib Mesylate ,Cancer research ,Bone marrow ,Tyrosine kinase ,K562 cells ,Chronic myelogenous leukemia - Abstract
The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
- Published
- 1996
50. UK Medical Research Council randomised, multicentre trial of interferon-αn1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response
- Author
-
Susan M. Richards, Patricia Shepherd, and N.C. Allan
- Subjects
Oncology ,medicine.medical_specialty ,Chemotherapy ,Intention-to-treat analysis ,business.industry ,medicine.medical_treatment ,Alpha interferon ,General Medicine ,Philadelphia chromosome ,medicine.disease ,Chronic phase chronic myelogenous leukemia ,Surgery ,Interferon ,Internal medicine ,medicine ,Sokal Score ,business ,Survival analysis ,medicine.drug - Abstract
Interferon-alpha may be better than cytotoxic drugs in the long-term management of patients with chronic myeloid leukaemia (CML) in chronic phase. To test this possibility 587 patients with CML in chronic phase were randomly allocated to receive lymphoblastoid cell-line interferon-alpha n1 (IFN-alpha, n = 293) or chemotherapy with busulphan or hydroxyurea (no IFN-alpha, n = 294) as maintenance after initial induction treatment with cytotoxic drugs. There was a significant survival benefit for patients in the IFN-alpha arm when analysed on the basis of intention to treat (2p = 0.0009). The median survival for those allocated IFN-alpha was 61 months and no IFN-alpha was 41 months. Out of 269 patients with Philadelphia-positive CML in the IFN-alpha arm with at least 6 months follow-up, 211 were evaluable for haematological response: 145 (68%) achieved good responses (A+ or A type), 37 (18%) had partial responses (B type) and 29 (14%) had poor responses (C type). Patients with types A and B responses had a better survival than those in the no IFN-alpha arm; patients with type C responses had survival equivalent to the no IFN-alpha arm. Of these 269 patients, 26 of whom had not started IFN-alpha, 59 (22%) achieved a significant degree of cytogenetic response but 210 (78%) did not have a response. Cytogenetic responders survived significantly longer than non-responders and even non-responders survived longer than patients in the no IFN-alpha arm. Since cytogenetic non-responders had worse than average prognostic features, they may also benefit from IFN-alpha therapy. We conclude that treatment with IFN-alpha prolongs the survival of patients with CML; benefits of IFN-alpha are not confined to cytogenetic responders but may extend to most, if not all patients receiving IFN-alpha treatment; and cytogenetic response to IFN-alpha treatment identifies patients with a relatively good prognosis.
- Published
- 1995
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