European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

doi:10.1182/BLOOD-2013-05-501569

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European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Journal Article•DOI•

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Michele Baccarani¹, Michael W. Deininger², Gianantonio Rosti¹, Andreas Hochhaus³, Simona Soverini¹, Jane F. Apperley⁴, Francisco Cervantes⁵, Richard E. Clark⁶, Jorge E. Cortes⁷, François Guilhot⁸, Henrik Hjorth-Hansen⁹, Timothy P. Hughes¹⁰, Hagop M. Kantarjian⁷, Dong-Wook Kim¹¹, Richard A. Larson¹², Jeffrey H. Lipton¹³, François Xavier Mahon¹⁴, Giovanni Martinelli¹, Jiri Mayer¹⁵, Martin C. Müller¹⁶, Dietger Niederwieser¹⁷, Fabrizio Pane¹⁸, Jerald P. Radich¹⁹, Philippe Rousselot, Giuseppe Saglio²⁰, Susanne Saußele¹⁶, Charles A. Schiffer²¹, Richard T. Silver²², Bengt Simonsson²³, Juan Luis Steegmann, John M. Goldman⁴, Rüdiger Hehlmann¹⁶ - Show less +28 more•Institutions (23)

University of Bologna¹, University of Utah², University of Jena³, Imperial College London⁴, University of Barcelona⁵, Royal Liverpool and Broadgreen University Hospital NHS Trust⁶, University of Texas MD Anderson Cancer Center⁷, University of Poitiers⁸, Norwegian University of Science and Technology⁹, University of Adelaide¹⁰, Catholic University of Korea¹¹, University of Chicago¹², University of Toronto¹³, University of Bordeaux¹⁴, Masaryk University¹⁵, Heidelberg University¹⁶, Leipzig University¹⁷, University of Naples Federico II¹⁸, Fred Hutchinson Cancer Research Center¹⁹, University of Turin²⁰, Wayne State University²¹, Cornell University²², Uppsala University²³

08 Aug 2013-Blood (American Society of Hematology)-Vol. 122, Iss: 6, pp 872-884

TL;DR: Optimal responders to chronic myeloid leukemia treatment should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

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About: This article is published in Blood.The article was published on 2013-08-08 and is currently open access. It has received 1679 citations till now. The article focuses on the topics: Imatinib mesylate & European LeukemiaNet.

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Book•

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

[...]

Stevens H. Swerdlow...

29 Sep 2017

TL;DR: Thank you very much for reading who classification of tumours of haematopoietic and lymphoid tissues, and maybe you have knowledge that, people have look hundreds of times for their chosen readings like this, but end up in malicious downloads.

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Abstract: WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

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13,835 citations

Cites background from "European LeukemiaNet recommendation..."

...With tar¬ geted TKI therapy and careful disease monitoring, the incidence of AP and BP has decreased, and the 10-year overall survival rate tor CML is 80-90% (207, 573,1602,1904)....
[...]

Journal Article•DOI•

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

[...]

Daniel A. Arber¹, Attilio Orazi², Robert P. Hasserjian³, Jürgen Thiele⁴, Michael J. Borowitz⁵, Michelle M. Le Beau⁶, Clara D. Bloomfield⁷, Mario Cazzola⁸, James W. Vardiman⁶ - Show less +5 more•Institutions (8)

Stanford University¹, Cornell University², Harvard University³, University of Cologne⁴, Johns Hopkins University⁵, University of Chicago⁶, Ohio State University⁷, University of Pavia⁸

19 May 2016-Blood

TL;DR: The 2016 edition of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition.

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7,147 citations

Cites background from "European LeukemiaNet recommendation..."

...In the era of tyrosine-kinase inhibitor (TKI) therapy, newly diagnosed patients may have a nearly normal lifespan, but regular monitoring for BCR-ABL1 burden and for evidence of genetic evolution anddevelopment of resistance toTKI therapy is essential to detect disease progression.(3,4)Although the acceleratedphase (AP) ofCML is becoming less common in the era of TKI therapy, there are no universally accepted criteria for its definition....
[...]

Journal Article•DOI•

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias

[...]

Jorge E. Cortes¹, Dong-Kee Kim², Javier Pinilla-Ibarz³, P. le Coutre⁴, Ronald Paquette⁵, Charles Chuah⁶, F. E. Nicolini⁷, Jane F. Apperley⁸, Hanna Jean Khoury⁹, Moshe Talpaz¹⁰, John F. DiPersio¹¹, Daniel J. DeAngelo¹², Elisabetta Abruzzese¹³, Delphine Rea¹⁴, Michele Baccarani¹⁵, Martin C. Müller¹⁶, Carlo Gambacorti-Passerini¹⁷, Stephane Wong, Stephanie Lustgarten¹⁸, Victor M. Rivera¹⁸, Timothy P. Clackson¹⁸, Christopher D. Turner¹⁸, Frank G. Haluska¹⁸, François Guilhot¹⁹, Michael W. Deininger²⁰, Andreas Hochhaus²¹, Timothy P. Hughes, J. M. Goldman⁸, Neil P. Shah²², Hagop M. Kantarjian¹ - Show less +26 more•Institutions (22)

University of Texas MD Anderson Cancer Center¹, Catholic University of Korea², University of South Florida³, Charité⁴, University of California, Los Angeles⁵, Singapore General Hospital⁶, Claude Bernard University Lyon 1⁷, Imperial College London⁸, Emory University⁹, University of Michigan¹⁰, Washington University in St. Louis¹¹, Harvard University¹², University of Rome Tor Vergata¹³, University of Paris¹⁴, University of Bologna¹⁵, Heidelberg University¹⁶, University of Milano-Bicocca¹⁷, ARIAD Pharmaceuticals, Inc.¹⁸, University of Poitiers¹⁹, University of Utah²⁰, University of Jena²¹, University of California, San Francisco²²

06 Nov 2013-The New England Journal of Medicine

TL;DR: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%.

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Abstract: Background Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonineto-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome– positive acute lymphoblastic leukemia (Ph-positive ALL). Methods We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Results Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

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897 citations

Journal Article•DOI•

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia

[...]

Andreas Hochhaus¹, Richard A. Larson², François Guilhot, Jerald P. Radich³, Susan Branford⁴, Timothy P. Hughes⁵, Michele Baccarani⁶, Michael W. Deininger⁷, Francisco Cervantes⁸, Satoko Fujihara⁹, Christine Elke Ortmann⁹, Hans D. Menssen⁹, Hagop M. Kantarjian¹⁰, Stephen G. O'Brien¹¹, Brian J. Druker¹² - Show less +11 more•Institutions (12)

University of Jena¹, University of Chicago², Fred Hutchinson Cancer Research Center³, University of South Australia⁴, University of Adelaide⁵, University of Bologna⁶, University of Utah⁷, University of Barcelona⁸, Novartis⁹, University of Texas MD Anderson Cancer Center¹⁰, Newcastle University¹¹, Oregon Health & Science University¹²

08 Mar 2017-The New England Journal of Medicine

TL;DR: Almost 11 years of follow-up showed that the efficacy of Imatinib persisted over time and that long‐term administration of imatinib was not associated with unacceptable cumulative or late toxic effects.

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Abstract: BackgroundImatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. MethodsIn this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. ResultsThe median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall s...

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823 citations

Journal Article•DOI•

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

[...]

Andreas Hochhaus¹, Michele Baccarani², Richard T. Silver³, Charles A. Schiffer⁴, Jane F. Apperley⁵, Francisco Cervantes, Richard E. Clark⁶, Jorge E. Cortes⁷, Michael W. Deininger⁸, François Guilhot, Henrik Hjorth-Hansen⁹, Timothy P. Hughes¹⁰, Jeroen Janssen¹¹, Hagop M. Kantarjian¹², Dong-Wook Kim¹³, Richard A. Larson¹⁴, Jeffrey H. Lipton¹⁵, Francois-Xavier Mahon¹⁶, Jiří Mayer¹⁷, Franck E. Nicolini, Dietger Niederwieser¹⁸, Fabrizio Pane¹⁹, Jerald P. Radich²⁰, Delphine Rea, Johan Richter²¹, Gianantonio Rosti², Philippe Rousselot, Giuseppe Saglio²², Susanne Saußele²³, Simona Soverini², Juan Luis Steegmann, Anna G. Turkina²⁴, Andrey Zaritskey, Ruediger Hehlmann²³ - Show less +30 more•Institutions (24)

University of Jena¹, University of Bologna², Cornell University³, Wayne State University⁴, Imperial College London⁵, University of Liverpool⁶, Georgia Regents University⁷, Huntsman Cancer Institute⁸, Norwegian University of Science and Technology⁹, University of South Australia¹⁰, University of Amsterdam¹¹, University of Texas MD Anderson Cancer Center¹², Catholic University of Korea¹³, University of Chicago¹⁴, University of Toronto¹⁵, University of Bordeaux¹⁶, Masaryk University¹⁷, Leipzig University¹⁸, University of Naples Federico II¹⁹, Fred Hutchinson Cancer Research Center²⁰, Lund University²¹, University of Turin²², Heidelberg University²³, Russian Academy²⁴

01 Apr 2020-Leukemia

TL;DR: An expert panel to critically evaluate and update the evidence to achieve goals to achieve a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR) in chronic myeloid leukemia.

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Abstract: The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

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683 citations

Cites background from "European LeukemiaNet recommendation..."

...In the last version of the recommendations, ACA were mentioned as a “warning” [8]....
[...]
...Since management goals and therapeutic scenarios continue to evolve, the ELN again appointed an international panel of experts to update the previous recommendations [8]....
[...]

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Journal Article•DOI•

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia

[...]

Stephen G. O'Brien¹, François Guilhot, Richard A. Larson², Insa Gathmann³, Michele Baccarani⁴, Francisco Cervantes⁵, Jan J. Cornelissen⁶, Thomas Fischer⁷, Andreas Hochhaus⁸, Timothy P. Hughes⁹, Klaus Lechner¹⁰, Johan Lanng Nielsen¹¹, Philippe Rousselot¹², Josy Reiffers¹³, Giuseppe Saglio, John D. Shepherd¹⁴, Bengt Simonsson¹⁵, Alois Gratwohl¹⁶, John M. Goldman¹⁷, Hagop M. Kantarjian¹⁸, Kerry Taylor, Gregor Verhoef¹⁹, Ann E. Bolton³, Renaud Capdeville³, Brian J. Druker²⁰ - Show less +21 more•Institutions (20)

Newcastle University¹, University of Chicago², Novartis³, University of Bologna⁴, University of Barcelona⁵, Erasmus University Rotterdam⁶, University of Mainz⁷, Heidelberg University⁸, Royal Adelaide Hospital⁹, Medical University of Vienna¹⁰, Aarhus University¹¹, University of Paris¹², University of Bordeaux¹³, University of British Columbia¹⁴, Uppsala University¹⁵, University of Basel¹⁶, Imperial College London¹⁷, University of Texas MD Anderson Cancer Center¹⁸, Katholieke Universiteit Leuven¹⁹, Oregon Health & Science University²⁰

13 Mar 2003-The New England Journal of Medicine

TL;DR: Imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML and was better tolerated than combination therapy.

...read moreread less

Abstract: Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...

...read moreread less

3,399 citations

"European LeukemiaNet recommendation..." refers background in this paper

...It is recommended that in practice outside of clinical trials, the firstline treatment of CP CML can be any of the 3 TKIs that have been approved for this indication and are available nearly worldwide, namely imatinib (400mg once daily), nilotinib (300mg twice daily), and dasatinib (100 mg once daily)....
[...]
...The use of TKI may require a change of the boundaries between CP, AP, and BP and modify to some extent the classic subdivision of CML in 3 phases, but the data are not yet sufficient for a revision....
[...]
...For several years, dasatinib and nilotinib have been approved for second-line treatment of CML patients intolerant of or in whom imatinib treatment failed, based on reported CCyR rates of 40% to 60%.5,42 Two major companysponsored, phase 2, single-arm studies have been updated, reporting anMMR rate of 28% after 2 years (nilotinib)43,44 and 42% after 5 years (dasatinib)45,46; stability of the CCyR, once achieved; and PFS of 57% at 4 years with nilotinib44 and of 56% at 5 yearswith dasatinib.46 However, in both studies the proportion of patients who were still taking core treatment at 4 to 5 years was only 30% and 31%, respectively....
[...]
...Currently, we recommend that a patient with CMLwho is responding optimally to treatment continues indefinitely at the standard recommended dose....
[...]
...Several studies of imatinib as first-line therapy have been updated or newly reported.(15-39) The proportion of patients who achieved CCyR and MMRafter 1 year of 400mg imatinib daily ranged from 49% to 77%, and from 18% to 58%, respectively(23,24,26,35-39) (supplemental Table 1, available on the Blood website)....
[...]

Journal Article•DOI•

Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia

[...]

Brian J. Druker¹, François Guilhot, Stephen G. O'Brien², Insa Gathmann³, Hagop M. Kantarjian⁴, Norbert Gattermann⁵, Michael W. Deininger⁶, Richard T. Silver⁷, John M. Goldman⁸, Richard Stone⁹, Francisco Cervantes¹⁰, Andreas Hochhaus¹¹, Bayard L. Powell¹², Janice Gabrilove¹³, Philippe Rousselot¹⁴, Josy Reiffers¹⁵, Jan J. Cornelissen¹⁶, Timothy P. Hughes¹⁷, Hermine Agis¹⁸, Thea Kolsen Fischer¹⁹, Gregor Verhoef²⁰, John D. Shepherd²¹, Giuseppe Saglio, Alois Gratwohl²², Johan Lanng Nielsen²³, Jerald P. Radich²⁴, Bengt Simonsson²⁵, Kerry Taylor²⁶, Michele Baccarani²⁷, Charlene So³, Laurie Letvak³, Richard A. Larson²⁸ - Show less +28 more•Institutions (28)

Oregon Health & Science University¹, Newcastle University², Novartis³, University of Texas MD Anderson Cancer Center⁴, University of Düsseldorf⁵, Leipzig University⁶, Cornell University⁷, National Institutes of Health⁸, Harvard University⁹, University of Barcelona¹⁰, Heidelberg University¹¹, Wake Forest University¹², Icahn School of Medicine at Mount Sinai¹³, University of Paris¹⁴, University of Bordeaux¹⁵, Erasmus University Rotterdam¹⁶, Royal Adelaide Hospital¹⁷, Medical University of Vienna¹⁸, University of Mainz¹⁹, Katholieke Universiteit Leuven²⁰, University of British Columbia²¹, University of Basel²², Aarhus University²³, Fred Hutchinson Cancer Research Center²⁴, Uppsala University²⁵, Mater Health Services²⁶, University of Bologna²⁷, University of Chicago²⁸

07 Dec 2006-The New England Journal of Medicine

TL;DR: 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.

...read moreread less

Abstract: BACKGROUND: 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 ...

...read moreread less

3,351 citations

"European LeukemiaNet recommendation..." refers background in this paper

...It is recommended that in practice outside of clinical trials, the firstline treatment of CP CML can be any of the 3 TKIs that have been approved for this indication and are available nearly worldwide, namely imatinib (400mg once daily), nilotinib (300mg twice daily), and dasatinib (100 mg once daily)....
[...]
...The use of TKI may require a change of the boundaries between CP, AP, and BP and modify to some extent the classic subdivision of CML in 3 phases, but the data are not yet sufficient for a revision....
[...]
...For several years, dasatinib and nilotinib have been approved for second-line treatment of CML patients intolerant of or in whom imatinib treatment failed, based on reported CCyR rates of 40% to 60%.5,42 Two major companysponsored, phase 2, single-arm studies have been updated, reporting anMMR rate of 28% after 2 years (nilotinib)43,44 and 42% after 5 years (dasatinib)45,46; stability of the CCyR, once achieved; and PFS of 57% at 4 years with nilotinib44 and of 56% at 5 yearswith dasatinib.46 However, in both studies the proportion of patients who were still taking core treatment at 4 to 5 years was only 30% and 31%, respectively....
[...]
...Currently, we recommend that a patient with CMLwho is responding optimally to treatment continues indefinitely at the standard recommended dose....
[...]
...Several studies of imatinib as first-line therapy have been updated or newly reported.(15-39) The proportion of patients who achieved CCyR and MMRafter 1 year of 400mg imatinib daily ranged from 49% to 77%, and from 18% to 58%, respectively(23,24,26,35-39) (supplemental Table 1, available on the Blood website)....
[...]

Journal Article•DOI•

Chronic myeloid leukemia.

[...]

Charles L. Sawyers¹•Institutions (1)

University of California, Los Angeles¹

29 Apr 1999-The New England Journal of Medicine

TL;DR: This work has demonstrated that CML can be curable through immune-mediated elimination of leukemia cells by allogeneic T lymphocytes, and specific inhibition of signal transduction by the tyrosine kinase Bcr-Abl has been found to be active in managing the disease.

...read moreread less

Abstract: Over the past twenty years, clinical and laboratory studies have led to important new insights into the biology of chronic myeloid leukemia. Basic science has defined the molecular pathogenesis of chronic myeloid leukemia (CML) as unregulated signal transduction by the Bcr-Abl tyrosine kinase. Clinical studies have demonstrated that CML can be curable through immune-mediated elimination of leukemia cells by allogeneic T lymphocytes. Recently, specific inhibition of signal transduction by the tyrosine kinase Bcr-Abl has been found to be active in managing the disease.

...read moreread less

1,603 citations

Journal Article•DOI•

Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

[...]

Giuseppe Saglio¹, Dong-Wook Kim², Surapol Issaragrisil³, Gabriel Etienne, Clarisse Lobo, Ricardo Pasquini⁴, Richard E. Clark⁵, Andreas Hochhaus⁶, Timothy P. Hughes⁷, Neil Gallagher⁸, Albert Hoenekopp⁸, Mei Dong⁸, Ariful Haque⁸, Richard A. Larson⁹, Hagop M. Kantarjian⁹ - Show less +11 more•Institutions (9)

University of Turin¹, Catholic University of Korea², Mahidol University³, Federal University of Paraná⁴, Royal Liverpool and Broadgreen University Hospital NHS Trust⁵, University of Jena⁶, Royal Adelaide Hospital⁷, Novartis⁸, University of Chicago⁹

16 Jun 2010-The New England Journal of Medicine

TL;DR: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML, and no patient with progression to the accelerated phase or blast crisis had a major molecular response.

...read moreread less

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<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P = 0.01 and P = 0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.)

...read moreread less

1,486 citations

"European LeukemiaNet recommendation..." refers background in this paper

...The ENESTnd study, testing nilotinib 300 mg twice daily vs imatinib 400 mg once daily, reported a significantly higher rate of CCyR after 1 and 2 years (80% vs 65%, and 87% vs 77%), a significantly higher rate of MMR after 1 year (50% vs 27%) and 3 years (73% vs 53%), and a significantly higher rate of MR after 3 years (32% vs 15%).(35-37) The DASISION study, testing dasatinib 100 mg once daily vs imatinib 400 mg once daily, reported a significantly higher rate of CCyR after 1 year (83% vs 72%) but not after 2 years (85% vs 82%), a significantly higher rate of MMR after 1 year (46% vs 23%) and 3 years (68% vs 55%), and a significantly higher rate of MR after 3 years (22% vs 12%)....
[...]
...It is recommended that in practice outside of clinical trials, the firstline treatment of CP CML can be any of the 3 TKIs that have been approved for this indication and are available nearly worldwide, namely imatinib (400mg once daily), nilotinib (300mg twice daily), and dasatinib (100 mg once daily)....
[...]
...The use of TKI may require a change of the boundaries between CP, AP, and BP and modify to some extent the classic subdivision of CML in 3 phases, but the data are not yet sufficient for a revision....
[...]
...For several years, dasatinib and nilotinib have been approved for second-line treatment of CML patients intolerant of or in whom imatinib treatment failed, based on reported CCyR rates of 40% to 60%.5,42 Two major companysponsored, phase 2, single-arm studies have been updated, reporting anMMR rate of 28% after 2 years (nilotinib)43,44 and 42% after 5 years (dasatinib)45,46; stability of the CCyR, once achieved; and PFS of 57% at 4 years with nilotinib44 and of 56% at 5 yearswith dasatinib.46 However, in both studies the proportion of patients who were still taking core treatment at 4 to 5 years was only 30% and 31%, respectively....
[...]
...Currently, we recommend that a patient with CMLwho is responding optimally to treatment continues indefinitely at the standard recommended dose....
[...]

Journal Article•DOI•

Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

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Hagop M. Kantarjian¹, Neil P. Shah², Andreas Hochhaus³, Jorge E. Cortes¹, Sandip Shah, Manuel Ayala, Beatriz Moiraghi, Zhixiang Shen⁴, Jiri Mayer⁵, Ricardo Pasquini, Hirohisa Nakamae⁶, Françoise Huguet, Concepción Boqué⁷, Charles Chuah⁸, Eric Bleickardt⁹, M. Brigid Bradley-Garelik⁹, Chao Zhu⁹, Ted Szatrowski⁹, David Shapiro⁹, Michele Baccarani¹⁰ - Show less +16 more•Institutions (10)

University of Texas MD Anderson Cancer Center¹, University of California, San Francisco², University of Jena³, Shanghai Jiao Tong University⁴, Masaryk University⁵, Osaka City University⁶, University of Barcelona⁷, Singapore General Hospital⁸, Bristol-Myers Squibb⁹, University of Bologna¹⁰

16 Jun 2010-The New England Journal of Medicine

TL;DR: Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long- term outcomes among patients with newly diagnosed chronic-phase CML.

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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<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. Conclusions Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)

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