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Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.

ABSTRACT: BACKGROUND:Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era. METHODS:A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis. RESULTS:The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ?58 years, lactate dehydrogenase level ?1227 IU/L, platelet count?

SUBMITTER: Jain P

PROVIDER: S-EPMC5673547 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.

Jain Preetesh P Kantarjian Hagop M HM Ghorab Ahmad A Sasaki Koji K Jabbour Elias J EJ Nogueras Gonzalez Graciela G Kanagal-Shamanna Rashmi R Issa Ghayas C GC Garcia-Manero Guillermo G Kc Devendra D Dellasala Sara S Pierce Sherry S Konopleva Marina M Wierda William G WG Verstovsek Srdan S Daver Naval G NG Kadia Tapan M TM Borthakur Gautam G O'Brien Susan S Estrov Zeev Z Ravandi Farhad F Cortes Jorge E JE

Cancer 20170725 22

<h4>Background</h4>Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.<h4>Methods</h4>A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. ...[more]

PMID: 28743165

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Project description:Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.

Dataset Information

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.

Publications

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.

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