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 blast phase CML (CML-BP) are historically dismal. We sought to analyse the characteristics, prognostic factors and survival outcomes in patients with CML-BP in the TKI era. Methods All patients with CML-BP (n=477) were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics which predicted for survival. Overall survival (OS) and failure free survival (FFS) were assessed. Optimal cut off points for specific parameters, were identified using CART (classification and regression tree). Results Median age was 53 years (range, 16 to 84); 64% were male. Eighty percent were initially diagnosed in chronic phase CML (CML-CP) median 41 months (0.7 to 298 months) before transformation to CML-BP. De-novo CML-BP occurred in 71 patients. Seventy two percent patients received TKI therapy prior to CML-BP. Initial therapy for CML-BP included, TKI alone (35%), TKI with chemotherapy (46%) and non-TKI therapies (19%). The median OS was 12 months and median FFS was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, LDH ≥1227 IU/L, platelet count <102 K/μL, no stem cell transplantation (SCT), blast phase from CP/AP and presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first line treatment predicted for better survival. Combination of TKI with intensive chemotherapy followed by stem cell transplant confer the best outcome. Conclusions Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes and require newer treatment approaches.

Incidence and outcome of BCR‐ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors

“…Although, therapeutic management of AP‐BP CML patients remains heterogeneous and mainly depends on the feasibility of TKI switch with or without high dose chemotherapy followed by AHSCT, the presence of a BCR‐ABL KD mutation is not associated with a worse outcome whatever the subgroup of mutation suggesting that BCR‐ABL KD mutations in late disease phases are one but not the main leukemic evolution driver. Moreover, irrespective of mutational status, none of the currently available TKIs has demonstrated a survival advantage in BP as recently demonstrated by Jain et al…”

“…[20][21][22][23] Although, therapeutic management of AP-BP CML patients remains heterogeneous and mainly depends on the feasibility of TKI switch with or without high dose chemotherapy followed by AHSCT, the presence of a BCR-ABL KD mutation is not associated with a worse outcome whatever the subgroup of mutation suggesting that BCR-ABL KD mutations in late disease phases are one but not the main leukemic evolution driver. Moreover, irrespective of mutational status, none of the currently available TKIs has demonstrated a survival advantage in BP as recently demonstrated by Jain et al 24 We next analyzed the outcome of patients in CP at the date of mutation analysis according to patient status at the date of TKI start (LCP vs ECP). As already reported in previous studies, LCP patients with BCR-ABL KD mutations have a poor outcome and, in this study the worst when compared to other groups.…”

Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin

“…After transformation from CP to BC, median survival in the German CML‐study IV was 7.9 months . In a study by the MD Anderson group, median survival for de novo BC patients was more than 2 years, while median survival for BC patients originally diagnosed in CP or AP was less than 1 year. In a population‐based setting, the Swedish CML register has recently published a median survival of de novo BC patients of 1.6 years .…”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…The joint inhibition of MNK and Bcr-Abl with the MNK inhibitor CGP57380 and with imatinib inhibits polysome assembly, decreasing proliferation and survival [119]. In patients who develop blast crisis (BC-CML), life expectancy is still less than 12 months [120]. The use of imatinib with MNK inhibitors prevents eIF4E phosphorylation in vivo with an antiproliferative effect that could help to combat late-stage disease and to understand other pathways and cellular processes that are dysregulated by Bcr-Abl [119].…”