Combination of a mitogen-activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion-based residual disease and prevents re-expansion of FLT3-ITD acute myeloid leukaemia
BRITISH JOURNAL OF HAEMATOLOGY
Authors: Zabkiewicz, Joanna; Lazenby, Michelle; Edwards, Gareth; Bygrave, Ceri A.; Omidvar, Nader; Zhuang, Lihui; Knapper, Steve; Guy, Carol; Hills, Robert K.; Burnett, Alan K.; Alvares, Caroline L.
Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of firstgeneration FMS-like tyrosine kinase 3 (FLT3) inhibitors in pre- and posttransplant regimes and as maintenance in FLT3-mutated AML. Pre-clinical progress is hampered by the lack of suitable modelling of residual disease and post-therapy relapse. In the present study, we investigated the nature of pro-survival signalling in primary residual tyrosine kinase inhibitor (TKI)-treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia-human stroma model to mimic the cell-cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma-driven leukaemic signalling was determined, and a synergistic combination with a mitogen-activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma-mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment-related toxicity.
Presence of copy number aberration and clinical prognostic factors in patients with acute myeloid leukemia: an analysis of effect modification
POLISH ARCHIVES OF INTERNAL MEDICINE-POLSKIE ARCHIWUM MEDYCYNY WEWNETRZNEJ
Authors: Banescu, Claudia; Tripon, Florin; Trifa, Adrian P.; Crauciuc, Andrei G.; Boglis, Alina; Lazar, Erzsebet; Dima, Delia; Macarie, Ioan; Duicu, Carmen; Iancu, Mihaela
INTRODUCTION Acute myeloid leukemia (AML) is characterized by multiple acquired genetic events, chromosomal abnormalities such as copy number aberrations (CNAs), disease progression, and low survival rates. OBJECTIVES We assessed the utility of a multiplex ligation-dependent probe amplification (MLPA) assay in AML as well as correlations of CNAs with various biological and clinical features of patients with AML, including somatic mutations in the FLT3, NPM1, and DNMT3A genes and survival. PATIENTS AND METHODS The study included 283 patients with AML. The MLPA was used for investigation of CNAs. The status of somatic mutations was analyzed in all cases. RESULTS The presence of CNAs was associated with the adverse (high) risk category according to the European LeukemiaNet (ELN) classification (P-FDR < 0.0001). The significant predictors of mortality were age of 65 years or older (hazard ratio [HR], 2.30; 95% CI, 1.71-3.09), ELN high-risk category (HR, 1.71; 95% CI, 1.15-2.56), and the Eastern Cooperative Oncologic Group Scale (ECOG) performance status grade of 3 or higher (HR, 2.43; 95% CI, 1.80-3.30), but not the presence of CNA. An interaction between CNAs and the ECOG performance status was shown (HR interaction, 2.24; 95% CI, 1.09-4.57, P = 0.02). The presence of CNAs was positively correlated with the risk of death in patients with an ECOG grade of 3 or higher (HR, 2.02; 95% CI, 1.30-3.12), while for patients with the performance status of 2 or lower, the presence of CNAs was a protective factor against the risk of death. CONCLUSIONS The presence of CNAs may modify the effect of the ECOG performance status on survival. Independent predictors of mortality in patients with AML include age, ELN adverse risk category, and the ECOG grade of at least 3.