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Dynamics of molecular response in AML patients with NPM1 and FLT3 mutations undergoing allogeneic stem cell transplant

Bone Marrow Transplantation volume 52, pages 1187–1190 (2017)Cite this article

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AML is a phenotypically and genetically heterogeneous disease. Advances in molecular genetics and epigenetics led the World Health Organization to propose a novel classification based on cytogenetics, morphology and molecular genetics.1 These new markers led to a better understanding of the leukemogenesis mechanism of AML, and provided insight into prognosis and potential targets for therapy. Furthermore, cytogenetically normal (CN)-AML has been identified as a heterogeneous disease with various mutations. The two most common genetic abnormalities in AML are frameshift mutations in nucleophosmin-1 (NPM1) and internal tandem duplications (ITDs) in feline mcdonough sarcoma (FMS)-related tyrosine kinase 3 (FLT3).2 Patients with NPM1 mutations (NPM1-m) account for 45–60% of CN-AML with concomitant FLT3 mutation in 30% of patients. NPM1-m has a favorable prognosis in CN-AML when it is not associated with FLT3-ITD, whereas the opposite is true for patients with FLT3-ITD.3 FLT3-ITD mutations are found in 20–30% of patients with AML and are more common in CN-AML.2, 4 Another class of FLT3 mutations is point mutations in the tyrosine kinase domain (TKD), the most common being a point mutation in aspartic acid residue at position 835 (D835) that leads to a permanently open configuration and leads to constitutive signaling. FLT3-TKD mutation accounts for 5–10% of (CN)-AML, however, it has controversial prognostic significance.5 Even though FLT3-ITD-positive patients have a similar CR rate, they usually present with a higher leukocyte count, and usually have shorter disease-free survival and overall survival, mainly due to frequent and early relapses. However, the recent use of sorafenib and other FLT3 inhibitors, and allogeneic stem cell transplantation (allo-SCT) has significantly improved outcome of FLT3-positive AML.6, 7

Even though NPM1 and FLT3 mutations have been extensively studied independently, there have not been many studies investigating either the prognosis, or the dynamics of molecular response of NPM1-m and FLT3 together.4, 8

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Acknowledgements

We thank the nursing staff for providing excellent care for our patients and the physicians in the Hematology and Oncology division at the American University of Beirut Medical Center and referring physicians from Lebanon and the Middle East region for their significant contributions and dedicated patients’ care.

Author contributions

JE-C contributed to study design, collected and analyzed data, performed statistical analysis, provided clinical care and wrote and revised the manuscript. RS and RM had equal contribution in this study, collected data and edited the manuscript. BH collected data and commented on the manuscript. RM performed molecular analysis and edited the manuscript. AB designed transplant program, contributed to study design, recruited patients, provided clinical care and edited the manuscript.

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Author notes

  1. R Salem and R Massoud: These authors contributed equally to this work.

Authors and Affiliations

  1. Bone Marrow Transplantation Program and Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Medical Center, Beirut, Lebanon

    R Salem, R Massoud, B Haffar, A Bazarbachi & J El-Cheikh

  2. Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon

    R Mahfouz

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  1. R Salem
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Correspondence to J El-Cheikh.

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Salem, R., Massoud, R., Haffar, B. et al. Dynamics of molecular response in AML patients with NPM1 and FLT3 mutations undergoing allogeneic stem cell transplant. Bone Marrow Transplant 52, 1187–1190 (2017). https://doi.org/10.1038/bmt.2017.82

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