Clinical Research Details

Descriptive Information
targeted therapy using arsenic trioxide (As) and all trans retinoic acid (ATRA) in acute myeloid leukemia (AML) patients with Nucleophosmin (NPM1) mutation.

Ali Bazarbachi


Translational Research - Laboratory Research Application and Preclinical Studies  

  • Hiba El Hajj
Radwan Massoud
Conditions and Keywords
Acute myeloid leukemia
Acute myeloid leukemia ,NPM1,targeted therapy,all trans retinoic acid,arsenic trioxide
Study Design
Basic / Translational
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Eligibility and IRB
Min: 18

Specific Aim: The aim of this study is to assess the presence of mutations of NPM1 and FLT3-ITD in Leukemic cells taken from AML patients, and assess the effect of certain drugs on these cells.

Bone marrow and blood from these patients will be collected as part of their normal clinical practice. A specific attention will be given to the patients karyotype and molecular profile (NPM1 and FTI3-ITD mutations). We will ask to slightly increase the amount of collected blood or bone marrow. We will use these leukemic cells to: 1- Test the effect of new drugs (such as retinoic acid, arsenic trioxide and others) on the viability of the leukemic cells using different methods such as cell count (trypan blue stain), proliferation assay etc. 2- Prepare DNA, RNA and proteins for analysis of DNA mutations, RNA expression and protein levels and intracellular localization using RT-PCR, western blot and confocal microscopy. 3- Inject leukemic cells in immunocompromised mice. These xenografted animals will be treated to assess the efficacy of our tested drugs in vivo. Leukemic cells from these animals may be injected into secondary or tertiary recipients.

For statistical analysis, we will use t-test to compare the efficacy of different treatments in vitro or in vivo.

All adult AML patients diagnosed at AUBMC will be included. 

All adult AML patients diagnosed at AUBMC will be included. No adult patient will be excluded but a specific attention will be given the patients with NPM1 mutation without FLIT3-ITD mutation.

Patients will be approached by the principal investigator or an MD from the list of co-investigators during his/her clinic visit or during admission to the hospital. A detailed explanation of the study will be given and a consent form will be signed in case the patient agrees to participate. 


Acute myeloid leukemia (AML), is a clonal disorder caused by malignant transformation of a bone marrow-derived, self-renewing stem or progenitor cell characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. The management of patients with AML is dictated by a number of factors including age, performance status and biological, genetic, and molecular characteristics inherent to the disease. Specific cytogenetic alterations determine AML classification in three risk based-categories: favorable, intermediate, and unfavorable with very different cure rates. Patients with normal karyotype belong to the intermediate risk category and recent data indicate that their prognosis is determined by specific genetic alterations particularly NPM1 mutation and FLT-3-ITD. NPM1 is an essential gene that encodes a nucleolar shuttling protein. NPM1 is the most frequently mutated gene in AML, accounting for more than one third of all AML patients, leading to the ectopic accumulation of the NPM1 mutants in the cytoplasm of leukemic cells. In AML, current induction chemotherapy regimens employing a backbone of cytarabine combined with an anthracycline produces a complete remission (CR) in almost 70% of patients. However, post-remission therapy is based on either several cycles of consolidation chemotherapy using high dose cytarabine or allogeneic bone marrow transplantation (BMT). In patients with normal diploid karyotype, NPM1 mutation, when present alone, confers a major survival advantage and lower risk of relapse. However, the presence of both NPM1 mutation and FLT3-ITD is associated with poor prognosis. Therefore, patients with unmutated NPM1 or patients with both NPM1 mutation and FLT3-ITD are generally referred to transplant in first CR. The presence of a well identified target (the mutated NPM1) and the differential prognosis (good if alone, bad if associated with FLT-3 ITD) makes this AML subtype an attractive model for the development of targeted therapies. In that sense, a recent study suggested that ATRA significantly improved survival only in AML patients harboring the NPM1 mutation in the absence of FLT3-ITD.