Case Study: Finding the Best Prognostic Outcome in a Patient With AML
The following case study focuses on a previously healthy 32-year-old male, who went to his primary care physician’s clinic for generalized ecchymoses and palpitations lasting two days. There were no other accompanying symptoms. Test your knowledge by reading the background information below and making the proper selection.
Vital signs and physical examination were significant only for tachycardia (HR=110) and multiple generalized ecchymoses. The rest of the physical exam findings and review of systems were unremarkable. The patient denied taking any medications. A complete blood count (CBC) showed the following: white blood count 2.4 x 103/μl, hemoglobin 9.5 g/dl, hematocrit 28, mean corpuscular volume 98.6 fl, platelet count 13 x 109/μL, absolute neutrophil count 1.2 x 103/μl, peripheral blasts 20 percent. A diagnosis of acute leukemia was suspected. The patient was referred to a hematologist who performed a bone marrow biopsy and confirmed the diagnosis of acute myeloid leukemia (AML). The patient had a normal male karyotype by metaphase cytogenetics. The hematologist ordered additional molecular tests to guide in the prognostic stratification of this patient.
Which findings will impart the best prognostic outcome after induction chemotherapy in this patient?
- Cytoplasmic nucleophosmin-1 (NPM-1) positive, FMS-like tyrosine kinase-3 (Flt-3) internal tandem duplication (ITD) negative
- Cytoplasmic NPM-1 negative, Flt-3 ITD positive
- Cytoplasmic NPM-1 positive, Flt-3 ITD negative
- Cytoplasmic NPM-1 positive, Flt-3 ITD positive
- Cytoplasmic NPM-1 negative, Flt-3 ITD negative
- Cytoplasmic NPM-1 positive, Flt-3 ITD negative
Nucleophosmin-1 (NPM-1) is a nucleocytoplasmic protein encoded by the NPM-1 gene located on chromosome 5q35.1. It serves many functions including centrosome assembly, regulation of protein shuttling through the nuclear membrane, control of ribosome biosynthesis, and regulation of the AFR/p53 suppressor pathway. It is normally localized in the nucleolus, but mutation of the NPM-1 gene results in cytoplasmic localization of the NPM-1 protein (NPM-1c) due to a combination of the loss of two key tryptophans, 288 and 290, which alters the localization of NPM away from the nucleoli as well as the generation of a new Rev-type nuclear export sequence at the C terminus. Patients with primary AML who have cytoplasmic localization of NPM-1 typically have normal cytogenetics. The presence of NPM-1c can be a good prognostic marker with regard to event-free survival (EFS) and overall survival (OS) after chemotherapy. FMS-like tyrosine kinase-3 (Flt-3) is a receptor found in normal hematopoietic stem/progenitor cells and is important in normal hematopoietic stem/progenitor cell survival, proliferation, and differentiation. Abnormalities of the Flt-3 receptor may include either an internal tandem duplication (ITD) of the juxtamembrane domain or a mutation of the tyrosine kinase domain (D835 or I836). The presence of the Flt-3 ITD mutation has been implicated in worse EFS and OS. Döhner and colleagues analyzed the results of induction chemotherapy in patients ≤60 years old with a normal karyotype enrolled in the AML HD93 and AML HD98-A trials. The results indicated that NPM-1 mutations predicted for better response to induction chemotherapy and improved OS only in the absence of the Flt-3 ITD mutation.
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- Kottaridis PD, Gale RE, Frew ME, et al. The presence of a Flt-3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752-9.
- Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740-6.
- Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109:874–85.
- Albiero E, Madeo D, Bolli N, et al. Identification and functional characterization of a cytoplasmic nucleophosmin leukaemic mutant generated by a novel exon-11 NPM1 mutation. Leukemia. 2007; 21:1099–103.
- Falini B, Bolli N, Shan J, et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood. 2006;107:4514–23.
- Falini B. Acute Myeloid Leukemia with Mutated Nucleophosmin. Clinical Leukemia. 2008;2:163-173.
Case study submitted by Ramon V. Tiu, MD, BS, of the Cleveland Clinic.