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Case 255

Case 255. Elizabeth Courville, MD Robert Hasserjian, MD Massachusetts General Hospital Society for Hematopathology/European Association for Haematopathology Workshop October 24, 2013. Clinical History. 79 year old man Low energy, poor appetite, nausea CBC:

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Case 255

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  1. Case 255 Elizabeth Courville, MD Robert Hasserjian, MD Massachusetts General Hospital Society for Hematopathology/European Association for Haematopathology Workshop October 24, 2013

  2. Clinical History • 79 year old man • Low energy, poor appetite, nausea • CBC: • WBC 11.7 x 109/L, 25% monocytes • Hgb 11.3 g/dL, MCV 101 fl • Platelets 163 x 109/L

  3. Aspirate Differential Count: 30% myeloid precursors, 40% erythroid precursors, 2% lymphs, 10% monocytes, 1% eosinophils, 1% basophils, 13% blasts and promonocytes, 3% plasma cells * * *

  4. First bone marrow specimen diagnosis: Chronic myelomonocytic leukemia-2 (CMML-2) • Patient was treated supportively • Three months after initial presentation: CBC • WBC 165.5 x 109/L • 44% monocytes, 8% promonocytes, 18% blasts • Hgb 7.6 g/dL • Platelets 109 x 109/L

  5. Aspirate Differential Count: 4% myeloid precursors, 16% erythroid precursors, 5% lymphs, 4% monocytes, 71% blastsand promonocytes, 3% plasma cells

  6. Cytogenetic findings: 46 XY [20] Cytoplasmic NPM1 staining; AML specimen Cytoplasmic NPM1 staining; CMML-2 specimen NPM1 WT (235 bp) MutatedNPM1 (239 bp) FLT3 WT (330 bp) FLT3-ITD, >335bp

  7. Second bone marrow specimen diagnosis: NPM1-mutated AML with myelodysplasia related changes (FLT3-ITD mutation also present)

  8. Second bone marrow specimen diagnosis: NPM1-mutated AML with myelodysplasia related changes AML-MRC defined by: • Previous history of a myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm • Myelodysplastic syndrome-related cytogenetic abnormality • Multilineage dysplasia Represent approximately 1/3 of all cases of AML Generally has a poor prognosis

  9. Second bone marrow specimen diagnosis: NPM1-mutatedAML with myelodysplasia related changes AML with mutated NPM1 • NPM1 mutation occurs in ≈ 30% of adult AML and in ≈ 50% of adult AML with a normal karyotype. • Usually associated with normal karyotype; although chromosomal aberrations are present 5-15% of the time. When they are present, cytogenetic aberrations do not appear to confer an adverse prognosis. (Haferlach, et al. Blood. 2009; 114: 3024-32) • 40% also carry a FLT3-ITD. Favorable prognosis in the absence of a FLT3-ITD mutation. Coexistence of a FLT3-ITD mutation: adversely affects prognosis • Multilineage dysplasia in AML with mutated NPM1: does not appear to confer an adverse prognosis (Falini, et al. Blood. 2010; 115: 3776-86).

  10. 318 pts with AML with de novo cytoplasmic/mutated NPM1. Myelodysplasia, as defined by 2008 WHO criteria, was detected in 23.3% of cases. • Gene expression profiling of a subset of the cases revealed separation based on NPM1 status but not the presence or absence of dysplasia. • No significant difference in overall survival or event free survival was observed between NPM1-mutated AML with and without multilineage dysplasia.

  11. Second bone marrow specimen diagnosis: NPM1-mutatedAML with myelodysplasia related changes AML with mutated NPM1 • Usually occur as de novo cases without therapy related disease or a history of any antecedent myeloid neoplasm. (Falini, et al. Blood. 2007; 109: 874-885). • One study (Schnittger S et al. Leukemia 2011; 25: 615-621 ), identified an NPM1 mutation in 37/283 (13.1%) of patients at diagnosis of secondary-AML following MDS or CMML.

  12. NPM1 mutations in MDS prior to development of AML - NPM1 + Modified from Schnittger S et al. Leukemia 2011; 25: 615-621

  13. NPM1 mutations are uncommon in CMML

  14. The few NPM1 positive CMML cases exhibit aggressive behavior

  15. Should NPM1-mutated CMML be considered an early de novo NPM1-mutated AML? • Screening of newly diagnosed cases of CMML for the NPM1 mutation may be warranted, with close clinical follow-up of positive cases.

  16. Patient Follow-up • The patient relapsed after induction chemotherapy and died 12 months after his AML diagnosis.

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