Submitting Author: Juntilla, Marisa M, MD, PhD
Institution: Stanford University Medical Center
Additional authors:Daniel Arber, MD, and Robert Ohgami, MD, PhD
Session: AML with myelodysplasia-related changes

The patient is a 58 year-old man with a history of type II diabetes, coronary artery disease and severe diverticulitis who underwent a colectomy one month prior with a complicated post-operative course and later re-admitted with failure to thrive. He was then noted to have blasts on the peripheral blood smear and a bone marrow biopsy was performed. The patient was not a candidate for chemotherapy given the ensuing development of sepsis and an open abdominal wound and was subsequently placed on comfort care only. Notably, the patient reported that he had normal CBCs at his yearly primary care visits.

CBC: WBC: 9.1 K/uL HGB: 7.7 g/dL MCV: 105.4 fL PLT: 602 K/uL ABS NEU: 2.5 K/uL DIFF: NEUTS 25% LYMPHS 21% MONOS 6% EOS 7% MYELOS 2% BLASTS 39%

The peripheral blood demonstrates a macrocytic normochromic anemia with mild anisopoikilocytosis, including ovalocytes and rare teardrop cells. Large blasts with round to irregular nuclear contours, fine chromatin, prominent nucleoli, and abundant basophilic cytoplasm account for 39% of total cells. Atypical monolobate eosinophils, hypogranular and hypolobate neutrophils, and circulating nucleated red blood cells with nuclear budding are identified. Platelets are increased and include hypogranular and giant forms. Rare circulating megakaryocyte nuclear fragments are also seen.

The aspirate shows a predominance of blasts with similar morphology to those seen in the peripheral blood that comprise 49% of all cells. The erythroid lineage shows marked dysplasia including nuclear budding, binucleation, and megaloblastoid changes. Myeloid cells are left shifted and included hypolobated forms. Megakaryocytes show dysplastic features including hypolobated and micromegakaryocyte forms, and many with widely separated nuclear lobes.

The core biopsy shows a monomorphic infiltration of blasts that account for approximately 60% of total cellularity. Background trilineage hematopoietic elements are reduced. Atypical megakaryocyte clustering is noted.

Blasts account for 51% of CD45+ events and express CD117, CD38, CD13, CD33, partial CD11c, dim partial CD4, partial CD64, partial CD15, partial dim MPO, and partial HLA-DR. The blasts are negative for CD34, cCD3, and cCD79a. The granulocyte maturation pattern of CD13/CD16 expression shows a markedly abnormal pattern, consistent with granulocytic dysplasia.

Normal male karyotype: 46,XY[23]; Negative by FISH for MLL gene rearrangement, nuc ish(MLLx2)[200]

Positive for insertion mutation in NPM1

Positive for IDH1 c.395G>A, p.R132H,

Positive for NRAS c.182A>C, p.Q61P

Negative for FLT3 ITD and FLT3 D835 mutations

Negative for PML-RARA by rtPCR

Negative for mutations in CEBPA

Negative for mutations in KIT exons 8 and 17

Negative for other mutations tested in the cancer somatic mutation panel: APC exon 16; BRAF exons 11, 15; CTNNB1 exon 3; DNM3TA exon 23; EGFR exons 18, 19, 20, 21; ERBB2/HER2 exon 20; IDH1 exon 4; KRAS exon 2; MYD88 exon 5; NOTCH1 exon 26; NRAS exon 2; PIK3CA exons 10, 21; PTEN exons 5,6,7; TP53 exons 7,8; SF3B1 exon 15

1) Molecular and cytogenetic studies reveal a normal male karyotype with an insertion mutation in NPM1 and wild-type FLT3. Given the additional findings of multilineage dysplasia in this acute myeloid leukemia, the overall diagnosis here is one of an acute myeloid leukemia with myelodysplasia related changes and we note the presence of an insertion mutation in NPM1. Cases with overt myelodysplasia are likely to benefit from the favorable prognosis of NPM1 mutations as AMLs with mutated NPM1 and myelodysplasia are reported to have a similar clinical outcome as NPM1-mutated cases without myelodysplasia (Falini et al. Blood, 2010). Likewise, a normal karyotype provides no additional prognostic information in patients carrying mutated NPM1 (Haferlach et al., Blood 2009). Thus, in the absence of multilineage dysplasia, NPM1- mutated AML with wild-type FLT3, regardless of karyotype, should be diagnosed as the provisional entity of AML with NPM1 mutations according to WHO 2008 criteria. However, if the case meets criteria for AML with myelodysplasia related changes, the diagnosis is one of AML- MRC. The presence of multilineage dysplasia without a history of MDS and without an MDS-associated karyotype, however, is of controversial significance (Weinberg et al Blood 2009; Wandt et al Blood 2008). For this reason, cases with a normal karyotype and multilineage dysplasia should probably be diagnosed as AML with myelodysplasia related changes with mutated NPM1 because these patients may have a clinically favorable outcome compared to patients with AML-MRC. AML with myelodysplasia related changes, normal karyotype, and NPM1 mutations are uncommon in our institution (1 of >50 NPM1-mutated cases examined). The prognostic relevance of having two relatively good factors (normal karyotype, NPM1 mutation) may not be lessened by the unfavorable prognosis associated with myelodysplasia.

2) Molecular analysis further revealed both NRAS and IDH1 mutations in this case, supporting the model of complementing class I and II mutations in AML, but providing no additional prognostic information (Damm et al., Blood 2011).

Acute myeloid leukemia with myelodysplasia related changes and an insertion mutation in NPM1

Acute myeloid leukemia with myelodysplasia-related changes (by morphology) and NPM1 mutation, IDH1 mutation, and NRAS mutation

Case 121