Case 318

Submitting Author: Yabe, Mariko, MD, PhD
Institution: SLRHC, Columbia University, University of Texas MD Anderson Cancer Center
Additional authors:Mariko Yabe, Bing Bai, Xiaohong I. Wang, Zhuang Zuo, C. Cameron Yin
Session: AML with recurrent genetic mutations Part II

HISTORY

The patient was a 28-year-old Caucasian woman who presented with leukocytosis in November 2009. She was diagnosed with AML without maturation (M1) with diploid karyotype and was positive for FLT3 internal tandem duplication (ITD). She was treated with cytarabine, anthracycline and midostaurin, and achieved complete remission. She further received consolidation therapy with high-dose cytarabine. Unfortunately, in February 2010, she developed relapsed disease. Her salvage therapy included mitoxantrone, etopside, cytarabine and sorafenib. She achieved second complete remission, and received matched, unrelated stem cell transplantation in June 2010. In September 2010, she had a second relapse, and came to our institution for further treatment options.

Upon presentation at our institution, her white blood cell count was 25.4 K/uL, hemoglobin 9.3 g/dL, platelet count 9 K/uL, with 81% blasts identified on the peripheral blood smear. She had an elevated serum lactate dehydrogenase level (2016 IU/L) and an elevated serum b2-microglobulin (7.9 mg/L). She received monotherapy with AC220 (a FLT3 inhibitor), and achieved a brief remission. Unfortunately, she relapsed again in September 2011, and deceased a month later (23 months after initial diagnosis of AML).

DETAILS

Bone marrow biopsy demonstrated a hypercellular marrow with trilineage hypoplasia and markedly increased blasts (84%).

IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY

Flow cytometry analysis demonstrated a population of blasts that were positive for CD13, CD33, CD34, CD38, CD64 (partial), CD117, HLA-DR, TdT (partial), myeloperoxidase, and negative for CD2, CD3, cytoplasmic CD3, CD5, CD7, CD10, CD14, CD19, CD20, CD41, CD56, consistent with myeloid immunophenotype.

CYTOGENETIC FINDINGS

Karyotypic analysis showed 46,XX,t(2;16)(p21;p11.2),t(11;14) (p13;p11.2)[16]/46,XX[4]. The translocation (11;14) was confirmed by fluorescent in situ hybridization (FISH) using Cytocell whole chromosome paint (wcp) probe for chromosome 11.

MOLECULAR FINDINGS

Molecular studies detected NPM1 exon 12 mutation in addition to FLT3 ITD. No mutation was identified in NRAS, KRAS, KIT or CEBPA genes. Multiplex reverse transcription-polymerase chain reaction for the detection of 11 different leukemia-associated fusion transcripts, including b3a2, b2a2 and e1a2 transcripts of BCR-ABL1/t(9;22)(q34;q11.2), short and long forms of PML-RARA/t(15;17)(q22;q21), A and D forms of CBFB-MYH11/inv(16)(p13;q22) or t(16;16)(p13;q22), RUNX1-RUNX1T1 /t(8;21)(q22;q22), E2A-PBX1/t(1;19)(q23;p13), MLL-AF4/t(4;11)(q12;q23) and TEL-AML1/ t(12;21)(p12;q22), was negative.

INTERESTING FEATURES

We report the first case of a relapsed AML with a novel cytogenetic abnormality, 46,XX,t(2;16)(p21;p11.2),t(11;14)(p13;p11.2), in a young patient with immature phenotype, high blast count, FLT3 ITD, NPM1 mutation, multi-chemo resistance, and a poor clinical outcome.

PROPOSED DIAGNOSIS

Novel Chromosomal Aberration, t(2;16)(p21;p11.2),t(11;14)(p13;p11.2), as evidence of clonal evolution in a case of relapsed acute myeloid leukemia

CONSENSUS DIAGNOSIS

Acute myeloid leukemia with mutated NPM1 and FL3T ITD mutations and clonal evolution including t(2;16)(p21;p11.2), t(11;14)(p13;p11.2)