AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); <i>GATA2, MECOM</i> (2024)

• A distinct acute myeloid leukemia (AML) subcategory recognized by presence of the pathognomonic cytogenetic abnormality inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] (Blood 2016;127:2391)
• Recognized as a separate entity in the acute myeloid leukemia (AML) category of the 2008 WHO classification and updated in the 2016 revision (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th Edition, 2008, Blood 2016;127:2391)
• May present as de novo disease or evolve from preexisting myelodysplastic syndrome (Cancer Genet 2019;230:28)
• Diagnosis requires ≥ 20% blasts (in peripheral blood or bone marrow) and is often clinically characterized by anemia, normal to elevated platelet counts and bone marrow hyperplasia with multilineage dysplasia of nonblast cells, particularly dysmegakaryocytopoiesis (Cancer Genet 2019;230:28)
• Aggressive form of AML with very poor prognosis and poor response to conventional induction chemotherapy (Cancer Genet 2019;230:28)

• Aggressive form of AML with very poor prognosis and poor response to conventional induction chemotherapy (Cancer Genet 2019;230:28)
• Diagnosed by presence of the pathognomonic cytogenetic abnormality inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] (Blood 2016;127:2391)
• End result is juxtaposition of the distalGATA2enhancer with theMECOM (EVI1) proto-oncogene(Blood 2016;127:2391)
• May present as de novo disease or evolve from preexisting myelodysplastic syndrome (Cancer Genet 2019;230:28)

• AML with inv(3)
• Acute myeloid leukemia with GATA2, MECOM
• AML with RPN1 / EVI1
• 3q21q26 syndrome (Hematology 2015;20:435)
• AML with RPN1-MECOM

• ICD-0: 9869/3 - acute myeloid leukemia with inv(3)(q21;q26.2) or t(13.3)(q21;q26.2); RPN1-EVI1 (NIH: Acute Myeloid Leukemia with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM [Accessed 16 July 2020])
• ICD-10: C92.0 - acute myeloblastic leukemia

• More frequent in people younger than 60 years (median age of 50 years) (Hematology 2015;20:435)
• Slight male predominance (54%) (Hematology 2015;20:435)
• 1 - 2% of all forms of AML (Cancer Genet 2019;230:28)

• Bone marrow
• Peripheral blood

• See Etiology

• Recurrent cytogenetic abnormality, inv(3)(q21q26.2) / t(3;3)(q21;q26.2), causes a juxtaposition of the distal GATA2 enhancer with MECOM (EVI1) (Blood 2016;127:2391)
• These rearrangements (not to be thought of as a fusion) result in the proto-oncogene MECOM (EVI1) at 3q26 (Blood 2016;127:2391, Cancer Cell 2014;25:415)
• Simultaneous GATA2 haploinsufficiency also results (Blood 2016;127:2391)
• Core mRNA splicing factor SF3B1 and RAS / RTK signaling pathways have been found to be important in the pathogenesis of this AML subtype (Blood 2019;134:917, Blood 2015;125:133)
• Secondary karyotypic abnormalities, including monosomy 7 (most common), complex karyotype and 5q deletion, are commonly present (Cancer Genet 2019;230:28, Hematology 2015;20:435, J Clin Oncol 2010;28:3890)

• Presence of at least 20% blasts in peripheral blood or bone marrow
• Often presents with anemia
• Elevated white blood cell count (sometimes low)
• Normal or elevated platelet count
• Association with central diabetes insipidus (Hematology 2015;20:435)
• Elevated LDH

• Requires enumeration of 20% blasts on peripheral blood smear or marrow aspirate differential count(s)
• Flow cytometry or immunohistochemical stains may assist in blast phenotyping
• Juxtaposition of GATA2 and MECOM, inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] can be detected by classic cytogenetics, FISH and other molecular / genetic studies including chromosome microarray, next generation sequencing, RT-PCR, etc.

• CBC with anemia
• Leukocytosis (sometimes leukopenia) with 20% blasts
• Normal or elevated platelet count
• Elevated LDH
• Flow cytometry analysis reveals increased dim CD45 events (blasts)

• inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)] finding in AML itself represents a very poor prognosis and predicts poor response to conventional induction chemotherapy (Hematology 2015;20:435, J Clin Oncol 2010;28:3890)
• Age greater than 60 years at diagnosis indicates poor prognosis (Hematology 2015;20:435)
• High WBC count at diagnosis confers poor prognosis (Hematology 2015;20:435)
• Presence of monosomy 7 has been reported to be an indicator of poor prognosis (J Clin Oncol 2010;28:3890)
  • However, this has not proven to be a consistent finding in other studies (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)

• Young woman with AML and concurrent central diabetes insipidus in the presence of inversion(3)(q21q26) (Blood Cells Mol Dis 2019;76:45)
• 25 year old woman with germline GATA2 mutation and acquired NRAS Q61K mutation who presents with rapid progression to AML (Leuk Res Rep 2019;12:100176)
• 77 year old man with a variant of AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) (MECOM) rearrangement (Mol Cytogenet 2015;8:68)
• Case series of AML with double inv(3)(q21q26.2) (J Clin Oncol 2010;28:3890)

• This subtype of AML is well known to show poor response to standard induction chemotherapy (such as the 7 + 3 regimen consisting of cytarabine and an anthracycline), with remission rates of only 10 - 30% and overall survival of < 10% at 8 - 10 months (Hematology 2015;20:435, J Clin Oncol 2010;28:3890, Clin Lymphoma Myeloma Leuk 2020;20:24)
• Combination of lenalidomide and a hypomethylating agent (azacitidine of decitabine), has shown promise with improved overall response rates, particularly when used as first line therapy (J Clin Oncol 2010;28:3890)
• Stem cell transplantation does not appear to conclusively improve overall survival in this subtype of AML (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)

• 20% blasts in the peripheral blood with or without dysplastic features
• Hypercellular (often) bone marrow with > 20% blasts (Int J Lab Hematol 2019;41:380)
• Multilineage dysplasia with variable bone marrow fibrosis (usually little or no reticulin fibrosis) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Prominence of mono or bilobed megakaryocytes in the bone marrow (Hematology 2015;20:435)
• Micromegakaryocytes have been described (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Binuclear granulocytes (pseudo-Pelger-Hüet neutrophils) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Morphological features often resemble AML without maturation and acute myelomonocytic leukemia (Blood 2016;127:2391)
  • However, a study of Asian patients found acute monoblastic and monocytic leukemia in nearly half of the patients (Int J Lab Hematol 2019;41:380)

Contributed by Alexa J. Siddon, M.D.

• Anemia with erythroid dysplasia
• Leukocytosis or leukopenia
• Binuclear granulocytes (pseudo-Pelger-Hüet neutrophils) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Thrombocytosis or thrombocytopenia

• See Flow cytometry description

• See Flow cytometry description

• No characteristic immunophenotypic profile
• Myeloperoxidase (33 - 42.3% of cases) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Expression of panmyeloid and immature markers: CD34, CD13, CD33, CD117, CD38 and HLA-DR (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• Aberrant expression of CD7, a lymphoid marker (42.3 - 60%) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• CD56 (20%) (Hematology 2015;20:435, Int J Lab Hematol 2019;41:380)
• CD41, a megakaryocytic marker in 15.8% of patients (Hematology 2015;20:435)
  • Less frequent expression in patients of Asian origin (Int J Lab Hematol 2019;41:380)

• inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3) / t(3;3)]
• Increased expression of EVI1 (MECOM)
• Relative haploinsufficiency of GATA2
• Associated monosomy 7, complex karyotype and 5q deletion
• Gene mutations identified include those of NRAS, GATA2, SF3B1, FLT3-ITD, KIT D816, PTPN11, CBL, KRAS and BCR-ABL1 and CEBPA (Blood 2015;125:133, Int J Lab Hematol 2019;41:380)

Images hosted on other servers:

• Right posterior iliac crest, core biopsy, aspirate smear, touch imprint and clot particle:
  • Acute myeloid leukemia with inv(3)(q21.3;q26.2); GATA2, MECOM (see comment)
  • Comment: The bone core biopsy demonstrates an increase in blasts and prominent dysmegakaryocytopoiesis. The presence of inv(3)(q21.3;q26.2) confirms above diagnosis.

• Other AML with recurrent cytogenetic abnormalities:
  • Presence of other subtype defining cytogenetic abnormalities different from inv(3) / t(3;3)
• MDS with inv(3):
  • Blast count < 20%

Which of the following is true about AML with inv(3) / t(3;3)?

1. CD41 positivity on immunophenotypic studies is a key part of the diagnostic criteria
2. Deletion of chromosome 5q is the most frequently associated cytogenetic abnormality
3. Expression of CD7 is not consistent with the entity
4. Expression of MECOM (EVI1) is commonly upregulated
5. GATA2 fusion with MECOM (EVI1) is the characteristic molecular feature

D. Expression of MECOM (EVI1) is commonly upregulated

Comment Here

Reference: AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2)

Which of the following is true about AML with inv(3) / t(3;3)?

1. Anemia and thrombocytopenia are hallmark findings on the peripheral smear
2. Bone marrow is often hypocellular with extensive fibrosis
3. Erythroid dysplasia is uncommon unlike in other subtypes of AML
4. Finding of pseudo-Pelger-Hüet neutrophils suggest an alternative diagnosis
5. Increased megakaryocytic dysplasia is commonly observed on bone marrow aspiration / biopsy

E. Increased megakaryocytic dysplasia is commonly observed on bone marrow aspiration / biopsy

Comment Here

Reference: AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2)