Final Diagnosis -- Acute myeloid leukemia (AML) with inv(3)(q21q26.2)


Acute myeloid leukemia (AML) with inv(3)(q21q26.2)


Peripheral Blood:
Acute myeloid leukemia (28% blasts)
Macrocytic anemia and monocytosis

Bone Marrow:
Acute myeloid leukemia (46% blasts)
Abundant iron stores and rare ring sideroblasts

In addition to the circulating blasts compatible with acute myeloid leukemia (AML), the peripheral blood is notable for immature megakaryocytes and giant platelets. The marrow is hypercellular with dysplastic megakaryocytes; the blasts show some immunocytochemical CD61 positivity, little CD61 and Factor VIII positivity by paraffin section immunohistochemical stains, and are largely negative for CD41 and CD61 by flow cytometric immunophenotypic studies performed on the aspirate. These studies suggest a possible megakaryoblastic component to the patient's AML. The presence of inv(3)(q21q26) would place the AML in the classification designated as "AML with recurrent genetic abnormalities" according to WHO (2008), and is compatible with the morphologic findings.


Acute myeloid leukemia (AML) with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); (RPN1-EVI1) may present de novo or arise from a prior myelodysplastic syndrome (MDS). It is often associated with normal or elevated peripheral blood platelet counts and has increased atypical bone marrow megakaryocytes with mono- or bi-lobated nuclei and associated multilineage dysplasia.[1]

Acute myeloid leukemia (AML) with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) represents 1-2.5% of all AML [2]. It mainly occurs in adults with an average age of 53 years [3], and has no sex predilection.[1]

Patients commonly present with anemia and a normal platelet count, although 7-22% of patients have a marked thrombocythemia which can approach 600 x 109/L [3]. The anemia is typically not as severe as that seen in AML patients with a diploid karyotype (average Hb of 9.1 vs 7.7 gm/dL, respectively [3]). A subset of patients may have a history of myelodysplastic syndrome (MDS). Lymphadenopathy is typically not seen although some patients may have hepatosplenomegaly.[1]

The peripheral blood may demonstrate hypogranular neutrophils with pseudo-Pelger-Huet anomaly, with or without circulating blasts. Giant and hypogranular platelets are often seen, and bare megakaryocyte nuclei may also be seen, as in this case. Red blood cells are usually morphologically unremarkable and teardrop cells are not seen. [1]

The blasts may morphologically and cytochemically resemble those of any subtype of AML other than acute promyelocytic leukemia. The most common blast morphologies include those seen with acute myeloid leukemia without maturation, acute myelomonocytic leukemia, and acute megakaryoblastic leukemia. Approximately 72% of cases show cytochemical positivity for myeloperoxidase although the range of percentages of positive blasts is quite variable (6-98%) [3]. A subset of cases will have <20% blasts at the time of diagnosis, including cases with features of chronic myelomonocytic leukemia.[1]

Among non-blast bone marrow cells, multilineage dysplasia is often seen with atypical megakaryocytes being the most common finding. Megakaryocytes can be normal or increased in number. They include small monolobated or bilobated forms, but other dysplastic megakaryocytic changes can also be seen. Erythroid and granulocytic dysplasia is also common. Marrow eosinophils, basophils, and/or mast cells may be increased. Marrow cellularity and fibrosis are variable. Most cases are hypercellular (average 80%) [3] although some cases may present as hypocellular AML. [1]

Flow cytometry immunophenotyping shows the blasts in most cases to express CD13, CD33, HLA-DR, CD34, and CD38. CD117 expression may be seen in approximately 89% of cases [3]. Approximately 22% of cases show aberrant expression of CD7, and approximately 61% are positive for CD52. Single cases have been reported to show aberrant surface expression of CD2, CD5, and CD9 (one case each). A subset of cases are positive for CD61 (approximately 18%) and CD41 [3]. [1]

EVI1 is an oncogene located at 3q26.2; its longer form MDS1-EVI1 and RPN1 are located at 3q21. Deletions, inversions, and translocations occur at both of these loci, termed the "3q21q26 syndrome," and occur in MDS and AML (0.5-2%), CML in blast crisis (20%), and myeloproliferative disorders.

RPN1 may enhance EVI1 expression and result in increased cell proliferation, impaired granulocytic differentiation, and induction of hematopoietic cell transformation. The up-regulation of GATA-2 in some patients suggests that it is a target of myeloid neoplasms associated with 3q21q26 [4], and in GATA-1-deficient mice GATA-2 overexpression facilitated aberrant megakaryopoiesis. In addition, JAK2 V617F is uncommon in myeloid neoplasms with aberrations of 3q21q26.2 suggesting its lack of a role in megakaryocyte hyperplasia or thrombocytosis. Overexpression of EVI1 and GATA2 are not specific for inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [1].

Approximately 50-80% of de novo cases show secondary karyotypic abnormalities, with monosomy 7 being the most common and accounting for approximately 40% of secondary abnormalities [3]. 5q deletions, complex karyotypes, and FLT3 mutations may also be seen and may precede the development of the 3q26.2 abnormality [1].

This subtype of AML is an aggressive disease with short survival and poor response to conventional chemotherapy[5,6]. Few patients may show response to arsenic trioxide with thalidomide. Patients treated with allogeneic stem cell transplantation may have better survival than those treated with chemotherapy alone (13.8 vs 8.0 months, respectively) [3]. Cases with <20% blasts should be monitored closely for development of more definite evidence of AML. [1]

This patient was informed that this AML has a poor prognosis especially given his comorbidities (severe chronic obstructive pulmonary disorder, recent spontaneous pneumothorax, current pneumonia and pleural effusion, high oxygen requirement). Palliative chemotherapy with Dacogen was recommended over standard induction chemotherapy or transplant due to the high risk of treatment-related complications. As of the time of this report, the patient wished to consider his treatment options at home and was strongly recommended to follow up with his hematologist/oncologist as an outpatient.


  1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. International Agency for Research on Cancer (IARC): Lyon, 2008.
  2. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities amongst 5876 younger adult patients treated in the UK Medical Research Council trials. Blood 2010;116:354-365.
  3. Sun J, Konoplev SN, Wang X, Cui W, Chen SS, Medeiros LJ, Lin P. De novo acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): a clinicopathologic and cytogenetic study of an entity recently added to the WHO classification. Mod Pathol. 2011 Mar;24(3):384-9.
  4. Lahortiga I, Vazquez I, Agirre X, et al. Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements. Genes Chromosomes Cancer. 2004;40:179-189.
  5. Cui W, Sun J, Cotta CV, Medeiros LJ, Lin P. Myelodysplastic syndrome with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) has a high risk for progression to acute myeloid leukemia. Am J Clin Pathol. 2011 Aug;136(2):282-8.
  6. Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Köhne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg B, Döhner H. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol. 2010 Aug 20;28(24):3890-8.

Contributed by Rashi Singhal, MD, and Lydia Contis, MD

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