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

Abstract

Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) is a rare type of leukemia recently added to the World Health Organization (WHO) classification scheme. In this study, we analyzed the clinicopathologic and cytogenetic features of 30 cases of de novo acute myeloid leukemia with inv(3)/t(3;3). The median patient age was 53 years (range, 27-77 years). The platelet count was variable (range, 21-597 Â 10 9 /l, median: 128 Â 10 9 /l), and two (6.7%) patients presented with thrombocytosis (4450 Â 10 9 /l). Morphologically, these neoplasms showed a spectrum of findings. Myelomonocytic differentiation was most common in 11 (37%) cases. Morphological evidence of dysplasia was observed in at least one lineage in 23 of 25 (92%) cases in which maturing elements could be assessed. In all, 5 (17%) patients had isolated inv(3) or t(3;3) and 25 (83%) patients had additional cytogenetic abnormalities, most often monosomy 7 (40%). Eleven (37%) patients had a complex karyotype (Z3 additional abnormalities). FLT3 gene mutation by internal tandem duplication was identified in 2 of 23 (9%) cases assessed. No clinical, pathological, or cytogenetic features independent of inv(3) or t(3;3) correlated with a worse outcome. However, patients treated with allogeneic stem cell transplantation (n ¼ 11) had a significantly better survival than did those treated with chemotherapy alone (n ¼ 17) (13.8 vs 8.0 months, P ¼ 0.041). We conclude that de novo acute myeloid leukemia associated with inv(3)/t(3;3) is an aggressive type of leukemia regardless of morphological or karyotypic findings, supporting the inclusion of this disease as a specific entity defined by inv(3)/t(3;3) in the WHO classification. Allogeneic stem cell transplantation seems to improve outcome in patients with this disease.

Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study

“…Such cases have a poor prognosis with a short median OS, and propensity to rapidly progress to AML. 1,5,6 Indeed the WHO 2008 recommends close follow up of these patients due to the aggressive clinical course and frequent development of AML. We undertook this multicenter study to collect a large number of de novo myeloid neoplasms with inv(3)/t(3;3) in order to better understand the clinical and pathological features of this disease.…”

“…The resulting overexpression of EVI1 promotes proliferation and impairs differentiation of myeloid cells. 2,6,14,15,[28][29][30] Animal models demonstrate that forced overexpression of EVI1 results in myeloid hyperproliferation, downregulation of genes related to myeloid differentiation, and cause a fatal disorder resembling human MDS. 20,21,30,31 In humans, rare cases have been reported of myelodysplasia with monosomy 7 related to overexpression of EVI1 caused by retroviral insertional activation during gene therapy.…”

“…Myelodysplastic syndrome (MDS) with inv(3)/t(3;3) is also a rare aggressive disorder which occurs in less than 1% of all MDS cases and has a high risk of progression to AML. 2,6,7 The inv(3)/t(3;3) can occur rarely in other myeloid neoplasms, such as myeloproliferative neoplasms (MPN) including chronic myelogenous leukemia (CML), mostly during accelerated phase or in blast crisis, and overlap MDS/MPNs including chronic myelomonocytic leukemia. AML with inv(3)/t(3;3) is commonly refractory to conventional chemotherapy and has poor prognosis.…”

“…6,7,[12][13][14] Dysregulation of EVI1 plays an important role in stem cell self-renewal and leukemogenesis. Overexpression of EVI1 promotes myeloid cell proliferation and impairment of differentiation, and may be related to the adverse prognosis of myeloid neoplasms with inv(3)/t(3;3).…”

The New Clinicopathologic and Molecular Findings in Myeloid Neoplasms With inv(3)(q21q26)/t(3;3)(q21;q26.2)

“…myeloid antigens (CD13, CD33, CD117, and MPO) and uncommitted antigens, such as CD34, HLA-DR, and CD56 (Figure 1, B). 13,14 Acute myeloid leukemia with inv(3)/t(3;3) can be either de novo 6,12,15 or therapy related, 12,16 and typically has a very poor prognosis, 6,7,[12][13][14] with a reported overall survival of 7.9 months. 12 Notably, the 3q21q26 syndrome can also be associated with central diabetes insipidus.…”