Tetraploidy in Acute Myeloid Leukemia Is Associated with Poor Outcomes Regardless of the Presence of Favorable Risk Features, and Requires an Allogeneic Stem Cell Transplant in First Remission

Abstract Introduction: While tetraploidy (92 chromosomes) and near-tetraploidy (>80 chromosomes) confer favorable prognosis in B-cell lineage pediatric acute lymphoblastic leukemia, their prognostic significance in acute myelogenous leukemia (AML) remains ill-defined. Moreover, the mechanisms underlying their pathobiology and impact on known prognostic factors in AML are unknown. Combining data collected at our institution along with a review of the literature, we provide the most complete analysis of tetraploidy and near-tetraploidy in AML including data on biology, treatment outcomes, impact on other prognostic markers, and survival to assist in clinical management. Patients and methods: A systematic literature search was performed and included studies published from June 1st, 1994 to June 1st, 2017 in PubMed, Embase, and Web of Science. We used the key words tetraploidy, near-tetraploidy, acute myeloid leukemia, acute myelogenous leukemia, and AML. Data was tabulated regarding the following seven variables: Fluorescence in situ hybridization (FISH) analysis, molecular analysis, karyotype, risk status, overall survival (OS), history of allogeneic stem cell transplantation, and chemotherapy. Data was reported as percent and total number of cases with available data of each variable. Results and discussion: We identified 104 AML cases with confirmed tetraploidy or near-tetraploidy (102 cases in 24 articles, and 2 cases from our institution). Incidence was nearly equal between tetraploidy (55/104) and near-tetraploidy (49/104). The median age at diagnosis was 54. A notable male predominance was observed with a male-to-female ratio of 2.2:1 (71 males and 33 females). While insufficient molecular data were available to include in risk stratification, cytogenetics including FISH and karyotype were available in all cases. We stratified our cases irrespective of tetraploidy or near-tetraploidy into favorable risk (defined by the presence of the following genetic alterations in core-binding factors: inv(16) or t(16;16) or t(8;21), or t(15;17)), unfavorable risk (defined by complex karyotype [≥3 clonal chromosomal abnormalities], monosomal karyotype, 5q-, 7q-, -5,-7, t(6;9), inv(3), t(3;3), 11q23 - non t(9;11), t(9;22)) and intermediate risk (the rest). Consistent with the literature, cases with other cytogenetic abnormalities in addition to those defined in the favorable-risk group, were included within the favorable-risk category (Byrd Blood 2002). Interestingly, t(8;21) was the only favorable risk feature represented, seen in 13 patients (12.5%), thus grouped under favorable-risk AML. 51 patients (49.0%) were grouped under unfavorable-risk AML and included 24 patients with complex karyotype, 9 patients with -7, 7 patients with 5q-, 4 patients with -5, 1 patient with 7q-, 1 patient with t(9;22), 3 patients with both -5 and -7, 1 patient with both 5q- and -7, and 1 patient with both -5 and 7q-. Intermediate risk was observed in 40 patients (38.5%) who were found to have normal or non-defined cytogenetics. We used the Kaplan-Meier method to stratify survival data, and the log-rank test to compare the survival between subgroups. The overall outcomes were poor, the median OS (mOS) of the whole cohort was 6 months (M) (Figure 1A). The prognosis was equally poor for both tetraploidy (mOS 6.2M) and near-tetraploidy (mOS 6M) (P=0.81; Figure 1B). Surprisingly, risk stratification showed no impact on overall survival (P=0.57; Figure 1C), which suggest that the unfavorable risk imposed by tetraploidy or near-tetraploidy may overcome favorable-risk features, such as t(8;21), challenging current data on AML risk stratification. Twenty-one patients (20.2%) had an allogeneic stem cell transplantation. Interestingly, we noticed a significant improvement in outcomes (mOS 17M) in patients who received an allogeneic stem cell transplantation compared to those who did not (mOS 4M) (P=0.0085; Figure 1D). Conclusion: Regardless of the risk status, the prognosis of tetraploid or near-tetraploid AML is dismal and should be incorporated within the unfavorable risk group. Prompt evaluation for allogeneic stem cell transplant should be initiated at diagnosis. Indeed, longer survival can be achieved with chemotherapy followed by allogeneic stem cell transplantation at first complete remission. Download : Download high-res image (133KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.