Trisomy 13: prevalence and clinicopathologic correlates of another potentially lenalidomide-sensitive cytogenetic abnormality

To the editor:

Therapy with lenalidomide has led to remissions in patients with myelodysplastic syndrome (MDS),¹  myelofibrosis,²  and acute myeloid leukemia (AML)³  with a del(5q) karyotypic abnormality. Fehniger et al reported in Blood⁴  complete remissions with lenalidomide in AML with an isolated trisomy 13. We sought to determine the prevalence and clinical correlations of isolated trisomy 13 in hematologic disease.

We identified 27 patients with an isolated trisomy 13 clone, out of a cytogenetic database denominator of 22 856 patients (1989-present; 26% with a diagnosis of AML or MDS) for a prevalence of 0.12% of bone marrows with corresponding karyotype studies from the Mayo Clinic. The majority had an isolated trisomy 13 as the sole karyotypic abnormality (96%).

Histologic analysis (obtained a median 0.18 months [range, 0-111 months] after diagnosis) showed the majority of patients in this series had either acute myeloid leukemia (56%) or MDS (33%); the incidence rate of trisomy 13 over this time period was 0.7% of all AML and 0.2% of all MDS patients. AML M0 was the most common diagnosis; these acute leukemias showed a high percentage of blasts without dysplastic features. In the 9 MDS cases (mainly with increased blasts), dysgranulopoiesis with hypogranular neutrophils was a common and prominent finding in all cases. Six of the 9 MDS patients also had small, monolobated megakaryocytes identified. Only 3 cases did not have an AML or MDS diagnosis. These included 1 case of primary myelofibrosis and 1 of chronic myelomonocytic leukemia (presented with a WBC = 264.8 × 10⁹/L). Interestingly, the remaining patient was diagnosed with pernicious anemia and had a very small clone (2/20 metaphases) with trisomy 13 and normal morphology. In addition, other than this latter case, it is notable that among the 74% of cases in our main Mayo patient karyotype database that were not AML or MDS (mainly myeloma, lymphoma, myeloproliferative, or cytopenia evaluations), isolated trisomy 13 was never identified.

Clinically, AML cases presented with aggressive phenotypes (see Table 1) with predominance of AML M0, of whom only 2 (7%) were younger than 60 years of age. Induction chemotherapy was given to 5 of the AML patients (33%), with 2 achieving a complete remission, only 1 of whom remains sustained. Therapy for the higher-risk MDS (Table 1) was largely supportive, but in the 2 patients who received hypomethylation therapy no response was seen. Serial karyotypic analysis was available in 4 patients (3 AML M0, 1 MDS-RAEB; obtained after 1-15 months), and demonstrated no evidence of clonal evolution nor the ability of therapy (induction chemotherapy in 2 patients, 5-azacytidine in 1) to eradicate the trisomy 13 clone. These results are in contrast to the report by Fehniger et al⁴  where lenalidomide led to a cytogenetic remission in 2 trisomy 13 patients. In our series, after a median duration of follow-up of 5.8 months (range, 0.5-24 months), Kaplan-Meier survival showed a median survival of 6.1 months for the entire cohort. When stratified by a higher burden of trisomy 13, those patients with more than 50% of metaphases involving the clone showed a trend of shorter survival (5.8 months vs 12.1 months; P = .11).

Trisomy 13 is a rare cytogenetic abnormality that clusters overwhelmingly with high-risk myeloid malignancy. The possibility that trisomy 13 is a marker for treatment response to lenalidomide therapy broadens the opportunity to understand better the drug's mechanism of action in general and to obtain additional insight into the pathogenesis of MDS and AML.