Therapy-Related AML (t-AML), a Heterogeneous Disease: Multicenter Analysis on Biological and Clinical Differences between Cases Following Breast Cancer and Lymphoma Treatment

Abstract

BACKGROUND Therapy related AML (tAML), a late complication of chemo and/or radiotherapy (RT) for a prior neoplasm, most often develops after breast cancer (BC) and lymphoproliferative disorders (LD). T-AML pathogenesis may involve 1) induction of a fusion oncogene, most often caused by use of topoisomerase II inhibitors, 2) genome instability, often amplified by p53 mutations, developped most frequently after alkylating agents and radiotherapy and 3) selection of pre-existing hematopoietic cell clones (a condition known as CHIP) under chemotherapy pressure. Moreover, genetic susceptibility, i.e. mutations in genes involved in DNA damage-sensing and repair (BRCA 1 and 2, p53, Fanconi genes, BCL2L10), may play a role in the development of a second cancer. Finally some cases of tAML, may be temporally consequent but not etiologically related to previous treatment, an event more likely if the primary cancer is more frequent in the general population (as, for example, breast cancer). The aforementioned etiological factors may be involved with greater or smaller importance in different tAML patients groups and result in clinical heterogeneity even in patients classified in the same WHO AML category, with heterogeneous disease features and response to therapy. AIM OF THE STUDY AND METHODS We analysed data about patients treated at two Italian hospitals, ASST Niguarda Ca' Granda (Milan) and Policlinico San Martino (Genoa) from year 2009 to 2019 for a tAML secondary to breast cancer or to LD (Hodgkin and non Hodgkin lymphoma) and looked for possible differences in the clinical and genetic characteristics and response to therapy (i.e. achievement of CR). Descriptive statistics was used for categorical variables. Furthermore, Fisher exact test was used to compare the frequency of different genetic prophiles and response to therapy in different tAML patient populations. RESULTS Clinical and genetic characteristics of the patients, as well as data on previous treatment and response to therapy of tAML cases are reported in the table. Median age and time to AML onset were similar in the two groups of patients (BC and LD) and both had been largely treated with chemotherapy (including anthracyclines and alkylators) and radiotherapy, even if the use of chemotherapy was more extensive in lymphomas, with a significant proportion of patients also receiving HD chemotherapy and ASCT. We found biological and clinical differences between the two cohorts of tAML patients: Patients with previous BC had a genetic profile that is closer to that of de novo AMLs, with an high frequency of normal karyotype or recurrent translocations, including cases of CBF AML and PML. A MDS-related karyotype was found only in a minority of patients. Conversely, patients treated for a previous lymphoma had a much higher proportion of MDS-related cytogenetics (14/23 in LD vs 5/20 in BC, Fisher test, p=0,03), with only 7/23 patients harbouring a normal karyotype. As regards response to chemotherapy, the proportion of patients achieving a CR was 16/20 in breast cancer group, compared to 11/23 in LD patiens, a difference nearly achieving statistical significance (Fisher test, p=0,06). This difference was observed in spite of a larger use of fludarabine containing regimens in the latter cohort (according to clinicians choice). CONCLUSIONS Our data suggest that tAMLs, even if categorized as a whole in WHO 2016 classification, are a heterogeneous entity as regards pathogenesis and clinical behaviour and may deserve a personalized approach. The use of a wide genetic screening may help to discriminate the biological characteristics and prognosis of each patient with possible implications in therapeutic choices. Figure Disclosures No relevant conflicts of interest to declare.