Pre-Existing Myeloid Subclones May Account for a Subset of Acute Myeloid Leukemias and Myelodysplastic Neoplasms in Patients with Pre-Existing or Contemporary Lymphoid Disorders
Authors: Mattei Agnese , Marconi Giovanni , Ronconi Sonia , Cangini Delia , Ceccolini Michela , Cerchione Claudio , Zacheo Irene , Giannini Maria Benedetta , Norata Marianna , Martinelli Giovanni , Ferrari Anna , Bochicchio Maria Teresa , Ghetti Martina , Marchesini Matteo , Simonetti Giorgia , Musuraca Gerardo , Nappi Davide 
Published: December 2023

Background:
Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are occasionally observed in association with lymphoid tumors. Most cases of myeloid disorders detected in patients with lymphoid tumors are attributed to chemotherapy, however, there is a subset of patients who receive a contemporary diagnosis of myeloid and lymphoid disease, and it is well known that, even in patients who were exposed to chemotherapy, the myeloid disease may both arise from clonal hematopoiesis substrate or harbor chemotherapy signature (Diamond, Blood 2023). Biological differences justified by the ontogenesis of the myeloid disease may justify prognosis and suggest appropriate intervention methods.
Methods:
We searched our patient database for AML and MDS which were diagnosed together with lymphoid diseases. Data was collected under the study NCT04298892, after approval of the ethical committee. Statistics were performed with Kaplan-Meyer estimation. Nonparametric tests were used as appropriate.
Results:
Out of 164 patients who were referred to our service from May 2021 to Jul 2023 for MDS or AML, 11 patients were diagnosed with AML or MDS together with a concomitant or previous lymphoid disease. In this population, the median age at AML or MDS diagnosis was 67 (range 58 - 82); 9/11 (82%) patients were male. Four out of 11 (36%) patients were diagnosed with AML, 7/11 with MDS (6 with blast &lt; 5% and 1 with blast ≥ 5%). The diagnosis of myeloid and lymphoid diseases was concomitant in 2 patients (18%) and sequential in 9 patients (82%). The lymphoid diseases were smoldering multiple myeloma (3/11, 27%), multiple myeloma (5/11, 45%), diffuse large B-cell lymphoma (1/11, 9%), mantle cell lymphoma (1/11, 9%), marginal zone lymphoma (1/11, 9%). Eight out of 11 patients (73%) with lymphoid and myeloid disease had a history of chemotherapy before the diagnosis of MDS or AML; 5 patients (45%) were exposed to high-dose alkylating agents, 2 (18%) low-dose alkylating agents, 2 (18%) anthracyclines. Interestingly, 7 patients (64%) were diagnosed while they were receiving lenalidomide after a median exposure to lenalidomide of 8.8 months (4.9 - 30.73). In the 9 patients with consecutive lymphoid and myeloid disease diagnosis, AML or MDS were diagnosed after a median of 23 months (range 8 - 76; history of patients is plotted in figure 1).
Regarding the AML or MDS, 3/11 patients (27%) had complex karyotype of which 1 had t(3;21)(q26;q22) RUNX1/MECOM rearrangement, 2/11 had TP53 mutation (both also had complex karyotype). The remaining patients mainly harbored methylation or splicing mutations and normal karyotype or karyotype single non-high-risk alterations. When compared, patients with complex alterations had similar times of onset from their first tumor and baseline characteristics; those patients however had an increased risk of death.
Conclusions:
The incidence of AML or MDS associated with lymphoid disease is low.Furthermore, the population is remarkably heterogeneous. The characteristics and the timing of onset of the disease account for different ontogenesis; a portion of the patient has a disease that harbors complex alterations, while the most frequent origin of AML and MDS can be researched in pre-existing or contemporary hematopoietic clones, that overall account for a whole bone-marrow disease. The relation between chemotherapy exposition and the biology of the AML or MDS is not univocal. This difference could be therapeutically relevant.