Are Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) Occurring during the Course of Lymphoma (Ly) Always Therapy Related?
Authors: Bigenwald Camille , Harel Stephanie , Chevillon Florian , Roos-Weil Damien , Bernard Olivier A. , Amorim Sandy , Brice Pauline , Lionel Ades , Nloga Anne Marie , Sébert Marie , Braun Thorsten , Eclache Virginie , Thieblemont Catherine , Fenaux Pierre 
Published: October 2019

Abstract
Background: The development of MDS or AML after treatment of lymphoma (Ly) by chemotherapy (CT), especially alkylating agents, topoisomerase II inhibitors (topo II inh), purine analogs, and autologous hematopoietic cell transplantation (auto ASCT) is well known. Those MDS/AML generally occur 3 to 7 years after CT, although often earlier (1 to 3 years) after topo II inh. Only occasional cases of MDS/AML have been described concomitantly or just after treatment of Ly, questioning their relationship with the underlying Ly. We investigated this occurrence in 2 French centers over a 6-year period.
Methods: By reviewing case records of Ly and MDS/AML seen at Hôpital St Louis/Paris 7 university and Hôpital Avicenne/Paris 13 university between 2008 and 2014, we retrospectively identified patients who suffered from both types of disorders. Treatment received for the Ly and interval between Ly and MDS/AML were computed. Patients were divided into 2 groups: those who had received for their Ly some form of CT considered to be potentially leukemogenic, or CT at least one year prior to MDS/AML diagnosis (group1); and patients where MDS/AML had been diagnosed before, concomitantly or within one year of Ly, or had received no or very limited CT (group 2).
Results: 42 patients presenting both MDS/AML and Ly were identified. Ly included 10 follicular lymphomas, 8 CLL, 7 DLCL, 4 Hodgkin's lymphoma, 4 MZL, 3 peripheral T cell lymphomas, 2 lymphoplasmacytic lymphomas, 1 MCL, 1 lymphocytic lymphoma, 1 lymphoblastic lymphoma, 1 gastric MALT lymphoma.
34 (81%) of the patients were allocated to group 1. Their median age at MDS/AML was 67.7 years; the median number of CT regimens received was 2, and 18 had received auto SCT; MDS/AML occurred at a median time of 7 years (range 1 to 26) after diagnosis of Ly. WHO diagnosis of MDS/AML was RAEB (n= 12), RA (n=8), AML (n= 8), CMML (n= 1), RCMD (n= 1) and unclassifiable MDS (n= 4). Marrow cytogenetics (analyzed in 31 cases) were normal in 9 cases, showed del(20q) in 2 cases, del(5q) in 1 case, were intermediate in 5 cases and complex in 12 cases, while one t(8;21) and one t(9;11) were observed in AML. 14 patients had died, 9 from MDS/AML (after a median of 0.84 years), and 4 from Ly. Survival at 2 years after MDS/AML diagnosis is 35%.
The remaining 8 (19%) patients were allocated to group 2. Their median age at MDS/AML diagnosis was 72.8 years; 4 were diagnosed concomitantly with Ly, 2 before (by 2 and 3 years) and 2 within one year of Ly diagnosis. WHO diagnosis of MDS/AML was CMML (n=2), RAEB (n=2), RA (n=2), M5 AML (n=1), unclassifiable MDS (n=1). Marrow cytogenetics were normal (n=7) and isolated del(5q) (n=1). Three patients had not been treated for their Ly, 1 had only been splenectomized, 2 had received Rituximab alone, 1 Rituximab, Vincristine and steroids (but MDS preceded the diagnosis of Ly), 1 with ABVD (but MDS was diagnosed during CT). Two of the 8 patients had died both from AML (1.5 and 2.5 years after Ly diagnosis respectively). Survival at 2 years after MDS/AML diagnosis is 80% and seems to be better in this group (p=0,26) but group 2 included only few patients, and follow up was still limited.
Conclusion: Our findings suggest that about 20% of MDS or AML occurring in patients with lymphoma do not appear to be a consequence of the treatment of the underlying lymphoid disorder. They have less severe features (and a better outcome). Whether lymphoid and myeloid disorders, in those patients, are fortuitous associations, reflect an underlying predisposition to both types of neoplasms or whether both malignancies emerge from the same or related abnormal hematopoietic clones is unknown. We are currently analyzing the last hypothesis by molecular biology in our patient series.

Disclosures
Fenaux: AMGEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.