Therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplantation in lymphoma patients

Abstract

Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.

Long-term outcomes of high dose treatment and autologous stem cell transplantation in follicular and mantle cell lymphomas – a single centre experience

“…Reinfusion of peripheral blood progenitor cells with previously damaged DNA can result in clonal abnormal hematopoiesis. 35 In this study, we had no hematological malignancies in either of our groups. Even though the number of our patients is relatively small we may assume that TBI with high doses of cyclophosphamide is a safe method of conditioning prior to transplantation in regard of the secondary hematological malignancies.…”

“…The TBI regimen has been linked to secondary malignancies, mostly hematological – myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). 17 , 26 , 33 - 35 The numbers vary among different studies – they range from a 5-year estimated risk of 3.8% 17 to a 7-year cumulative probability of 8.9% 34 and a 6-year incidence of 12%. 33 The therapy-related-MDS/therapy-related-AML (t-MDS/t-AML) also depended on amount of radiation used for TBI.…”

Mortality Patterns Among Recipients of Autologous Hematopoietic Stem Cell Transplantation for Lymphoma and Myeloma in the Past Three Decades

“…During the past 3 decades, the field of ASCT has greatly evolved, with the use of a better tolerated high-dose regimen, 16,17 increased use of peripheral blood stem cell transplantation, 18 improvements in supportive care, [19][20][21][22] and a better understanding of transplantrelated complications. Similar advances have occurred in other fields, such as transfusion medicine, critical care medicine, infectious disease, cardiology, and nephrology, among the many fields in medicine.…”

Autologous hematopoietic stem cell transplantation in lymphoma patients is associated with a decrease in the double strand break repair capacity of peripheral blood lymphocytes

“…Patients that undergo autologous hematopoietic stem cell transplant (aHCT) for the treatment of a persistent or relapsed/refractory Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) are at high risk of a secondary therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML), which constitutes a fatal complication of aHCT [ 1 – 7 ]. The major risk factors for t-MDS/AML (reviewed in [ 8 ] and [ 9 ]) include the cumulative dose of chemotherapeutic treatment to which individuals were exposed, especially alkylating agents and topoisomerase II inhibitors, as well as the use of high-dose total body irradiation as conditioning regimen for the aHCT [ 5 , 6 , 10 – 15 ].…”

“…Even among aHCT patients, the absolute risk of t-MDS/AML is still fairly low, with a measured incidence extending from 1.0% to 11.7% of patients (reviewed in [ 8 ]). Genetic factors could help explain why some individuals are more susceptible than others.…”