Subsequent Malignant Neoplasms after Hematopoietic Cell Transplantation

Abstract

Subsequent malignant neoplasms (SMNs) developing after hematopoietic cell transplantation (HCT) are a well-described complication (1–6). The magnitude of risk of SMNs after HCT ranges from 4-fold to 11-fold that of the general population. The estimated actuarial incidence is reported to be 3.5% at 10 years, increasing to 12.8% at 15 years among recipients of allogeneic HCT. The differing clinicopathologic characteristics of SMNs preclude assessment of risk factors in aggregate. It has become conventional practice to classify SMNs into three distinct groups (7): (i) myelodysplasia (t-MDS)/acute myeloid leukemia (t-AML); (ii) lymphoma, including lymphoproliferative disorders; and (iii) solid tumors. While t-MDS/AML and lymphoma develop relatively early in the post-transplantation period, secondary solid tumors have a longer latency. The magnitude of risk and associated risk factors for the development of SMNs are summarized in Table 1, and detailed in the sections below. Table 1 Magnitude of Risk and Populations at Increased Risk of Subsequent Malignant Neoplasms after Hematopoietic cell Transplantation Magnitude of Risk of Subsequent Malignant Neoplasm Therapy-related myelodysplasia/ acute myeloid leukemia The cumulative probability of developing t-MDS/t-AML ranges from 1.1% to 24.3% at 20 to 43 months after autologous HCT. In patients treated with alkylating agents, t-MDS/t-AML usually appears 4 to 7 years after exposure. The majority of patients present with multilineage dysplasia and peripheral cytopenias. There is a high prevalence of abnormalities involving chromosomes 5 (−5/del[5q]) and 7 (−7/del[7q]). AML secondary to topoisomerase II inhibitors presents as overt leukemia. The latency ranges from 6 months to 5 years, and is associated with balanced translocations involving chromosome bands 11q23 or 21q22. The common and nonspecific nature of cytopenias after autologous HCT has necessitated the creation of criteria for diagnosing t-MDS/t-AML after HCT. These include (i) significant marrow dysplasia in at least two cell lines, (ii) peripheral cytopenias without alternative explanations, and (iii) blasts in the marrow defined by French-American-British classification (8). Because many patients may not have an increase in blasts, presence of a clonal cytogenetic abnormality in addition to morphologic criteria of dysplasia may aid in making this diagnosis. An increased risk of t-MDS/t-AML is associated with older age at HCT (1), pretransplantation therapy with alkylating agents, topoisomerase II inhibitors, and radiation therapy (3), use of peripheral blood hematopoietic cells, stem cell mobilization with etoposide, difficult stem cell harvests, conditioning with TBI, number of CD34+ cells infused, and a history of multiple transplants (1, 3, 9–11). The diagnosis of t-MDS/t-AML after autologous HCT confers a poor prognosis, with a median survival of 6 months in patients treated with conventional chemotherapy. In fact, t-MDS/t-AML is a major cause of nonrelapse mortality in patients undergoing autologous HCT (3, 12). Allogeneic HCT has been attempted with actuarial survival ranging from 0% to 24% at 3 years (13). Among t-MDS/t-AML patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor (14). Treatment-related mortality (TRM) and relapse were reported to be 41% and 27% at 1 year and 48% and 31% at 5 years, respectively in large cohort of patients undergoing allogeneic HCT (15). Disease-free (DFS) and overall survival (OS) were 32% and 37% at 1 year and 21% and 22% at 5 years, respectively. Age older than 35 years; poor-risk cytogenetics; t-AML not in remission or advanced t-MDS; and donor other than an HLA-identical sibling or a partially or well-matched unrelated donor had adverse impacts on DFS and OS. Because the poor outcomes of allogeneic transplant for t-MDS/t-AML are related in part to the high risk of TRM, it is important to evaluate the role of reduced intensity conditioning approaches in this setting. Preliminary reports suggest that allogeneic HCT using reduced-intensity conditioning is feasible and may result in improved outcomes.