Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation – Follow up
Authors: Heilmeier Bernhard , Stowasser Nadine , Socie Gerard , van Lint Maria Teresa , Tichelli Andre , Salooja Nina , Nekolla Elke , Ljungman Per T. , Jacobsen Niels , van Weel Marie , Tischer Johanna , Ledderose Georg , Fliedner Theodor M. , Kolb Hans-Jochem 
Published: April 2020

Abstract
Patients who receive allogeneic hematopoietic stem cell transplants have an increased risk for new malignancies because of several risk factors, including conditioning with radiation and chemotherapy, immune modulation, and malignant primary disease. The frequency of and risk factors for malignant neoplasm in long-term survivors should be assessed. A former analysis of the EBMT observing the 1036 patients of this study with a median observation time of 10.7 years showed older patient age and immunosuppressive treatment of chronic graft-versus-host disease as main risk factors for secondary malignancies. We have tried to determine the cumulative incidence and define potential risk factors for new malignancies in long-term survivors after marrow transplantation in a retrospective multi center follow-up study. This study of the Late Effects Working Party was performed with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Patients were transplanted before December 1985 and had survived more than 5 years. Reports on malignant neoplasms were evaluated, and the cumulative incidence was compared to that in the matched general population. Patient age and sex, primary disease and disease stage at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. Univariate analysis was performed using the log rank test for the time until malignancy occurred; significant risk factors were studied in multivariate analysis (Cox regression). Median follow-up since transplantation was 17.9 years (range, 5 to 32.3 years). Malignant neoplasms were seen in 114 patients; the cumulative incidence was 4.0% at 10 years, 8.5% at 15 years, 14.0% at 20 years and 21.0% at 25 years. The rate of new malignant disease was 6-fold higher than that in an age-matched control population (P &lt;0.001). The most frequent malignant diseases were neoplasms of the skin (23 patients), breast (16 patients), thyroid gland (13 patients), oral cavity (12 patients), uterus including cervix (7 patients), and glial tissue (3 patients). Median ages of patients and their donors at the time of transplantation were 21 years for both groups (range 0.5 – 52 years). Follow up data were avaible in 636 patients, 100 patients were deceased at the time of prior analysis, 300 patients were lost to follow up. Compared with the analysis of the same cohort of patients 10 years ago, the most striking increase in secondary malignancies was seen in breast cancer (4-fold), thyroid cancer (3-fold) and neoplasms of the skin and oral cavity (2-fold). In multivariate analysis patient age above 30 years (hazard ratio 1.8, 95% CI 1.2 – 2.6; p=0.006), radiotherapy for conditioning (hr 2.3, CI 1.2 – 4.3; p=0.01) and immunosuppression (hr 1.5, CI 1.0 – 2.2; p=0.05) (in particular cyclosporine or methotrexate) were risk factors for new malignancies after hematopoietic stem cell transplantation. In conclusion longer followup shows the continuous increase of the cumulative incidence of secondary neoplasms in long-term survivors. With longer follow-up a shift in the risk factors occurs: Until 10–15 years after allogeneic transplantation immunosuppression is the major risk factor for new malignancies, whereas more than 15 years after transplantation radiotherapy becomes the dominant risk factor.