Long-Term HSC Donor Follow-up: Malignancy Incidences after Donation Are Identical Compared to a Matched Control Sample of Registered Donors, but Different to Expected General Population Rates
Authors: Mengling Thilo , Hernandez Frederick Camila J. , Fandel Daniel , Sauter Jürgen , Schetelig Johannes , Schmidt Alexander H. , Ehninger Gerhard 
Published: October 2019

Abstract
Introduction:
HSC donation is an established procedure with few, manageable short term side effects. As donation is, especially for unrelated volunteer donors, an entirely altruistic act with no direct health benefits, careful and systematic long-term follow-up is crucial. However, interpretation of follow-up data requires a suitable control group. Here, we report first results from a matched pair donor follow-up study. Since 2009, DKMS has extended the routine questionnaire-based donor follow-up to a control group of registered potential stem cell donors who had not actually donated at that time. Donors in the control group (CG) were matched for age, sex and, if possible, HLA to stem cell donors. Eligibility for controls was evaluated using the standard health questionnaire from confirmatory typing stage. After study recruitment, controls were sent identical follow-up questionnaires in the same intervals as real donors. As of July 1st, 2015, our data set for analysis extended to 170,484 questionnaires (58,306 from 21,633 unrelated donors (URD), and 112,178 from 65,543 controls (CG)). Of the URD, 17,472 have donated peripheral blood stem cells (PBSC), 3,735 bone marrow and 145 are donors of both, marrow and PBSC. For statistical reasons, 281 donors requested for donation but deferred at medical pre-examination are included in the donor group.
Results:
A total of 157 malignancies (excluding ICD-10 C44 neoplasms of skin other than malignant melanoma) have been reported (URD 63, CG 94). In multivariate analysis, significantly more malignancies were observed in females (p <0.001; OR 2.07, 95% CI 1.55 - 2.78), and with increasing age. No difference in the overall malignancy incidence was seen between the URD and control group. In both groups, incidences were significantly lower than the expected rates based on the standard incidences in the German population (standard incidence ratio (SIR) 0.64, 95% CI 0.54 - 0.74). SIR analysis for single ICD malignancy groups revealed significant or close to significant scarcity of reported neoplasms of the lung, oral cavity and colon, all known to correlate with certain health-related behavior (smoking, misuse of alcohol, diet).
Due to the administration of GCSF to healthy volunteers for PBSC donation, any hematological malignancies in this group are of particular interest. In the URD group, 1 single case of leukemia (AML) and 2 cases of lymphoma (2 Hodgkin's lymphoma, 1 cutaneous T-cell lymphoma) have been reported from PBSC donors. Because eligibility for the control group was assessed by a confirmatory typing (CT) stage health questionnaire without physical examination, we have included potential donors who where originally cleared at CT stage but deferred during work-up process for medical reasons as part of the URD group for enhanced comparability ('intention to donate'). One case of multiple myeloma was seen in this subgroup (reason for deferral: monoclonal gammopathy). No cases were reported from donors who had donated via bone marrow extraction. In the control group, a total of 8 hematological malignancies were reported (2 Hodgkin's lymphoma, 4 NHL, 1 multiple myeloma, 1 Langerhans cell histiocytosis). No increased incidences of hematological malignancies were observed in either the URD or control group.
Discussion:
For evaluation of long-term HSC donor follow-up, the applicability of general population data for comparison must be discussed critically. Our data suggest that registered donors as a group are distinct from the general population regarding health-related behavior and attitude or disease susceptibility. Malignancy incidences lower than expected from epidemiological data can most likely be explained by selection effects. People willing to donate stem cells likely represent a healthy sample of the general population. While incomplete reporting cannot be ruled out, it should have affected both URD and CG in the same way. Thus, our approach to include registered potential donors as a control sample is a viable and thorough approach to identify (late) health hazards, further increasing safety and confidence for volunteer stem cell donors. Even more, our study will allow to evaluate donor follow-up data where epidemiological data is insufficient or not applicable, e.g. for autoimmune diseases or general well-being.

Disclosures
No relevant conflicts of interest to declare.