retrospective analysis of 37 287 observation years after peripheral blood stem cell donation

Accepted Manuscript Title: Retrospective Analysis of 37,287 Observation Years after Peripheral Blood Stem Cell Donation Author: Alexander H Schmidt, Thilo Mengling, Camila J HernándezFrederick, Gabi Rall, Julia Pingel, Johannes Schetelig, Gerhard Ehninger PII: DOI: Reference: S1083-8791(17)30302-6 http://dx.doi.org/doi: 10.1016/j.bbmt.2017.02.014 YBBMT 54587 To appear in: Biology of Blood and Marrow Transplantation Received date: Accepted date: 2-12-2016 20-2-2017 Please cite this article as: Alexander H Schmidt, Thilo Mengling, Camila J HernándezFrederick, Gabi Rall, Julia Pingel, Johannes Schetelig, Gerhard Ehninger, Retrospective Analysis of 37,287 Observation Years after Peripheral Blood Stem Cell Donation, Biology of Blood and Marrow Transplantation (2017), http://dx.doi.org/doi: 10.1016/j.bbmt.2017.02.014 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Retrospective analysis of 37,287 observation years after peripheral blood stem cell donation Alexander H Schmidt, MD, PhD1*, Thilo Mengling, MD1*, Camila J Hernández-Frederick PhD1, Gabi Rall1, Julia Pingel, PhD1, Johannes Schetelig, MD, MSc2,3, and Gerhard Ehninger, MD3 DKMS, Tübingen, Germany DKMS, Clinical Trials Unit, Dresden, Germany Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany * AHS and TM contributed equally to this work Short title: Analysis of 37,287 observation years after PBSC Corresponding author: Thilo Mengling DKMS Scheidtweilerstr 63-65 50933 Cologne Germany E-mail: mengling@dkms.de Page of 30 Phone: +49-221-940582-3421 Fax: +49-221-940582-3499 Authors’ contributions AHS, TM, GR, and GE designed the study TM collected data AHS, TM, CJHF, JP, and GE analyzed data All authors contributed to data interpretation AHS prepared the manuscript with support by TM, CJHF, JP, JS and GE All authors revised and approved the manuscript Financial Disclosure Statement The authors report no conflict of interest Keywords: recombinant human granulocyte-colony stimulating factor (rhG-CSF), hematopoietic stem cell donor, follow-up, peripheral blood stem cells, bone marrow Word count: Abstract: 217 words Main text: 3,522 words Number of tables: Number of figures: Supplemental file: Page of 30 Highlights  Retrospective survey of 15,445 individuals who donated peripheral blood stem cells (PBSC) or bone marrow (BM) between 1992 and 2009  Almost 95% of responders assessed their health conditions as very good or good  No differences in the frequency of reported health events between PBSC and BM donors  No evidence that either PBSC or BM donation are associated with increased risks of malignancies Abstract Donor safety is of utmost importance in the setting of hematopoietic stem cell donation Follow-up is indicated to detect potential long-term risks for donors We sent a follow-up questionnaire to 15,445 donors of peripheral blood stem cells (PBSC) or bone marrow (BM) within a retrospective study design The return rate was 91.3% resulting in 37,287 observation years for PBSC donors and 25,656 for BM donors Most donors assessed their health conditions as very good or good, and had not been hospitalized or received long-term medical treatment including prescribed medication for more than weeks since donation While there were no differences in the frequency of reported health events, BM donors more often rated their general health as very good or good Ninety-five percent of donors after BM or PBSC donation respectively would consider a second stem cell donation In total, 93 malignancies were reported The standardized incidence ratio (SIR) for a diagnosis of any type of cancer after PBSC donation was 0.94 (95%-CI, 0.70 - 1.24) with a SIR below indicating a lower risk than in the ageand sex-matched population The SIR for a diagnosis of leukemia was (95%-CI, - 1.88) In summary, we found no evidence that either PBSC or BM donation are associated with increased risks of malignancies or other severe health problems Introduction Allogeneic stem cell donors undergo either bone marrow (BM) harvest in general anesthesia or leukapheresis after mobilization of hematopoietic stem cells with recombinant human granulocyte-colony stimulating factor (rhG-CSF) Although both procedures are regarded as safe,1-6 it is common understanding that there is a need for long-term follow-up of large donor cohorts in order to identify and further minimize potential risks for donors.2, 7-9 Long-term donor follow-up is of special relevance for peripheral blood stem cell (PBSC) donors as concern was raised, based on experimental results10 or clinical data,11 regarding potential correlations between short-term rhG-CSF application and the development of Page of 30 hematological malignancies Increased incidences of very rare events are difficult to prove for methodological reasons.12 From March 1992 to January 2009, 16,270 stem cell donations of 15,531 donors from DKMS Germany had been carried out, thereof 11,540 PBSC and 4,730 BM donations Single-center results of DKMS’ prospective PBSC donor follow-up have been published before.4 A small but statistically significant lower absolute neutrophil count within the normal range was observed after the follow-up period of five years in that study Four hematological malignancies among 12 total cancer diagnoses had been observed: one acute myeloid leukemia (AML) case, one chronic lymphatic leukemia (CLL) case, and two cases of Hodgkin lymphoma Statistically, the incidence of Hodgkin lymphoma differed significantly from the age- and gender-adjusted German population In this work, we present analyses based on a retrospective follow-up project that included the mailing of questionnaires to all DKMS donors who had donated PBSC or BM from March 1992 to January 2009 and telephone-based interviews of initial non-responders In our analyses we especially focused on malignancies, autoimmune disorders, and mental and psychosocial disorders Malignancies were considered due to the discussion regarding potential long-term risks of rhG-CSF application.10, 11 Regarding autoimmune disorders, there is evidence that they may be induced or boosted by rhG-CSF application.13, 14 Positive psychosocial effects of stem cell donation have been described.15 There is, however, also potential for negative emotional stress, for example, in the case of patient death after hematopoietic stem cell transplantation.16 Materials and methods Donations Page of 30 An overview of all donations by donors from DKMS Germany between March 1992 and January 2009 is given in Table Generally, DKMS’ respective policy sets a limit of two PBSC plus two BM donations per donor It follows from Table that nearly all donors donated once (95.3%) or twice (4.6%) The standard mobilization protocol for PBSC donation consisted of daily doses of 7.5 µg/kg lenograstim for 5-6 days In few cases, daily doses of 10 µg/kg filgrastim or single doses of 12 mg PEG-filgrastim17 were applied BM harvest was carried out under general anesthesia Follow-up data Follow-up questionnaires were sent out from December 2008 to February 2009 to all DKMS donors who had donated PBSC or BM between March 1992 and January 2009 Only exceptions were known cases of death (n=20) and donors who previously had asked not to be contacted again or were not contactable for other reasons as, for example, emigration (n=66) In total, 15,445 donors were contacted (Figure 1) The study was approved by the Ethics Committee of the Technical University of Dresden, Germany Donors were asked about general health condition (Question #1, four categories ranging from “very good” to “reduced”), hospitalization or long-term medical treatment since donation (Question #2, “yes” or “no”), use of prescription drugs regularly or for more than weeks since donation (Question #3, “yes” or “no”), and willingness to donate again (Question #4, four categories from “yes” to “no”) Donors with hospitalization or long-term treatment were asked to give comments and to make an assignment to one of 11 categories including, for example, cardiovascular system and malignancies Users of prescribed drugs were asked to list the drugs The questionnaire is included in the Supplementary Information Page of 30 A reminder was sent to all donors who did not answer within ≈50 days We tried to contact initial non-responders (n=2,319) by phone between August 2011 and December 2011 in order to complete the questionnaire PBSC donors who donated between January 1996 and January 2008 at the apheresis center in Dresden are also included in the study by Hölig et al As with any self-report survey, certain limitations to validity are inherent To minimize a potential bias, we focused our analyses either on conditions that are unlikely to be underreported and clarified any ambiguous report, or on subjective self-assessment Question #3 about medication was primarily included to cross-check reported diagnoses Definitions Health disorders that were reported under Question #2 were encoded according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) (Supplementary Information) Malignancies, systemic autoimmune disorders and health conditions leading to permanent exclusion from further stem cell donations were clarified by DKMS physicians If necessary for correct classification and donor consented, medical reports were obtained For example, all reported cases of bladder cancer were evaluated to distinguish between invasive and non-invasive urothelial carcinomas Statistical analyses were carried out for malignancies, autoimmune disorders, and mental and psychosocial disorders Definitions of the three disease groups are given in the Supplementary Information Statistical analyses Page of 30 2 tests were used for univariate significance testing Binary logistic regression analyses were performed with SPSS (version 21.0) (IBM, Armonk, NY, USA) For general answers to Questions #1-4, p values below 0.01 were regarded as significant due to large sample sizes and multiple testing For adverse events a ‘test-wise’ significance level of 5% was chosen Numbers of expected cases for various malignancies in the donor samples (PBSC donors, BM donors, PBSC+BM donors) were calculated based on age- and gender-adjusted malignancy incidences of the German population.18, 19 Standard incidence ratios (SIRs) and corresponding 95% confidence intervals (CI) based on the Poisson distribution were calculated according to Estève et al.20 This approach is based on the assumption that potential increases of malignancy risks after PBSC or BM donation are equally distributed over time Results Return rates In total, 14,094 donors returned the questionnaire in written form or answered questions on the phone including signed or verbal informed consent Return rates were 91.3% (all donors), 91.1% (PBSC donors), 91.5% (BM donors), and 92.4% (donors of both PBSC and BM) The total observation period was 64,933 donor years (37,287 for PBSC donors, 25,656 for BM donors, and 1990 for donors of both PBSC and BM) Characteristics of responding donors are given in Tables and 1,351 (8.7%) donors were non-responders as they did not return the questionnaire, did not give informed consent or declined to participate in the study Page of 30 A comparison between responders (n=14,094) and non-responders (n=1,351) showed a significantly higher number of young (18-40 years) and male donors among the nonresponders (2 tests, p