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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
1
DKMS, Tübingen, Germany
2
DKMS, Clinical Trials Unit, Dresden, Germany
3
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: [email protected] 1 Page 1 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: 6 Number of figures: 1 Supplemental file: 1
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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 4 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 1 indicating a lower risk than in the ageand sex-matched population. The SIR for a diagnosis of leukemia was 0 (95%-CI, 0 - 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 3 Page 3 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
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An overview of all donations by donors from DKMS Germany between March 1992 and January 2009 is given in Table 1. Generally, DKMS’ respective policy sets a limit of two PBSC plus two BM donations per donor. It follows from Table 1 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 4 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.
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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. 4
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
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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 2 and 3.
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.
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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<0.001).
In order to check for a potential bias caused by donors who died in the interval between donation and the mailing of the questionnaire, we analyzed a sample of 140 non-responding donors. 36 of these donors were in contact with DKMS for various reasons after the questionnaire had been sent out, 43 could be reached by phone, and for the remaining 61 donors registration office inquiries provided no evidence that they were not alive. Taken together, there was no evidence for a considerable bias due to donor deaths between donation and the mailing of the questionnaire.
General results – univariate analysis
Answers provided by study donors are shown in Table 3. Most donors assessed their health conditions as very good or good (94.9%), had not been hospitalized or received long-term medical treatment since donation (82.4%), and neither used prescription drugs regularly nor had used them for more than four weeks since donation (77.7%). Moreover, the majority of donors (95.0%) would be willing (“yes” or “probably yes”) to donate again if asked to do so.
PBSC and BM donors showed no significant differences regarding their general health conditions (Question #1, 2 test, p=0.06). For this analysis, pre-defined answers were combined (very good/good vs. moderate/reduced).
Contrary to Question #1 that asked for subjective assessments, Questions #2 (hospitalization or long-term treatment) and #3 (prescription drugs) focused on specific indications for health-related problems. For these questions, answers of PBSC and BM
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donors differed significantly (2 tests, p<0.001), with less PBSC donors reporting healthrelated problems. Answers to Questions #2 and #3 also differed significantly between male and female donors, between younger (18-40 years) and older (≥41 years) donors, and between donors with more (<5 years) and less (>5 years) recent donations (2 tests, p<0.001). Male donors, younger donors and donors with more recent donations less often reported health-related problems. The PBSC sample included significantly more male, younger (18-40 years) and more recent (<5 years) donors than the BM group (2 tests, p<0.001). The strong effect of time since donation may result from the fact that Questions #2 and #3 refer to incidents in the interval since donation.
Willingness to donate again (Question #4) did not differ significantly between PBSC and BM donors (2 test, p=0.30). PBSC+BM donors were significantly less often willing to donate again (2 tests, p<0.001). However, the fact that 89.8% of these donors who already donated at least twice were willing to donate again is remarkable. Similar to the analysis of Question #1, pre-defined answers were combined for analysis (yes/probably yes vs. probably not/no).
General results – multivariate analysis
In multivariate regression analysis, there were no significant differences between PBSC, BM and PBSC+BM donors with respect to Questions #2-4 (Table 4). Expectedly, odds ratios (OR) for Questions #2 and #3 essentially show a continuous increase of reported healthrelated problems with increasing donor age and increasing observation periods. In spite of similar frequencies of reported health-related problems in PBSC and BM donors, BM donors assessed their general health condition significantly more often as very good or good than PBSC donors (OR=1.58, p<0.001). This finding is even more apparent when the subset of donors is analyzed that did not report a specific health issue or medication. In this group, PBSC donors reported a ‘moderate’ or ‘reduced’ health status with an OR of 2.94 (p<0.001)
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compared to BM donors. Females assessed their health less often as very good/good (OR=1.55, p=0.009). Time since donation had no impact on self-assessment.
Malignancies
93 malignancies were reported by 90 donors within the study, thereof 56 malignancies of 53 PBSC donors, 33 of BM donors, and four of donors of both PBSC and BM (Supplementary Table S1 includes a complete list of cases). Six hematological malignancies were reported: two cases of Hodgkin lymphoma (both in PBSC donors), plasmocytoma (PBSC donor), AML (BM donor), Non-Hodgkin lymphoma (BM donor), and CLL (donor of both PBSC and BM).
There was no significant difference between PBSC and BM donors in multivariate analysis (OR=1.08, 95% CI: [0.64, 1.80]). However, we observed a significant difference between female donors and male donors (OR=1.64, 95% CI: [1.07, 2.52]). Higher donor age also was a significant risk factor for the occurrence of malignancies.
Table 6 shows observed and expected numbers for various malignancies and resulting SIR values with 95% CI. We obtained significantly increased SIR values (lower bound of 95% CI >1) for 2 combinations of diseases or disease groups and donation methods: CLL in BM+PBSC donors (one case observed, 0.02 expected, SIR=51.44, 95% CI: [1.54, 286.51]) and malignant neoplasms of unspecified female genital organs in PBSC donors (one case observed, 0.02 expected, SIR=41.13, 95% CI: [1.23, 229.09]).
A trend to a lower rate of malignancies compared to the age- and gender-adjusted malignancy incidences of the German population was found for all donors (SIR 0.84, 95%CI: [0.68 – 1.03]). The SIR of a cancer diagnosis was lower than expected (SIR 0.7, 95%-CI: [0.48 – 0.99]) for BM donors but not for PBSC donors (SIR 0.94, 95%-CI: [0.70 – 1.24]). Also, no increased risk was observed for the diagnosis of leukemia (ICD-10: C91-C95) after 10 Page 10 of 30
PBSC donation (no case observed, 1.60 cases expected, SIR=0.00, 95% CI: [0.00, 1.88]). As indicated by the 95% confidence interval an increase in the risk of leukemia after PBSC donation by more than 1.88 times can be excluded with a 2.5% error probability based on this analysis. With the same argument, a twofold or higher increase of the risk for NonHodgkin lymphoma (ICD-10: C82-C85; no case observed, 2.17 cases expected, SIR=0.00, 95% CI: [0.00, 1.38]), a seven-fold or stronger increase of the risk for Hodgkin lymphoma (ICD-10: C81; two cases observed, 1.07 cases expected, SIR=1.87, 95% CI: [0.22, 6.74]), and a 14-fold or stronger increase of the risk for plasmocytoma (ICD-10: C90; one case observed, 0.41 cases expected, SIR=2.45, 95% CI: [0.07, 13.65]) can be rejected for PBSC donors at the same significance level all under the assumption that additional malignancy cases were evenly distributed over time.
SIRs with an upper bound of the 95% CI below 1 were observed for 6 combinations of malignancies and donation methods: malignant neoplasms of the skin other than melanoma in all donors (7 cases observed, 19.13 expected, SIR=0.37, 95% CI: [0.15, 0.75]) and in BM donors (one case observed, 8.51 expected, SIR=0.12, 95% CI: [0.00, 0.65]), lung cancer in all donors (one case observed, 7.39 expected, SIR=0.14, 95% CI: [0.00, 0.75]) and in BM donors (no case observed, 3.38 expected, SIR=0.00, 95% CI: [0.00, 0.89]), malignant neoplasms of lips, oral cavity and pharynx in all donors (no case observed, 5.03 expected, SIR=0.00, 95% CI: [0.00, 0.60]), and all malignancies excluding malignant neoplasms of the skin other than melanoma in BM donors (32 cases observed, 45.41 expected, SIR=0.70, 95% CI: [0.48, 0.99]).
Autoimmune disorders
106 autoimmune disorders were reported by 102 donors (Supplementary Table S2). PBSC donors reported significantly less often autoimmune disorders than BM donors (OR=0.60,
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95% CI: [0.39, 0.94]). Besides, autoimmune disorders were reported significantly more often by female compared to male donors (OR=1.78, 95% CI: [1.19, 2.64]).
Mental and psychosocial disorders
371 donors reported mental or psychosocial disorders (Supplementary Table S2) or the use of psychiatric medication. There were no significant differences between PBSC and BM donors (OR=1.03, 95% CI: [0.81, 1.33]). Female donors significantly more often reported mental or psychosocial disorders or the use of psychiatric medication (OR=2.27, 95% CI: [1.84, 2.79]). A negative effect of multiple donations could not be observed (OR=1.01, 95% CI: [0.55, 1.87]).
Discussion
In this work, we present results of a retrospective follow-up study based on an easy-tocomplete questionnaire that was mailed to 15,445 individuals who had previously donated PBSC or BM. Most donors reported very good or good general health conditions and would donate again if asked to do so.
In multivariate analysis, no significant differences regarding health-related problems between PBSC and BM donors could be observed. The use of prescription drugs was less often reported by PBSC donors but significance was not reached. Differences between PBSC and BM donors with respect to health-related problems could be explained by differences in eligibility criteria for PBSC and BM donation. For example, donors with autoimmune disorders such as autoimmune hypothyroidism, vitiligo or alopecia areata were excluded from PBSC but not from BM donation, donors with spine affections from BM, but might be allowed for PBSC. 12 Page 12 of 30
Though they did not report health-related problems significantly less often than PBSC donors, BM donors assessed their general health conditions significantly more often as very good or good. The even more pronounced correlation of worse health assessment with PBSC donation in the subset of donors who did not report any specific health issue or medication indicates that different non-eligibility criteria cannot explain this result, as most of these pre-existing conditions would have been replied to questions # 2 and 3. In this context, it may be relevant that the final choice about the donation method is made by the donor. We know from donor center practice that about 10% of the potential donors consent only to one of the procedures with a clear majority of these donors preferring PBSC donation. Therefore, both donor groups may differ systematically with respect to health-related attitudes. Such differences could potentially cause varying subjective assessments of the general health status without detectable differences regarding indications for health-related problems. However, the reason for the worse subjective assessment of the health condition by PBSC donors remains obscure.21 More research is needed in order to delineate the underlying cause.
One donor safety issue lies in the question if short-term application of rhG-CSF may lead to an increased risk to develop hematological malignancies.5-8,
10
We observed no significant
deviations from expected incidences for hematological malignancies of PBSC or BM donors in our study. This holds also for Hodgkin lymphoma for which a significant increase was observed before.4 This increase was based on two cases that are also included in our analysis. As the observation period of PBSC donors has increased from 8,234 to 37,287 donor years without additional cases of Hodgkin lymphoma, significance has been lost. Given the upper limit of the 95% confidence interval for the SIR for leukemia after PBSC donation of 1.88, an increase above factor two is highly unlikely based on this analysis.
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The two significantly increased SIR values (Table 5) – CLL in PBSC+BM donors and malignant neoplasms of unspecified female genital organs in PBSC donors – were induced by one observed case and are, therefore, hardly interpretable.
A significant decrease was observed for incidences of lung cancer, malignant neoplasms of lip, oral cavity and pharynx, and malignant neoplasms of the skin other than melanoma. A correlation between malignancy development and a lack of health-conscious behavior (smoking, misuse of alcohol) is well-known for lung cancer and malignant neoplasms of lips, oral cavity and pharynx. One might, therefore, hypothesize that stem cell donors show more often health-conscious behavior than the general population.
Most malignancy incidences that were determined in our study lie within ranges that would be expected from epidemiological data of the German population.18 Theoretically, this result could be a combined effect of increased malignancy risks through stem cell donation and underreporting of occurring malignancies. However, increased malignancy risks after BM donation have not been discussed in the literature and do not seem to be plausible. The same holds for correlations of many non-hematological malignant diseases with PBSC donation. Therefore, we conclude that the SIRs obtained in our study are not heavily affected by underreporting.
In our study, PBSC donors reported significantly less often autoimmune disorders than BM donors. It does not seem plausible that the incidence or severity of autoimmune disorders are increased by BM donation or reduced by PBSC donation. Therefore, this result most probably reflects the stricter eligibility criteria regarding some autoimmune disorders – as, for example, autoimmune thyroiditis – for PBSC donors.
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The retrospective approach of our study that resembles the telephone-based study by Anderlini and colleagues22 has specific advantages and disadvantages compared to common prospective donor follow-up programs4, 23-25.
Prospective donor follow-up is essential due to the possibilities to obtain detailed donor information including results of blood analysis and/or physical examination and to collect longitudinal data. The major problem of prospective donor follow-up lies in a decrease of response rates over time. As a consequence, long-term response rates are relatively low as, for example, 42.5% at five years after donation in the study by Hölig and colleagues4. Donor drop-out can be explained by low motivation of healthy donors to be followed-up for several years.
We intended, therefore, to obtain high response rates with a short one-time questionnaire that focused on few meaningful indicators of donor health status. This goal could be reached as the return rate of 91.3% in a donor group with a median (average) time since donation of 3.8 (4.6) years demonstrates. Though the quality of the retrospective data collected in this study should be lower than that of prospective follow-up data, especially with respect to the time of occurrence of specific health problems, we think it is sufficient to identify major health disorders. The SIRs we obtained for malignant diseases support this conclusion.
We conclude that retrospective studies like the one presented in this work are not suited to replace common prospective follow-up programs but can be valuable complements to such programs. Especially the collection of additional data of donors who donated several years ago and have already dropped out of the prospective follow-up may be helpful.
Several issues make the interpretation of minor outcome differences between stem cell donors and the general population difficult: First, donors should be healthier than an age-
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and gender-adjusted sample of the general population due to medical clearing before donation. Second, individuals who register as stem cells donors may be more healthconscious than the general population or may show specific characteristics that correlate with disease susceptibilities. Third, each stem cell donor is – at least nearly – HLA-identical to an individual suffering from a severe disease of the blood or immune system. To account for these differences between registered donors and the general population, it is desirable to include HLA-matched registered donors who did not donate into follow-up programs.
Summarized, we found no indication suggesting that PBSC or BM donation might be unsafe procedures. Especially, we found no evidence for increased hematological malignancy risks after PBSC donation. Beyond this, we can exclude a twofold or stronger increase of the risk to develop leukemia as late effect of PBSC donation with a high likelihood under the assumption that an increased leukemia risk would be equally distributed over time.
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Donation until January 31, 2009 (n = 15,531)
Excluded (n = 86) • Cases of death (n = 20) • Unwilling to be contacted again or not contactable (e.g., due to emigration) (n = 66)
Contacted (n = 15,445)
PBSC donors (n = 10,830)
BM donors (n = 4,285)
Analyzed (n = 3,919 )
No questionnaire or no informed consent (n = 25)
No questionnaire or no informed consent (n = 366)
No questionnaire or no informed consent (n = 960)
Analyzed (n = 9,870 )
PBSC+BM donors (n = 330)
Analyzed (n = 305 )
Figure 1: Description of the study population. The study population included 15,531 donors from DKMS Germany who donated peripheral blood stem cells (PBSC), bone marrow (BM) or both (PBSC+BM) until January 2009. In total 15,445 donors were contacted of which 14,094 gave informed consent and responded the follow-up questionnaire (9,870 PBSC donors, 3,919 BM donors and 305 PBSC+BM donors respectively). 21 Page 21 of 30
Table 1: Number of peripheral blood stem cell (PBSC) and bone marrow (BM) donors from DKMS Germany between March 1992 and January 2009.
PBSC donors 1 donation 2 donations BM donors 1 donation 2 donations PBSC+BM donors 1 PBSC + 1 BM 2 PBSC + 1 BM 1 PBSC + 2 BM Total donors
Absolute number 10,863 10,522 341 4,337 4,279 58 331 322 5 4 15,531
Table 2: Characteristics of donors who responded to the questionnaire (n=14,094). For donors who donated more than once, values for “age at donation” and “time since donation” refer to the first donation. NA: not applicable.
Donors, n (%) Age at survey (years) median range interquartile range Age at donation (years) median range Interquartile range Time since donation (months) median range Interquartile range Donor sex Female, n (%) Male, n (%) Number of donations 1 donation, n (%) 2 donations, n (%) 1 PBSC + 1 BM 2 PBSC + 1 BM 1 PBSC + 2 BM
PBSC 9,870 (70.0)
BM 3,919 (27.8)
PBSC+BM 305 (2.2)
38.5 18.7 - 67.8 30.7 - 44.5
40.6 19.1 - 69.9 33.7 - 46.5
41.4 20.5 - 64.5 35.7 - 46.4
34.1 18.3 - 60.9 27.2 - 40.3
33.2 18.5 - 60.7 27.3 - 39.3
34.8 19.0 - 58.5 28.5 - 39.8
39 1 - 176 17 - 67
71 1 - 229 31 - 124
77 4 - 181 39 - 113
2,813 (28.5) 7,057 (71.5)
1,363 (34.8) 2,556 (65.2)
101 (33.1) 204 (66.9)
9,549 (96.7) 321 (3.3) NA NA NA
3,864 (98.6) 55 (1.4) NA NA NA
NA NA 296 (97.0) 5 (1.6) 4 (1.3)
22 Page 22 of 30
Table 3: Additional characteristics of donors who responded to the questionnaire and overview on answers to Questions #1 to #4. Number of donors Q #1: Health condition who responded to Number of replies for categories the questionnaire (%) “very good” or “good” (%)
Q #2: Hospitalization or long-term treatment Number of replies for category “No” (%)
Q #3: Use of prescription drugs Number of replies for category “No” (%)
Q #4: Willing to donate again Number of replies for categories “yes” or “probably yes” (%)
Type of donation PBSC
9870 (70.0)
9,310 (94.7)
8,291 (84.2)
7,779 (79.5)
9,301 (95.0)
BM
3919 (27.8)
3,721 (95.5)
3,061 (78.2)
2,877 (73.6)
3,719 (95.4)
PBSC+BM
305 (2.2)
277 (92.6)
238 (78.5)
226 (74.8)
273 (89.8)
1
13413 (95.2)
12,677 (94.9)
11,056 (82.6)
10,364 (77.8)
12,684 (95.2)
>1
681 (4.8)
631 (93.6)
534 (78.8)
518 (76.9)
609 (90.4)
Female
4277 (30.3)
4,006 (94.2)
3,356 (78.6)
2,975 (70.0)
3,966 (93.3)
Male
9817 (69.7)
9,302 (95.2)
8,234 (84.1)
7,907 (81.1)
9,327 (95.7)
18-25
1486 (10.5)
1,439 (97.1)
1,349 (90.9)
1,310 (88.9)
1,436 (97.0)
26-30
1809 (12.8)
1,742 (96.8)
1,602 (88.9)
1,543 (86.0)
1,702 (95.4)
31-35
2129 (15.1)
2,062 (97.0)
1,839 (86.5)
1,787 (84.5)
2,023 (95.6)
36-40
2729 (19.4)
2,593 (95.5)
2,269 (83.4)
2,184 (80.6)
2,562 (94.5)
41-45
2899 (20.6)
2,715 (93.9)
2,311 (79.8)
2,184 (75.8)
2,720 (94.3)
46-50
1781 (12.6)
1,628 (92.3)
1,353 (76.3)
1,183 (66.8)
1,683 (94.9)
51-55
751 (5.3)
674 (90.3)
540 (72.0)
453 (60.6)
705 (94.4)
56-60
357 (2.5)
319 (90.1)
241 (67.5)
173 (48.7)
326 (93.1)
61-65
123 (1.0)
108 (88.5)
73 (59.3)
47 (38.2)
111 (91.7)
≥66
30 (0.2)
28 (93.3)
13 (44.8)
18 (60.0)
25 (92.6)
2198 (15.6)
2,120 (96.8)
2,041 (93.0)
1,863 (85.0)
2,097 (95.8)
Number of donations
Donor sex
Donor age at survey (years)
Time since donation (years) <1*
23 Page 23 of 30
1-5*
6655 (47.2)
6,330 (95.5)
5,719 (86.2)
5,323 (80.6)
6,269 (94.9)
5-10*
3880 (27.5)
3,617 (93.6)
2,934 (75.8)
2,808 (73.0)
3,658 (95.0)
>10*
1361 (9.7)
1,241 (92.2)
896 (66.0)
888 (65.5)
1,269 (94.1)
Total
14094 (100.0)
13,308 (94.9)
11,590 (82.4)
10,882 (77.7)
13,293 (95.0)
*: Values refer to first donations.
24 Page 24 of 30
Table 4: Results of multivariate logistic regression analyses of follow-up data. Q #1: Health condition reported moderate or reduced Q2 and Q3 answered with No
Q #1: Health condition reported moderate or reduced p value Type of donation
OR (99% CI)
†
<0.001 BM
p value
OR (99% CI)
†
<0.001
<0.001
BM+PBSC
0.074
1.58 (1.21-2.05) 1.80 (0.77-4.19)
p value
1 <0.001 0.058
OR (99% CI)
†
0.777
1
PBSC
Q #2: Hospitalization or long-term treatment needed during follow-up
2.94 (1.50-5.76) 4.63 (0.58-36.98)
Q #3: Prescription drugs needed during follow up
p value
0.528
†
0.216 1
0.776
OR (99% CI)
0.98 (0.86-1.13) 1.13 (0.69-1.86)
Q #4: Not willing to donate again
p value
OR (99% CI)
†
0.238 1
0.087 0.646
0.92 (0.80-1.05) 0.92 (0.56-1.49)
1 0.094 0.456
1.18 (0.92-1.52) 1.23 (0.61-2.49)
Number of donations 1 >1
1 0.775
0.94 (0.52-1.70)
1 0.342
0.57 (0.13-2.61)
1 0.522
1.09 (0.77-1.53)
1 0.419
0.89 (0.64-1.26)
1 <0.001
1.95 (1.21-3.15)
Donor sex Male
1.00
Female
0.012
Donor age at survey (years)
<0.001
18-25 26-30
0.897
31-35
0.648
36-40
0.085
41-45
0.001
46-50
<0.001
51-55
<0.001
56-60
<0.001
61-65
<0.001
≥66
0.468
Time since donation (years)
1.23 (0.99-1.52)
0.009
1.55 (1.01-2.39)
0.005
0.033
5-10*
<0.001
>10*
<0.001
<0.001
1.48 (1.26-1.61)
<0.001
1.00 <0.001
1.92 (1.71-2.15)
<0.001
1.00 <0.001
1.64 (1.34-2.02)
0.006
1
1
1
1
1
0.78 (0.32-1.85) 0.76 (0.32-1.80) 1.04 (0.47-2.29) 1.49 (0.70-3.17) 2.05 (0.92-4.58) 1.73 (0.58-5.12) 0.54 (0.04-7.83) 4.19 (0.56-31.39) 7.86 (0.47-131.61)
1.57 (0.53-4.64) 1.84 (0.67-5.06) 2.18 (0.78-5.72) 2.47 (0.93-6.60) 2.82 (1.06-7.50) 3.54 (1.33-9.44) 4.18 (1.56-11.22) 4.41 (1.63-11.92) 4.62 (1.69-12.62)
0.36 (0.12-1.07) 0.51 (0.19-1.41) 0.79 (0.29-2.13) 1.00 (0.37-2.68) 1.53 (0.57-4.07) 2.02 (0.75-5.39) 2.65 (0.98-7.12) 2.91 (1.07-7.86) 3.64 (1.34- 9.94)
1.54 (0.94-2.51) 1.53 (0.94-2.47) 1.94 (1.23-3.07) 2.10 (1.27-3.17) 1.79 (1.09-2.94) 1.95 (1.09-3.50) 2.38 (1.20-4.74) 2.89 (1.10-7.58) 2.64 (0.38-18.56)
0.451 0.408 0.909 0.172 0.022 0.194 0.556 0.067 0.059 0.602
1.34 (0.94-1.90) 1.66 (1.15-2.40) 2.19 (1.38-3.46)
0.281 0.123 0.052 0.017 0.006 0.001 <0.001 <0.001 <0.001 <0.001
1
1-5*
1.00
1.03 (0.60-1.75) 0.91 (0.54-1.54) 1.38 (0.85-2.22) 1.87 (1.18-2.96) 2.33 (1.44-3.77) 2.94 (1.72-5.00) 2.96 (1.58-5.54) 3.35 (1.42-7.91) 1.73 (0.25-12.06)
<0.001
<1*
1.00
1 0.755 0.589 0.465
1.07 (0.61-1.89) 0.87 (0.44-1.71) 1.33 (0.49-3.61)
0.016 0.088 0.539 1.000 0.268 0.066 0.011 0.006 0.001 <0.001
1 <0.001 <0.001 <0.001
1.39 (1.14-1.69) 2.39 (1.95-2.93) 4.89 (3.66-6.53)
0.024 0.025 <0.001 <0.001 0.003 0.003 0.001 0.005 0.201 0.530
1 0.480 0.005 <0.001
1.06 (0.87-1.28) 1.24 (1.02-1.52) 1.56 (1.22-1.99)
1 0.415 0.846 0.558
1.10 (0.81-1.51) 0.97 (0.69-1.38) 1.11 (0.70-1.75)
*: Values refer to first donations. †
: Odds ratio (OR) and 99% confidence interval (CI)
25 Page 25 of 30
Table 5: Number of donors that reported incidences of specific health disorders based on answers to Question #2 (and Question #3 for mental or psychosocial disorders) and results of multivariate logistic regression analyses of the responses. p values < 0.05 are regarded as significant. Malignancies Number of donors that reported incidences
(%)
Type of donation
p value
OR (95% CI)*
0.871 BM
33
(0.8)
PBSC
53
(0.5)
0.775
BM+PBSC
4
(1.3)
0.677
1
83
(0.6)
>1
7
(1.0)
Male
51
(0.5)
Female
39
(0.9)
18-25
1
(0.1)
26-30
4
(0.2)
0.090
31-35
3
(0.1)
0.016
36-40
13
(0.5)
0.003
41-45
18
(0.6)
<0.001
46-50
19
(1.1)
<0.001
51-55
14
(1.9)
<0.001
56-60
9
(2.5)
<0.001
61-65
5
(4.1)
<0.001
≥66
4
(13.3)
<0.001
1 1.08 (0.64-1.80) 0.72 (0.16-3.32)
Autoimmune disorders Number of donors with (%) p value OR (95% CI)* reported incidences 0.036 49 (1.3) 1 0.60 49 (0.5) 0.025 (0.39-0.94) 0.21 4 (1.3) 0.166 (0.02-1.91)
Mental or psychosocial disorders Number of donors with (%) p value OR (95% CI)* reported incidences 0.914 122 (3.1) 1 1.03 237 (2.4) 0.791 (0.81-1.33) 0.87 12 (3.9) 0.754 (0.38-2.03)
Number of donations 0.883
1 1.09 (0.34-3.53)
97
(0.7)
1 0.34 (0.05-2.46)
348
(2.6)
5
(0.7)
23
(3.4)
1 1.64 (1.07-2.52)
56
(0.6)
1 1.78 (1.19-2.64)
190
(1.9)
46
(1.1)
181
(4.2)
1 3.32 (0.83-13.30) 4.68 (1.33-16.43) 5.93 (1.79-19.59) 9.80 (3.05-31.53) 15.92 (4.89-51.84) 20.43 (6.06-68.84) 65.11 (13.44-315.37) 35.55 (7.95-158.94) 93.78 (9.58-917.90)
3
(0.2)
1
21
(1.4)
10
(0.6)
0.998
-
23
(1.3)
0.911
8
(0.4)
0.998
-
47
(2.2)
0.558
23
(0.8)
0.998
-
73
(2.7)
0.599
20
(0.7)
0.998
-
90
(3.1)
0.564
25
(1.4)
0.998
-
67
(3.8)
0.659
6
(0.8)
0.998
-
29
(3.9)
0.758
5
(1.4)
0.998
-
16
(4.5)
0.867
2
(1.6)
0.998
-
4
(3.3)
0.824
0
(0.0)
0.998
-
1
(3.3)
0.952
0.286
0.975
1 1.01 (0.55-1.87)
Donor sex
Donor age at survey (years)
0.022 <0.001
0.004 0.399
<0.001
1 2.27 (1.84-2.79)
0.063 1 0.88 (0.09-8.23) 0.54 (0.07-4.25) 0.58 (0.08-4.44) 0.55 (0.07-4.15) 0.64 (0.09-4.76) 0.73 (0.09-5.47) 0.84 (0.11-6.37) 1.26 (0.16-9.81) 0.94 (0.12-7.35)
26 Page 26 of 30
Time since donation (years)
Total
0.031 <1*
2
(0.1)
1-5*
27
(0.4)
0.670
5-10*
39
(1.0)
0.088
>10*
22
(1.6)
0.012
90
(0.6)
<0.001 1 1.14 (0.63-2.07) 1.82 (0.92-3.60) 6.95 (1.53-31.53)
2
(0.1)
25
(0.4)
0.889
51
(1.3)
0.001
24
(1.8)
0.001
102
(0.7)
<0.001 1 0.96 (0.56-1.65) 3.03 (1.56-5.89) 11.89 (2.64-53.51)
22
(1.0)
126
(1.9)
0.514
165
(4.3)
0.002
58
(4.3)
<0.001
371
(2.6)
1 0.89 (0.64-1.25) 1.81 (1.25-2.61) 3.36 (1.95-5.76)
*: Odds ratio (OR) and 95% confidence interval (CI)
27 Page 27 of 30
Table 6: Observed (Obs.) and expected (Exp.) incidences of various malignancies and resulting standard incidence rates (SIR) with 95% confidence intervals (CI). All donors Type or localization of malignancy (ICD-10 code)
Exp.
Obs .
SIR (95% CI)
PBSC donors Exp.
Obs .
SIR (95% CI)
BM donors Exp.
Obs .
All Cases (C00-97 without C44)*
102.7 5
86
0.84
(0.68 - 1.03)
54.0 8
51
0.94
(0.70 - 1.24)
45.4 1
32
Leukemias (C91-C95)
2.87
2
0.70
(0.08 - 2.52)
1.60
0
0.00
(0.00 - 1.88)
1.19
1
Chronic lymphatic leukemia - CLL (C91.1) †
0.62
1
1.62
(0.05 - 9.00)
0.32
0
0.00
(0.00 - 9.24)
0.27
0
Acute myeloid leukemia - AML (C92.0) †
0.82
1
1.22
(0.04 - 6.78)
0.45
0
0.00
(0.00 - 6.63)
0.34
1
Hodgkin lymphoma (C81)
1.83
2
1.09
(0.13 - 3.94)
1.07
2
1.87
(0.22 - 6.74)
0.71
0
Non-Hodgkin lymphoma (C82-C85)
3.92
1
0.25
(0.01 - 1.42)
2.17
0
0.00
(0.00 - 1.38)
1.63
1
Malignant melanoma (C43)
9.23
13
1.41
(0.75 - 2.41)
5.05
5
0.99
(0.32 - 2.31)
3.88
8
Testis (C62)
8.42
11
1.31
(0.65 - 2.34)
5.15
7
1.36
(0.55 - 2.80)
3.02
3
Breast (C50)
17.22
18
1.05
(0.62 - 1.65)
8.09
9
1.11
(0.51 - 2.11)
8.54
9
Thyroid gland (C73)
3.82
4
1.05
(0.29 - 2.68)
2.03
3
1.48
(0.31 - 4.33)
1.67
1
Pancreas (C25)
1.80
0
0.00
(0.00 - 1.67)
0.93
0
0.00
(0.00 - 3.21)
0.81
0
Colon (C18-C21)
8.87
7
0.79
(0.32 - 1.63)
4.65
6
1.29
(0.47 - 2.81)
3.95
1
Ovary (C56)
1.39
1
0.72
(0.02 - 4.01)
0.66
0
0.00
(0.00 - 4.56)
0.68
1
Cervix uteri (C53)
2.67
6
2.25
(0.82 - 4.89)
1.30
4
3.08
(0.84 - 7.89)
1.28
2
Uterus (C54-C55)
1.36
1
0.74
(0.02 - 4.10)
0.62
1
1.61
(0.05 - 8.99)
0.69
0
Bladder (C67)
1.67
2
1.20
(0.14 - 4.32)
0.87
1
1.15
(0.03 - 6.38)
0.75
1
Larynx (C32)
1.12
0
0.00
(0.00 - 2.67)
0.60
0
0.00
(0.00 - 5.03)
0.49
0
Lung (C33, C34)
7.39
1
0.14
(0.00 - 0.75)
3.77
1
0.26
(0.01 - 1.48)
3.38
0
SIR (95% CI) 0.7 0 0.8 4 0.0 0 2.9 1 0.0 0 0.6 1 2.0 6 0.9 9 1.0 5 0.6 0 0.0 0 0.2 5 1.4 6 1.5 6 0.0 0 1.3 4 0.0 0 0.0
(0.48 - 0.99) (0.03 - 4.70) (0.00 - 10.93) (0.09 - 16.22) (0.00 - 4.25) (0.02 - 3.42) (0.89 - 4.06) (0.20 - 2.90) (0.48 - 2.00) (0.02 - 3.33) (0.00 - 3.70) (0.01 - 1.41) (0.04 - 8.14) (0.19 - 5.63) (0.00 - 4.32) (0.04 - 7.47) (0.00 - 6.08) (0.00 - 0.89)
PBSC+BM donors Exp Obs . . 3.2 6 0.0 9 0.0 2 0.0 3 0.0 6 0.1 2 0.3 0 0.2 5 0.5 8 0.1 3 0.0 6 0.2 8 0.0 5 0.0 9 0.0 5 0.0 5 0.0 3 0.2
3 1 1
SIR (95% CI) 0.92 11.3 0 51.4 4
(0.19 - 2.69) (0.34 - 62.94) (1.54 286.51) (0.00 117.79)
0
0.00
0
0.00
(0.00 - 54.43)
0
0.00
(0.00 - 24.38)
0
0.00
(0.00 - 10.11)
1
3.96
(0.12 - 22.04)
0
0.00
(0.00 - 5.16)
0
0.00
(0.00 - 23.89)
0
0.00
(0.00 - 53.53)
0
0.00
(0.00 - 10.68)
0
0.00
(0.00 - 64.77)
0
0.00
(0.00 - 32.91)
0
0.00
(0.00 - 65.06)
0
0.00
(0.00 - 58.18)
0
0.00
(0.00 - 85.93)
0
0.00
(0.00 - 13.01)
28 Page 28 of 30
0 Stomach (C16)
2.93
1
0.34
(0.01 - 1.90)
1.57
1
0.64
(0.02 - 3.55)
1.27
0
Lips, oral cavity and pharynx (C00-14)
5.03
0
0.00
(0.00 - 0.60)
2.73
0
0.00
(0.00 - 1.10)
2.14
0
Central nervous sytem (C70-C72)
3.04
2
0.66
(0.08 - 2.37)
1.71
1
0.58
(0.02 - 3.26)
1.24
1
Kidney, ureter, urethra (C64-C66, C68)
3.37
1
0.30
(0.01 - 1.66)
1.82
1
0.55
(0.02 - 3.05)
1.43
0
Prostate (C61)
4.81
6
1.25
(0.46 - 2.71)
2.36
4
1.70
(0.46 - 4.34)
2.32
1
Esophagus (C15)
1.35
1
0.74
(0.02 - 4.11)
0.72
1
1.39
(0.04 - 7.77)
0.59
0
Skin (C44) ‡
19.13
7
0.37
(0.15 - 0.75)
10.0 0
5
0.50
(0.16 - 1.17)
8.51
1
Connective and soft tissue (C49) ‡
0.96
2
2.09
(0.25 - 7.54)
0.54
0
0.00
(0.00 - 5.56)
0.39
2
Plasmocytoma (C90)
0.77
1
1.29
(0.04 - 7.20)
0.41
1
2.45
(0.07 - 13.65)
0.34
0
Defined digestive organs (C26) ‡
0.12
1
8.53
(0.26 - 47.53)
0.06
1
(0.48 - 89.88)
0.05
0
Secondary malignant neoplasm of other sites (C79) Malignant neoplasm of other and unspecified female genital organs (C57) ‡
N/A
1
1
0
0.02
1
N/A (1.23 229.09)
N/A
1
N/A (0.57 106.01)
N/A
0.05
N/A 19.0 3
0.03
0
16.1 4 N/A 41.1 3
3
0.0 0.0 (0.00 - 2.37) 0 9 0.0 0.1 (0.00 - 1.40) 0 6 0.8 0.1 (0.02 - 4.51) 1 0 0.0 0.1 (0.00 - 2.09) 0 1 0.4 0.1 (0.01 - 2.40) 3 3 0.0 0.0 (0.00 - 5.05) 0 4 0.1 0.6 (0.00 - 0.65) 2 1 5.1 0.0 (0.62 - 18.58) 5 3 0.0 0.0 (0.00 - 8.79) 0 2 0.0 0.0 (0.00 - 58.25) 0 0 N/A N/A N/A 0.0 (0.00 0.0 0 113.42) 0
0
0.00
(0.00 - 32.48)
0
0.00
(0.00 - 18.89)
0
0.00
(0.00 - 31.16)
0
0.00
(0.00 - 28.05)
1
7.51
(0.23 - 41.82)
0
0.00
(0.00 - 71.30)
1
1.63
(0.05 - 9.08)
0
0.00
(0.00 - 99.86)
0
0.00
0
0.00
0
N/A
0
0.00
(0.00 125.46) (0.00 806.32) N/A (0.00 1688.81)
*: Seven malignant neoplasms of skin other than melanoma (ICD-10 code C44) were not considered in SIR calculations for all cancers, as these entities are not included in the age- and gender-adjusted malignancy incidences of the German population. †: SIR for the two cases of leukemia reported (included in leukemias, ICD-10 codes C91-C95) were additionally calculated for each specific type. ‡: Based on age- and gender-adjusted incidence rates. Color coding of cells: significantly lower than expected SIRs were highlighted in light blue, significantly higher than expected SIRs in green.
29 Page 29 of 30
30 Page 30 of 30
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
1
DKMS, Tübingen, Germany
2
DKMS, Clinical Trials Unit, Dresden, Germany
3
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: [email protected] 1 Page 1 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: 6 Number of figures: 1 Supplemental file: 1
2 Page 2 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 4 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 1 indicating a lower risk than in the ageand sex-matched population. The SIR for a diagnosis of leukemia was 0 (95%-CI, 0 - 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 3 Page 3 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
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An overview of all donations by donors from DKMS Germany between March 1992 and January 2009 is given in Table 1. Generally, DKMS’ respective policy sets a limit of two PBSC plus two BM donations per donor. It follows from Table 1 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 4 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.
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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. 4
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
6 Page 6 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 2 and 3.
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.
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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<0.001).
In order to check for a potential bias caused by donors who died in the interval between donation and the mailing of the questionnaire, we analyzed a sample of 140 non-responding donors. 36 of these donors were in contact with DKMS for various reasons after the questionnaire had been sent out, 43 could be reached by phone, and for the remaining 61 donors registration office inquiries provided no evidence that they were not alive. Taken together, there was no evidence for a considerable bias due to donor deaths between donation and the mailing of the questionnaire.
General results – univariate analysis
Answers provided by study donors are shown in Table 3. Most donors assessed their health conditions as very good or good (94.9%), had not been hospitalized or received long-term medical treatment since donation (82.4%), and neither used prescription drugs regularly nor had used them for more than four weeks since donation (77.7%). Moreover, the majority of donors (95.0%) would be willing (“yes” or “probably yes”) to donate again if asked to do so.
PBSC and BM donors showed no significant differences regarding their general health conditions (Question #1, 2 test, p=0.06). For this analysis, pre-defined answers were combined (very good/good vs. moderate/reduced).
Contrary to Question #1 that asked for subjective assessments, Questions #2 (hospitalization or long-term treatment) and #3 (prescription drugs) focused on specific indications for health-related problems. For these questions, answers of PBSC and BM
8 Page 8 of 30
donors differed significantly (2 tests, p<0.001), with less PBSC donors reporting healthrelated problems. Answers to Questions #2 and #3 also differed significantly between male and female donors, between younger (18-40 years) and older (≥41 years) donors, and between donors with more (<5 years) and less (>5 years) recent donations (2 tests, p<0.001). Male donors, younger donors and donors with more recent donations less often reported health-related problems. The PBSC sample included significantly more male, younger (18-40 years) and more recent (<5 years) donors than the BM group (2 tests, p<0.001). The strong effect of time since donation may result from the fact that Questions #2 and #3 refer to incidents in the interval since donation.
Willingness to donate again (Question #4) did not differ significantly between PBSC and BM donors (2 test, p=0.30). PBSC+BM donors were significantly less often willing to donate again (2 tests, p<0.001). However, the fact that 89.8% of these donors who already donated at least twice were willing to donate again is remarkable. Similar to the analysis of Question #1, pre-defined answers were combined for analysis (yes/probably yes vs. probably not/no).
General results – multivariate analysis
In multivariate regression analysis, there were no significant differences between PBSC, BM and PBSC+BM donors with respect to Questions #2-4 (Table 4). Expectedly, odds ratios (OR) for Questions #2 and #3 essentially show a continuous increase of reported healthrelated problems with increasing donor age and increasing observation periods. In spite of similar frequencies of reported health-related problems in PBSC and BM donors, BM donors assessed their general health condition significantly more often as very good or good than PBSC donors (OR=1.58, p<0.001). This finding is even more apparent when the subset of donors is analyzed that did not report a specific health issue or medication. In this group, PBSC donors reported a ‘moderate’ or ‘reduced’ health status with an OR of 2.94 (p<0.001)
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compared to BM donors. Females assessed their health less often as very good/good (OR=1.55, p=0.009). Time since donation had no impact on self-assessment.
Malignancies
93 malignancies were reported by 90 donors within the study, thereof 56 malignancies of 53 PBSC donors, 33 of BM donors, and four of donors of both PBSC and BM (Supplementary Table S1 includes a complete list of cases). Six hematological malignancies were reported: two cases of Hodgkin lymphoma (both in PBSC donors), plasmocytoma (PBSC donor), AML (BM donor), Non-Hodgkin lymphoma (BM donor), and CLL (donor of both PBSC and BM).
There was no significant difference between PBSC and BM donors in multivariate analysis (OR=1.08, 95% CI: [0.64, 1.80]). However, we observed a significant difference between female donors and male donors (OR=1.64, 95% CI: [1.07, 2.52]). Higher donor age also was a significant risk factor for the occurrence of malignancies.
Table 6 shows observed and expected numbers for various malignancies and resulting SIR values with 95% CI. We obtained significantly increased SIR values (lower bound of 95% CI >1) for 2 combinations of diseases or disease groups and donation methods: CLL in BM+PBSC donors (one case observed, 0.02 expected, SIR=51.44, 95% CI: [1.54, 286.51]) and malignant neoplasms of unspecified female genital organs in PBSC donors (one case observed, 0.02 expected, SIR=41.13, 95% CI: [1.23, 229.09]).
A trend to a lower rate of malignancies compared to the age- and gender-adjusted malignancy incidences of the German population was found for all donors (SIR 0.84, 95%CI: [0.68 – 1.03]). The SIR of a cancer diagnosis was lower than expected (SIR 0.7, 95%-CI: [0.48 – 0.99]) for BM donors but not for PBSC donors (SIR 0.94, 95%-CI: [0.70 – 1.24]). Also, no increased risk was observed for the diagnosis of leukemia (ICD-10: C91-C95) after 10 Page 10 of 30
PBSC donation (no case observed, 1.60 cases expected, SIR=0.00, 95% CI: [0.00, 1.88]). As indicated by the 95% confidence interval an increase in the risk of leukemia after PBSC donation by more than 1.88 times can be excluded with a 2.5% error probability based on this analysis. With the same argument, a twofold or higher increase of the risk for NonHodgkin lymphoma (ICD-10: C82-C85; no case observed, 2.17 cases expected, SIR=0.00, 95% CI: [0.00, 1.38]), a seven-fold or stronger increase of the risk for Hodgkin lymphoma (ICD-10: C81; two cases observed, 1.07 cases expected, SIR=1.87, 95% CI: [0.22, 6.74]), and a 14-fold or stronger increase of the risk for plasmocytoma (ICD-10: C90; one case observed, 0.41 cases expected, SIR=2.45, 95% CI: [0.07, 13.65]) can be rejected for PBSC donors at the same significance level all under the assumption that additional malignancy cases were evenly distributed over time.
SIRs with an upper bound of the 95% CI below 1 were observed for 6 combinations of malignancies and donation methods: malignant neoplasms of the skin other than melanoma in all donors (7 cases observed, 19.13 expected, SIR=0.37, 95% CI: [0.15, 0.75]) and in BM donors (one case observed, 8.51 expected, SIR=0.12, 95% CI: [0.00, 0.65]), lung cancer in all donors (one case observed, 7.39 expected, SIR=0.14, 95% CI: [0.00, 0.75]) and in BM donors (no case observed, 3.38 expected, SIR=0.00, 95% CI: [0.00, 0.89]), malignant neoplasms of lips, oral cavity and pharynx in all donors (no case observed, 5.03 expected, SIR=0.00, 95% CI: [0.00, 0.60]), and all malignancies excluding malignant neoplasms of the skin other than melanoma in BM donors (32 cases observed, 45.41 expected, SIR=0.70, 95% CI: [0.48, 0.99]).
Autoimmune disorders
106 autoimmune disorders were reported by 102 donors (Supplementary Table S2). PBSC donors reported significantly less often autoimmune disorders than BM donors (OR=0.60,
11 Page 11 of 30
95% CI: [0.39, 0.94]). Besides, autoimmune disorders were reported significantly more often by female compared to male donors (OR=1.78, 95% CI: [1.19, 2.64]).
Mental and psychosocial disorders
371 donors reported mental or psychosocial disorders (Supplementary Table S2) or the use of psychiatric medication. There were no significant differences between PBSC and BM donors (OR=1.03, 95% CI: [0.81, 1.33]). Female donors significantly more often reported mental or psychosocial disorders or the use of psychiatric medication (OR=2.27, 95% CI: [1.84, 2.79]). A negative effect of multiple donations could not be observed (OR=1.01, 95% CI: [0.55, 1.87]).
Discussion
In this work, we present results of a retrospective follow-up study based on an easy-tocomplete questionnaire that was mailed to 15,445 individuals who had previously donated PBSC or BM. Most donors reported very good or good general health conditions and would donate again if asked to do so.
In multivariate analysis, no significant differences regarding health-related problems between PBSC and BM donors could be observed. The use of prescription drugs was less often reported by PBSC donors but significance was not reached. Differences between PBSC and BM donors with respect to health-related problems could be explained by differences in eligibility criteria for PBSC and BM donation. For example, donors with autoimmune disorders such as autoimmune hypothyroidism, vitiligo or alopecia areata were excluded from PBSC but not from BM donation, donors with spine affections from BM, but might be allowed for PBSC. 12 Page 12 of 30
Though they did not report health-related problems significantly less often than PBSC donors, BM donors assessed their general health conditions significantly more often as very good or good. The even more pronounced correlation of worse health assessment with PBSC donation in the subset of donors who did not report any specific health issue or medication indicates that different non-eligibility criteria cannot explain this result, as most of these pre-existing conditions would have been replied to questions # 2 and 3. In this context, it may be relevant that the final choice about the donation method is made by the donor. We know from donor center practice that about 10% of the potential donors consent only to one of the procedures with a clear majority of these donors preferring PBSC donation. Therefore, both donor groups may differ systematically with respect to health-related attitudes. Such differences could potentially cause varying subjective assessments of the general health status without detectable differences regarding indications for health-related problems. However, the reason for the worse subjective assessment of the health condition by PBSC donors remains obscure.21 More research is needed in order to delineate the underlying cause.
One donor safety issue lies in the question if short-term application of rhG-CSF may lead to an increased risk to develop hematological malignancies.5-8,
10
We observed no significant
deviations from expected incidences for hematological malignancies of PBSC or BM donors in our study. This holds also for Hodgkin lymphoma for which a significant increase was observed before.4 This increase was based on two cases that are also included in our analysis. As the observation period of PBSC donors has increased from 8,234 to 37,287 donor years without additional cases of Hodgkin lymphoma, significance has been lost. Given the upper limit of the 95% confidence interval for the SIR for leukemia after PBSC donation of 1.88, an increase above factor two is highly unlikely based on this analysis.
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The two significantly increased SIR values (Table 5) – CLL in PBSC+BM donors and malignant neoplasms of unspecified female genital organs in PBSC donors – were induced by one observed case and are, therefore, hardly interpretable.
A significant decrease was observed for incidences of lung cancer, malignant neoplasms of lip, oral cavity and pharynx, and malignant neoplasms of the skin other than melanoma. A correlation between malignancy development and a lack of health-conscious behavior (smoking, misuse of alcohol) is well-known for lung cancer and malignant neoplasms of lips, oral cavity and pharynx. One might, therefore, hypothesize that stem cell donors show more often health-conscious behavior than the general population.
Most malignancy incidences that were determined in our study lie within ranges that would be expected from epidemiological data of the German population.18 Theoretically, this result could be a combined effect of increased malignancy risks through stem cell donation and underreporting of occurring malignancies. However, increased malignancy risks after BM donation have not been discussed in the literature and do not seem to be plausible. The same holds for correlations of many non-hematological malignant diseases with PBSC donation. Therefore, we conclude that the SIRs obtained in our study are not heavily affected by underreporting.
In our study, PBSC donors reported significantly less often autoimmune disorders than BM donors. It does not seem plausible that the incidence or severity of autoimmune disorders are increased by BM donation or reduced by PBSC donation. Therefore, this result most probably reflects the stricter eligibility criteria regarding some autoimmune disorders – as, for example, autoimmune thyroiditis – for PBSC donors.
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The retrospective approach of our study that resembles the telephone-based study by Anderlini and colleagues22 has specific advantages and disadvantages compared to common prospective donor follow-up programs4, 23-25.
Prospective donor follow-up is essential due to the possibilities to obtain detailed donor information including results of blood analysis and/or physical examination and to collect longitudinal data. The major problem of prospective donor follow-up lies in a decrease of response rates over time. As a consequence, long-term response rates are relatively low as, for example, 42.5% at five years after donation in the study by Hölig and colleagues4. Donor drop-out can be explained by low motivation of healthy donors to be followed-up for several years.
We intended, therefore, to obtain high response rates with a short one-time questionnaire that focused on few meaningful indicators of donor health status. This goal could be reached as the return rate of 91.3% in a donor group with a median (average) time since donation of 3.8 (4.6) years demonstrates. Though the quality of the retrospective data collected in this study should be lower than that of prospective follow-up data, especially with respect to the time of occurrence of specific health problems, we think it is sufficient to identify major health disorders. The SIRs we obtained for malignant diseases support this conclusion.
We conclude that retrospective studies like the one presented in this work are not suited to replace common prospective follow-up programs but can be valuable complements to such programs. Especially the collection of additional data of donors who donated several years ago and have already dropped out of the prospective follow-up may be helpful.
Several issues make the interpretation of minor outcome differences between stem cell donors and the general population difficult: First, donors should be healthier than an age-
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and gender-adjusted sample of the general population due to medical clearing before donation. Second, individuals who register as stem cells donors may be more healthconscious than the general population or may show specific characteristics that correlate with disease susceptibilities. Third, each stem cell donor is – at least nearly – HLA-identical to an individual suffering from a severe disease of the blood or immune system. To account for these differences between registered donors and the general population, it is desirable to include HLA-matched registered donors who did not donate into follow-up programs.
Summarized, we found no indication suggesting that PBSC or BM donation might be unsafe procedures. Especially, we found no evidence for increased hematological malignancy risks after PBSC donation. Beyond this, we can exclude a twofold or stronger increase of the risk to develop leukemia as late effect of PBSC donation with a high likelihood under the assumption that an increased leukemia risk would be equally distributed over time.
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Kaatsch P, Spix C, Hentschel S, et al. Beiträge zur Gesundheitsberichterstattung des
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EKN. Datenbank des epidemiologischen Krebsregisters Niedersachsen. 2016 [cited
2013 October]; Available from: http://www.krebsregister-niedersachsen.de/index.php/daten 20.
Esteve J, Benhamou E, Raymond L. Statistical methods in cancer research. Volume
IV. Descriptive epidemiology. IARC Sci Publ. 1994;128):1-302. 21.
Switzer GE, Bruce JG, Harrington D, et al. Health-related quality of life of bone
marrow versus peripheral blood stem cell donors: a prespecified subgroup analysis from a phase III RCT-BMTCTN protocol 0201. Biol Blood Marrow Transplant. 2014;20(1):118-127. 22.
Anderlini P, Champlin RE. Biologic and molecular effects of granulocyte colony-
stimulating factor in healthy individuals: recent findings and current challenges. Blood. 2008;111(4):1767-1772. 23.
de la Rubia J, de Arriba F, Arbona C, et al. Follow-up of healthy donors receiving
granulocyte colony-stimulating factor for peripheral blood progenitor cell mobilization and collection. Results of the Spanish Donor Registry. Haematologica. 2008;93(5):735-740. 24.
Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408
unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113(15):3604-3611.
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25.
Martino M, Console G, Dattola A, et al. Short and long-term safety of lenograstim
administration in healthy peripheral haematopoietic progenitor cell donors: a single centre experience. Bone Marrow Transplant. 2009;44(3):163-168.
20 Page 20 of 30
Donation until January 31, 2009 (n = 15,531)
Excluded (n = 86) • Cases of death (n = 20) • Unwilling to be contacted again or not contactable (e.g., due to emigration) (n = 66)
Contacted (n = 15,445)
PBSC donors (n = 10,830)
BM donors (n = 4,285)
Analyzed (n = 3,919 )
No questionnaire or no informed consent (n = 25)
No questionnaire or no informed consent (n = 366)
No questionnaire or no informed consent (n = 960)
Analyzed (n = 9,870 )
PBSC+BM donors (n = 330)
Analyzed (n = 305 )
Figure 1: Description of the study population. The study population included 15,531 donors from DKMS Germany who donated peripheral blood stem cells (PBSC), bone marrow (BM) or both (PBSC+BM) until January 2009. In total 15,445 donors were contacted of which 14,094 gave informed consent and responded the follow-up questionnaire (9,870 PBSC donors, 3,919 BM donors and 305 PBSC+BM donors respectively). 21 Page 21 of 30
Table 1: Number of peripheral blood stem cell (PBSC) and bone marrow (BM) donors from DKMS Germany between March 1992 and January 2009.
PBSC donors 1 donation 2 donations BM donors 1 donation 2 donations PBSC+BM donors 1 PBSC + 1 BM 2 PBSC + 1 BM 1 PBSC + 2 BM Total donors
Absolute number 10,863 10,522 341 4,337 4,279 58 331 322 5 4 15,531
Table 2: Characteristics of donors who responded to the questionnaire (n=14,094). For donors who donated more than once, values for “age at donation” and “time since donation” refer to the first donation. NA: not applicable.
Donors, n (%) Age at survey (years) median range interquartile range Age at donation (years) median range Interquartile range Time since donation (months) median range Interquartile range Donor sex Female, n (%) Male, n (%) Number of donations 1 donation, n (%) 2 donations, n (%) 1 PBSC + 1 BM 2 PBSC + 1 BM 1 PBSC + 2 BM
PBSC 9,870 (70.0)
BM 3,919 (27.8)
PBSC+BM 305 (2.2)
38.5 18.7 - 67.8 30.7 - 44.5
40.6 19.1 - 69.9 33.7 - 46.5
41.4 20.5 - 64.5 35.7 - 46.4
34.1 18.3 - 60.9 27.2 - 40.3
33.2 18.5 - 60.7 27.3 - 39.3
34.8 19.0 - 58.5 28.5 - 39.8
39 1 - 176 17 - 67
71 1 - 229 31 - 124
77 4 - 181 39 - 113
2,813 (28.5) 7,057 (71.5)
1,363 (34.8) 2,556 (65.2)
101 (33.1) 204 (66.9)
9,549 (96.7) 321 (3.3) NA NA NA
3,864 (98.6) 55 (1.4) NA NA NA
NA NA 296 (97.0) 5 (1.6) 4 (1.3)
22 Page 22 of 30
Table 3: Additional characteristics of donors who responded to the questionnaire and overview on answers to Questions #1 to #4. Number of donors Q #1: Health condition who responded to Number of replies for categories the questionnaire (%) “very good” or “good” (%)
Q #2: Hospitalization or long-term treatment Number of replies for category “No” (%)
Q #3: Use of prescription drugs Number of replies for category “No” (%)
Q #4: Willing to donate again Number of replies for categories “yes” or “probably yes” (%)
Type of donation PBSC
9870 (70.0)
9,310 (94.7)
8,291 (84.2)
7,779 (79.5)
9,301 (95.0)
BM
3919 (27.8)
3,721 (95.5)
3,061 (78.2)
2,877 (73.6)
3,719 (95.4)
PBSC+BM
305 (2.2)
277 (92.6)
238 (78.5)
226 (74.8)
273 (89.8)
1
13413 (95.2)
12,677 (94.9)
11,056 (82.6)
10,364 (77.8)
12,684 (95.2)
>1
681 (4.8)
631 (93.6)
534 (78.8)
518 (76.9)
609 (90.4)
Female
4277 (30.3)
4,006 (94.2)
3,356 (78.6)
2,975 (70.0)
3,966 (93.3)
Male
9817 (69.7)
9,302 (95.2)
8,234 (84.1)
7,907 (81.1)
9,327 (95.7)
18-25
1486 (10.5)
1,439 (97.1)
1,349 (90.9)
1,310 (88.9)
1,436 (97.0)
26-30
1809 (12.8)
1,742 (96.8)
1,602 (88.9)
1,543 (86.0)
1,702 (95.4)
31-35
2129 (15.1)
2,062 (97.0)
1,839 (86.5)
1,787 (84.5)
2,023 (95.6)
36-40
2729 (19.4)
2,593 (95.5)
2,269 (83.4)
2,184 (80.6)
2,562 (94.5)
41-45
2899 (20.6)
2,715 (93.9)
2,311 (79.8)
2,184 (75.8)
2,720 (94.3)
46-50
1781 (12.6)
1,628 (92.3)
1,353 (76.3)
1,183 (66.8)
1,683 (94.9)
51-55
751 (5.3)
674 (90.3)
540 (72.0)
453 (60.6)
705 (94.4)
56-60
357 (2.5)
319 (90.1)
241 (67.5)
173 (48.7)
326 (93.1)
61-65
123 (1.0)
108 (88.5)
73 (59.3)
47 (38.2)
111 (91.7)
≥66
30 (0.2)
28 (93.3)
13 (44.8)
18 (60.0)
25 (92.6)
2198 (15.6)
2,120 (96.8)
2,041 (93.0)
1,863 (85.0)
2,097 (95.8)
Number of donations
Donor sex
Donor age at survey (years)
Time since donation (years) <1*
23 Page 23 of 30
1-5*
6655 (47.2)
6,330 (95.5)
5,719 (86.2)
5,323 (80.6)
6,269 (94.9)
5-10*
3880 (27.5)
3,617 (93.6)
2,934 (75.8)
2,808 (73.0)
3,658 (95.0)
>10*
1361 (9.7)
1,241 (92.2)
896 (66.0)
888 (65.5)
1,269 (94.1)
Total
14094 (100.0)
13,308 (94.9)
11,590 (82.4)
10,882 (77.7)
13,293 (95.0)
*: Values refer to first donations.
24 Page 24 of 30
Table 4: Results of multivariate logistic regression analyses of follow-up data. Q #1: Health condition reported moderate or reduced Q2 and Q3 answered with No
Q #1: Health condition reported moderate or reduced p value Type of donation
OR (99% CI)
†
<0.001 BM
p value
OR (99% CI)
†
<0.001
<0.001
BM+PBSC
0.074
1.58 (1.21-2.05) 1.80 (0.77-4.19)
p value
1 <0.001 0.058
OR (99% CI)
†
0.777
1
PBSC
Q #2: Hospitalization or long-term treatment needed during follow-up
2.94 (1.50-5.76) 4.63 (0.58-36.98)
Q #3: Prescription drugs needed during follow up
p value
0.528
†
0.216 1
0.776
OR (99% CI)
0.98 (0.86-1.13) 1.13 (0.69-1.86)
Q #4: Not willing to donate again
p value
OR (99% CI)
†
0.238 1
0.087 0.646
0.92 (0.80-1.05) 0.92 (0.56-1.49)
1 0.094 0.456
1.18 (0.92-1.52) 1.23 (0.61-2.49)
Number of donations 1 >1
1 0.775
0.94 (0.52-1.70)
1 0.342
0.57 (0.13-2.61)
1 0.522
1.09 (0.77-1.53)
1 0.419
0.89 (0.64-1.26)
1 <0.001
1.95 (1.21-3.15)
Donor sex Male
1.00
Female
0.012
Donor age at survey (years)
<0.001
18-25 26-30
0.897
31-35
0.648
36-40
0.085
41-45
0.001
46-50
<0.001
51-55
<0.001
56-60
<0.001
61-65
<0.001
≥66
0.468
Time since donation (years)
1.23 (0.99-1.52)
0.009
1.55 (1.01-2.39)
0.005
0.033
5-10*
<0.001
>10*
<0.001
<0.001
1.48 (1.26-1.61)
<0.001
1.00 <0.001
1.92 (1.71-2.15)
<0.001
1.00 <0.001
1.64 (1.34-2.02)
0.006
1
1
1
1
1
0.78 (0.32-1.85) 0.76 (0.32-1.80) 1.04 (0.47-2.29) 1.49 (0.70-3.17) 2.05 (0.92-4.58) 1.73 (0.58-5.12) 0.54 (0.04-7.83) 4.19 (0.56-31.39) 7.86 (0.47-131.61)
1.57 (0.53-4.64) 1.84 (0.67-5.06) 2.18 (0.78-5.72) 2.47 (0.93-6.60) 2.82 (1.06-7.50) 3.54 (1.33-9.44) 4.18 (1.56-11.22) 4.41 (1.63-11.92) 4.62 (1.69-12.62)
0.36 (0.12-1.07) 0.51 (0.19-1.41) 0.79 (0.29-2.13) 1.00 (0.37-2.68) 1.53 (0.57-4.07) 2.02 (0.75-5.39) 2.65 (0.98-7.12) 2.91 (1.07-7.86) 3.64 (1.34- 9.94)
1.54 (0.94-2.51) 1.53 (0.94-2.47) 1.94 (1.23-3.07) 2.10 (1.27-3.17) 1.79 (1.09-2.94) 1.95 (1.09-3.50) 2.38 (1.20-4.74) 2.89 (1.10-7.58) 2.64 (0.38-18.56)
0.451 0.408 0.909 0.172 0.022 0.194 0.556 0.067 0.059 0.602
1.34 (0.94-1.90) 1.66 (1.15-2.40) 2.19 (1.38-3.46)
0.281 0.123 0.052 0.017 0.006 0.001 <0.001 <0.001 <0.001 <0.001
1
1-5*
1.00
1.03 (0.60-1.75) 0.91 (0.54-1.54) 1.38 (0.85-2.22) 1.87 (1.18-2.96) 2.33 (1.44-3.77) 2.94 (1.72-5.00) 2.96 (1.58-5.54) 3.35 (1.42-7.91) 1.73 (0.25-12.06)
<0.001
<1*
1.00
1 0.755 0.589 0.465
1.07 (0.61-1.89) 0.87 (0.44-1.71) 1.33 (0.49-3.61)
0.016 0.088 0.539 1.000 0.268 0.066 0.011 0.006 0.001 <0.001
1 <0.001 <0.001 <0.001
1.39 (1.14-1.69) 2.39 (1.95-2.93) 4.89 (3.66-6.53)
0.024 0.025 <0.001 <0.001 0.003 0.003 0.001 0.005 0.201 0.530
1 0.480 0.005 <0.001
1.06 (0.87-1.28) 1.24 (1.02-1.52) 1.56 (1.22-1.99)
1 0.415 0.846 0.558
1.10 (0.81-1.51) 0.97 (0.69-1.38) 1.11 (0.70-1.75)
*: Values refer to first donations. †
: Odds ratio (OR) and 99% confidence interval (CI)
25 Page 25 of 30
Table 5: Number of donors that reported incidences of specific health disorders based on answers to Question #2 (and Question #3 for mental or psychosocial disorders) and results of multivariate logistic regression analyses of the responses. p values < 0.05 are regarded as significant. Malignancies Number of donors that reported incidences
(%)
Type of donation
p value
OR (95% CI)*
0.871 BM
33
(0.8)
PBSC
53
(0.5)
0.775
BM+PBSC
4
(1.3)
0.677
1
83
(0.6)
>1
7
(1.0)
Male
51
(0.5)
Female
39
(0.9)
18-25
1
(0.1)
26-30
4
(0.2)
0.090
31-35
3
(0.1)
0.016
36-40
13
(0.5)
0.003
41-45
18
(0.6)
<0.001
46-50
19
(1.1)
<0.001
51-55
14
(1.9)
<0.001
56-60
9
(2.5)
<0.001
61-65
5
(4.1)
<0.001
≥66
4
(13.3)
<0.001
1 1.08 (0.64-1.80) 0.72 (0.16-3.32)
Autoimmune disorders Number of donors with (%) p value OR (95% CI)* reported incidences 0.036 49 (1.3) 1 0.60 49 (0.5) 0.025 (0.39-0.94) 0.21 4 (1.3) 0.166 (0.02-1.91)
Mental or psychosocial disorders Number of donors with (%) p value OR (95% CI)* reported incidences 0.914 122 (3.1) 1 1.03 237 (2.4) 0.791 (0.81-1.33) 0.87 12 (3.9) 0.754 (0.38-2.03)
Number of donations 0.883
1 1.09 (0.34-3.53)
97
(0.7)
1 0.34 (0.05-2.46)
348
(2.6)
5
(0.7)
23
(3.4)
1 1.64 (1.07-2.52)
56
(0.6)
1 1.78 (1.19-2.64)
190
(1.9)
46
(1.1)
181
(4.2)
1 3.32 (0.83-13.30) 4.68 (1.33-16.43) 5.93 (1.79-19.59) 9.80 (3.05-31.53) 15.92 (4.89-51.84) 20.43 (6.06-68.84) 65.11 (13.44-315.37) 35.55 (7.95-158.94) 93.78 (9.58-917.90)
3
(0.2)
1
21
(1.4)
10
(0.6)
0.998
-
23
(1.3)
0.911
8
(0.4)
0.998
-
47
(2.2)
0.558
23
(0.8)
0.998
-
73
(2.7)
0.599
20
(0.7)
0.998
-
90
(3.1)
0.564
25
(1.4)
0.998
-
67
(3.8)
0.659
6
(0.8)
0.998
-
29
(3.9)
0.758
5
(1.4)
0.998
-
16
(4.5)
0.867
2
(1.6)
0.998
-
4
(3.3)
0.824
0
(0.0)
0.998
-
1
(3.3)
0.952
0.286
0.975
1 1.01 (0.55-1.87)
Donor sex
Donor age at survey (years)
0.022 <0.001
0.004 0.399
<0.001
1 2.27 (1.84-2.79)
0.063 1 0.88 (0.09-8.23) 0.54 (0.07-4.25) 0.58 (0.08-4.44) 0.55 (0.07-4.15) 0.64 (0.09-4.76) 0.73 (0.09-5.47) 0.84 (0.11-6.37) 1.26 (0.16-9.81) 0.94 (0.12-7.35)
26 Page 26 of 30
Time since donation (years)
Total
0.031 <1*
2
(0.1)
1-5*
27
(0.4)
0.670
5-10*
39
(1.0)
0.088
>10*
22
(1.6)
0.012
90
(0.6)
<0.001 1 1.14 (0.63-2.07) 1.82 (0.92-3.60) 6.95 (1.53-31.53)
2
(0.1)
25
(0.4)
0.889
51
(1.3)
0.001
24
(1.8)
0.001
102
(0.7)
<0.001 1 0.96 (0.56-1.65) 3.03 (1.56-5.89) 11.89 (2.64-53.51)
22
(1.0)
126
(1.9)
0.514
165
(4.3)
0.002
58
(4.3)
<0.001
371
(2.6)
1 0.89 (0.64-1.25) 1.81 (1.25-2.61) 3.36 (1.95-5.76)
*: Odds ratio (OR) and 95% confidence interval (CI)
27 Page 27 of 30
Table 6: Observed (Obs.) and expected (Exp.) incidences of various malignancies and resulting standard incidence rates (SIR) with 95% confidence intervals (CI). All donors Type or localization of malignancy (ICD-10 code)
Exp.
Obs .
SIR (95% CI)
PBSC donors Exp.
Obs .
SIR (95% CI)
BM donors Exp.
Obs .
All Cases (C00-97 without C44)*
102.7 5
86
0.84
(0.68 - 1.03)
54.0 8
51
0.94
(0.70 - 1.24)
45.4 1
32
Leukemias (C91-C95)
2.87
2
0.70
(0.08 - 2.52)
1.60
0
0.00
(0.00 - 1.88)
1.19
1
Chronic lymphatic leukemia - CLL (C91.1) †
0.62
1
1.62
(0.05 - 9.00)
0.32
0
0.00
(0.00 - 9.24)
0.27
0
Acute myeloid leukemia - AML (C92.0) †
0.82
1
1.22
(0.04 - 6.78)
0.45
0
0.00
(0.00 - 6.63)
0.34
1
Hodgkin lymphoma (C81)
1.83
2
1.09
(0.13 - 3.94)
1.07
2
1.87
(0.22 - 6.74)
0.71
0
Non-Hodgkin lymphoma (C82-C85)
3.92
1
0.25
(0.01 - 1.42)
2.17
0
0.00
(0.00 - 1.38)
1.63
1
Malignant melanoma (C43)
9.23
13
1.41
(0.75 - 2.41)
5.05
5
0.99
(0.32 - 2.31)
3.88
8
Testis (C62)
8.42
11
1.31
(0.65 - 2.34)
5.15
7
1.36
(0.55 - 2.80)
3.02
3
Breast (C50)
17.22
18
1.05
(0.62 - 1.65)
8.09
9
1.11
(0.51 - 2.11)
8.54
9
Thyroid gland (C73)
3.82
4
1.05
(0.29 - 2.68)
2.03
3
1.48
(0.31 - 4.33)
1.67
1
Pancreas (C25)
1.80
0
0.00
(0.00 - 1.67)
0.93
0
0.00
(0.00 - 3.21)
0.81
0
Colon (C18-C21)
8.87
7
0.79
(0.32 - 1.63)
4.65
6
1.29
(0.47 - 2.81)
3.95
1
Ovary (C56)
1.39
1
0.72
(0.02 - 4.01)
0.66
0
0.00
(0.00 - 4.56)
0.68
1
Cervix uteri (C53)
2.67
6
2.25
(0.82 - 4.89)
1.30
4
3.08
(0.84 - 7.89)
1.28
2
Uterus (C54-C55)
1.36
1
0.74
(0.02 - 4.10)
0.62
1
1.61
(0.05 - 8.99)
0.69
0
Bladder (C67)
1.67
2
1.20
(0.14 - 4.32)
0.87
1
1.15
(0.03 - 6.38)
0.75
1
Larynx (C32)
1.12
0
0.00
(0.00 - 2.67)
0.60
0
0.00
(0.00 - 5.03)
0.49
0
Lung (C33, C34)
7.39
1
0.14
(0.00 - 0.75)
3.77
1
0.26
(0.01 - 1.48)
3.38
0
SIR (95% CI) 0.7 0 0.8 4 0.0 0 2.9 1 0.0 0 0.6 1 2.0 6 0.9 9 1.0 5 0.6 0 0.0 0 0.2 5 1.4 6 1.5 6 0.0 0 1.3 4 0.0 0 0.0
(0.48 - 0.99) (0.03 - 4.70) (0.00 - 10.93) (0.09 - 16.22) (0.00 - 4.25) (0.02 - 3.42) (0.89 - 4.06) (0.20 - 2.90) (0.48 - 2.00) (0.02 - 3.33) (0.00 - 3.70) (0.01 - 1.41) (0.04 - 8.14) (0.19 - 5.63) (0.00 - 4.32) (0.04 - 7.47) (0.00 - 6.08) (0.00 - 0.89)
PBSC+BM donors Exp Obs . . 3.2 6 0.0 9 0.0 2 0.0 3 0.0 6 0.1 2 0.3 0 0.2 5 0.5 8 0.1 3 0.0 6 0.2 8 0.0 5 0.0 9 0.0 5 0.0 5 0.0 3 0.2
3 1 1
SIR (95% CI) 0.92 11.3 0 51.4 4
(0.19 - 2.69) (0.34 - 62.94) (1.54 286.51) (0.00 117.79)
0
0.00
0
0.00
(0.00 - 54.43)
0
0.00
(0.00 - 24.38)
0
0.00
(0.00 - 10.11)
1
3.96
(0.12 - 22.04)
0
0.00
(0.00 - 5.16)
0
0.00
(0.00 - 23.89)
0
0.00
(0.00 - 53.53)
0
0.00
(0.00 - 10.68)
0
0.00
(0.00 - 64.77)
0
0.00
(0.00 - 32.91)
0
0.00
(0.00 - 65.06)
0
0.00
(0.00 - 58.18)
0
0.00
(0.00 - 85.93)
0
0.00
(0.00 - 13.01)
28 Page 28 of 30
0 Stomach (C16)
2.93
1
0.34
(0.01 - 1.90)
1.57
1
0.64
(0.02 - 3.55)
1.27
0
Lips, oral cavity and pharynx (C00-14)
5.03
0
0.00
(0.00 - 0.60)
2.73
0
0.00
(0.00 - 1.10)
2.14
0
Central nervous sytem (C70-C72)
3.04
2
0.66
(0.08 - 2.37)
1.71
1
0.58
(0.02 - 3.26)
1.24
1
Kidney, ureter, urethra (C64-C66, C68)
3.37
1
0.30
(0.01 - 1.66)
1.82
1
0.55
(0.02 - 3.05)
1.43
0
Prostate (C61)
4.81
6
1.25
(0.46 - 2.71)
2.36
4
1.70
(0.46 - 4.34)
2.32
1
Esophagus (C15)
1.35
1
0.74
(0.02 - 4.11)
0.72
1
1.39
(0.04 - 7.77)
0.59
0
Skin (C44) ‡
19.13
7
0.37
(0.15 - 0.75)
10.0 0
5
0.50
(0.16 - 1.17)
8.51
1
Connective and soft tissue (C49) ‡
0.96
2
2.09
(0.25 - 7.54)
0.54
0
0.00
(0.00 - 5.56)
0.39
2
Plasmocytoma (C90)
0.77
1
1.29
(0.04 - 7.20)
0.41
1
2.45
(0.07 - 13.65)
0.34
0
Defined digestive organs (C26) ‡
0.12
1
8.53
(0.26 - 47.53)
0.06
1
(0.48 - 89.88)
0.05
0
Secondary malignant neoplasm of other sites (C79) Malignant neoplasm of other and unspecified female genital organs (C57) ‡
N/A
1
1
0
0.02
1
N/A (1.23 229.09)
N/A
1
N/A (0.57 106.01)
N/A
0.05
N/A 19.0 3
0.03
0
16.1 4 N/A 41.1 3
3
0.0 0.0 (0.00 - 2.37) 0 9 0.0 0.1 (0.00 - 1.40) 0 6 0.8 0.1 (0.02 - 4.51) 1 0 0.0 0.1 (0.00 - 2.09) 0 1 0.4 0.1 (0.01 - 2.40) 3 3 0.0 0.0 (0.00 - 5.05) 0 4 0.1 0.6 (0.00 - 0.65) 2 1 5.1 0.0 (0.62 - 18.58) 5 3 0.0 0.0 (0.00 - 8.79) 0 2 0.0 0.0 (0.00 - 58.25) 0 0 N/A N/A N/A 0.0 (0.00 0.0 0 113.42) 0
0
0.00
(0.00 - 32.48)
0
0.00
(0.00 - 18.89)
0
0.00
(0.00 - 31.16)
0
0.00
(0.00 - 28.05)
1
7.51
(0.23 - 41.82)
0
0.00
(0.00 - 71.30)
1
1.63
(0.05 - 9.08)
0
0.00
(0.00 - 99.86)
0
0.00
0
0.00
0
N/A
0
0.00
(0.00 125.46) (0.00 806.32) N/A (0.00 1688.81)
*: Seven malignant neoplasms of skin other than melanoma (ICD-10 code C44) were not considered in SIR calculations for all cancers, as these entities are not included in the age- and gender-adjusted malignancy incidences of the German population. †: SIR for the two cases of leukemia reported (included in leukemias, ICD-10 codes C91-C95) were additionally calculated for each specific type. ‡: Based on age- and gender-adjusted incidence rates. Color coding of cells: significantly lower than expected SIRs were highlighted in light blue, significantly higher than expected SIRs in green.
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