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Toxicity in related versus unrelated HSC donors
Although attempting to link observed pain at one year directly to PBSC donation was not one of our objectives, an observation that we made may shed light on this ques- tion. We performed additional assessments of RD at one and six months; we noted that the donation pain levels do not fully recover at one month, and remain at heightened levels at six and 12 months (P>0.001) (Online Supplementary Figure S3), suggesting that persistently ele- vated pain levels are a consequence of donation.
Given that elevated post-donation pain levels were only grade 1 or 2 (mild/moderate), are these findings clinically significant? This is an important question because self- reported pain from individuals can vary based on charac- teristics such as gender or cultural differences. To define whether the persistent pain we detected was clinically meaningful, we performed an analysis of the relation of reported pain to donor HR-QoL. In a companion study imbedded in our protocol, 186 RD and URD were ran- domly chosen for assessment of HR-QoL. We noted that at one month and one year after donation, those reporting grade 2 pain or toxicities had significantly lower physical scores measured by the SF36 multidimensional HR-QoL measure compared to those not reporting pain or toxici- ties [P=0.002 (1 month) and 0.004 (1 year)] (Online Supplementary Figure S4). The findings of our HR-QoL companion study (reported separately) support the out- comes we report (e.g. RD reported the donation to be more painful than URD; at 1 year RD were less likely to feel back to normal and reported a longer period of recov- ery). These observations allow us to conclude that the per- sistent pain is clinically meaningful, but the cause of high- er levels of persistent pain in RD is unclear. Future studies could explore potential contributing factors, such as the possibility of G-CSF increasing inflammation in donors with comorbid conditions or the relationship of persistent pain to psychological stressors experienced by family donors.
With this in mind, should RD at highest risk of pain or non-recovery consider deferral? Deferring RD who would have been deferred by the NMDP (our highest risk group) is in line with a recent Worldwide Network for Blood and Marrow Transplantation task force recommendation to screen RD using URD registry standards.9,28 It is likely that unless transplant centers collecting RD accept limits on screening and collection similar to URD registries, RD will remain at higher risk for pain/toxicity and lack of recov- ery. But should pre-donation standards for deferral of a RD be similar to those for URD? Although there is no clear medical benefit from donation, there is evidence that both URD and RD may experience psychosocial benefits, including feelings of enhanced self-worth. For RD, there are additional benefits of alleviating the suffering or saving the life of a loved one and closer family relationships.29-31 While some family members may willingly accept increased medical risk in exchange for psychosocial bene- fits, others may hesitate and feel coerced by family obliga- tions. Striking a balance is a challenge, as transplant cen- ters should support the wishes of RD who are ambivalent about donation and protect those in whom donation could be a serious risk. But at the same time, RD should
have the choice as to whether to shoulder some level of increased risk.
This study identified a series of risk factors that could either motivate a transplant center to recommend against use of a given donor, or allow a donor with multiple risk factors to understand their risk and choose to forgo dona- tion (Tables 3 and 4). A desired outcome from this study is to motivate transplant centers to test interventions aimed at minimizing discomfort or preventing persistent pain or symptoms experienced by high-risk RD. The data on risks presented herein should be shared with RD as part of their counseling regarding the donation process.
In summary, this study showed for the first time that adult RD of PBSC are at increased risk for higher levels of pain and symptoms in the short-term after a collection procedure and one year later compared to URD. The pres- ence of comorbidities in a prospective donor heightens this risk, and comorbidities in combination with other fac- tors described in this study should be carefully considered as transplant teams and individuals make decisions regarding BM or PBSC donation.
Funding
The study was funded by R01 HL085707 through the NHLBI. Additional funding for MAP was provided by 2UG1HL069254 (NHLBI/NCI) and the Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant. The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 1U24HL138660 from NHLBI and NCI; a contract HHSH250201700006C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-17-1- 2388, N00014-17-1-2850 and N00014-18-1-2045 from the Office of Naval Research; and grants from Adaptive Biotechnologies; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; *CytoSen Therapeutics, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; *Kite Pharma, Inc.; Medac, GmbH; *Mediware; The Medical College of Wisconsin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Pharmaceuticals Corporation; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Swedish Orphan Biovitrum, Inc.; *Takeda Oncology; and University of Minnesota. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members.
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