The Effect of Aging and Pre-Donation Comorbidities on the Related PBSC Donor Experience: A Report from the Related Donor Safety Study (RDSafe)

Abstract

The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18–79 enrolled in the Related Donor Safety Study (RDSafe). RD >60 had a lower median CD34+ level pre-apheresis compared to younger RD (age >60, 59×10⁶/L; age 41–60, 81×10⁶/L; age 18–40, 121×10⁶/L; p<0.001). This resulted in older donors undergoing more apheresis procedures (49% vs. 30% ≥2 collections, p<0.001) and higher collection volumes (52% vs. 32% >24L, p<0.001), leading to high percentages of donors >60 with post-collection thrombocytopenia <50×10⁹/L (26% and 57% after 2 and 3 days of collection, respectively). RD age 18–40 had a higher risk of grade 2–4 pain and symptoms peri-collection, but donors above age 40 had more persistent pain at 1, 6, and 12 months (OR1.7, p=0.02) and a higher rate of non-recovery to pre-donation levels (OR 1.7, p=0.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by NMDP unrelated donor standards had an increased risk for persistent grade 2–4 pain (OR=2.41, p<0.001) and failure to recover to pre-donation baseline for other symptoms (OR=2.34, p=0.004). This information should be used in counseling RD regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

INTRODUCTION

Over the past decade, registries such as the National Marrow Donor Program (NMDP) have published detailed data describing the unrelated donor (URD) experience, identifying individuals at increased risk for pain and collection related symptoms, slower recovery, need for placement of a central venous line (CVL), and severe adverse events.^1–6 In spite of the fact that roughly half of allogeneic hematopoietic cell (HSC) donations come from related donors (RD), data describing details of early toxicities and longer-term outcomes in these individuals are scarce, with only one large recent study that focused mainly on severe adverse events.⁷ A possible explanation for the paucity of RD outcome studies is that URD are handled by large registries that have a mandate to report detailed safety data, whereas in many countries, RD are treated by local transplant centers that are primarily focused on care of the recipient and rarely collect data on RD experiences.

Inadequate data regarding RD is concerning for a number of reasons. While unrelated donor registries have specific guidelines regarding donor clearance,⁸ there are not generally accepted guidelines about when to reject a RD, although a recent publication from the Worldwide Network for Blood and Marrow Transplant (WBMT) advocates for transplant centers to adopt standards similar to URD registries.⁹ In addition, RD vary tremendously in age (from infants to individuals in their seventies) and they are often willing to donate to family members in spite of significant comorbidities or potentially increased donor risk.

With these concerns in mind a group of North American Investigators teamed with the NMDP and the Resources for Clinical Investigators in BMT (RCI-BMT) at the Center for International Blood and Marrow Transplant Research (CIBMTR) to conduct a prospective observational trial of RD of all ages collected at 53 transplant centers in the United States. The trial design included a primary comparison of RD with URD between age 18 and 60 (subject of a separate manuscript), as well as detailed study of the outcomes of pediatric donors (separate manuscript) and those over age 60. This report focuses on the effect of age and the presence of comorbidities on the adult peripheral blood stem cell (PBSC) RD experience from their pre-donation baseline through 1 year post-donation, including recovery to pre-donation health. We also focus on the donation experience of related PBSC donors above age 60, comparing their outcomes to younger donors, as safety data on this potentially more frail population are scarce.^10–13

METHODS

A total of 1211 RD ≥ age 18 participated in the study. Prior to donation, RD underwent a comprehensive medical evaluation including a detailed history, physical examination, blood tests, and further work up as necessary per center standards. If approved for donation, RD were approached for consent for this IRB approved study if they were willing and able to complete symptom reviews at 1, 6 and 12 months after donation administered by the CIBMTR Survey Research Group.

Data Collection

A pre-donation form including history of pre-existing medical conditions (comorbidities) was completed at the time of donor clearance. Details on collection related symptoms and pain were collected at five time points: pre-donation, peri-donation (just prior to the first day of apheresis), and 1, 6 and 12 months post-donation. Toxicity was defined by common toxicity criteria (CTC) measures (grades 0–4) for symptoms commonly noted during PBSC and bone marrow (BM) collection (fever, fatigue, skin rash, local reactions to an injection, nausea, vomiting, anorexia, insomnia, dizziness, and syncope) and is called the Modified Toxicity Criteria (MTC). This approach has been extensively validated by NMDP and published previously.^2,3,14,15 Pain was assessed for the following sites: back, bones, head, hip, IV site, joints, limbs, muscles, neck, throat, or other. Pain was graded on a scale of 0–4 as none, mild, moderate, severe, or disabling. Pain and toxicity measures were assessed by the transplant center at pre-donation and peri-donation time points, and the CIBMTR Survey Research group was responsible for follow up assessments.

A product specific collection form detailed information on the collection procedure. Donors were also followed to assess long-term psychological recovery (reported previously^16–18).

Endpoints

Skeletal pain represented pain in at least one of the following sites: back, bone, head, hip, joints, limbs, and neck. Severity of skeletal pain was defined as the maximum grade among these pain sites. Body symptoms were assessed using the MTC outlined above and the peak toxicity level across symptoms was analyzed. Recovery to pre-donation levels by 1 year was defined as a pain or symptom score less than or equal to the score at pre-donation.

Pre-donation comorbidity ascertainment included assessment for a history of bleeding, gastrointestinal, genitourinary, hematologic, hepatic, pulmonary, cardiovascular, psychiatric, CNS, endocrine, autoimmune disorders, or other significant coexisting diseases. For the purposes of analysis we divided comorbidities into three categories: 1) comorbidities that would not result in deferral from URD donation according to NMDP standards,^19,20 2) comorbidities that clearly would have resulted in NMDP deferral, and 3) comorbidities that could possibly have led to a deferral, but more detailed donor clinical data would be needed to make that judgment.

Statistical Methods

Chi-square tests or Fisher’s Exact tests as appropriate were used to compare the incidences of skeletal pain and MTC symptoms as well as recovery to pre-donation levels in univariate analyses of donor age groups. Because event rates were substantially different on the first day of collection prior to apheresis vs. at post-collection time points, separate multivariate analyses were done for these different time periods. Multivariate analyses using logistic regression models were conducted to examine impact of age on pain and MTC symptoms on the first day of collection prior to apheresis, as well as for non-recovery to pre-donation baseline pain and symptom levels at 1 year, while adjusting for other donor characteristics. Generalized estimating equations were used to compare age groups on pain and MTC symptoms across subsequent longitudinal time points of 1 month, 6 months, and 1 year, while adjusting for the correlation within subjects using a sandwich variance estimate. All effects were estimated via odds ratios (ORs). Donor age was a main effect forced into all models; stepwise model selection was used to determine additional donor characteristics to be included. The following donor and donation characteristics were considered for inclusion in the multivariate model: donor race/ethnicity, sex, BMI, comorbidity classification, pre-donation baseline counts (white blood cells (WBC), hemoglobin, platelets, neutrophils, and mononuclear cells), CD34+ cell counts just prior to the first apheresis procedure, collection parameters (number of days of apheresis, volume of blood processed, CVL placement, G-CSF dose, and year of donation), and pre-donation symptoms (skeletal pain and max MTC grade). Interactions between donor age and other factors were tested for, but none were significant. For the generalized estimating equations model, we additionally considered a time post collection effect, as well as assessed interaction between other factors and time point; no significant interactions with time were found.

RESULTS

Age Effect on Demographics, Collection, and Comorbidities

Table 1 shows characteristics of related PBSC donors in 3 age categories, 18–40 (n=261), 41–60 (n=695), and > 60 years (n=255) at donation. Notably, younger donors are more diverse in racial background. Older donors were at higher risk for requiring multiple days of collection (8% with ≥ 3 collections vs. 3% in both younger groups, p<0.001) and had higher volumes of blood processed during their collection procedures (32%, 40% and 52% of younger, middle and older donors had >24L processed, p<0.001). Rates of CVL placement did not vary with age, but women were 2–3 times more likely to require CVL placement (37% of RD females had a CVL placed).

Table 1.

Characteristics of related PBSC adult donors by age at donation

Variable	Age 18 to 40 N (%)	Age 41 to 60 N (%)	Age 61 and older N (%)	p-valuea
Number of donors	261	695	255
Number of transplant centers	35	38	33
Donor-related
Donor age at donation				<0.001
18 to 30	115 (44)	0	0
31 to 40	146 (56)	0	0
41 to 50	0	267 (38)	0
51 to 60	0	428 (62)	0
61 to 70	0	0	228 (89)
71 or older	0	0	27 (11)
Median (range)	32 (18–41)	53 (41–61)	65 (61–79)	<0.001
Donor sex				0.152
Male	145 (56)	392 (56)	126 (49)
Female	116 (44)	303 (44)	129 (51)
Donor race / ethnicity				<0.001
Non-Hispanic White	184 (70)	604 (87)	225 (88)
Hispanic	29 (11)	34 ( 5)	10 ( 4)
Black / African American	23 ( 9)	35 ( 5)	10 ( 4)
Asian / Pacific Islander	17 ( 7)	12 ( 2)	7 ( 3)
American Indian / Alaska Native	2 ( 1)	4 ( 1)	0
Other / multiple race	3 ( 1)	4 ( 1)	2 ( 1)
Decline / unknown	3 ( 1)	2 (<1)	1 (<1)
Donor BMI, kg/m2				0.061
Underweight (< 18.5)	1 (<1)	2 (<1)	0
Normal (18.5–24.9)	73 (30)	136 (21)	50 (20)
Overweight (25–29.9)	75 (30)	250 (38)	85 (34)
Obese (≥ 30)	98 (40)	270 (41)	112 (45)
Unknown	14 (N/A)	37 (N/A)	8 (N/A)
Median (range)	28.2 (18.5–57.0)	28.7 (17.8–57.9)	29.3 (18.7–48.5)	0.212
Donor comorbidity-Male				<0.001
Absent	84 (58)	148 (38)	29 (23)
Present-accept	23 (16)	75 (19)	12 (10)
Present-indeterminate	34 (23)	137 (35)	60 (48)
Present-defer	4 ( 3)	32 ( 8)	25 (20)
Donor comorbidity-female				<0.001
Absent	60 (52)	111 (37)	29 (22)
Present-accept	21 (18)	52 (17)	15 (12)
Present-indeterminate	28 (24)	98 (32)	68 (53)
Present-defer	7 ( 6)	42 (14)	17 (13)
Mobilization-related
Number of days agent administered				<0.001
1	2 ( 1)	0	1 (<1)
2	0	3 (<1)	1 (<1)
3	2 ( 1)	12 ( 2)	4 ( 2)
4	130 (50)	281 (41)	95 (37)
5	97 (37)	322 (47)	105 (41)
6	28 (11)	71 (10)	42 (16)
7	1 (<1)	1 (<1)	5 ( 2)
8	0	1 (<1)	2 ( 1)
10	1 (<1)	0	0
Unknown	0 (N/A)	4 (N/A)	0 (N/A)
Mobilizing agents				0.233
G-CSF	260 (>99)	692 (>99)	253 (99)
G-CSF+GM-CSF	1 (<1)	0	0
G-CSF+Plerixafor	0	3 (<1)	2 ( 1)
G-CSF average daily dose, µg/day
N Eval	252	666	249
Median (range)	960 (480–1920)	912 (300–2040)	900 (480–1764)	0.562
G-CSF average daily dose per donor weight, µg/kg/day
N Eval	252	662	247
Median (range)	10.3 (4.7–21.1)	10.3 (4.7–22.1)	10.5 (4.7–22.8)	0.404
Collection-related
Year of donation				0.744
2010	35 (13)	78 (11)	27 (11)
2011	83 (32)	218 (31)	79 (31)
2012	92 (35)	283 (41)	103 (40)
2013	51 (20)	116 (17)	46 (18)
Number of days of apheresis				<0.001
1	184 (70)	462 (66)	131 (51)
2	69 (26)	214 (31)	103 (40)
3	5 ( 2)	11 ( 2)	17 ( 7)
4	3 ( 1)	7 ( 1)	1 (<1)
5	0	1 (<1)	3 ( 1)
Volume of whole blood processed, L				<0.001
< 18	124 (48)	255 (37)	64 (25)
18 to 24	53 (20)	164 (24)	59 (23)
≥ 24	84 (32)	275 (40)	132 (52)
Unknown	0 (N/A)	1 (N/A)	0 (N/A)
Median (range)	18.0 (0.3–56.1)	20.0 (0.4–112.6)	24.0 (0.6–100.8)	<0.001
Central line placement-Male				0.365
No	131 (90)	339 (86)	107 (85)
Yes	14 (10)	53 (14)	19 (15)
Central line placement-Female				0.738
No	70 (60)	189 (62)	84 (65)
Yes	46 (40)	114 (38)	45 (35)
Central Line site				0.569
Femoral	1 ( 2)	7 ( 4)	2 ( 3)
Internal jugular	54 (90)	154 (92)	59 (92)
Subclavian	5 ( 8)	6 ( 4)	3 ( 5)

^aThe Pearson chi-square test was used for comparing discrete variables; the Kruskal-Wallis test was used for comparing continuous variables.

Comorbidities increased significantly with age, with 45%, 63%, and 77% of RD reporting at least one comorbidity in the younger, middle, and older age groups. (p<0.001, Table 1). Notably, in males over age 60, there was a significant increase in donors who would have definitely been deferred by NMDP standards (20%, compared to 3% and 8% in the younger cohorts, p<0.001). Looking at specific categories of comorbidities, as might be expected, there was a notable increase between the youngest and oldest groups in almost all categories, but the increase was most prominent and statistically significant in cardiovascular (9–53%, p<0.001), endocrine (8–25%, p<0.001), and genitourinary conditions (2–8%, p=0.003; Figure 1 and Supplemental Table 1). More than half of the donors above age 60 had cardiovascular comorbidities, mainly hypertension.

Figure 1.

Classification of comorbidities in related PBSC adult donors by age at donation. (Note that a donor can have more than one comorbidity. The orange fill represents donors who would have been deferred by NMDP standards, the green fill indicates donors with comorbidities that were indeterminate regarding deferral, and the blue fill represents comorbidities that would not have resulted in deferral.)

Age Effect on Hematological Parameters and CD34+ Mobilization

Table 2 shows key hematologic measures at pre-donation baseline, pre-apheresis on collection day 1 and post-apheresis on collection days 1 and 2, Figure 2 illustrates ranges of WBC, hemoglobin, and platelets from pre-cytokine administration through the mobilization and collection process by age group. Older donors (>60) had a trend toward lower WBC (p=0.07) and platelets (p=0.09) pre-donation. A significantly lower pre-donation hemoglobin was noted in older male RD (vs. younger males, p=0.004) and higher hemoglobin in older female RD (vs. younger females, p=0.001). Cytokine mobilization resulted in lower median WBC values in older donors (46.3, 42.0, and 41.6×10⁹/L in younger, middle, and older donors, p<0.001). Apheresis decreased hemoglobin by a mean of 1.56–1.86 g/dL from pre-donation (significantly more in women >40, p=0.01) and decreased platelets a mean of 120–129×10⁹/L, but most hematological changes before and after individual apheresis procedures were not clinically meaningful. One important potential hematological risk was noted, however, with significant thrombocytopenia occurring after multiple and larger volume apheresis procedures in older donors (26% of donors > age 60 post-apheresis day 2 and 57% post-apheresis day 3 had platelet counts <50×10⁹/L).

Table 2.

Hematologic parameters in related PBSC adult donors by age at donation

Variable	Age 18 to 40 N (%)	Age 41 to 60 N (%)	Age 61 and older N (%)	p-valuea
Number of donors	261	695	255
Pre-donation baseline
WBC, ×109/L
N Eval	259	689	253
Median (range)	6.5 (2.7–13.6)	6.4 (2.9–15.3)	6.2 (2.9–12.3)	0.073
Hemoglobin-Male, g/dL
N Eval	144	389	124
Median (range)	15.4 (11.5–17.6)	15.1 (10.2–18.6)	14.8 (11.4–17.3)	0.004
Hemoglobin-female, g/dL
N Eval	115	300	129
Median (range)	13.2 (10.8–5.7)	13.6 (9.8–16.8)	13.7 (11.1–15.9)	0.001
Platelets, ×109/L
N Eval	259	688	253
Median (range)	242 (136–445)	237 (128–435)	233 (124–410)	0.092
Collection day 1 pre-apheresis
WBC, ×109/L
N Eval	256	680	246
Median (range)	46.3 (9.9–97.3)	42 (14.2–103.4)	41.6 (8.4–94.8)	<0.001
Hemoglobin-male, g/dL
N Eval	139	376	120
Median (range)	14.9 (11.3–16.6)	14.6 (11.3–17.7)	14.2 (11.2–17.2)	<0.001
Hemoglobin-female, g/dL
N Eval	113	288	122
Median (range)	12.7 (11.0–15.1)	13 (9.5–15.4)	13 (10.1–15.9)	0.108
Platelets, ×109/L
N Eval	256	680	246
Median (range)	225 (97–438)	215 (79–564)	208 (83–336)	<0.001
CD34 cells, ×106/L
N Eval	147	392	124
Median (Range)	121 (17–1342)	81 (7–1001)	59 (3–1761)	<0.001
[Interquartile Range]	[68–194]	[47–136]	[31–111]
Collection day 1 post-apheresis
WBC, ×109/L				<0.001
< 30	31 (21)	142 (41)	46 (43)
30 to 49.9	96 (64)	184 (53)	55 (51)
≥ 50	22 (15)	23 ( 7)	7 ( 6)
Unknown	112 (N/A)	346 (N/A)	147 (N/A)
Median (range)	37.6 (11.6–75.4)	32.5 (12.8–74.1)	31.5 (16.1–70.2)	<0.001
Hemoglobin-male, g/dL				0.002
< 10	0	1 (1)	0
10 to 11.9	4 ( 5)	12 ( 6)	12 (24)
12 to 13.9	46 (56)	119 (61)	28 (56)
≥ 14	32 (39)	64 (33)	10 (20)
Unknown	63 (N/A)	196 (N/A)	76 (N/A)
Median (range)	13.7 (10.3–15.7)	13.4 (8.9–16.3)	13.2 (10.5–15.8)	0.070
Hemoglobin-female, g/dL
< 10	2 ( 3)	8 ( 5)	1 ( 2)	0.549
10 to 11.9	47 (70)	92 (60)	34 (59)
12 to 13.9	18 (27)	52 (34)	22 (38)
≥ 14	0	1 (1)	1 (2)
Unknown	49 (N/A)	150 (N/A)	71 (N/A)
Median (range)	11.4 (8.9–13.4)	11.6 (8.5–14.6)	11.6 (9.5–14.5)	0.134
Platelets, ×109/L				<0.001
< 50	2 ( 1)	7 ( 2)	3 ( 3)
50 to 79	12 ( 8)	59 (17)	23 (21)
80 to 99	20 (13)	64 (18)	26 (24)
100 to 149	65 (44)	163 (47)	39 (36)
≥ 150	50 (34)	56 (16)	16 (15)
Unknown	112 (N/A)	346 (N/A)	148 (N/A)
Median (range)	129 (18–277)	113 (39–244)	101 (44–233)	<0.001
Collection day 2 post-apheresis
WBC, ×109/L				0.563
< 30	10 (25)	48 (37)	23 (37)
30 to 49.9	25 (63)	68 (53)	35 (56)
≥ 50	5 (13)	13 (10)	4 ( 6)
Unknown	37 (N/A)	104 (N/A)	62 (N/A)
Median (range)	37.2 (7.9–55.9)	34 (12.1–77.9)	32.4 (17.4–82.5)	0.252
Hemoglobin-male, g/dL				0.203
< 10	0	0	0
10 to 11.9	3 (18)	4 ( 7)	7 (23)
12 to 13.9	8 (47)	32 (57)	18 (58)
≥ 14	6 (35)	20 (36)	6 (19)
Unknown	20 (N/A)	48 (N/A)	28 (N/A)
Median (range)	13.7 (11.4–15.5)	13.4 (10.5–15.2)	12.7 (10.1–15.0)	0.028
Hemoglobin-female, g/dL				0.870
< 10	2 ( 9)	9 (12)	3 (10)
10 to 11.9	16 (70)	40 (55)	20 (65)
12 to 13.9	5 (22)	23 (32)	8 (26)
≥ 14	0	1 (1)	0
Unknown	17 (N/A)	56 (N/A)	34 (N/A)
Median (range)	11.2 (9.5–13.3)	11.5 (8.1–14.3)	11.2 (8.7–13.3)	0.368
Platelets, ×109/L				0.685
< 50	9 (23)	28 (22)	16 (26)
50 to 79	13 (33)	49 (38)	23 (37)
80 to 99	5 (13)	24 (19)	13 (21)
100 to 149	11 (28)	20 (16)	8 (13)
≥ 150	2 ( 5)	8 ( 6)	2 ( 3)
Unknown	37 (N/A)	104 (N/A)	62 (N/A)
Median (range)	77 (31–157)	75 (14–209)	66 (21–165)	0.254

Figure 2.

Related PBSC adult donor hematology at baseline and collection, by age at donation. (The graphs show Minimum, Lower quartile, Median, Upper quartile, and Maximum. Day 5 is the first day of apheresis; Pre and Post refer to the apheresis procedure.)

A. White blood cell (WBC) counts

B. Hemoglobin level

C. Platelet counts

In line with the lower median WBC in older donors noted above, there was a dramatic decrease in CD34+ cell concentration just prior to apheresis in older donors. Donors ages 18–40 had a median pre-apheresis CD34+ count of 121×10⁶/L (range 17–1342, see Table 2 for interquartile ranges), while donors age 41–60 had a median of 81×10⁶/L (range 7–1001) and donors >60 had a median less than half of the youngest donor group (59×10⁶/L [range 3–1761]; p<0.001).

The lower pre-collection CD34+ levels in older donors had clinical consequences, as lower CD34+ cell concentrations pre-collection had strong associations with numbers of procedures and risk of low platelet counts after collection. Median pre-collection CD34+ cell concentration for donors undergoing a single apheresis procedure was 92×10⁶/L, while those undergoing 2 and 3 or more procedures was 46×10⁶/L and 29×10⁶/L, respectively (Supplemental Table 2). Donors experiencing platelet counts below 50×10⁹/L after day 1 of collection had a median pre-collection CD34+ level of 37 ×10⁶/L, while those not going below platelet counts of 50 ×10⁹/L after day 1 of collection had a median CD34+ level of 92 ×10⁶/L.

Finally, it is well understood in the mobilization literature that donors with pre-collection CD34+ counts <20×10⁶/L or especially <10×10⁶/L are highly likely to fail collection. The likelihood of this occurring significantly increased with age in our cohort: in the youngest cohort only 1% vs. 11% in the oldest cohort had CD34+ cell concentrations <20×10⁶/L pre-collection, while 0 versus 4% had CD34+ cell concentrations <10×10⁶/L (p<0.001 and 0.002 respectively, Supplemental Table 3).

Age Effect on Pain, MTC Toxicities, and Recovery to Pre-donation Health: Univariate Analysis

Table 3 and Figures 3A and 3B show an unexpected finding, with the highest overall level and intensity of pain associated with PBSC collection reported by the youngest age group (18–40), and progressively lower levels of peri-collection pain reported by older donor groups (grade 2–4 pain and 3–4 pain 52% and 20% in donors age 18–40 vs 31% and 11% those >60; p<0.001 and 0.007, respectively). This observation was also true peri-collection for grade 2–4 MTC symptoms (24% in the youngest and 15% in the oldest group; p=0.012). Specific locations of pain and a types of symptoms noted by age are shown in Figures 4A and 4B.

Table 3.

Univariate analysis of skeletal pain and body symptoms experienced by related PBSC adult donors at pre-donation, on the first day of collection prior to apheresis, and at 1 month, 6 months, and 1 year post-donation, by age at donation. (Skeletal pain represents pain in at least one of the following sites: back, bone, headache, hip, joints, limbs, and neck. The severity of skeletal pain is defined as the maximum grade among these pain sites. Body symptoms include fever in absence of infections, fatigue, skin rash, injection site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The toxicity level is defined as the maximum grade among these symptoms.)

	Age 18 to 40			Age 41 to 60			Age 61 and older
Event and time point	N	# of events (%)	95% CIa	N	# of events (%)	95% CIa	N	# of events (%)	95% CIa	p-valueb
Skeletal pain
Pre-donation, grade 2–4	261	14 ( 5)	(3–9)	695	65 ( 9)	(7–12)	255	23 ( 9)	(6–13)	0.122
First day of collection, grade 2–4	260	134 (52)	(45–58)	690	281 (41)	(37–44)	254	78 (31)	(25–37)	<0.001
First day of collection, grade 3–4	260	52 (20)	(15–25)	690	86 (12)	(10–15)	254	29 (11)	(8–16)	0.007
At 1 month, grade 2–4	207	14 ( 7)	(4–11)	626	70 (11)	(9–14)	244	39 (16)	(12–21)	0.009
At 6 months, grade 2–4	200	18 ( 9)	(5–14)	616	99 (16)	(13–19)	243	33 (14)	(10–19)	0.039
At 1 year, grade 2–4	191	14 ( 7)	(4–12)	584	98 (17)	(14–20)	234	42 (18)	(13–23)	0.002
Non-recovery at 1 month	207	38 (18)	(13–24)	626	170 (27)	(24–31)	244	77 (32)	(26–38)	0.005
Non-recovery at 6 months	200	49 (25)	(19–31)	616	176 (29)	(25–32)	243	75 (31)	(25–37)	0.327
Non-recovery at 1 year	191	49 (26)	(20–32)	584	201 (34)	(31–38)	234	79 (34)	(28–40)	0.071
Body Symptoms
Pre-donation, grade 2–4	255	13 ( 5)	(3–9)	678	10 ( 1)	(1–3)	250	7 ( 3)	(1–6)	0.009
First day of collection, grade 2–4	260	62 (24)	(19–30)	691	110 (16)	(13–19)	255	39 (15)	(11–20)	0.012
At 1 month, grade 2–4	207	10 ( 5)	(2–9)	627	40 (6)	(5–9)	244	14 ( 6)	(3–9)	0.756
At months, grade 2–4	200	12 ( 6)	(3–10)	615	40 ( 7)	(5–9)	243	11 ( 5)	(2–8)	0.575
At 1 year, grade 2–4	192	10 ( 5)	(3–9)	585	38 ( 6)	(5–9)	235	13 ( 6)	(3–9)	0.813
Non-recovery at 1 month	202	44 (22)	(16–28)	610	125 (20)	(17–24)	239	51 (21)	(16–27)	0.897
Non-recovery at 6 months	195	39 (20)	(15–26)	598	109 (18)	(15–22)	239	42 (18)	(13–23)	0.793
Non-recovery at 1 year	187	25 (13)	(9–19)	569	102 (18)	(15–21)	232	34 (15)	(10–20)	0.271

^aExact confidence interval

^bFisher’s Exact Test p-value

Figure 3.

Skeletal pain and body symptoms experienced by related PBSC adult donors at pre-donation baseline, on the first day of collection prior to apheresis, and at 1 month, 6 months, and 1 year post-donation, by age at donation.

A. Skeletal pain. (Skeletal pain represents pain in at least one of the following sites: back, bone, headache, hip, joints, limbs, and neck. The severity of skeletal pain is defined as the maximum grade among these pain sites.)

B. Highest toxicity level across all body symptoms. (Body symptoms include fever in absence of infections, fatigue, skin rash, injection site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The toxicity level is defined as the maximum grade among these symptoms.)

Figure 4.

Severity of pain at various sites and body symptoms experienced by related PBSC adult donors on the first day of collection prior to apheresis, by age at donation

A. Pain sites

B. Body symptoms

For pain at other time points, however, older donors fared worse. Older donors had higher pre-donation levels of pain vs. younger donors, and a higher percentage of older donors reported pain at 1-year post collection (7% vs. 17% vs. 18% of donors in the youngest to oldest age groups reported grade 2–4 pain at 1 year, p=0.002). Older donors were also more likely than younger donors to fail to return to their pre-donation pain levels (18% of 18–40 year olds failed to return to pre-donation levels of pain at 1 month vs. 27% of 41–60 year old and 32% of >60 year old donors, p=0.005; differences persisted at one year, although the p-value fell short of significance, p=0.07). As opposed to pain, MTC symptoms reported by RD of all ages gradually returned to pre-donation baseline over the first year after donation (Figure 3B).

Age Effect on Pain, MTC Toxicities, and Recovery to Pre-donation Health: Multivariate Analysis

Peri-Collection Pain and Symptoms

Table 4A shows a multivariate analysis of factors contributing to risk for peri-collection grade 2–4 pain and MTC symptoms. Older donors were less likely to experience pain (OR 0.41 for >60 year olds vs the youngest donors; p<0.001), while females, donors with pre-donation baseline pain, Hispanic donors, donors undergoing a single day of apheresis, and donors receiving a daily dose of G-CSF >960 micrograms were more likely to experience grade 2–4 pain on the first day of collection prior to apheresis. For grade 2–4 MTC symptoms, again, older donors had a lower risk (OR 0.53 for >60 year olds vs the youngest donors; p=0.006). Donors with pre-donation baseline pain and Hispanic donors had an increased risk, while black donors had a lower risk for MTC toxicities.

Table 4A.

Logistic regression model for grade 2–4 skeletal pain and grade 2–4 body symptoms on the first day of collection prior to apheresis. (Skeletal pain represents pain in at least one of the following sites: back, bone, headache, hip, joints, limbs, and neck. The severity of skeletal pain is defined as the maximum grade among these pain sites. Body symptoms include fever in absence of infections, fatigue, skin rash, injection site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The toxicity level is defined as the maximum grade among these symptoms.)

Variable	OR	95% CI	p-value
Skeletal pain grade 2–4
Donor age at donation			<0.001
18 to 40	1.00
41 to 60	0.64	(0.47–0.87)	0.004
61 and older	0.41	(0.28–0.60)	<0.001
Donor sex
Male	1.00
Female	1.48	(1.15–1.90)	0.002
Donor race / ethnicity			0.009
Non-Hispanic White	1.00
Hispanic	2.34	(1.39–3.91)	0.001
Black / African American	1.05	(0.62–1.76)	0.863
Other / Unknown	1.44	(0.82–2.51)	0.203
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	2.19	(1.66–2.89)	<0.001
Number of days of apheresis
1	1.00
>1	0.72	(0.56–0.94)	0.014
G-CSF average daily dose, µg/day			0.007
0 to 960	1.00
>960	1.54	(1.18–2.02)	0.002
Unknown	1.07	(0.54–2.11)	0.844
Body symptoms grade 2–4
Donor age at donation			0.003
18 to 40	1.00
41 to 60	0.56	(0.39–0.81)	0.002
61 and older	0.53	(0.33–0.83)	0.006
Donor race / ethnicity			0.023
Non-Hispanic White	1.00
Hispanic	1.70	(0.99–2.92)	0.054
Black	0.35	(0.14–0.90)	0.030
Other / unknown	0.76	(0.35–1.66)	0.493
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	1.94	(1.40–2.70)	<0.001

Abbreviations: OR is odds ratio; CI is confidence interval

Post-Collection Pain and Symptoms at 1 month, 6 months, and 1 year

Table 4B shows that donors above age 40 had a 65–71% increase in risk for grade 2–4 pain after collection when measured at 1 month, 6 months, and 1 year. This persistent pain did not improve over time (Table 4B and Figure 3A). Female donors and donors with pre-donation baseline pain were also at increased risk for persistent grade 2–4 pain. Of note, donors who reported no comorbidities and those who reported acceptable comorbidities had the lowest risk for post-collection pain, while donors who had comorbidities that were indeterminate or who would have been deferred by NMDP standards had significantly increased risk for post-collection pain (OR vs no comorbidities 1.39 and 2.41, p=0.054 and <0.001, respectively). Post-collection MTC symptoms were not affected by age, however females were at highest risk (OR 2.37, p<0.001) followed by donors with pre-donation baseline levels of pain (OR 1.67, p=0.007).

Table 4B.

Generalized Estimating Equations Model for longitudinal binary data of grade 2–4 skeletal pain and grade 2–4 body symptoms at 1 month, 6 month, and 1 year post-donation. (Skeletal pain represents pain in at least one of the following sites: back, bone, headache, hip, joints, limbs, and neck. The severity of skeletal pain is defined as the maximum grade among these pain sites. Body symptoms include fever in absence of infections, fatigue, skin rash, injection site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The toxicity level is defined as the maximum grade among these symptoms.)

Variable	OR	95% CI	p-value
Skeletal pain
Donor age at donation			0.022
18 to 40	1.00
41 to 60	1.71	(1.12–2.60)	0.013
61 and older	1.65	(1.03–2.66)	0.038
Donor sex
Male	1.00
Female	1.51	(1.16–1.96)	0.002
Comorbidity			0.005
Absent	1.00
Present-accept	1.19	(0.78–1.81)	0.419
Present-indeterminate	1.39	(0.99–1.93)	0.054
Present-defer	2.41	(1.55–3.75)	<0.001
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	2.89	(2.21–3.79)	<0.001
Time post-donation			0.006
1 month	1.00
6 months	1.30	(1.05–1.61)	0.016
1 year	1.43	(1.14–1.80)	0.002
Body symptoms
Donor age at donation			0.331
18 to 40	1.00
41 to 60	1.19	(0.75–1.89)	0.455
61 and older	0.89	(0.51–1.55)	0.687
Donor sex
Male	1.00
Female	2.37	(1.66–3.39)	<0.001
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	1.67	(1.15–2.41)	0.007

Abbreviations: OR is odds ratio; CI is confidence interval

Non-Recovery to Pre-donation Baseline Pain and Symptom Level at 1 Year

Table 4C shows multivariate analysis of risks associated with the inability of individual donors to return to their pre-donation baseline pain and MTC symptom status. Age again had an important effect with donors ages 41–60 and >60 having a 1.75 and 1.66 OR of non-recovery to pre-donation pain levels (P= 0.003, 0.022, respectively). Females were also at increased risk (OR 1.46, P=0.006). Of note, those who started with pain at pre-donation baseline were more likely to return to their pre-donation level of pain, pointing out that most of the pain reported in donors at 1 year occurred in donors who did not report pain at pre-donation baseline. Age did not appear to affect the risk of non-recovery to pre-donation levels of MTC symptoms, however, donors reporting comorbidities that warranted more investigation to know if NMDP deferral would have occurred were at increased risk (OR 1.74, p=0.012) and those who would have been deferred by NMDP standards were at even higher risk of non-recovery to pre-donation baseline MTC symptoms (OR 2.34, p=0.004). Skeletal pain at pre-donation baseline increased risk of non-recovery to pre-donation levels of MTC symptoms. In addition, the presence of MTC symptoms at pre-donation baseline increased the likelihood of recovery to that pre-donation value. Of note, for both pain and MTC symptoms, donors entering the study during the later years of enrollment had an improved chance of recovering to pre-donation baseline.

Table 4C.

Logistic regression model for non-recovery to pre-donation skeletal pain and body symptoms at 1 year. (Skeletal pain represents pain in at least one of the following sites: back, bone, headache, hip, joints, limbs, and neck. The severity of skeletal pain is defined as the maximum grade among these pain sites. Body symptoms include fever in absence of infections, fatigue, skin rash, injection site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The toxicity level is defined as the maximum grade among these symptoms.)

Variable	OR	95% CI	p-value
Skeletal pain
Donor age at donation			0.013
18 to 40	1.00
41 to 60	1.75	(1.20–2.55)	0.003
61 and older	1.66	(1.08–2.56)	0.022
Donor sex
Male	1.00
Female	1.46	(1.12–1.92)	0.006
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	0.39	(0.28–0.55)	<0.001
Year of donation
2010–2011	1.00
2012–2013	0.72	(0.55–0.94)	0.016
Body symptoms
Donor age at donation			0.233
18 to 40	1.00
41 to 60	1.24	(0.76–2.03)	0.382
61 and older	0.87	(0.48–1.56)	0.639
Comorbidity			0.018
Absent	1.00
Present-accept	1.51	(0.89–2.57)	0.126
Present-indeterminate	1.74	(1.13–2.68)	0.012
Present-defer	2.34	(1.31–4.20)	0.004
Pre-donation skeletal pain
Grade 0	1.00
Grade 1–4	1.77	(1.19–2.64)	0.005
Pre-donation body symptoms
Grade 0	1.00
Grade 1–4 Year	0.22	(0.11–0.44)	<0.001
Year of donation
2010–2011	1.00
2012–2013	0.65	(0.46–0.92)	0.014

Abbreviations: OR is odds ratio; CI is confidence interval

DISCUSSION

Previous studies of the experience of PBSC collection and recovery in RD have made only limited comments on the effect of aging.^7,21–27 While a number of studies have shown a decline in the number of CD34+ cells mobilized with older age, donor numbers assessed have been small.^10–13 Additionally, previous studies have not looked at how this decrease in donor CD34+ yield influenced the overall experience of older donors. Our study shows that the median yield in donors above age 60 is half that of donors age 18–40; additionally 11% of older donors are very poor mobilizers, with pre-apheresis CD34+ levels <20×10⁶/L. This leads to older donors undergoing both more episodes of apheresis and higher volumes of apheresis compared to younger donors. This then means that a much higher percentage of older donors are experiencing significant thrombocytopenia associated with the collection process (26% of donors >60 post-apheresis day 2 and 57% post-apheresis day 3 had platelet counts <50×10⁹/L).

Previous studies have also looked at SAEs and some have assessed pain.^7,23,24 These studies have shown that most donors have mild-moderate pain and the process is generally well tolerated. They have not, however, shown the effect of age on pain and symptoms, and they also have not followed donors closely for these symptoms for an extended time period afterward. The analysis we report allows us to have a much more comprehensive understanding of the RD experience and to individualize how we counsel RD. Knowing a donor’s age, gender, and ethnicity, we can explain individually their risk of pain and other symptoms as well as their risk of having lingering mild discomfort as long as a year after the collection process.

It is important to note that while PBSC donors >60 are at lower risk of significant acute pain compared to younger donors, they are less likely to recover to their pre-donation level of pain. It should be noted that older and younger donors who had pain at pre-donation baseline actually recovered to that pre-donation level more often. This means that the older donors who have some mild-moderate pain and have not recovered to their pre-donation level are generally donors who start with no pre-donation pain. Of note, in spite of this finding, we showed in an earlier publication that RD >60 have equivalent health-related quality of life outcomes compared to donors age 18–60.¹⁶ Lack of recovery to baseline pain and symptoms varied over the study period, with donors enrolled during the later part of the study having a better chance of recovery. Study methodology did not change, so the reason for this observation is unclear. Possible explanations include center changes in donor management due to closer attention paid to donors because of study participation or changes over time in the types of donors collected by the centers. Analysis of our data did not reveal a clear answer to why recovery changed over time.

While we show that age is an important criterion in assessing risk of a donor for significant pain or MTC symptoms, our study is also the first to show that the presence of reported comorbidities in a donor has an effect on their likelihood of reporting pain at 1, 6, and 12 months after the collection and their likelihood of non-recovery to their pre-donation baseline level of symptoms. Likely because of numbers we were not able to find associations of worse outcomes with a specific comorbidity or category of comorbidities, but we do note that donors who had no comorbidities or those who had comorbidities that would have been acceptable according to NMDP screening standards^19,20 were at lower risk than donors who clearly would have been rejected as an NMDP donor or for whom it was unclear whether they would have been rejected. This categorization of comorbidities is a broad way of determining the seriousness of a given reported comorbidity, and indicates that comorbidities matter and should be important in the assessment and counseling of related PBSC donors. It also suggests that RD centers should consider adopting screening recommendations similar to those of unrelated donor registries, as suggested and outlined in a consensus paper from the Standing Committee on Donor Issues of the Worldwide Network for Blood and Marrow Transplantation (WBMT).⁹ This recommendation should be assessed in the context of understanding what donor options are available for a given recipient, and the willingness of a given RD to assume some level of increased risk for their family member.

In summary, age matters with the process of RD PBSC collection. Older donors have more chronic pain at pre-donation baseline and a higher number of and more significant comorbidities. After G-CSF mobilization older donors have lower levels of pre-apheresis CD34+ cells, leading to a higher likelihood of multiple apheresis procedures or higher volume procedures. This in turn leads to a higher risk of post-apheresis thrombocytopenia. Most significantly, even though donors over age 60 are less likely to report significant pain and symptoms during the collection than younger donors, they are more likely to have non-recovery to pre-donation baseline up to one year after the procedure. These findings should be considered by RD during the consent process and studies or center practices aimed at preventing or improving the donor experience should be encouraged.

Highlights.

• Older PBSC donors have lower CD34+ yields leading to higher volume collections.

• Higher volume and number of collections leads to high rates of thrombocytopenia.

• Younger PBSC donors have higher rates of acute pain and symptoms with PBSC collection.

• Older PBSC donors have a higher rate of non-recovery to baseline at one year.

• Donors with comorbidities are at increased risk for pain and symptoms at one year.