Abstract
Background:
Ethnic minority donors are essential on international donor registries to ensure access to all patients requiring an allogeneic stem cell transplant. Current literature regarding bone marrow (BM) donation-associated pain and toxicity in donors with Sickle Cell trait (ST), a condition that disproportionally affects minorities, is very limited. Improved communication with potential donors with ST about donation-associated toxicities is important to address misconceptions about the donation and may increase the likelihood of participation by minority donors.
Objective:
The aim of this study was to determine the impact of ST on peri-collection pain and toxicities experienced by unrelated BM donors with ST.
Study design:
The study population comprised first-time unrelated donors with ST and subset of unrelated donors without ST from the United States whose BM donation was facilitated by NMDP between 2010 and 2019. Donors in the control group (donors without ST) were selected for propensity score matching based on age categories, sex, race/ethnicity and pre-donation skeletal pain. Logistic regression models were conducted to compare the donors with and without ST for pain and toxicities associated with donation adjusting for differences in donor characteristics. Descriptive statistics were used to report SAE. Univariate probabilities of complete recovery from donation were calculated using the Kaplan-Meier estimator.
Results:
A total of 346 BM donors (87 with ST and 259 without ST) were included in this study. The majority of the donors were male (52%), African American (64%) and overweight or obese (77%) in both cohorts. Stem cell collection parameters including BM harvest volume, requirement for autologous blood transfusion post-harvest and duration of anesthesia were comparable between the two cohorts. Two days post-donation, 68.9% of BM donors with ST and 83.1% of BM donors without ST experienced skeletal pain (p<0.01). Although, grade 1 pain was more common in donors without ST (51.4% vs. 35.6%), grade 2–4 pain was comparable between the two cohorts (P=0.98). At 1-month post donation, grade 2 to 4 pain was comparable between the donors with and without ST (p=0.25). By 6-months post donation, the rates of persistent pain were low at 5.7% and 6.5% in donors with or without ST. Donation-related Modified Toxicity Criteria (MTC) at 2 days post donation was comparable between donors with and without ST (P=0.59). The median times to recovery in donors with and without ST were 23.5 and 22.0 days, respectively. The rate of reported AEs was slightly higher in donors with ST (2.29%) compared to donors without ST (1.59%).
Conclusion:
BM donation appeared well tolerated in donors with ST with similar rates of post-donation pain and general symptoms compared with the donors without ST. BM donation has a small risk of perioperative mortality which is similar to that in donors without ST. This report provides, to our knowledge, the first comprehensive analysis of the impact of ST on toxicities and recovery after BM donation and adds to our understanding of safety of BM donation in donors with ST.
Introduction:
Bone marrow (BM) remains a crucial source of hematopoietic stem cells (HSCs) accounting for 11% of total NMDP products provided in 2024 (1). BM donation is a reasonably safe procedure; peri-donation adverse events, although frequent, are mostly transient, self-limited and without long-term consequences. The risk of serious complications leading to death peri BM donation is estimated to be 1 in 10,000 (2). To ensure donor and recipient safety, as well as the quality of the BM products, the World Marrow Donor Association (WMDA) and the NMDP have established suitability criteria and recommendations for evaluating unrelated donors. Based on the WMDA recommendations, subjects with sickle cell β-thalassemia minor may be suitable for BM donation if the hemoglobin values fall within the normal range (3,4). However, the recommendation is to avoid granulocyte colony-stimulating factor (G-CSF) in donors with sickle cell β-thalassemia, sickle cell disease, or other complex sickle hemoglobinopathies which may lead to development of sickle cell crisis due to hyperleukocytosis, neutrophil activation and cytokine release.(5,6). Similarly, based on current NMDP recommendations (5), individuals with sickle cell trait (ST) are eligible to donate BM but not peripheral blood stem cells (PBSC).
ST is a genetic condition that is more prevalent among African Americans. While ST represents an asymptomatic carrier state, it is certainly not an entirely harmless condition (7,8). The presence of Hemoglobin S (HbS) in ST may contribute to specific disease processes, particularly under extreme conditions such fluid loss, hypoxia and acidosis which can occur during surgical procedures. Current literature regarding stem cell donation-associated pain and toxicity in donors with ST is limited to a few small studies of PBSC donation (8, 9, 10). Currently, no study to date has evaluated donation-associated toxicities in BM donors with ST.
There are several factors that affect the availability of donors including the ambivalence about safety of donation (doubts and worries about the chances of a donation-related complication) and distrust of the medical community (13). Therefore, providing more information to potential donors with ST about donation associated toxicities is necessary to address misconceptions about the donation which may lead to increased minority donor participation. Herein, we aim to determine the impact of ST on peri-collection pain and acute toxicities experienced by unrelated BM donors with ST.
METHODS
Study population
The study population consisted of all first-time unrelated donors with ST and a subset of unrelated donors without ST from the United States whose BM donation was facilitated by NMDP between 2010 and 2019. Granulocyte colony-stimulating factor (G-CSF)-mobilized BM donations were excluded. Unrelated donors with ST were identified based on screening blood test to detect the presence of Hemoglobin S (Hb S) or sickle hemoglobin. Sickle hemoglobin screening is currently required to assess the unrelated donor’s suitability for donation. Due to a small number of donors with ST (n=87), donors in the control group (donors without ST) were selected for propensity score matching based on age categories (18–30, 30–50, and >50 years of age), sex, race/ethnicity and pre-donation skeletal pain. A total of 259 donors were selected for the matched control group, for a 3:1 ratio comparison with the donors with ST. Data on donors and donation characteristics were collected using standard NMDP forms. For donors who had 2 or more donations, analysis was limited to the first donation, and follow-up time was truncated at the time of the second collection. All donors provided written informed consent for participation in the Center for International Blood and Marrow Transplant Research (CIBMTR) studies approved by the NMDP Institutional Review Board (IRB). This study was conducted in accordance with the Declaration of Helsinki.
Data collection
Data collection for recovery and side effects was performed by telephone administered surveys using NMDP questionnaires. BM donors, were contacted by either the donor center or the NMDP survey research group at 2 days and 1-week post-collection and then weekly thereafter until the donor reported full recovery from donation; donor questionnaires were also completed at 1, 6, 12 months post-collection.
Endpoints
The primary endpoints of this study were donor symptoms associated with BM donation. Donor toxicities were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). These symptoms included the incidence of grade 2 to 4 skeletal pain and the highest toxicity level across selected body symptoms frequently associated with donation or maximum modified toxicity criteria (MTC) including fever in the absence of signs of infection, fatigue, skin rash, local reactions, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. Skeletal pain was defined as pain in at least 1 site including back, bone, headache, hip, limb, joint, or neck. The severity of skeletal pain was defined as the maximum grade of pain among these sites. Endpoints were analyzed at the following time points: first assessment after BM collection (48 hours after completing the collection when pain and toxicities are expected to be at highest level); and at 1 month and at 6 months after donation.
The secondary endpoints were time to recovery and the incidence of serious adverse events (SAE) occurring peri-donation and thereafter. Time to recovery was defined as time from donation (day of harvest for BM) to report of complete recovery, which was determined by donor reports of return to baseline physical status and no ongoing or new symptoms associated with the collection procedure. SAE was defined as an event experienced by the donor that resulted in one of the following outcomes: death; a life-threatening adverse experience; in-patient hospitalization; a persistent or significant disability. Relatedness of the SAE was classified as: Definite, Probable, Possible, Unlikely, or Unrelated. The presence and relatedness of the SAE, as well as whether the SAE represented an expected or unexpected event was adjudged independently by two of the investigators (NF, HS).
Statistical analysis
Pre-donation baseline variables were compared between donors with and without ST using the Pearson χ test for categorical variables and the Kruskal-Wallis test for continuous variables. Multivariable analyses using mixed effect logistic regression models were conducted to compare the donors with and without ST for pain and toxicities associated with BM donation adjusting for donor characteristics as fixed effects and using matched pairs as random effects. The following donor-related variables were considered in the multivariable analysis; donor’s BMI, pre-donation hemoglobin, pre-donation white blood cell count, pre-donation platelet count, total volume of bone marrow harvested, duration of anesthesia, year of donation, and baseline pain and toxicities. Stepwise regression with a selection threshold of p<0.05 was used to select variables for inclusion in the model, with ST forced into the model. All analyses were performed using SAS 9.4 (Cary, NC). Based on preliminary power calculation, with sample sizes of 87 donors with ST and 259 donors without ST, we have 80% power to detect an increase in the grade 2–4 skeletal pain from 30% to 47% in the ST donors (17% absolute increase in pain).
Descriptive statistics were used to report AES in donors with and without ST. Differences for categorical variables in donors with ST who did experience an AES versus those who did not were compared by the Chi Square test. Univariate probabilities of complete recovery from donation were calculated using the Kaplan-Meier estimator. A multivariable model using Cox proportional hazards regression compared the time to complete recovery between the two cohorts after adjusting for donor characteristics and baseline measurements and accounting for matched pairs using a frailty term. A p-value<0.05 was considered for statistical significance.
RESULTS:
Characteristics of BM Donors
A total of 346 BM donors (87 with ST and 259 without ST) between 2010 and 2019 were included in this study. The baseline demographic and collection characteristics are summarized in Table 1. Among propensity-score matched populations, the median age of the donors was 35.0 years in both cohorts. Majority of the donors were male, African American (64%) and overweight or obese (approximately 77%) in both cohorts. Stem cell collection parameters including BM harvest volume, requirement for autologous blood transfusion post-harvest and duration of anesthesia were comparable between the two cohorts.
Table 1.
Characteristics of first-time unrelated BM donors in the United States between 2010 and 2019
| Sickle Trait: |
|||||||||
|---|---|---|---|---|---|---|---|---|---|
| Characteristic | Positive | Negative | P-Value | ||||||
| No. of patients | 87 | 259 | |||||||
| No. of centers | 29 | 56 | |||||||
| Donor age, years - no. (%) | 0.98a | ||||||||
| Median (min-max) | 35 (19–57) | 35 (20–57) | |||||||
| 18–29 | 26 (29.9) | 78 (30.1) | |||||||
| 30–49 | 52 (59.8) | 156 (60.2) | |||||||
| >=50 | 9 (10.3) | 25 (9.7) | |||||||
| Donor sex - no. (%) | 0.95a | ||||||||
| Male | 46 (52.9) | 136 (52.5) | |||||||
| Female | 41 (47.1) | 123 (47.5) | |||||||
| Donor race/ethnicity - no. (%) | 1.00a | ||||||||
| Caucasian | 8 (9.2) | 24 (9.3) | |||||||
| African/African-American | 56 (64.4) | 166 (64.1) | |||||||
| Asian/Pacific Islander | 1 (1.1) | 3 (1.2) | |||||||
| Hispanic | 9 (10.3) | 27 (10.4) | |||||||
| Native American | 1 (1.1) | 3 (1.2) | |||||||
| Multiple | 12 (13.8) | 36 (13.9) | |||||||
| African/African-American + Asian/Pacific Islander | 1 (8.3) | 0 (0.0) | |||||||
| + Native American | |||||||||
| African/African-American + Hispanic | 0 (0.0) | 1 (2.8) | |||||||
| African/African-American + Missing | 0 (0.0) | 1 (2.8) | |||||||
| African/African-American + Native American | 2 (16.7) | 0 (0.0) | |||||||
| Asian/Pacific Islander + Hispanic + Native American | 0 (0.0) | 1 (2.8) | |||||||
| Caucasian + African/African-American | 2 (16.7) | 0 (0.0) | |||||||
| Caucasian + African/African-American + Native | 2 (16.7) | 1 (2.8) | |||||||
| American | |||||||||
| Caucasian + Asian/Pacific Islander | 0 (0.0) | 3 (8.3) | |||||||
| Caucasian + Hispanic + Native American | 0 (0.0) | 1 (2.8) | |||||||
| Caucasian + Native American | 1 (8.3) | 19 (52.8) | |||||||
| Hispanic + Native American | 2 (16.7) | 7 (19.4) | |||||||
| Native American + Missing | 2 (16.7) | 2 (5.6) | |||||||
| Donor weight (kg) | 0.94b | ||||||||
| n | 87 | 259 | |||||||
| Median (min-max) | 83.0 (43.5–150.6) | 84.4 (40.4–155.0) | |||||||
| Missing | 0 | 0 | |||||||
| Donor BMI - no. (%) | 0.95a | ||||||||
| Underweight (<18.5) | 1 (1.1) | 2 (0.8) | |||||||
| Normal (18.5–24.9) | 19 (21.8) | 52 (20.1) | |||||||
| Overweight (25–29.9) | 32 (36.8) | 103 (39.8) | |||||||
| Obese (30+) | 35 (40.2) | 101 (39.0) | |||||||
| Missing | 0 (0.0) | 1 (0.4) | |||||||
| Recipient weight available - no. (%) | 0.49a | ||||||||
| No | 14 (16.1) | 47 (18.2) | |||||||
| Yes | 42 (48.3) | 136 (52.5) | |||||||
| N/A: Data not collected | 31 (35.6) | 76 (29.3) | |||||||
| Donor weight: Recipient weight (ratio) | 0.39b | ||||||||
| n | 42 | 136 | |||||||
| Median (min-max) | 1.4 (0.6–21.5) | 1.6 (0.4–22.0) | |||||||
| 5th-95th pctl | 0.6–14.7 | 0.7–12.8 | |||||||
| Missing | 45 | 123 | |||||||
| Pre-donation hemoglobin (g/dL) | 0.09b | ||||||||
| n | 86 | 257 | |||||||
| Median (min-max) | 13.1 (9.8–16.8) | 13.3 (9.0–17.0) | |||||||
| 5th-95th pctl | 10.8–15.6 | 10.7–15.9 | |||||||
| Missing | 1 | 2 | |||||||
| Pre-donation white blood cells (x109/L) | 0.11b | ||||||||
| n | 86 | 257 | |||||||
| Median (min-max) | 5.4 (2.3–12.9) | 5.9 (2.3–12.3) | |||||||
| 5th-95th pctl | 3.7–8.2 | 3.6–9.7 | |||||||
| Missing | 1 | 2 | |||||||
| Pre-donation platelets (x109/L) | 0.75b | ||||||||
| n | 86 | 257 | |||||||
| Median (min-max) | 234.5 (142.0–423.0) | 237.0 (38.0–486.0) | |||||||
| 5th-95th pctl | 168.0–341.0 | 161.0–360.0 | |||||||
| Missing | 1 | 2 | |||||||
| Total volume collected/donor weight (mL/kg) | 0.03b | ||||||||
| n | 87 | 256 | |||||||
| Median (min-max) | 14.1 (0.9–23.8) | 13.0 (1.8–24.1) | |||||||
| 5th-95th pctl | 3.7–21.1 | 4.3–20.7 | |||||||
| Missing | 0 | 3 | |||||||
| Total volume collected/donor weight (mL/kg) - no. (%) | 0.20a | ||||||||
| <10 mL/kg | 21 (24.1) | 77 (29.7) | |||||||
| 10 to <15 mL/kg | 26 (29.9) | 95 (36.7) | |||||||
| 15 to <20 mL/kg | 29 (33.3) | 63 (24.3) | |||||||
| >= 20 mL/kg | 11 (12.6) | 21 (8.1) | |||||||
| Missing | 0 (0.0) | 3 (1.2) | |||||||
| Autologous red cells given1 - no. (%) | 0.15a | ||||||||
| No | 37 (42.5) | 126 (48.6) | |||||||
| Yes | 49 (56.3) | 133 (51.4) | |||||||
| Missing | 1 (1.1) | 0 (0.0) | |||||||
| TNC (x106/mL) | 0.04b | ||||||||
| n | 87 | 256 | |||||||
| Median (min-max) | 14.9 (4.8–52.0) | 16.6 (3.6–47.3) | |||||||
| 5th-95th pctl | 9.2–30.5 | 9.1–30.0 | |||||||
| Missing | 0 | 3 | |||||||
| Duration of collection (minutes) | 0.77b | ||||||||
| n | 87 | 258 | |||||||
| Median (min-max) | 56.0 (9.0–180.0) | 53.0 (14.0–175.0) | |||||||
| 5th-95th pctl | 26.0–154.0 | 19.0–114.0 | |||||||
| Missing | 0 | 1 | |||||||
| Duration of anesthesia (minutes) | 0.39b | ||||||||
| n | 86 | 257 | |||||||
| Median (min-max) | 104.5 (50.0–248.0) | 98.0 (42.0–230.0) | |||||||
| 5th-95th pctl | 68.0–214.0 | 60.0–160.0 | |||||||
| Missing | 1 | 2 | |||||||
| Type of anesthesia - no. (%) | 0.20a | ||||||||
| General | 85 (97.7) | 254 (98.1) | |||||||
| Local | 1 (1.1) | 0 (0.0) | |||||||
| Spinal | 1 (1.1) | 5 (1.9) | |||||||
| Skeletal pain grade, baseline - no. (%) | 0.81a | ||||||||
| 0 | 81 (93.1) | 243 (93.82) | |||||||
| 1 | 6 (6.90) | 16 (6.18) | |||||||
| MTC grade, baseline - no. (%) | 0.21a | ||||||||
| 0 | 84 (96.55) | 246 (94.98) | |||||||
| 1 | 1 (1.15) | 10 (3.86) | |||||||
| 2 | 1 (1.15) | 3 (1.16) | |||||||
| Missing | 1 (1.15) | 0 (0) | |||||||
| MTC grade 2–4, baseline - no. (%) | 0.22a | ||||||||
| No | 85 (97.70) | 256 (98.84) | |||||||
| Yes | 1 (1.15) | 3 (1.16) | |||||||
| Missing | 1 (1.15) | 0 (0) | |||||||
| Year of collection - no. (%) | 0.14a | ||||||||
| 2010 | 9 (10.3) | 17 (6.6) | |||||||
| 2011 | 13 (14.9) | 27 (10.4) | |||||||
| 2012 | 12 (13.8) | 27 (10.4) | |||||||
| 2013 | 12 (13.8) | 46 (17.8) | |||||||
| 2014 | 3 (3.4) | 28 (10.8) | |||||||
| 2015 | 9 (10.3) | 23 (8.9) | |||||||
| 2016 | 8 (9.2) | 37 (14.3) | |||||||
| 2017 | 7 (8.0) | 27 (10.4) | |||||||
| 2018 | 10 (11.5) | 24 (9.3) | |||||||
| 2019 | 4 (4.6) | 3 (1.2) | |||||||
a Pearson chi-square test;
b Kruskal-Wallis test
Only 1 of the 346 donors received an allogeneic RBC transfusion; this individual also tested positive for sickle cell trait.
Toxicities experiences of BM donors with and without ST
Table 2 describes the time course and degree of toxicities experienced by BM donors with ST vs. those without ST. Two days (48 hours) post-donation, 68.9% of BM donors with ST and 83.1% of BM donors without ST experienced skeletal pain (p<0.01). Although, grade 1 pain was more common in donors without ST than those with ST (51.4% vs. 35.6%), grade 2–4 pain was comparable between the two cohorts (33.3% of BM donors with ST and 32.4% of BM donors without ST; P=0.98). The rates of grade 3–4 pain were low in both donors with and without ST, 0% vs. 0.8% respectively (p=0.71).
Table 2.
Description of the time course and degree of toxicities experienced by bone marrow donors
| Characteristic | ST Positive | ST Negative | P-Value |
|---|---|---|---|
| No. of patients | 87 | 259 | |
| Skeletal pain grade, 2-days post-donation - no. (%) | <.01a | ||
| 0 | 22 (25.3) | 28 (10.8) | |
| 1 | 31 (35.6) | 133 (51.4) | |
| 2 | 29 (33.3) | 82 (31.7) | |
| 3 | 0 (0.0) | 2 (0.8) | |
| 4 | 0 (0.0) | 0 (0.0) | |
| Not reported | 5 (5.7) | 14 (5.4) | |
| Skeletal pain grade 2–4, 2-days post-donation - no. (%) | 0.98a | ||
| No | 53 (60.9) | 161 (62.2) | |
| Yes | 29 (33.3) | 84 (32.4) | |
| Missing | 5 (5.7) | 14 (5.4) | |
| Skeletal pain grade 3–4, 2-days post-donation - no. (%) | 0.71a | ||
| No | 82 (94.3) | 243 (93.8) | |
| Yes | 0 (0.0) | 2 (0.8) | |
| Missing | 5 (5.7) | 14 (5.4) | |
| MTC grade, 2-days post-donation - no. (%) | 0.59a | ||
| 0 | 32 (36.8) | 80 (30.9) | |
| 1 | 36 (41.4) | 129 (49.8) | |
| 2 | 14 (16.1) | 36 (13.9) | |
| Not reported | 5 (5.7) | 14 (5.4) | |
| Skeletal pain grade, 1-month post-donation - no. (%) | 0.25a | ||
| 0 | 70 (80.5) | 213 (82.2) | |
| 1 | 10 (11.5) | 27 (10.4) | |
| 2 | 0 (0.0) | 8 (3.1) | |
| 3 | 0 (0.0) | 0 (0.0) | |
| 4 | 0 (0.0) | 1 (0.4) | |
| Not reported | 7 (8.0) | 10 (3.9) | |
| Skeletal pain grade, 6-months post-donation - no. (%) | 0.93a | ||
| 0 | 65 (74.7) | 194 (74.9) | |
| 1 | 4 (4.6) | 11 (4.2) | |
| 2 | 1 (1.1) | 6 (2.3) | |
| 3 | 0 (0.0) | 1 (0.4) | |
| 4 | 0 (0.0) | 0 (0.0) | |
| Not reported | 17 (19.5) | 47 (18.1) | |
| Time from donation to recovery or last follow-up (days) | 0.48b | ||
| n | 86 | 259 | |
| Min | 2.0 | 2.0 | |
| 25th pctl | 10.0 | 13.0 | |
| Median | 23.5 | 22.0 | |
| 75th pctl | 43.0 | 35.0 | |
| Max | 444.0 | 397.0 | |
| TNC per recipient weight (x108/kg) | 0.48b | ||
| n | 42 | 133 | |
| Min | 1.2 | 1.2 | |
| 25th pctl | 2.3 | 2.8 | |
| Median | 3.2 | 4.0 | |
| 75th pctl | 7.9 | 7.1 | |
| Max | 24.5 | 38.8 | |
| Severe adverse event - no. (%) | 0.64a | ||
| No | 85 (97.7) | 255 (98.5) | |
| Yes | 2 (2.3) | 4 (1.5) |
MTC, modified toxicity criteria; ST, Sickle cell trait; TNC, Total nucleated cell.
Pearson chi-square test;
Kruskal-Wallis test
At 1-month post donation, grades 1 to 4 pain were comparable between the donors with and without ST, 11.5% and 13.9% respectively (p=0.25). By 6-months post donation, the rates of persistent pain were low with only 5.7% and 6.5% of donors with or without ST experiencing donation associated pain (p=0.93). MTC at 2 days post donation was comparable between donors with and without ST (63.2% vs. 69.1%; P=0.59).
Multivariable (MVA) analysis of risks associated with experiencing significant levels of pain and toxicities is shown in Table 3a and b. In the MVA, the presence of ST was not associated with pain and toxicities after BM donation. Irrespective of donor ST status, female sex was significantly associated with grade 2–4 pain (OR 1.83, 95% CI 1.14–2.93, p=. 01) and max MTC (OR 7.3, 95% CI 3.27–16.3, p<. 0001) compared to male at 2 days post donation.
Table 3a.
Multivariable model of skeletal pain grade 2–4 at day 2 by sex and sickle cell trait
| 95% CI | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Level | N | Events | OR | Lower Limit | Upper Limit | P-value |
| Sickle trait | No | 241 | 82 | 1.00 | |||
| Yes | 81 | 29 | 1.09 | 0.64 | 1.86 | 0.750 | |
| Sex | M | 168 | 47 | 1.00 | |||
| F | 154 | 64 | 1.83 | 1.14 | 2.93 | 0.012 | |
Table 3b.
Multivariable analysis of max MTC grade ≥ 2 at day 2 by sex and sickle cell trait
| 95% CI | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Level | N | Events | OR | Lower Limit | Upper Limit | P-value |
| Sickle trait | No | 241 | 35 | 1.00 | |||
| Yes | 81 | 14 | 1.29 | 0.63 | 2.64 | 0.492 | |
| Sex | M | 168 | 8 | 1.00 | |||
| F | 154 | 41 | 7.30 | 3.27 | 16.30 | <0.001 | |
Probability of complete recovery
The median time to recovery in donors with and without ST were 23.5 and 22.0 days, respectively (Table 2; figure 1). Sickle trait was not significantly associated with recovery as shown in Table 4 (HR=0.79, 95% CI 0.61–1.01, p=0.065). The only factor that was associated with increased time to recovery was longer duration of anesthesia (treated as a continuous predictor, with the HR of 0.75 corresponding to a 1 hour increase in duration) (Table 4).
Figure 1. Probability of complete recovery after bone marrow donation.
Table 4.
Multivariate cox frailty model of time to donor recovery by sickle cell trait and duration of anesthesia
| 95% CI | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Level | N | Events | HR | Lower | Upper | P-value |
| Sickle cell trait | No | 255 | 251 | 1.00 | |||
| Yes | 85 | 84 | 0.79 | 0.61 | 1.01 | 0.065 | |
| Duration of anesthesia (hours) | 0.75 | 0.62 | 0.92 | 0.005 | |||
Severe Adverse Events among the BM donors with and without ST
The rate of 2 or more nights of hospitalization due to complications associated with donation was low in both cohorts (1.1% in donors with ST and 0.4% in donors without ST). A total of 7 SAEs were confirmed in 6 (1.73%) of the 346 donors. Of these, 2 SAEs occurred in BM donors with ST (2.29%), and 5 (1.59%) occurred in BM donors without ST. Table 5 summarizes donor and event characteristics for each SAE. The SAEs were cardiovascular in four donors, and musculoskeletal in three donors. One donor with ST experienced cardiac event due to anesthesia complications during the procedure requiring resuscitation and intubation and resulted in death. All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. Symptoms resembling a sickle crisis was not reported.
Table 5:
List of severe adverse event reported after bone marrow harvest
| Sickle cell trait status (Y/N) | Year | Time from BM harvest to AE onset, (days) | Description of the event | Intervention | Outcome | Hospitalization requirement (Y/N) |
Relation to BM harvest |
|---|---|---|---|---|---|---|---|
| Yes | 2019 | 0 | Cardiac arrest during BM collection | Cardiac resuscitation | Death | Y | Probably related |
| Yes | 2010 | 0 | Symptomatic hypotension and anemia | Intravenous fluid | Resolved | Y | Definitely related |
| No | 2010 | 0 | Symptomatic hypotension and anemia | Intravenous fluid | Resolved | Y | Definitely related |
| No | 2012 | 2 | Back pain requiring ED visit | Intravenous pain medication | Resolved | N | Probably related |
| No | 2012 | 12 | Vasovagal episode requiring ED visit |
No intervention | Resolved | N | Possibly related |
| No | 2016 | 8 | Hip pain, nausea, insomnia requiring ED visit |
Oral pain medication and antiemetics | Resolved | N | Definitely related |
| No | 2017 | 21 | Hip pain | Oral pain medication | Resolved | N | Possibly related |
DISCUSSION:
ST is one of the most common hemoglobinopathies in the world. Individuals with ST are generally asymptomatic and present with no significant clinical or hematologic manifestations. However, certain environmental conditions, such as hypoxia, acidosis and dehydration during operation, can promote HbS polymerization and systemic sickling leading to rhabdomyolysis, thromboembolic events, acute kidney injury and even death (14–19). These reports may raise concern regarding BM donation in stem cell donors with ST. To our knowledge, this is the first study that formally evaluates the impact of ST on donation-associated acute toxicities and time to recovery in adult BM donors. Based on the results of this study, BM donation appeared well tolerated in the donors with ST with similar rates of post-donation grade 2–4 pain and general symptoms compared to the donors without ST. The incidence of grade 3–4 pain was low for both cohorts, consistent with prior reports. Moreover, this study showed prompt recovery of the BM donors irrespective of ST status. There was no difference between BM donors with and without ST in rate or extent of recovery. Median time to recovery of BM donors with and without ST was approximately 3 weeks, similar to that reported by prior studies (20).
While BM donation is a reasonably safe procedure, adverse events do occur. The rate of SAEs noted in our study (2.02 %) is in line with the prior reports of 2.38% in BM donors by applying the FDA SAE definition which includes unplanned hospitalization for expected events (21). The rate of reported SAEs was slightly higher in donors with ST (2.29%) compared to donors without ST (1.59%). Symptoms resembling a sickle crisis were not reported in donors with ST who underwent marrow harvest. The majority of SAEs occurred in ST donors were cardiovascular events including hypotension and syncope which may be attributed to more high-volume BM harvest (>15 ml/kg) in the cohort with ST (45.9%) compared with those without ST (32.4%). In our study, one cardiac arrest was reported in an African American BM donor with ST. Although exceedingly rare, death has been described among marrow and peripheral blood HCT donors. In a study by NMDP evaluating adverse events of stem cell donation, 6 deaths are documented among the 9061 related BM donors. Two of the reported deaths in related BM donors (both from cardiac arrest) occurred before the donation procedure, the remaining 4 were from cardiovascular events including ventricular fibrillation, respiratory arrest, myocardial infarction and pulmonary embolism. No donation-related death was reported in unrelated donors (22) . Donor fatalities and severe adverse events were also investigated in a European survey study including 51,024 first allogeneic hematopoietic stem cell transplantations, of which 27,770 were bone marrow and 23,254 peripheral blood (23). Five related donor fatalities, one after a related BM donation due to pulmonary embolism 15 days after donation, and four after related peripheral blood donation were reported. Donor fatalities among unrelated donors is exceedingly rare given strict eligibility criteria compared to related donors.
Based on the current literature, in general population the risk of cardiovascular events in individuals with ST does not seem to be higher than individuals without ST. The largest meta-analysis to date examining the association between ST and incidence of cardiovascular disease among 1034 African American individuals, suggests that the ST is generally not associated with an increased risk of major cardiovascular events like myocardial infarction or coronary artery disease (24). Some studies indicate a potential for subtle increased risk of certain cardiovascular complications, particularly under specific conditions like extreme stress or low oxygen levels. Nevertheless, all donors must be carefully evaluated and fully informed prior to BM donation with good understanding of the potential procedure related complications. Moreover, specific precautions must be taken to ensure the donors’ safety including adequate fluid replacement during and after the harvest, close communication with anesthesia at several points before and during the procedure to coordinate and optimize the donor’s care prior to surgery (1).
This study has several limitations which must be acknowledged. ST is a heterogeneous disease for which multiple factors including HbS levels can influence a particular patient’s symptoms. Unfortunately, detailed data regarding hemoglobin variants and HbS level was not available for the donors in the cohort. Moreover, although there was no significant difference in the proportion the donors with ST experiencing peri-donation pain and toxicities compared to those without ST, this comparison is limited by statistical power due to a relatively small sample size (80% power to detect 17% absolute increase in pain in ST donors). In addition, while extensive research affirms the safety of bone marrow donation (25), the potential longer-term late effects specific to donors with sickle cell trait remain warrant further investigation. Although concerns regarding late effects following stem cell donation are primarily linked to the potential long-term impact of G-CSF exposure, which was not a factor in our study as G-CSF–mobilized BM donations were excluded. Lastly, due to the rarity of SAEs, the associations of SAE with specific comorbidities or a development of a risk score would require a much larger study.
In summary, BM donation is a safe procedure in donors with ST with very low rates of serious adverse events. This report provides the first comprehensive analysis of the impact of ST on toxicities and recovery after BM donation and adds to our understanding of safety of BM donation in donors with ST. The results of this study can be used to adequately inform prospective donors with ST about risks of BM donation and may address some of the misconceptions about the donation in setting of ST.
Highlights.
Bone marrow (BM) donation is a safe procedure in donors with sickle cell trait (ST)
BM donors with and without ST had with similar rates of post-donation toxicities.
The time to recovery did not differ between BM donors with and without ST.
Acknowledgments
Supported by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); and N00014-24-1-2057 and N00014-25-1-2146 from the Office of Naval Research. Additional federal support is provided by U01AI184132 from the National Institute of Allergy and Infectious Diseases (NIAID); and UG1HL174426 from the National Heart, Lung, and Blood Institute (NHLBI). Support is also provided by the Medical College of Wisconsin, NMDP, Gateway for Cancer Research, Pediatric Transplantation and Cellular Therapy Consortium and from the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc; Adaptimmune LLC; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Alexion; AlloVir, Inc; Amgen, Inc; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics; Autolus Limited; BeiGene; BioLineRx; Blue Spark Technologies; bluebird bio, Inc; Blueprint Medicines; Bristol Myers Squibb Co; CareDx Inc; Caribou Biosciences, Inc; CSL Behring; CytoSen Therapeutics, Inc; DKMS; Editas Medicine; Elevance Health; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd; Gift of Life Biologics; Gift of Life Marrow Registry; HistoGenetics; In8bio, Inc; Incyte Corporation; Iovance; Janssen Research & Development, LLC; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc; Karius; Kashi Clinical Laboratories; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Labcorp; Legend Biotech; Mallinckrodt Pharmaceuticals; Med Learning Group; Medac GmbH; Merck & Co.; Mesoblast, Inc; Millennium, the Takeda Oncology Co.; Miller Pharmacal Group, Inc; Miltenyi Biotec, Inc; MorphoSys; MSA-EDITLife; Neovii Pharmaceuticals AG; Novartis Pharmaceuticals Corporation; Omeros Corporation; Orca Biosystems, Inc; OriGen BioMedical; Ossium Health, Inc; Pfizer, Inc; Pharmacyclics, LLC, An AbbVie Company; Registry Partners; Rigel Pharmaceuticals; Sanofi; Sarah Cannon; Seagen Inc; Sobi, Inc; Sociedade Brasileira de Terapia Celular e Transplante de Medula Óssea (SBTMO); Stemcell Technologies; Stemline Technologies; STEMSOFT; Takeda Pharmaceuticals; Talaris Therapeutics; Vertex Pharmaceuticals; Vor Biopharma Inc; Xenikos BV.
Footnotes
Conflict-of-Interest disclosure:
N.F: Advisory board member for Incyte; consultancy for Omeros, received speaker fees from Incyte; data safety monitoring committee member for chronic Graft-Versus-Host Disease Consortium; Blood and Marrow Transplant Clinical Trial Network (BMT CTN) medical monitor
L.G: consulting for Deloitte, honoraria from BMS
K.S: Past chair of the NMDP Donor and Patient Safety Monitoring Advisory Group
M.S: is an employee of Canadian Blood Services, Past-president, World Marrow Donor Association (WMDA)
A.S: consulting for Medexus Inc, Vertex Pharmaceuticals, Sangamo Therapeutics, Editas Medicine, BioLineRx, Gamida Cell. Honoraria for lectures, Blackwood CME. DSMB member for the Data Safety and Monitoring Board, Children’s Hospital of Philadelphia. Other interests, Clinical Trial site-PI: CRISPR Therapeutics (2018-Present), Vertex Pharmaceuticals (2018-Present), Novartis Pharmaceuticals (2019-Present), Magenta Therapeutics (2022–2023), Beam Therapeutics (2022-Present). Grant from National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI) – 1U01HL163983, Member, ASTCT Committee on Cellular Therapy, Member, Scientific Executive Committee, Sickle Cell Transplant Advocacy & Research Alliance (STAR), Member, Stem Cell Engineering Committee, International Society for Cell & Gene Therapy (ISCT), Vice Chair, PTCTC Supportive Care Committee, Co-Chair, Pediatric Cancer Working Committee, Center for International Bone Marrow Transplant Research (CIBMTR), Chair, ASTCT Committee on Trainees and Junior Faculty, Member, ASH Aplastic Anemia Guideline Panel, Member, ASH Sickle Cell Disease Research Priorities Working Group, Member, ASTCT Committee on Gene Therapy.
H.G.R: consulting for, Medexus, Vertex Therapeutics. Travel support EDITAS medicine
M.B: grants from BMS, Kite/Gilead, Astra Zeneca/Gracell, Janssen, consulting for Janssen, Kite, BMS, Novartis, Sanofi, honoraria from Janssen, Kite, BMS, Novartis, Sanofi, membership CIBMTR, stock in Ahura Biopharma, Viking Therapeutics
B.S: consulting for OrcaBio
All other authors have no disclosures.
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