Blood Res 2023; 58(1):
Published online March 31, 2023
https://doi.org/10.5045/br.2023.2022167
© The Korean Society of Hematology
Correspondence to : Awatif AlAnazi, M.D.
Department of Pediatric Hematology/Oncology, MBC 53, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
E-mail: aawatif@kfshrc.edu.sa
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Reduced harvest volumes in pediatric donors appear to have the potential to reduce donor-associated risks while maintaining engraftment in recipients; however, the allowable harvest volume reduction remains undefined.
Methods
We retrospectively analyzed the data pairs of 553 bone marrow (BM) harvests from pediatric (age at harvest <18 yr) sibling donors and clinical outcomes of 553 pediatric (age at infusion <14 yr) transplant-naïve recipients to assess the optimal BM harvest volume needed from pediatric donors to obtain the desired CD34+ cell count (≥3.0×106 cells per kg of recipient weight), and to study its impact on the clinical outcomes of transplantation in pediatric recipients.
Results
The minimum desired CD34+ cell count of ≥3.0×106 per kg of recipient weight was achieved for 506 (95.3%) of donor-recipient pairs. The median CD34+ cell yield was 6.4×106 per kg of recipient weight (range, 1.2‒33.8×106) in donors younger than 5 years old at harvest, 4.7×106 (range, 0.3‒28.5×106) in donors aged 5‒10 years and 2.1×106 (range, 0.3‒11.3×106) in donors older than 10 years (P<0.001).
Conclusion
The infused CD34+ cell dose (×106 cells/kg of recipient weight) had no impact on GRFS; however, a CD34+ cell dose of >7×106 cells/kg of recipient weight did not improve hematopoietic recovery.
Keywords: Marrow transplant, Harvest volume, Pediatric donors
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality that provides a cure or produces long-term survival for a variety of pediatric diseases, including certain hematologic malignancies, bone marrow (BM) failure, hemoglobinopathies, immuno-deficiencies, and metabolic disorders [1, 2]. The development of BM, umbilical cord blood, and mobilized peripheral blood as graft sources for hematopoietic stem cell transplantation has occurred [3]. Despite the increased use of mobilized peripheral blood and umbilical cord blood, BM remains the primary graft source in pediatric patients [2]. HLA-matched siblings are considered the best donors for HSCT due to the reduced risk of transplant-related complications and improved clinical outcomes [1, 2, 4]. BM donation is a well-tolerated procedure with few complications, most of which are perioperative events, including anesthesia-related events, postoperative pain, and anemia [5, 6]. Stroncek
The National Marrow Donor Program (NMDP) recommends that the collected BM volume not exceed 20 mL/kg of donor body weight to minimize the risk associated with the BM harvesting procedure on the donor and to have a sufficient volume of collected BM; this volume was determined based on adult donors and is suitable for children as well [6]. Furey
Age-related changes in human hematopoietic stem/progenitor cells have been reported [8], and Yabe
This retrospective study determined the optimal amount of BM for pediatric recipients from matched sibling donors. Additionally, we examined transplant survival, post-transplant infections in the first 100 days, and Graft-Versus-Host Disease (GVHD) free or relapse-free survival (GRFS) to CD34+ cell dose per kg of recipient weight. We validated the algorithm proposed by Furey
In this retrospective study, we reviewed the medical records of all pediatric sibling donors (age at harvest <18 yr) who had undergone a single BM harvest between January 2007 and December 2017 at our center. The medical records of all consecutive pediatric transplant-naïve recipient-donor pairs were obtained from the computerized patient information management system. Data of the volume of BM harvested relative to donor weight, harvest-related hospitalization days and side effects, transplant characteristics, and outcome-related parameters for recipients were collected. The parents or legal guardians provided written informed consent as per institutional practice.
Multiple punctures were used to harvest BM from the posterior iliac crest under general anesthesia. With each attempt, a volume of approximately 5 mL was aspirated [11, 12]. The target volume was 15–20 mL/kg of recipient weight and did not exceed 20 mL/kg of donor weight [13]. The BM product was processed in a stem cell laboratory, and flow cytometry was used to count CD34+ and CD3+ cells.
We used a range of ±5 kg to determine whether the donor’s weight was the same, lower, or higher than that of the recipient. Overall survival (OS) was defined as survival with or without the primary disease. However, transplant-related mortality (TRM) was defined as death due to any cause other than relapse of malignant disease. Acute GVHD was defined according to the method described by Glucksberg
All infections in transplant recipients from day 0 to day 100 post-transplantation were reviewed. Bacteremia was defined as the presence of viable bacteria in the blood. Viremia was defined as a cytomegalovirus load >500 copies/mL, an Epstein-Barr virus load >1,000 copies/mL, or an adenovirus load >1,000 copies/mL based on PCR results [17]. Definitions of invasive fungal infections were performed as previously described by Satwani
Descriptive statistics for continuous variables were provided as medians and ranges, and categorical variables were presented as numbers and percentages. We used the chi-square or Fisher’s exact test to test the significance of the associations between categorical variables. Independent-sample Mann–Whitney U tests and Kruskal–Wallis tests were used to test the significance of the differences between two and more than two categories of continuous variables, respectively. Spearman’s correlation coefficient was used to calculate correlations between continuous variables. Binary logistic regression was used to test the effects of CD34+ cell dose per kg of recipient weight on GVHD, survival, and GRFS. SPSS Statistics for Windows (version 20.0, IBM Corp., Armonk, NY, USA) was used to analyze the data.
We included the data of 531 donor-recipient pairs in this study. The median age of the recipients was 4.4 years, and >50% of them were boys (N=298, 56.1%). Most recipients underwent transplantation for nonmalignant disorders. Table 1 shows demographic and transplant characteristics. The median CD34+ cell dose infused was 7.0×106 (1.3–17.7) per kg of recipient weight.
Table 1 Demographic and transplants characteristics of the recipients (N=531).
Variables of interest | Observations |
---|---|
Age at infusion, year, median (range) | 4.4 (0.04–17.4) |
Male, sex, N (%) | 298 (56.1%) |
Malignant and pre-malignant disease, N (%) | 125 (23.5%) |
Acute lymphoblastic leukemia | 53 (42.4%) |
Acute myelogenous leukemia | 45 (36.0%) |
Chronic myeloid leukemia | 7 (5.6%) |
Myelodysplastic syndromes | 8 (6.4%) |
Other leukemia | 7 (5.6%) |
Hodgkin’s disease | 1 (0.8%) |
Non-Hodgkin’s lymphoma | 4 (3.2%) |
Nonmalignant disease, N (%) | 406 (76.5%) |
Immunodeficiency | 159 (39.2%) |
Hemoglobinopathies | 108 (26.6%) |
Bone marrow failure including severe aplastic anemia | 86 (21.2%) |
Histiocytic disorders | 29 (7.1%) |
Metabolic disorders | 19 (4.7%) |
D isorders related to platelet defects | 5 (1.2%) |
Conditioning regimen, N (%) | |
No conditioning | 67 (12.6%) |
Myeloablative | 451 (84.9%) |
Reduced intensity | 13 (2.4%) |
The study cohort comprised all pediatric (age at harvest <18 yr) sibling donors who underwent a single BM harvest and their recipients. Of the 531 donor-recipients pairs, 276 (52.0%) donors were boys, 146 (27.5%) were younger than 5 years old at harvest, 182 (34.3%) were between 5 and 10 years old, and the remaining 203 (38.2%) were 10 years old or older; the median donor age was 8.4 years (1.0–18.0), 66 (12.4%) donors weighed less than their recipients, 108 (20.3%) had equivalent weights, and 357 (67.2%) weighed more.
The median BM volume harvested per kg of donor weight was significantly higher for lower-weight donors than for equivalent or higher-weight donors (15.7 mL/kg vs. 14.6 mL/kg or 9.0 mL/kg, respectively,
The median hemoglobin (Hb) levels before harvest were significantly lower in lower-weight donors than in equivalent or higher-weight donors (115.0 vs. 119.0 or 125.0 g/L, respectively,
Given the indication for PRBC transfusion, including symptomatic anemia (hypotension not responding to fluid boluses, tachycardia) or Hb below 80 g/L, 47 (8.9%) donors required allogeneic PRBC transfusions post-harvest. The need for PRBC transfusion for donors was significantly associated with their age group at harvest (
For post-harvest PRBC-transfused donors, the median pre- and post-harvest hemoglobin concentrations were 112.0 g/L (91–143 g/L) and 89.0 g/L (75.0–128.0 g/L), respectively, with a median decrease in the hemoglobin level of 26.0 g/L (2.0–62.0 g/L). The median pre-harvest hemoglobin concentration, post-harvest hemoglobin concentration, and decrease in the hemoglobin level were 124 g/L (91.0–169.0 g/L), 106.0 g/L (66.0–152.0 g/L) and 18.0 g/L (0.0–51.0 g/L), respectively, for donors who did not require post-harvest PRBC transfusion (
The CD34+ cell yield per kilogram of recipient weight was significantly higher in younger donors. In particular, the median CD34+ cell yield was 6.4×106 (1.2–33.8×106) in donors younger than 5 years old at harvest, while the yields were 4.7×106 (0.3–28.5×106) for those aged 5–10 years and 2.1×106 (0.3–11.3×106) for those older than 10 years of age (
Harvested BM was able to satisfy the minimum CD34+ cell dose of ≥3.0×106 per kg of recipient weight [19] in 506 (95.3%) paired recipients. In this subgroup of 506 donor-recipient pairs, the median CD34+ cell yield (×106 per kg of recipient weight) was higher for the youngest donor group (8.0 vs. 7.5 vs. 7.0,
Table 2 Harvest volume (mL) per donor age (yr) and weight (kg) for minimum CD34+ cell dose of ≥3.0×106 per kg of recipient weight (N=506) with respect to actual CD34+ cell yield ×106 per kg of recipient weight.
Harvests meeting minimum CD34+ dose required and CD34+ cell yield (per kg recipient) | Harvest volume (mL/kg donor) | CD34+ cell yield (per kg donor) | ||||
---|---|---|---|---|---|---|
N=506 | Median (range) | Median (range)a) | Median (range)a) | |||
Donor age, years (N) | ||||||
Less than 5 (N=146) | 140 (95.9%) | 8.0 (3.3–30.7)b) | 12.8 (3.8–21.8) | 6.5 (1.2–33.8) | ||
5–10 (N=182) | 179 (98.4%) | 7.5 (3.1–31.9)b) | 11.6 (1.7–21.2) | 4.7 (0.3–28.5) | ||
10 and above (N=203) | 187 (92.1%) | 7.0 (3.0–28.0)b) | 8.1 (1.4–20.1) | 2.2 (0.3–11.3) | ||
Donor’s weight (kg) compared to Rec (N) | ||||||
Lower (N=66) | 60 (90.9%) | 5.1 (3.2–15.8)a) | 15.6 (8.3–20.7) | 9.4 (4.5–33.8) | ||
Equivalent within ±5 kg (N=108) | 104 (96.3%) | 6.4 (3.6–24.8)a) | 14.2 (5.8–21.8) | 6.5 (3.2–16.6) | ||
Higher (N=357) | 342 (95.8%) | 8.1 (3.0–31.9)a) | 9.0 (1.4–19.0) | 2.9 (0.3–28.5) |
a)
The median time for neutrophil engraftment was 16 days (10–37), and platelet recovery was 29 days (6–148 days). No correlation was found between the infused CD34+ cell dose (×106 per kg of recipient weight) and platelet recovery time (Spearman’s rho=0.02,
Among all recipients, ANC engraftment by day +28 was observed in 450 (84.7%), whereas 72 (13.6%) did not achieve this milestone, and late ANC engraftment (beyond day +28) was recorded in 9 (1.7%). The median CD34+ cell dose infused (×106 per kg of recipient weight) was higher in the recipients who achieved ANC engraftment by day +28 than in those who achieved engraftment after day +28 [6.8×106, (1.5–17.22) vs. 6.5×106, (1.3–11.0),
Infections during the first 100 days after transplantation were recorded in 168 (31.6 %) recipients. Of the 247 isolates, 156 (63.2%) were bacterial, 51 (20.6%) were viral, 38 (15.4%) were fungal, and 2 (0.8%) were parasitic. No significant association between the CD34+ cell dose infused (×106 per kg of recipient weight) and the incidence of infection was found (odds ratio, 0.982; 95% CI, 0.939–1.03;
With a median follow-up time of 64.3 months (95% CI, 58.5–70.0 mo) and 100 mortality events, the 3- and 5-year cumulative OS probabilities for our cohort were 81.7±1.7% (events=95) and 80.6±1.8% (events=99), respectively. The 1-year TRM was 15.6% (N=82). The infused CD34+ cell (×106 per kg of recipient weight) and TNC (per kg of recipient weight) doses were not associated with overall mortality (
The BM volume harvested from the sibling donors at our institution was within ±2.0 mL/kg of donor weight, as specified in the NMDP guidelines of up to 20 mL/kg of donor weight. However, compared with the optimum harvest volume calculated according to the formula proposed by Furey
Table 3 Harvest volume (mL/kg per donor weight) by ANC engraftment.
ANC recovery (-)(N=72) | ANC recovery (+)(N=459) | Total (N=531) | ||
---|---|---|---|---|
Harvest volume per donor weight (N=531) | 0.001 | |||
Less than equivalent | 1 (2.3%) | 42 (97.7%) | 43 (8.1%) | |
Equivalenta) | 13 (8.7%) | 136 (91.3%) | 149 (28.1%) | |
2–6 mL above equivalent | 28 (13.5%) | 180 (86.5%) | 208 (39.2%) | |
6–14 mL above equivalent | 29 (22.7%) | 99 (77.3%) | 128 (24.1%) | |
≥14 mL above equivalent | 1 (33.3%) | 2 (66.7%) | 3 (0.6%) | |
Harvest volume per donor weight (non-primed only) | N=64 | N=264 | N=328 | 0.017 |
Less than equivalent | 0 (0.0%) | 8 (100.0%) | 8 (2.4%) | |
Equivalenta) | 12 (13.2%) | 79 (86.8%) | 91 (27.7%) | |
2–6 mL above equivalent | 25 (17.7%) | 116 (82.3%) | 141 (43.0%) | |
6–14 mL above equivalent | 27 (31.4%) | 59 (68.6%) | 86 (26.2%) | |
≥14 mL above equivalent | 0 (0.0%) | 2 (100.0%) | 2 (0.6%) |
a)±2.0 mL/kg calculated as proposed by Furey
This is among the most extensive retrospective single-center studies to date, reporting and analyzing the relationship between BM harvest volume and infused CD34+ cell doses (×106 per kg of recipient weight) in the pediatric population. In this study, several important observations were made. A CD34+ cell count of >7×106 per kg of recipient weight was not associated with improved hematopoietic recovery. Harvesting Large volumes may result in an unnecessarily high CD34+ cell count, and the volume of BM harvested can be safely reduced for younger donors. The proposed Furey
BM donation is a safe and well-tolerated procedure. In a prospective study conducted by the European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party, the risk of blood transfusion after BM harvest was associated with donors younger than 4 years and a BM harvest volume exceeding 20 mL/kg [2]. In our study, the need for allogeneic blood transfusions was significantly associated with age at harvest, especially in donors younger than 5 years old and donors with disproportionately low weight relative to the recipient’s weight. This may lead to careful consideration of the maximum volume of BM that can be harvested from young children.
The impact of infused CD34+ cell dose (×106 per kg of recipient weight) on clinical outcomes in children undergoing allogeneic HSCT, mainly with unrelated donors, has been reported. PBSCT and UD BMT showed that infusion of a higher CD34+ cell dose (×106 per kg of recipient weight) is associated with improved patient outcomes [20, 21]. A few studies have reported the outcome of CD34+ cell doses from a matched sibling donor, and a recommended dose of ≥3×106 CD34+ cells per kg of recipient weight was associated with hematopoietic reconstitution [6, 10]. We found that the infused CD34+ cell dose (×106 per kg of recipient weight) was not associated with recipient OS, EFS, or GRFS. We did not observe any correlation between the infused CD34+ cell dose (×106 per kg of recipient weight) and platelet recovery time or the incidence of infections in the first 100 days. Our data showed that a CD34+ cell dose of >7×106 per kg recipient weight did not improve hematopoietic recovery in children with an HLA-matched sibling donor. As previously reported [9, 19, 22], our data confirm that a CD34+ cell dose (×106 per kg of recipient weight) is significantly related to donor age; donors younger than 5 years yielded higher concentrations of CD34+ cells, suggesting that the harvested volume can be reduced safely without a negative impact on the CD34+ cell count [6, 9].
Increasing collected BM volume boosts CD34+ cell yield. However, increasing the collected volume can increase anesthesia time, puncture sites, and blood loss [23]. Our data showed that in BM harvested at volumes up to 20 mL/kg of donor weight, CD34+ cell doses ≥3×106 per kg of recipient weight were collected from 506 (95.3%) donors.
Few studies demonstrated a positive correlation between the total harvested BM and TNC number [12, 24]. However, we found no positive correlations between the total BM volume and TNC number or CD34+ cell count (×106 per kg of recipient weight), suggesting that the collected BM volume can be decreased in pediatric donors, especially in those below 5 years.
Using our data, we validated the algorithm proposed by Furey
In conclusion, this is the largest retrospective study to report and analyze the relationship between marrow harvest volume and CD34+ cell dose (×106 per kg of recipient weight) in the pediatric population from a single transplant center. Unmanipulated CD34+ cell dose >7×106 per kg of recipient weight did not improve hematopoietic recovery. It was not correlated with platelet recovery time, infectious toxicity, GVHD incidence, mortality, or GRFS. Small BM can safely be harvested in younger donors. The proposed algorithm could determine the BM harvest volume needed to obtain the desired CD34+ cell dose, reducing the harvested volume safely in pediatric donors. A larger observational study is needed to determine the ideal minimum CD34+ cells dose for pediatric sibling allogeneic HSCT.
No potential conflicts of interest relevant to this article were reported.
Blood Res 2023; 58(1): 28-35
Published online March 31, 2023 https://doi.org/10.5045/br.2023.2022167
Copyright © The Korean Society of Hematology.
Awatif AlAnazi, Amer Nadeem, Khawar Siddiqui, Ali AlAhmari, Ibrahim Ghemlas, Abdullah AlJefri, Hawazen AlSaedi, Saadiya Khan, Mouhab Ayas
1Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Correspondence to:Awatif AlAnazi, M.D.
Department of Pediatric Hematology/Oncology, MBC 53, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
E-mail: aawatif@kfshrc.edu.sa
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Reduced harvest volumes in pediatric donors appear to have the potential to reduce donor-associated risks while maintaining engraftment in recipients; however, the allowable harvest volume reduction remains undefined.
Methods
We retrospectively analyzed the data pairs of 553 bone marrow (BM) harvests from pediatric (age at harvest <18 yr) sibling donors and clinical outcomes of 553 pediatric (age at infusion <14 yr) transplant-naïve recipients to assess the optimal BM harvest volume needed from pediatric donors to obtain the desired CD34+ cell count (≥3.0×106 cells per kg of recipient weight), and to study its impact on the clinical outcomes of transplantation in pediatric recipients.
Results
The minimum desired CD34+ cell count of ≥3.0×106 per kg of recipient weight was achieved for 506 (95.3%) of donor-recipient pairs. The median CD34+ cell yield was 6.4×106 per kg of recipient weight (range, 1.2‒33.8×106) in donors younger than 5 years old at harvest, 4.7×106 (range, 0.3‒28.5×106) in donors aged 5‒10 years and 2.1×106 (range, 0.3‒11.3×106) in donors older than 10 years (P<0.001).
Conclusion
The infused CD34+ cell dose (×106 cells/kg of recipient weight) had no impact on GRFS; however, a CD34+ cell dose of >7×106 cells/kg of recipient weight did not improve hematopoietic recovery.
Keywords: Marrow transplant, Harvest volume, Pediatric donors
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality that provides a cure or produces long-term survival for a variety of pediatric diseases, including certain hematologic malignancies, bone marrow (BM) failure, hemoglobinopathies, immuno-deficiencies, and metabolic disorders [1, 2]. The development of BM, umbilical cord blood, and mobilized peripheral blood as graft sources for hematopoietic stem cell transplantation has occurred [3]. Despite the increased use of mobilized peripheral blood and umbilical cord blood, BM remains the primary graft source in pediatric patients [2]. HLA-matched siblings are considered the best donors for HSCT due to the reduced risk of transplant-related complications and improved clinical outcomes [1, 2, 4]. BM donation is a well-tolerated procedure with few complications, most of which are perioperative events, including anesthesia-related events, postoperative pain, and anemia [5, 6]. Stroncek
The National Marrow Donor Program (NMDP) recommends that the collected BM volume not exceed 20 mL/kg of donor body weight to minimize the risk associated with the BM harvesting procedure on the donor and to have a sufficient volume of collected BM; this volume was determined based on adult donors and is suitable for children as well [6]. Furey
Age-related changes in human hematopoietic stem/progenitor cells have been reported [8], and Yabe
This retrospective study determined the optimal amount of BM for pediatric recipients from matched sibling donors. Additionally, we examined transplant survival, post-transplant infections in the first 100 days, and Graft-Versus-Host Disease (GVHD) free or relapse-free survival (GRFS) to CD34+ cell dose per kg of recipient weight. We validated the algorithm proposed by Furey
In this retrospective study, we reviewed the medical records of all pediatric sibling donors (age at harvest <18 yr) who had undergone a single BM harvest between January 2007 and December 2017 at our center. The medical records of all consecutive pediatric transplant-naïve recipient-donor pairs were obtained from the computerized patient information management system. Data of the volume of BM harvested relative to donor weight, harvest-related hospitalization days and side effects, transplant characteristics, and outcome-related parameters for recipients were collected. The parents or legal guardians provided written informed consent as per institutional practice.
Multiple punctures were used to harvest BM from the posterior iliac crest under general anesthesia. With each attempt, a volume of approximately 5 mL was aspirated [11, 12]. The target volume was 15–20 mL/kg of recipient weight and did not exceed 20 mL/kg of donor weight [13]. The BM product was processed in a stem cell laboratory, and flow cytometry was used to count CD34+ and CD3+ cells.
We used a range of ±5 kg to determine whether the donor’s weight was the same, lower, or higher than that of the recipient. Overall survival (OS) was defined as survival with or without the primary disease. However, transplant-related mortality (TRM) was defined as death due to any cause other than relapse of malignant disease. Acute GVHD was defined according to the method described by Glucksberg
All infections in transplant recipients from day 0 to day 100 post-transplantation were reviewed. Bacteremia was defined as the presence of viable bacteria in the blood. Viremia was defined as a cytomegalovirus load >500 copies/mL, an Epstein-Barr virus load >1,000 copies/mL, or an adenovirus load >1,000 copies/mL based on PCR results [17]. Definitions of invasive fungal infections were performed as previously described by Satwani
Descriptive statistics for continuous variables were provided as medians and ranges, and categorical variables were presented as numbers and percentages. We used the chi-square or Fisher’s exact test to test the significance of the associations between categorical variables. Independent-sample Mann–Whitney U tests and Kruskal–Wallis tests were used to test the significance of the differences between two and more than two categories of continuous variables, respectively. Spearman’s correlation coefficient was used to calculate correlations between continuous variables. Binary logistic regression was used to test the effects of CD34+ cell dose per kg of recipient weight on GVHD, survival, and GRFS. SPSS Statistics for Windows (version 20.0, IBM Corp., Armonk, NY, USA) was used to analyze the data.
We included the data of 531 donor-recipient pairs in this study. The median age of the recipients was 4.4 years, and >50% of them were boys (N=298, 56.1%). Most recipients underwent transplantation for nonmalignant disorders. Table 1 shows demographic and transplant characteristics. The median CD34+ cell dose infused was 7.0×106 (1.3–17.7) per kg of recipient weight.
Table 1 . Demographic and transplants characteristics of the recipients (N=531)..
Variables of interest | Observations |
---|---|
Age at infusion, year, median (range) | 4.4 (0.04–17.4) |
Male, sex, N (%) | 298 (56.1%) |
Malignant and pre-malignant disease, N (%) | 125 (23.5%) |
Acute lymphoblastic leukemia | 53 (42.4%) |
Acute myelogenous leukemia | 45 (36.0%) |
Chronic myeloid leukemia | 7 (5.6%) |
Myelodysplastic syndromes | 8 (6.4%) |
Other leukemia | 7 (5.6%) |
Hodgkin’s disease | 1 (0.8%) |
Non-Hodgkin’s lymphoma | 4 (3.2%) |
Nonmalignant disease, N (%) | 406 (76.5%) |
Immunodeficiency | 159 (39.2%) |
Hemoglobinopathies | 108 (26.6%) |
Bone marrow failure including severe aplastic anemia | 86 (21.2%) |
Histiocytic disorders | 29 (7.1%) |
Metabolic disorders | 19 (4.7%) |
D isorders related to platelet defects | 5 (1.2%) |
Conditioning regimen, N (%) | |
No conditioning | 67 (12.6%) |
Myeloablative | 451 (84.9%) |
Reduced intensity | 13 (2.4%) |
The study cohort comprised all pediatric (age at harvest <18 yr) sibling donors who underwent a single BM harvest and their recipients. Of the 531 donor-recipients pairs, 276 (52.0%) donors were boys, 146 (27.5%) were younger than 5 years old at harvest, 182 (34.3%) were between 5 and 10 years old, and the remaining 203 (38.2%) were 10 years old or older; the median donor age was 8.4 years (1.0–18.0), 66 (12.4%) donors weighed less than their recipients, 108 (20.3%) had equivalent weights, and 357 (67.2%) weighed more.
The median BM volume harvested per kg of donor weight was significantly higher for lower-weight donors than for equivalent or higher-weight donors (15.7 mL/kg vs. 14.6 mL/kg or 9.0 mL/kg, respectively,
The median hemoglobin (Hb) levels before harvest were significantly lower in lower-weight donors than in equivalent or higher-weight donors (115.0 vs. 119.0 or 125.0 g/L, respectively,
Given the indication for PRBC transfusion, including symptomatic anemia (hypotension not responding to fluid boluses, tachycardia) or Hb below 80 g/L, 47 (8.9%) donors required allogeneic PRBC transfusions post-harvest. The need for PRBC transfusion for donors was significantly associated with their age group at harvest (
For post-harvest PRBC-transfused donors, the median pre- and post-harvest hemoglobin concentrations were 112.0 g/L (91–143 g/L) and 89.0 g/L (75.0–128.0 g/L), respectively, with a median decrease in the hemoglobin level of 26.0 g/L (2.0–62.0 g/L). The median pre-harvest hemoglobin concentration, post-harvest hemoglobin concentration, and decrease in the hemoglobin level were 124 g/L (91.0–169.0 g/L), 106.0 g/L (66.0–152.0 g/L) and 18.0 g/L (0.0–51.0 g/L), respectively, for donors who did not require post-harvest PRBC transfusion (
The CD34+ cell yield per kilogram of recipient weight was significantly higher in younger donors. In particular, the median CD34+ cell yield was 6.4×106 (1.2–33.8×106) in donors younger than 5 years old at harvest, while the yields were 4.7×106 (0.3–28.5×106) for those aged 5–10 years and 2.1×106 (0.3–11.3×106) for those older than 10 years of age (
Harvested BM was able to satisfy the minimum CD34+ cell dose of ≥3.0×106 per kg of recipient weight [19] in 506 (95.3%) paired recipients. In this subgroup of 506 donor-recipient pairs, the median CD34+ cell yield (×106 per kg of recipient weight) was higher for the youngest donor group (8.0 vs. 7.5 vs. 7.0,
Table 2 . Harvest volume (mL) per donor age (yr) and weight (kg) for minimum CD34+ cell dose of ≥3.0×106 per kg of recipient weight (N=506) with respect to actual CD34+ cell yield ×106 per kg of recipient weight..
Harvests meeting minimum CD34+ dose required and CD34+ cell yield (per kg recipient) | Harvest volume (mL/kg donor) | CD34+ cell yield (per kg donor) | ||||
---|---|---|---|---|---|---|
N=506 | Median (range) | Median (range)a) | Median (range)a) | |||
Donor age, years (N) | ||||||
Less than 5 (N=146) | 140 (95.9%) | 8.0 (3.3–30.7)b) | 12.8 (3.8–21.8) | 6.5 (1.2–33.8) | ||
5–10 (N=182) | 179 (98.4%) | 7.5 (3.1–31.9)b) | 11.6 (1.7–21.2) | 4.7 (0.3–28.5) | ||
10 and above (N=203) | 187 (92.1%) | 7.0 (3.0–28.0)b) | 8.1 (1.4–20.1) | 2.2 (0.3–11.3) | ||
Donor’s weight (kg) compared to Rec (N) | ||||||
Lower (N=66) | 60 (90.9%) | 5.1 (3.2–15.8)a) | 15.6 (8.3–20.7) | 9.4 (4.5–33.8) | ||
Equivalent within ±5 kg (N=108) | 104 (96.3%) | 6.4 (3.6–24.8)a) | 14.2 (5.8–21.8) | 6.5 (3.2–16.6) | ||
Higher (N=357) | 342 (95.8%) | 8.1 (3.0–31.9)a) | 9.0 (1.4–19.0) | 2.9 (0.3–28.5) |
a)
The median time for neutrophil engraftment was 16 days (10–37), and platelet recovery was 29 days (6–148 days). No correlation was found between the infused CD34+ cell dose (×106 per kg of recipient weight) and platelet recovery time (Spearman’s rho=0.02,
Among all recipients, ANC engraftment by day +28 was observed in 450 (84.7%), whereas 72 (13.6%) did not achieve this milestone, and late ANC engraftment (beyond day +28) was recorded in 9 (1.7%). The median CD34+ cell dose infused (×106 per kg of recipient weight) was higher in the recipients who achieved ANC engraftment by day +28 than in those who achieved engraftment after day +28 [6.8×106, (1.5–17.22) vs. 6.5×106, (1.3–11.0),
Infections during the first 100 days after transplantation were recorded in 168 (31.6 %) recipients. Of the 247 isolates, 156 (63.2%) were bacterial, 51 (20.6%) were viral, 38 (15.4%) were fungal, and 2 (0.8%) were parasitic. No significant association between the CD34+ cell dose infused (×106 per kg of recipient weight) and the incidence of infection was found (odds ratio, 0.982; 95% CI, 0.939–1.03;
With a median follow-up time of 64.3 months (95% CI, 58.5–70.0 mo) and 100 mortality events, the 3- and 5-year cumulative OS probabilities for our cohort were 81.7±1.7% (events=95) and 80.6±1.8% (events=99), respectively. The 1-year TRM was 15.6% (N=82). The infused CD34+ cell (×106 per kg of recipient weight) and TNC (per kg of recipient weight) doses were not associated with overall mortality (
The BM volume harvested from the sibling donors at our institution was within ±2.0 mL/kg of donor weight, as specified in the NMDP guidelines of up to 20 mL/kg of donor weight. However, compared with the optimum harvest volume calculated according to the formula proposed by Furey
Table 3 . Harvest volume (mL/kg per donor weight) by ANC engraftment..
ANC recovery (-)(N=72) | ANC recovery (+)(N=459) | Total (N=531) | ||
---|---|---|---|---|
Harvest volume per donor weight (N=531) | 0.001 | |||
Less than equivalent | 1 (2.3%) | 42 (97.7%) | 43 (8.1%) | |
Equivalenta) | 13 (8.7%) | 136 (91.3%) | 149 (28.1%) | |
2–6 mL above equivalent | 28 (13.5%) | 180 (86.5%) | 208 (39.2%) | |
6–14 mL above equivalent | 29 (22.7%) | 99 (77.3%) | 128 (24.1%) | |
≥14 mL above equivalent | 1 (33.3%) | 2 (66.7%) | 3 (0.6%) | |
Harvest volume per donor weight (non-primed only) | N=64 | N=264 | N=328 | 0.017 |
Less than equivalent | 0 (0.0%) | 8 (100.0%) | 8 (2.4%) | |
Equivalenta) | 12 (13.2%) | 79 (86.8%) | 91 (27.7%) | |
2–6 mL above equivalent | 25 (17.7%) | 116 (82.3%) | 141 (43.0%) | |
6–14 mL above equivalent | 27 (31.4%) | 59 (68.6%) | 86 (26.2%) | |
≥14 mL above equivalent | 0 (0.0%) | 2 (100.0%) | 2 (0.6%) |
a)±2.0 mL/kg calculated as proposed by Furey
This is among the most extensive retrospective single-center studies to date, reporting and analyzing the relationship between BM harvest volume and infused CD34+ cell doses (×106 per kg of recipient weight) in the pediatric population. In this study, several important observations were made. A CD34+ cell count of >7×106 per kg of recipient weight was not associated with improved hematopoietic recovery. Harvesting Large volumes may result in an unnecessarily high CD34+ cell count, and the volume of BM harvested can be safely reduced for younger donors. The proposed Furey
BM donation is a safe and well-tolerated procedure. In a prospective study conducted by the European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party, the risk of blood transfusion after BM harvest was associated with donors younger than 4 years and a BM harvest volume exceeding 20 mL/kg [2]. In our study, the need for allogeneic blood transfusions was significantly associated with age at harvest, especially in donors younger than 5 years old and donors with disproportionately low weight relative to the recipient’s weight. This may lead to careful consideration of the maximum volume of BM that can be harvested from young children.
The impact of infused CD34+ cell dose (×106 per kg of recipient weight) on clinical outcomes in children undergoing allogeneic HSCT, mainly with unrelated donors, has been reported. PBSCT and UD BMT showed that infusion of a higher CD34+ cell dose (×106 per kg of recipient weight) is associated with improved patient outcomes [20, 21]. A few studies have reported the outcome of CD34+ cell doses from a matched sibling donor, and a recommended dose of ≥3×106 CD34+ cells per kg of recipient weight was associated with hematopoietic reconstitution [6, 10]. We found that the infused CD34+ cell dose (×106 per kg of recipient weight) was not associated with recipient OS, EFS, or GRFS. We did not observe any correlation between the infused CD34+ cell dose (×106 per kg of recipient weight) and platelet recovery time or the incidence of infections in the first 100 days. Our data showed that a CD34+ cell dose of >7×106 per kg recipient weight did not improve hematopoietic recovery in children with an HLA-matched sibling donor. As previously reported [9, 19, 22], our data confirm that a CD34+ cell dose (×106 per kg of recipient weight) is significantly related to donor age; donors younger than 5 years yielded higher concentrations of CD34+ cells, suggesting that the harvested volume can be reduced safely without a negative impact on the CD34+ cell count [6, 9].
Increasing collected BM volume boosts CD34+ cell yield. However, increasing the collected volume can increase anesthesia time, puncture sites, and blood loss [23]. Our data showed that in BM harvested at volumes up to 20 mL/kg of donor weight, CD34+ cell doses ≥3×106 per kg of recipient weight were collected from 506 (95.3%) donors.
Few studies demonstrated a positive correlation between the total harvested BM and TNC number [12, 24]. However, we found no positive correlations between the total BM volume and TNC number or CD34+ cell count (×106 per kg of recipient weight), suggesting that the collected BM volume can be decreased in pediatric donors, especially in those below 5 years.
Using our data, we validated the algorithm proposed by Furey
In conclusion, this is the largest retrospective study to report and analyze the relationship between marrow harvest volume and CD34+ cell dose (×106 per kg of recipient weight) in the pediatric population from a single transplant center. Unmanipulated CD34+ cell dose >7×106 per kg of recipient weight did not improve hematopoietic recovery. It was not correlated with platelet recovery time, infectious toxicity, GVHD incidence, mortality, or GRFS. Small BM can safely be harvested in younger donors. The proposed algorithm could determine the BM harvest volume needed to obtain the desired CD34+ cell dose, reducing the harvested volume safely in pediatric donors. A larger observational study is needed to determine the ideal minimum CD34+ cells dose for pediatric sibling allogeneic HSCT.
No potential conflicts of interest relevant to this article were reported.
Table 1 . Demographic and transplants characteristics of the recipients (N=531)..
Variables of interest | Observations |
---|---|
Age at infusion, year, median (range) | 4.4 (0.04–17.4) |
Male, sex, N (%) | 298 (56.1%) |
Malignant and pre-malignant disease, N (%) | 125 (23.5%) |
Acute lymphoblastic leukemia | 53 (42.4%) |
Acute myelogenous leukemia | 45 (36.0%) |
Chronic myeloid leukemia | 7 (5.6%) |
Myelodysplastic syndromes | 8 (6.4%) |
Other leukemia | 7 (5.6%) |
Hodgkin’s disease | 1 (0.8%) |
Non-Hodgkin’s lymphoma | 4 (3.2%) |
Nonmalignant disease, N (%) | 406 (76.5%) |
Immunodeficiency | 159 (39.2%) |
Hemoglobinopathies | 108 (26.6%) |
Bone marrow failure including severe aplastic anemia | 86 (21.2%) |
Histiocytic disorders | 29 (7.1%) |
Metabolic disorders | 19 (4.7%) |
D isorders related to platelet defects | 5 (1.2%) |
Conditioning regimen, N (%) | |
No conditioning | 67 (12.6%) |
Myeloablative | 451 (84.9%) |
Reduced intensity | 13 (2.4%) |
Table 2 . Harvest volume (mL) per donor age (yr) and weight (kg) for minimum CD34+ cell dose of ≥3.0×106 per kg of recipient weight (N=506) with respect to actual CD34+ cell yield ×106 per kg of recipient weight..
Harvests meeting minimum CD34+ dose required and CD34+ cell yield (per kg recipient) | Harvest volume (mL/kg donor) | CD34+ cell yield (per kg donor) | ||||
---|---|---|---|---|---|---|
N=506 | Median (range) | Median (range)a) | Median (range)a) | |||
Donor age, years (N) | ||||||
Less than 5 (N=146) | 140 (95.9%) | 8.0 (3.3–30.7)b) | 12.8 (3.8–21.8) | 6.5 (1.2–33.8) | ||
5–10 (N=182) | 179 (98.4%) | 7.5 (3.1–31.9)b) | 11.6 (1.7–21.2) | 4.7 (0.3–28.5) | ||
10 and above (N=203) | 187 (92.1%) | 7.0 (3.0–28.0)b) | 8.1 (1.4–20.1) | 2.2 (0.3–11.3) | ||
Donor’s weight (kg) compared to Rec (N) | ||||||
Lower (N=66) | 60 (90.9%) | 5.1 (3.2–15.8)a) | 15.6 (8.3–20.7) | 9.4 (4.5–33.8) | ||
Equivalent within ±5 kg (N=108) | 104 (96.3%) | 6.4 (3.6–24.8)a) | 14.2 (5.8–21.8) | 6.5 (3.2–16.6) | ||
Higher (N=357) | 342 (95.8%) | 8.1 (3.0–31.9)a) | 9.0 (1.4–19.0) | 2.9 (0.3–28.5) |
a)
Table 3 . Harvest volume (mL/kg per donor weight) by ANC engraftment..
ANC recovery (-)(N=72) | ANC recovery (+)(N=459) | Total (N=531) | ||
---|---|---|---|---|
Harvest volume per donor weight (N=531) | 0.001 | |||
Less than equivalent | 1 (2.3%) | 42 (97.7%) | 43 (8.1%) | |
Equivalenta) | 13 (8.7%) | 136 (91.3%) | 149 (28.1%) | |
2–6 mL above equivalent | 28 (13.5%) | 180 (86.5%) | 208 (39.2%) | |
6–14 mL above equivalent | 29 (22.7%) | 99 (77.3%) | 128 (24.1%) | |
≥14 mL above equivalent | 1 (33.3%) | 2 (66.7%) | 3 (0.6%) | |
Harvest volume per donor weight (non-primed only) | N=64 | N=264 | N=328 | 0.017 |
Less than equivalent | 0 (0.0%) | 8 (100.0%) | 8 (2.4%) | |
Equivalenta) | 12 (13.2%) | 79 (86.8%) | 91 (27.7%) | |
2–6 mL above equivalent | 25 (17.7%) | 116 (82.3%) | 141 (43.0%) | |
6–14 mL above equivalent | 27 (31.4%) | 59 (68.6%) | 86 (26.2%) | |
≥14 mL above equivalent | 0 (0.0%) | 2 (100.0%) | 2 (0.6%) |
a)±2.0 mL/kg calculated as proposed by Furey