Optimizing total nucleated cell yield in bone marrow harvests for hematopoietic stem cell transplantation

Introduction

Background

The transplantation of hematopoietic stem cells (HSCs) has become part of the routine management of malignant and non-malignant blood cell disorders, autoimmune diseases, and inborn errors of immunity and metabolism (1). HSC are collected from human leucocyte antigen (HLA) matched related or unrelated volunteer donors or less commonly from stored umbilical cord blood (2). HSC from volunteer donors is collected by bone marrow harvest (BMH) or granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSCs) (3). While overall survival rates are similar for adult recipients of PBSC and BMH, PBSC is associated with faster hematologic recovery and a lower risk of graft failure, while carrying a higher risk for chronic graft-versus-host-disease (GvHD) due to an increased presence of T-cells in peripheral blood (4-6). BMH carries lower mortality rates and lower acute and chronic GvHD risks than PBSC in children and adolescents suffering from leukemia (7). BMH also shows lower transplant related mortality rates than PBSC in children with non-malignant blood disorders (8).

Today, 80.3% of HSC are generated by PBSC worldwide, while 10.6% come from BMH and 9% from banked cord blood (9). BMH remains an important source of HSC in non-malignant blood disorders when graft-versus-malignancy effects are not important (10), in pediatric HSC recipients (7,8) and in conditions when GvHD is a clinical concern. GvHD risks are increased for patient age >50 years, donor age >32 years, a diagnosis of chronic myeloid leukemia, a lack of anti-T cell globulin for the conditioning regimen, a high/very high Dana Farber Disease Risk Index, an unrelated donor HSC source, HLA-mismatching, or a high-parity female donor (5,11-13). Associated with the decreasing use of BMH has been a decline in the quality of the procedure as measured by the total nucleated cell (TNC) dose collected in recent years. Fewer collection centers have accumulated the necessary expertise for optimal procedure outcomes. Centers performing at least 30 BMH per year show better TNC yield than smaller programs (14).

Rationale and knowledge gap

The MedStar Georgetown University Hospital Blood and Marrow Collection Program (MGUH-BMCP) is the largest BMH center in the US with more than 250 allogeneic harvest procedures per year. In 2023, 292 allo-BMH were performed at the program which constitute 10.6% of all BMH recorded worldwide by the World Marrow Donor Association (9). The program is a dedicated partner of the National Marrow Donor Program (NMDP) and a member of the NMDP alliance of collection centers (15). This clinical review shall help collection centers and proceduralists to optimize TNC yield in allogeneic BMH based on the experience with more than 1,300 procedures conducted at MGUH-BMCP between January 2018 and June 2024. The review will discuss clinical aspects of BMH from donor selection through technical considerations of the procedure itself and post-procedure donor care emphasizing the optimization of TNC yield. The integration of donor anthropometric and laboratory data with clinical procedural experiences has not been done at this time. It can help stem cell collection centers to develop guidelines for their own clinical best practice.

Objective

Optimizing TNC yield in BMHs is a multi-faceted process. Transplantation outcomes and recipient survival depend on high quality harvest products. Best-practice guidelines and clinical reviews can help stem cell collection centers to deliver that quality.

Methods

This review discusses individual aspects of the BMH process for allogeneic donors in detail using data analysis from MGUH-BMCP donors together with the relevant current literature to support statements and recommendations. Anthropometric and hematological donor characteristics are summarized using mean and standard deviation (SD) for continuous and percentages for categorical variables (Table 1). T-testing is used to compare continuous variables after controlling for normality and testing for equal variance, while categorical variables like smoker status or the use of pre-procedural blood donation are compared by Chi-squared testing. Spearman’s correlation coefficients are computed to assess the correlation between variables. Linear and multiple regression models are fitted to evaluate the association between variables and TNC yield including the computation of R² levels. 95% confidence intervals (CI) are determined, and P values of less than 0.05 are considered statistically significant. Stata^® 18^th edition software is used for the statistical analysis.

Results and discussion

Donor characteristics—donor age

The donor-recipient matching process depends on the compatibility of donor and recipient HLA pairs. While HLA-identical sibling donors are available to a minority of patients, 70% of recipients rely on unrelated HLA-matched donors. European transplant centers consider a 10/10 match for the HLA-A, -B, -C, -DRB1, and -DQB1 alleles their gold standard. The US-based NMDP uses an 8/8 match of HLA-A, -B, -C, and -DRB1 (16,17). Newer techniques in high-resolution HLA-typing can help to understand the effects of “non-classical” HLA types on graft failure or GvHD (18,19), while improved immunosuppressive therapeutics like anti-thymocyte globulin (20) or post-transplant cyclophosphamide allow for the transplantation of mismatched HLA alleles (21,22).

Beyond the genetic matching of HLA alleles, a variety of donor factors may affect the quality of the stem cell product and patient outcomes. Donor age appears to be inversely related to recipient survival (19,23). The grafts from younger donors contain more CD34⁺ cells while those of older donors have increased numbers of natural killer (NK) cells and carry more “antigen-experienced” memory T-cells, which might be responsible for chronic GvHD (12), particularly in donor ages beyond 50 years (24,25). Case studies report that patients with advanced myelodysplastic syndrome and acute lymphoblastic leukemia have better 5-year overall survival (26) and lower relapse rates (27) when they receive HSC transplants from younger unrelated donors than older HLA-identical siblings. Donor cytomegalovirus (CMV) status, ABO blood group, gender and parity are of lesser importance (28).

The donors at MGUH-BMCP are mostly young adults in their 20s and 30s (Table 1), making the study of the effects of age on TNC yield difficult. The correlation between donor age and TNC yield at the center is weakly negative (Spearman coefficient r=−0.086; P=0.001) and reflects the narrow age range of the center’s donor population.

Donor characteristics—donor size

It is well known that with increasing volume of the BMH product, cell density decreases. This is largely due to the dilution of marrow with peripheral blood during higher harvest volumes (29-31). Studies reporting a positive correlation between donor weight and body mass index (BMI) on the one side and TNC yield on the other (29,31,32) often fail to make a connection between donor size, recipient cell needs and harvest volume. Anthias et al. (33) found that BMHs generated from donors weighing less than their respective recipients were less likely to reach engraftment thresholds of 2×10⁸ TNC/kg of recipient weight.

Using the donor-recipient weight ratio rather than donor weight or BMI (34) and the percentage of donor estimated blood volume harvested rather than total harvest volume (35) allows to connect recipient needs with donor characteristics (Figure 1).

Figure 1 The effects of donor-recipient weight ratio and percentage of blood volume harvested on TNC yield per mL (left). The effects of donor BMI and total marrow volume harvested on TNC yield per mL (right). Spearman correlation coefficients and P values are added. The data are expressed logarithmically to reduce the effects of outliers and facilitate graphic representation. TNC, total nucleated cell; BMI, body mass index.

While it is important to know how donor characteristics influence TNC density per milliliter of marrow, it is more important to determine, how donor characteristics affect the goal to meet recipients’ TNC requirements. Here, the donor-recipient weight ratio is an informative variable accounting for 80% of the variance of TNC yield per kg of recipient weight (Figure 2). When the donor’s weight is less than 60% of the recipient’s, the threshold for engraftment (2×10⁸ TNC/kg) can barely be reached in 50% of cases. Meeting the engraftment threshold can be guaranteed with 90% certainty only when the donor is heavier than the recipient (Table 2).

Figure 2 The donor-recipient weight ratio’s effect on TNC per kg of recipient weight. The data are expressed logarithmically to reduce the effects of outliers and facilitate graphic representation. Spearman correlation coefficient and P value are displayed and indicate a strong correlation. TNC, total nucleated cell.

Donor characteristics—smoker status

Donors who identify as current smokers have been reported as having higher TNC counts per mL than non-smokers (35). Hematopoiesis in smokers may be stimulated by toxin effects on TET2 mutations (36), stimulation of receptors by nicotine (37), or by cytokine release of pulmonary alveolar macrophages (38). Donors identifying as current smokers at MGUH-BMCP show a slightly higher TNC yield per mL than nonsmokers (20.05×10⁶/mL vs. 19.17×10⁶/mL; 95% CI: 0.09, 1.66; P=0.029). This difference becomes insignificant (P=0.074) when looking at TNC yield per kg of recipient weight. We are also unable to control data for the extent and duration of donors’ smoking habits.

Donor characteristics—laboratory indicators

Matching donors with recipients is important not only with respect to their genetic compatibility but also with respect to their size. In addition, laboratory markers generated prior to the procedure can give the proceduralist indications about the cellularity of the bone marrow at the time (Figure 3). white blood cell (WBC) (r=0.363; P<0.001) and platelet count (r=0.191; P<0.001) correlate with TNC yield per mL of bone marrow with mild impact on cell yield per kg of recipient weight (WBC: r=0.164; P<0.001; platelet: r=0.101; P<0.001).

Figure 3 The impact of donor WBC, platelets, and hemoglobin levels on TNC yield per mL (left) and on TNC yield per kg of recipient weight (right). Spearman correlation coefficients and P values are displayed. WBC, white blood cell; TNC, total nucleated cell.

HSC-niche components like the sinusoidal endothelium, perivascular stromal cells, macrophages, megakaryocytes, osteoblasts, and sympathetic nerves interact with cytokines, growth factors and a variety of chemical influences to stimulate and regulate thrombopoiesis, granulopoiesis and hematopoiesis within the bone marrow. This can explain the correlation between WBC and platelet levels and TNC density within the marrow (39-41).

Donor hemoglobin (Hb) levels are barely associated with cell yield per mL and do not affect TNC levels per kg of recipient weight. Nevertheless, Hb levels are important to assess the potential marrow volume that can be accessed safely for harvesting. At MGUH-BMCP, female donors experience a 1-g/dL drop in their Hb for each 300 mL of bone marrow harvested irrespective of the starting Hb level, making this a simple and reliable method to predict procedural blood loss. Hb levels in male donors drop by slightly less (Figure 4). Alternatively, proceduralists can roughly calculate post-procedure hematocrit levels using the equation: [estimated blood volume × Hct − harvest volume × 0.3 (assumed bone marrow Hct) − estimated soft tissue blood loss × Hct]/estimated blood volume = post-procedure Hct (15).

Figure 4 Decrease in post-procedural Hb levels for different bone marrow harvest volumes in female and male bone marrow donors. Hb levels were measured before and 6 hours after the end of the procedure. Hb, hemoglobin.

In a linear regression analysis, all studied donor laboratory characteristics influence TNC/mL levels to a minor degree (between 1% for Hb and 12% for WBC). Applying a multiple regression analysis with stepwise backward elimination to the model, all characteristics retain their significance in influencing TNC/mL. The complete model explains 22.7% of the TNC/mL variance (Table 3).

The regression analysis looks very different when analyzing the effects of donor characteristics on TNC/kg of recipient weight. Only the donor-recipient weight ratio and donor WBC are significantly related to the TNC/kg of recipient weight. The donor-recipient weight ratio explains 80% of the TNC/kg variance with WBC accounting for a mere 0.7% (Table 3). This underlines the importance of the donor-recipient weight ratio for providing the recipient with an adequate TNC count (34).

Procedure characteristics—pre-procedure autologous blood donation (PAD)

While many BMH centers have abandoned the collection of pre-procedural autologous blood units for post-procedural reinfusion (42,43), others continue the practice for prospective large volume bone marrow collections (44). Associated risks include bacterial contamination, the erroneous use of incompatible blood units, hemolysis, wastage of unused blood products and the incomplete Hb recovery prior to the BMH (45-48).

Comparing female and male donors with and without PAD who donated at least 1,000 mL of bone marrow at MGUH-BMCP, we notice that donors with PAD do not recover their pre-PAD Hb levels at the time of the BMH, neutralizing the potential benefits of PAD for post-harvest Hb recovery. Consequently, post-harvest Hb levels are similar for donors with and without PAD, except for a few female donors without PAD, who drop their Hb levels below a transfusion threshold of 7 g/dL (Table 4). These donors all donated more than 30% of their total estimated blood volume during the procedure. Therefore, the lowest of 30% of estimated blood volume, 18 mL/kg of donor weight, or 1,500 mL collection volume have been established at MGUH-BMCP as the volume limit for BMHs in female donors, while maintaining the lowest of 33% of estimated blood volume, 20 mL/kg, or 1,500 mL for their male counterparts.

Procedure characteristics—single syringe aspiration volumes and aspiration needle type

The impact of individual syringe aspiration volume during BMHs has been discussed in the past. While some studies advocate the use of small 2–5 mL aspiration volumes as a strategy to maximize TNC yield (49,50), others find no significant differences between small and large aspiration volumes while emphasizing the value of fewer bone penetrations for donor recovery (51,52). Studies reporting large differences between small and large aspiration volumes used single terminal hole aspiration needles (49,50). Others emphasize that the use of multi-hole fenestrated needles allows for the aspiration of marrow from multiple directions simultaneously making the choice of aspiration volume in each syringe less relevant (53,54).

At MGUH-BMCP we find that 10 mL aspiration volumes yield a higher TNC content per mL than 20 mL aspiration volumes (27.8×10⁶/mL vs. 25.1×10⁶/mL; 95% CI: 1.17, 4.39; P=0.001) using multi-hole fenestrated aspiration needles. These values are controlled for procedure volume by only including bone marrow collections of 600 mL. Procedures using 10 mL aspirations last 54.7% longer than procedures using 20 mL aspiration volumes (11.82 vs. 7.64 minutes; 95% CI: 3.56, 4.80; P<0.001).

The impact of individual syringe aspiration volume may increase with larger total collection volumes, and proceduralists should consider multiple variables including donor-recipient weight ratio, percentage of donor blood volume to be harvested, procedure duration, ease of marrow flow during collection, donor WBC count, type of needle used, mid-procedure TNC count and final target TNC count when deciding on the individual syringe volumes to be employed.

Procedure characteristics—mid-procedural TNC count

Collecting a mid-procedural TNC measurement allows the proceduralist to predict the necessary final BMH volume and adjust procedural technique (15,54). For example, a lower-than-expected TNC count would invite the proceduralist to reduce single syringe aspiration volumes for the second half of the procedure in order to maximize TNC yield. Conversely, with higher-than-expected TNC counts the proceduralist may increase aspiration volumes to reduce the number of needle penetrations and limit procedure time.

At MGUH-BMCP, we notice a linear correlation between TNC drop and collection volume (35) (Figure 5). This allows the proceduralist to estimate the remaining harvest volume necessary to meet recipient cell needs, once a mid-procedural TNC count has been established at the 600 mL collection point. For example, the final TNC yield/mL for a 1,500 mL collection would be 5×10⁶ lower than the TNC count generated at the 600 mL collection point. We advise proceduralists to subtract 5×10⁶/mL from the mid-procedural TNC count to estimate the necessary remaining collection volume. If the requested TNC count is 250×10⁸ and the mid-procedural TNC yield is 25×10⁶/mL, the final volume required is: 250/(25 − 5) × 100 = 1,250 mL.

Figure 5 Drop in TNC yield with increasing harvest volume. Spearman correlation coefficient and P value are displayed. BMH, bone marrow harvest; TNC, total nucleated cell.

Procedure characteristics—intraprocedural fluid replacement

The recommendations for intraoperative fluid management during BMHs include the replacement of colloid bone marrow with crystalloid fluids such as Ringer’s Lactate at a 2:1 ratio with an additional aliquot given postoperatively for a total of 3:1 fluid replacement. Alternatively, colloid fluids such as 5% albumin can be used at a 1:1 ratio to limit total fluid replacement volumes (15). Proceduralists might be tempted to reduce fluid replacement volumes assuming a negative correlation between the donor’s hydration level and TNC yield.

At MGUH-BMCP, a negative correlation between fluid replacement and TNC yield cannot be confirmed. In fact, there is a mildly positive correlation between fluid-harvest volume ratio and TNC/mL of marrow (Spearman correlation coefficient r=0.082; P=0.016) for harvests of at least 1,000mL. The coefficient for TNC yield per kg of recipient weight is equally positive (r=0.086; P=0.011) indicating that more rather than less fluid replacement contributes slightly to TNC yield. In a regression analysis, the fluid-harvest volume ratio contributes 0.6% to TNC/mL yield (R²=0.006; 95% CI: 0.09, 1.08; P=0.02) and 0.6% to TNC yield per kg of recipient weight (R²=0.006; 95% CI: 0.05, 0.57; P=0.017) for harvest volumes of at least 1,000 mL.

Donors who were able to leave the hospital on the day of the procedure had received an average of 2.0 times their marrow donation volume intraoperatively as crystalloid replacement, while donors who had to spend a night at the hospital postoperatively received 1.8 times their donation volume intraoperatively (95% CI: 0.09, 0.27; P<0.001). Similarly, donors who experienced orthostasis after the procedure received less fluid replacement than their asymptomatic counterparts (1.58 vs. 1.73 times harvest volume; 95% CI: 0.06, 0.25; P=0.002). These differences disappear when looking only at harvest volumes of at least 1,000 mL. Consequently, there is no reason to reduce intraoperative fluid replacement. Fluid restriction does not increase TNC yield while causing potential post-procedural discomfort to the donor.

Limitations

This clinical review is based on the experiences generated at a single center. Nevertheless, this center provides the majority of all BMH performed in the US. All BMH reviewed come from unrelated young adult donors, making suggested relations between donor age and TNC yield less reliable. Data on donor smoking status could not be specified for duration or intensity of smoking. The investigation of single syringe volume effects on TNC yield has been limited to small total volume collections to limit the confounding effects of total harvest volume. It may be advisable to conduct a similar investigation with larger harvest volumes. Intraprocedural fluid management at the MGUH-BMCP is based on crystalloid replacement fluids. At other centers, colloid fluids like 5% albumin solution may be a preferred management option. A comparison between different fluid replacement strategies may be of interest.

Highlights

• The donor-recipient weight ratio accounts for 80% of TNC/kg of recipient weight variance.
• Donor WBC and platelets counts correlate mildly with TNC yield.
• Donor Hb levels do not correlate with TNC yield but affect potential total harvest volume.
• Pre-PAD is not recommended.
• Limiting harvest volumes to 30% of estimated blood volume in female donors prevents the need for post-procedure transfusion.
• Smaller individual aspiration volumes can increase TNC yield but must be weighed against procedure time and number of bone penetrations.
• Mid-point TNC measurements facilitate the estimation of final TNC yield.
• Restricting intra-procedural fluid replacement does not enhance TNC yield and can be associated with post-procedural complications.

Conclusions

BMH remains a valuable tool in the HSC transplantation process for adult and pediatric recipients. With fewer centers engaging in high procedure volumes, proceduralists can benefit from strategic guidelines to maintain and improve training and skill levels. Donor characteristics beyond the HLA-matching process and technical procedure aspects affect TNC yield and eventual outcome for the HSC transplantation recipients.

When selecting the right HLA-matched donor, the donor-recipient weight ratio has the greatest impact on the eventual TNC yield per kg of recipient weight. Donor age and donor laboratory characteristics like WBC and platelet counts also have minor influence on TNC yield but much less than the donor-recipient weight ratio.

Donor Hb levels do not impact TNC yield but are important measures to assess the potential marrow volume that can be accessed safely for BMH. Preprocedural autologous blood donation has no advantage for cell yield but may affect donor care negatively. It should be abandoned as a routine measure. Rather, judicious harvest volume limitations should be employed to maintain maximal donor safety.

During the procedure, smaller individual syringe aspiration volumes are associated with higher TNC yield but must be weighed against procedure time and potential donor discomfort related to more numerous needle penetrations. Proceduralists are advised to consider the donor-recipient weight ratio, donor laboratory characteristics, mid-procedure TNC yield, ease of marrow flow, TNC goals and procedure time when deciding on a prospective single syringe aspiration volume. The mid-procedure TNC yield is a helpful measure to estimate the further necessary collection volume.

Intra-procedural fluid restriction carries no advantage for TNC yield and may compromise donor safety. Fluid replacement with crystalloid solution should aim to replace marrow volume harvested in a 3:1 fashion, using two aliquots during the procedure and a further aliquot afterwards.

Optimizing TNC yield in BMHs is a multi-faceted process. Transplantation outcomes and recipient survival depend on high quality harvest products. Best-practice guidelines and clinical reviews can help stem cell collection centers to deliver that quality.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-19/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-19/coif). The author has no conflicts of interest to declare.

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