To the Editor:
In a previous, widely-read article in LEUKEMIA we discussed why, in umbilical cord blood (UCB) transplants, numbers of CD34-positive cells in a graft are best estimated by blood volume (BV) rather than by body weight (BW) [1]. We also showed, within the dose range we interrogated, there is no threshold dose for posttransplant bone marrow recovery using granulocyte recovery as a surrogate. These observations have important clinical implications which should change current clinical practice guidelines and expert consensus recommendations [2,3,4,5]. Following our publication, several experts quite reasonably asked whether these conclusions apply to conventional blood cell grafts. The answer, which is yes, follows.
To address this question we analyzed data from 746 consecutive subjects receiving blood cell transplants from HLA-matched siblings (Supplement Fig. 1; Supplementary Table 1). 635 were from the Institute of Hematology, Chinese Academy of Medical Sciences (Tianjin, China) 1 December, 2013–1 June, 2021 and 111 from the First Affiliated Hospital of University of Science and Technology of China (Hefei, China) 1 January, 2015–31 December, 2020.
391 (52%) recipients were male. Median age was 39 years (InterQuartile Range [IQR], 30–47 years). Median body height and weight were 166 cm (IQR, 160–172 cm) and 62 kg (IQR, 54–70 kg) with a median body mass index (BMI) of 23 (IQR, 20–25). Median estimated blood volume (calculated based on sex, age, body height and weight; https://skirt-calculator.shinyapps.io/CD34-positive_Cell_Dose_Calculator/ [1, 6]) was 4.0 L (IQR, 3.5–4.5 L). Correlation between body weight and estimated blood volume was 0.83 (95% Confidence Interval [CI], 0.81, 0.85).
Grafts were mobilized blood cells collected 4 days after starting granulocyte colony-stimulating factor (G-CSF). Median absolute total number of infused CD34-positive cells was 170 × 10E+6 (IQR, 137–227 × 10E+6). Granulocyte recovery was defined as reaching a granulocyte concentration > 0.5 × 10E+9/L that was sustained for ≥ 3 consecutive days whilst not receiving G-CSF. Median interval to granulocyte recovery was 13 days (IQR, 12–14 days). 5 subjects dying at a median of 14 days posttransplant (range, 7–16 days) before granulocyte recovery were right-censored and included in our analyses (Supplementary Table 2).Footnote 1
We compared 2 metrics for CD34-positive cell dose: CD34-positive cells/BW and CD34-positive cells/BV. Median CD34-positive cells/BW was 2.7 × 10E+6/kg (range, 0.7–19.8 × 10E+6/kg; IQR, 2.3–3.4 × 10E+6/kg) whilst median CD34-positive cells/BV, 4.2 × 10E+7/L (range, 0.9–27.3 × 10E+7/L; IQR, 3.5–5.5 × 10E+7/L). 92% of high CD34-positive cells/BW values (> 90th percentile) corresponded to high CD34-positive cells/BV values (> 90th percentile) whilst 69% of low CD34-positive cells/BW values (< 10th percentile) corresponded to low CD34-positive cells/BV values (< 10th percentile). In contrast, for values between the 10th and 90th percentiles correspondence between the 2 metrics was poor (40% matching; Fig. 1A). Rank discrepancy between CD34-positive cells/BW and CD34-positive cells/BV often occurred when the BMI was extreme. In both sexes, there was a U-shaped relationship between rank discrepancy and BMI (Fig. 1B).
Using Cox regression and assuming a linear relationship between CD34-positive cell dose and granulocyte recovery we estimated that for each 10E+6/kg increment in CD34-positive cells/BW the hazard for granulocyte recovery increased by 18% (P < 0.001). For each 10E+7/L increment in CD34-positive cells/BV the hazard increased by 12% (P < 0.001). These data indicate both metrics correlated significantly with speed of granulocyte recovery.
There was a clear trend mean interval to granulocyte recovery decreased as dose metric (CD34-positive cells/BW or CD34-positive cells/BV) increased (Fig. 2A). However, the rank correlation between mean interval to granulocyte recovery and CD34-positive cells/BW was –0.49 versus –0.60 with CD34-positive cells/BV (P = 0.03; boot-strapping test).
Removing linearity assumption we used Bayesian restricted cubic splines to estimate the relationship between CD34-positive cell dose and speed of granulocyte recovery [1, 7]. The hazard function of CD34-positive cells/BW for granulocyte recovery was not monotonously increasing and had up-and-down swings (Fig. 2B). Put otherwise, the lowest and highest CD34-positive cells/BW values did not correspond to the slowest and fastest rates of granulocyte recovery. In contrast, the hazard function of CD34-positive cells/BV was strictly monotonously increasing (Fig. 2B).
Interestingly, the hazard for granulocyte discovery stayed ≥ 0.8 for both dose metrics even when CD34-positive cell dose was much lower than the widely-accepted threshold of 4–5 × 10E+6/kg (Fig. 2B) [3, 5]. Consistent with concepts we previously discussed and within the dose range we interrogated there is no threshold dose of CD34-positive cells needed for granulocyte recovery, a surrogate for recovery of bone marrow function [1].
In sensitivity analyses focusing only on subjects with acute leukaemia or myelodysplastic neoplasms (n = 625) or only on those receiving intensive pretransplant conditioning (n = 650) our conclusions were unchanged (Supplement Figs. 2 and 3).
Elsewhere we discuss it is highly improbable numbers of CD34-positive cells would accurately correlate with numbers of haematopoietic stem cells [1]. Nonetheless, physicians may want an estimate of the speed of granulocyte recovery based on numbers of CD34-positive cells in a graft. Our data indicate numbers of CD34-positive cells/BV rather than CD34-positive cells/BW is the more accurate predictor of rate of granulocyte recovery, a surrogate of posttransplant bone marrow recovery and should replace CD34-positive cells/BW in updated clinical practice guidelines and expert consensus recommendations.
Equally important, our data indicate within the dose range we interrogated there is no threshold dose of CD34-positive cells/BW or /BV needed for posttransplant bone marrow recovery. This should make many more umbilical cord blood cell units usable for adults and prevent unnecessary repeat leukaphereses of blood cell transplant donors. This knowledge should result in revised clinical practice guidelines and expert consensus recommendations.
We acknowledge it is difficult or impossible to change ingrained physician practices. However, a Xianbei saying goes, better titbits of jade than a slab of clay.
Data availability
Clinical data are available upon reasonable request to JC and consistent with the laws of China.
Code availability
We described the computational algorithm in detail previously in the Supplemental Material of ref. [1].
Notes
2, 2 and 1 had aplastic anaemia, acute myeloid leukaemia (1 in 1st complete remission; 1 not in remission) and myelodysplastic neoplasm. 4 had CD34-positive cells/BW and CD34-positive cells/BV > the 25th-percentile values of the study cohort (> 2.3 × 10E+6/kg and > 3.5 × 10E+7/L). 4 had infection pretransplant and died of septic shock posttransplant. 1 died of cardiac failure starting pretransplant.
References
Chen J, Gale RP, Feng Y, Hu Y, Qi S, Liu X, et al. Are haematopoietic stem cell transplants stem cell transplants, is there a threshold dose of CD34-positive cells and how many are needed for rapid posttransplant granulocyte recovery? Leukemia. 2023;37:1963–8.
Barker JN, Kurtzberg J, Ballen K, Boo M, Brunstein C, Cutler C, et al. Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies. Biol Blood Marrow Transpl. 2017;23:882–96.
Ayuk F, Balduzzi A. Donor selection for adults and pediatrics. In: Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies, 7th edn. Cham (CH): Springer; 2019. pp 87–97.
Dehn J, Spellman S, Hurley CK, Shaw BE, Barker JN, Burns LJ, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR. Blood. 2019;134:924–34.
Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009;23:1904–12.
Raes A, Van Aken S, Craen M, Donckerwolcke R, Vande Walle J. A reference frame for blood volume in children and adolescents. BMC Pediatr. 2006;6:3.
Gauthier J, Wu QV, Gooley TA. Cubic splines to model relationships between continuous variables and outcomes: a guide for clinicians. Bone Marrow Transpl. 2020;55:675–80.
Acknowledgements
Prof. Ted Gooley (FHCRC) kindly reviewed the typescript. RPG acknowledges support from the UK National Institute of Health Research (NIHR) Biomedical Research Center.
Funding
Supported, in part, by grants from the National Natural Science Foundation of China (82370212 and 62306340 to JC; 82070192 to EJ), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-001 and 2022-I2M-2-003 to JC), National Key Research and Development Program of China (2023YFC2508902 to EJ), Tianjin Natural Science Foundation (23JCZXJC00220 to EJ), the Ministry of Science and Technology of China (84000-51200002 to RPG), the National Natural Science Foundation of China (81470350 to ZS), the Fundamental Research Funds for the Central Universities (WK9110000001 to ZS) and Union Stem Cell & Gene Engineering Co., Ltd. (JC and ZS).
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JC and RPG conceived the study. JC oversaw the study. YHe, DY, AP, HL and EC collected the data under supervision of MH, ZS and EJ. YHu, YJ, MW and XG compiled and curated the data with WY, QS, WZ, HL, XZhang, MC, EC and XZhai’s assistance. YF, SQ and YHu did the analyses with assistance from WY and WZ. All authors contributed to interpretation of the results and discussion. YF, SQ, YHu, WY, RPG and JC prepared the typescript with assistance from MW. YF, SQ, YHu and WY developed the Figures and Tables. The authors reviewed the typescript, take responsibility for the content and agreed to submit it for publication.
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RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.
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Approved by the Academic Committee (IIT2021006) of the Institute of Hematology, Chinese Academy of Medical Sciences (IHCAMS) and the Ethics Review Committees of IHCAMS (IIT2021006-EC-1) and the First Affiliated Hospital of University of Science and Technology of China (FAHUSTC; 2022-RE-070). Subjects gave written informed consent consistent with precepts of the Helsinki Declaration.
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Feng, Y., Qi, S., Hu, Y. et al. New criteria for estimating numbers of CD34-positive cells in a graft needed for posttransplant bone marrow recovery. Leukemia (2024). https://doi.org/10.1038/s41375-024-02424-2
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DOI: https://doi.org/10.1038/s41375-024-02424-2