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The effect of CD34+ cell dose on patient outcome in allogeneic stem cell transplantation (allo-SCT) using peripheral blood stem cells (PBSCs) as the stem cell source has not yet been established. Whilst a low CD34+ cell dose has been reported to lead to engraftment failure, delayed engraftment and inferior outcome, conflicting reports have been published for transplantations using a high CD34+ cell dose. To evaluate the impact of infused CD34+ cell doses on PBSC allo-SCT matched-related donor outcomes, Yasuhisa Yokoyama, University of Tsukuba, Tsukuba, JP, and colleagues conducted a retrospective analysis using a large cohort of patients from a Japanese nationwide registry database.
Given as high-CD34+ vs low-CD34+
Table 1. Key patient characteristics with statistically significant differences between CD34+ cell doses
|
High-CD34+ |
Low-CD34+ |
p value |
---|---|---|---|
Donor: median age, years (range) |
42 (12–74) |
46 (11–69) |
0.045 |
Infused CD34+ cell dose (×106/kg, range) |
6.00 (4.50–21.1) |
3.00 (0.65–4.49) |
< 0.001 |
Sex mismatch Female to male, % |
17.4 |
33.1 |
< 0.001 |
Table 2. Analysis of outcomes by CD34+ cell dose
|
High-CD34+ |
Low-CD34+ |
p value |
---|---|---|---|
Engraftment rates |
|||
Neutrophil, days |
13 |
14 |
0.0153 |
Platelet, days |
20 |
23 |
< 0.001 |
DFS at three-years |
|||
Total, % |
51.7 |
45.4 |
0.2030 |
High-risk, % |
31.4 |
30.4 |
0.5750 |
Low-risk, % |
64.9 |
55.5 |
0.0415 |
OS at three-years |
|||
Total, % |
49.0 |
48.0 |
0.5610 |
High-risk, % |
29.2 |
30.9 |
0.5980 |
Low-risk, % |
64.5 |
60.7 |
0.1440 |
CIR |
|||
Total, % |
28.3 |
34.9 |
0.1260 |
High-risk, % |
41.5 |
42.7 |
0.9960 |
Low-risk, % |
19.6 |
29.6 |
0.0356 |
NRM |
|||
Total, % |
20.0 |
19.8 |
0.8750 |
High-risk, % |
27.0 |
26.9 |
0.6430 |
Low-risk, % |
15.5 |
14.9 |
0.8460 |
CIR, cumulative incidence of relapse; DFS, disease-free survival; NRM, non-relapse mortality; OS, overall survival
* Values indicated in bold are statistically significant
The cumulative incidence of acute GvHD (aGvHD) at Day 100, Grade II–IV or III–IV, and the incidence of chronic GvHD (cGvHD) at three-years, overall or extensive, did not differ by CD34+ cell dose or by disease risk as shown in Table 3.
Table 3. GvHD risk by acute vs chronic and disease risk
|
High-CD34+ |
Low-CD34+ |
p value |
---|---|---|---|
Cumulative incidence of aGvHD at Day 100 |
|||
Total cohort |
|
|
|
Grade II–IV, % |
32.9 |
31.9 |
0.794 |
Grade III–IV, % |
15.9 |
11.3 |
0.152 |
Disease risk: low |
|
|
|
Grade II–IV, % |
28.8 |
29.2 |
0.921 |
Grade III–IV, % |
13.7 |
8.3 |
0.159 |
Disease risk: high |
|
|
|
Grade II–IV, % |
39.4 |
36.0 |
0.609 |
Grade III–IV, % |
19.1 |
15.7 |
0.546 |
Cumulative incidence of cGvHD at three-years post-transplant |
|||
Total cohort |
|
|
|
Overall, % |
43.7 |
45.8 |
0.757 |
Extensive, % |
28.1 |
30.0 |
0.580 |
Disease risk: low |
|
|
|
Overall, % |
44.3 |
50.3 |
0.424 |
Extensive, % |
28.9 |
32.4 |
0.517 |
Disease risk: high |
|
|
|
Overall, % |
42.6 |
39.1 |
0.594 |
Extensive, % |
26.6 |
26.3 |
0.954 |
GvHD, graft-versus-host disease; aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease
Multivariate analysis found that high-CD34+ cell dose and development of Grade III–IV aGvHD were significantly associated with DFS whilst Grade III–IV aGvHD was also associated with OS. No other factors such as performance status, conditioning regimen, or GvHD prophylaxis were associated with DFS or OS.
Outcome analysis for transplantation of excessive CD34+ cell count (> 8 × 106/kg vs 4.5–8.0 × 106/kg), found no significant associations in relation to three-year DFS (p = 0.713), OS (p = 0.791), overall cGvHD (p = 0.179) or extensive cGvHD (p = 0.489). However, excessive CD34+ cell dose (> 8.0 × 106/kg) led to significantly higher levels of aGvHD:
While no correlation between outcome and CD34+ cell dose was found for high-risk patients, patients with low-risk disease receiving high-CD34+ cell dose had a reduced risk of relapse and improved DFS without a concomitant increase in GvHD incidence. However, an excessive dose of CD34+ was found to increase the first of Grade II–III and II–IV aGvHD and should be avoided. The importance of disease stratification is also shown in this analysis to ensure patients receive the appropriate dose of CD34+ cells.
Therefore, the authors of this retrospective study recommend a CD34+ cell dose of 4.5–8.0 × 106/kg for patients with low-risk diseases receiving PBSC as donor source in HLA-matched related transplantation.
Yokoyama Y. et al. A high CD34+ cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors. Bone Marrow Trans. 2020 Feb 10. DOI: 1038/s41409-020-0817-5
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