The CD34+ Cell Dose, Even in an "Acceptable" Range, Affects Outcome of Allogeneic Blood Stem Cell Transplantation.
Authors: Singhal Seema , Gordon L. , Meagher R. , Evens A. , Tallman M. , Williams S. , Winter J. , Grinblatt D. , Kaminer L. , Mehta J. 
Published: October 2019

The number of CD34+ cells infused affects the outcome of allogeneic HSCT significantly. Low cell doses result in higher treatment-related mortality (TRM) and lower overall survival (OS) (<2 x 106/kg. Singhal et al. Bone Marrow Transplant2000;26:489–96). Very high doses result in significantly increased GVHD but no directly obvious detrimental effect on OS (>8 x 106/kg. Przepiorka et al. Blood2001; 98:1695–1700. Zaucha et al. Blood2001;98:3221–7). No data are available on the effect of CD34+ cell doses in the intevening range. Based upon the limited published data, we have tried to aim for an allograft CD34+ cell dose of between 2 and 8 x 106/kg ideal body weight (IBW). We analyzed the outcome of 58 allogeneic HSCT recipients (31–66 y, median 52; 25 lymphoma/CLL, 18 acute leukemia, 15 myeloma) who received an "acceptable" CD34+ cell dose (2−8 x 106/kg) from HLA-matched siblings (n=37), 10/10 allele-matched unrelated donors (n=15), or 1-locus/allele mismatched sibling/unrelated donors (n=6). Patients receiving lower (<2) or higher (>8) CD34+ cell doses were excluded. The conditioning regimen was 100 mg/m2 melphalan with (n=40; no prior autograft) or without (n=18; prior autograft) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate for HLA-identical sibling donor grafts and tacrolimus-mycophenolate for the rest. No growth factors were administered, and all supportive care was uniform. The actual CD34+ cell dose was 2.1–7.7 (median 5.0) x 106/kg IBW. A threshold of 6 x 106 CD34 + cells/kg was chosen for detailed analysis as it provided a significant cutpoint for OS comparison using the logrank statistic (P=0.039). Other cutpoints (≤5 vs >5 and ≤5.5 vs >5.5) showed superiority for higher cell doses but did not reach statistical significance. The cell dose was >6 x 106/kg in 11 and ≤6 x 106/kg in 47. 13 patients experienced TRM; all in the ≤6 group (P=0.045; Fisher’s exact test). The following factors were analyzed in a Cox model for their effect on OS: chemosensitive (n=24) vs refractory disease (n=34), age ≤55 (n=40) vs >55 (n=18), normal (n=29) vs abnormal (n=29) LDH, HLA match (n=52) vs mismatch (n=6), prior autograft or not, performance status 0–1 (n=45) vs 2–3 (n=13).

Favorable factor RR (95% CI) P Chemosensitive disease 4.4 (1.7–11.6) 0.003 Performance status 0–1 3.6 (1.5–8.3) 0.003 Normal LDH 3.0 (1.4–6.4) 0.005 CD34+ cell dose >6 3.5 (1.0–12.0) 0.043

As the table shows, a CD34+ cell dose >6 was independently associated with superior survival.

Figure. Figure.

Figure 1 shows OS by CD34+ cell dose plotted at the means of the other covariates using the Cox analysis. Our data suggest that even within the broad range considered acceptable based on current literature, higher CD34+ cell doses appear to improve OS by reducing TRM. Further work in larger patient groups is required to define the optimum CD34+ cell dose to be used for allogeneic HSCT so that this clinically modifiable parameter can be eliminated as a variable potentially affecting outcome adversely. Until additional data are available, we suggest infusing a CD34+ cell dose that is >6 but <8 x 106 per kg IBW for allogeneic HSCT.