The Effect of Increasing CD34+ Cell Doses on Time to Engraftment after Autotransplantation for Hematologic Malignancies

It is thought that 2 x 10⁶/kg is the minimum CD34+ cell dose needed for autotransplantation, while the ideal dose is generally accepted to be 5 x 10⁶/kg. Whether infusing cell doses higher than 5 x 10⁶/kg offers additional benefit is unknown. The relationship between time to standard engraftment endpoints (0.5 x 10⁹/L Neutrophils – ANC 0.5, 1 x 10⁹/L neutrophils – ANC 1.0, 20 x 10⁹/L platelets – PLT 20, and 50 x 10⁹/L platelets – PLT 50) and the CD34+ cell doses infused was explored in 754 autografts performed for malignant diseases in adult patients: 32 leukemia, 195 lymphoma, 514 myeloma, 13 other. The conditioning regimens used were standard (high-dose melphalan, BEAM, busulfan-cyclophosphamide, or busulfan-etoposide in >90%). All patients received G-CSF after stem cell infusion: from day 0 in <10% and from day +5 in >90%. Cell dose calculations were based upon ideal body weight. Table 1 shows the distribution of the CD34+ cell ranges infused.

Table 1: CD34+ cell numbers infused (10⁶/kg IBW)

CD34+ cell dose	n	CD34+ cell dose	n
≤3	42	>3	712
≤4	109	>4	645
≤5	260	>5	494
≤6	434	>6	320
≤7	534	>7	220
≤8	586	>8	168
≤9	619	>9	135
≤10	646	>10	108
≤15	714	>15	40

Figure 1 shows the mean days to achieving the 4 engraftment endpoints under study by the number of CD34+ cells infused. It is clear that increasing CD34+ cell doses hasten platelet recovery significantly through the entire range of CD34+ cell dose ranges studied. Increasing CD34+ cell doses appear to hasten neutrophil recovery too, but the benefit seems to level off beyond 10 x 10⁶ CD34+ cells per kg. The effect of a CD34+ cell dose of ≤2 x 10⁶/kg was not analyzed because only 7 patients received this small quantity of cells.

Figure 1: The effect of different CD34+ cell dose ranges on various engraftment endpoints

The relationship between CD34+ cell doses and engraftment holds true even when the data are analyzed in a dichotomous fashion as shown in Figure 2.

Figure 2: Differences in engraftment based upon CD34+ cell doses

Table 2 shows the significance of the differences illustrated in Figure 2.

Table 2: Significance of differences in time to engraftment

CD34+ cell dose bands	ANC 0.5	ANC 1.0	PLT 20	PLT 50
≤3/>3	0.28	0.003	0.083	0.43
≤4/>4	0.029	0.0007	0.027	0.39
≤5/>5	0.002	0.001	0.0004	0.031
≤6/>6	<0.0001	<0.0001	0.002	0.076
≤7/>7	<0.0001	<0.0001	0.0002	0.009
≤8/>8	<0.0001	<0.0001	0.0002	0.006
≤9/>9	<0.0001	<0.0001	0.0004	0.005
≤10/>10	<0.0001	<0.0001	<0.0001	0.006
≤15/>15	0.005	0.001	0.003	0.004

These data suggest that increasing CD34+ cell numbers hasten hematologic recovery – even beyond a cell dose of 15 x 10⁶/kg. It remains to be seen if more rapid engraftment resulting from infusion of higher number of CD34+ cells results in practical benefits such as more robust/durable engraftment, decreased toxicity, and improved survival.