Introduction

Stem cell dose expressed as CD34+ cells per kg is an important factor in determining rate of engraftment following autograft.^{1, 2} Recent reports have suggested that stem cell doses calculated from ideal body weight (IBW) may correlate better with engraftment than those calculated from actual body weight (ABW).^{3, 4, 5, 6} In addition, using IBW may reduce the number of harvesting procedures needed and would remove any concerns over changes in stem cell dose per kg should the patient's weight alter substantially between stem cell collection and transplant. The aims of this study were to show whether stem cell dose correlates better with engraftment when calculated using IBW rather than ABW and to confirm that the use of IBW to calculate stem cell dose is safe in our clinical setting. We assessed this proposition in consecutive peripheral blood stem cell (PBSC) autografts for haematological malignancy at a single centre over a 6½-year period.

Patients and methods

Case notes and engraftment data were reviewed for all patients transplanted using autologous PBSC at Glasgow Royal Infirmary between February 1999 and September 2006. All patients had given written consent for their records to be examined for the purposes of retrospective data analysis. Patients were excluded if they had any diagnosis other than acute leukaemia, CLL, lymphoma and myeloma or failed to engraft by day 28. Since more than half the autografts performed at our centre are for myeloma, these patients were also analysed separately.

Stem cells were collected using the Cobe Spectra cell separator (Gambro BCT, Lakewood, CO, USA). The target CD34 dose for stem cell collection and transplantation was 4 10⁶ CD34+ cells/kg ABW. CD34+ cells were enumerated using standard techniques.⁷ Stem cell mobilization regimes generally included chemotherapy plus GCSF (either Filgrastim or Lenograstim), with the GCSF administered at a dose of 5 g/kg for between 5 and 10 days depending on the regimen.

All conditioning regimes for patients with myeloma included Melphalan; 88 single agent, 22 with Busulphan, seven with Treosulphan and one with total body irradiation (TBI). BEAM (Carmustine, Etoposide, Cytarabine, Melphalan) was used for 85 lymphoma patients, with the remaining 10 lymphoma and five acute leukaemia patients receiving a TBI containing regime with either Cyclophosphamide (11), Etoposide (2) or Melphalan (2). GCSF at a dose of 105 g was commenced on day +1 post-transplant and continued until neutrophils >0.5 10⁹/l for 2 consecutive days.

Neutrophil engraftment for this study was taken to be the first day neutrophils >0.5 10⁹/l were recorded. Platelet engraftment was more difficult to record due to prophylactic platelet transfusion for symptoms or when the platelet count was below 10 10⁹/l. Any record of platelets >20 10⁹/l before day +7 was disregarded with the patient being excluded from that part of the analysis.

All patients had their height and weight recorded at the time of stem cell collection and again at transplant. IBW (kg) was calculated by a standard formula using gender and height: 50+{2.3 (height in inches-60)} for males and 45.5+{2.3 (height in inches-60)} for females.⁸

Statistics

Plots of days to engraftment vs stem cell dose were generated to compare engraftment patterns by stem cell dose calculation method. The correlation of these data with an inverse curve best fitting engraftment was calculated and expressed as r². Time to engraftment was compared for CD34+ cell dose values below and above our target dose for both ABW and IBW calculations (<3.5 vs 3.5 and <5 vs 5) using Wilcoxon's rank sum test (otherwise know as the Mann–Whitney U test). These limits were chosen on the basis of work ongoing in the department examining engraftment kinetics to establish a safe minimum stem cell dose. In addition, engraftment was compared between those who would have failed to reach our target CD34+ threshold of 4 10⁶ by both methods, those meeting the requirement by both methods and those failing only by ABW.

Results

Patient selection and characteristics

A total of 226 PBSC autografts were performed at Glasgow Royal Infirmary between February 1999 and September 2006 in the setting of haematological malignancy. Eight were excluded from this study. One patient died of sepsis on day +3 before engraftment could be assessed. Four were excluded due to failed engraftment by 28 days, with subsequent neutrophil recovery being presumed to be constitutive in origin. These four patients all received stem cell doses well over 5 10⁶/kg, and failure to engraft was felt most likely to be due to viral infection. Three patients (two CML, one myelofibrosis) were excluded as they had extremely high CD34 doses out of keeping with the rest of the cohort. The data from 218 patients was therefore suitable for analysis (Table 1). A total of 118 of these patients were transplanted for Myeloma, and had received similar treatment including mobilization and conditioning regimes: they therefore represent a relatively homogeneous group. Before analysis of platelet engraftment, a further five patients were excluded due to lack of data (1) or recorded engraftment before 7 days—likely to be transfusional (4). A total of 22 patients were identified as poor mobilizers due to requiring three or more apheresis procedures to achieve target stem cell dose. Of these, seven (32%) would not have needed more than two procedures if stem cell dose had been calculated by IBW.

Table 1 - Patient demographics.

Full table

Height, weight, stem cell dose and engraftment

The median height for the group was 167 cm: however, among those with myeloma, it was 2 cm less at 165 cm. Thirty patients (14%) weighed less than their IBW, eight of whom (4%) weighed less than 90% IBW. The median ABW:IBW ratio was 1.21, with 44% of patients exceeding their IBW by 25% or more. Between stem cell collection and transplant, there was an overall 1% increase in weight; 34 patients gained >5% body weight, while 11 patients lost >5% (Table 2). The median stem cell dose per kg achieved as calculated by ABW was 5.0 10⁶ but was over 20% greater at 6.1 10⁶ when calculated by IBW.

Table 2 - Summary of results.

Full table

In 69/218 (32%) cases, the target dose of 4 10⁶ CD34+ve cells/kg ABW was not met. Of these, 35 (51%) would have met the target if CD34+cells per kg IBW had been used. For both the overall group and the myeloma group, inverse correlations were plotted between cell dose/kg (ABW and IBW) and days to engraftment of neutrophils and platelets. In all comparisons, there was a stronger correlation when cell dose by IBW was used (Table 3) (Figure 1). The differences were more marked in the myeloma group.

Figure 1.

Correlation between time to neutrophils >0.5 and stem cell dose as calculated by actual or ideal body weight—there is a better correlation between stem cell dose and time to neutrophil engraftment when this is calculated by ideal body weight rather than actual body weight.

Full figure and legend (29K)

Table 3 - Summary of correlations between time to engraftment and stem cell dose.

Full table

Data comparison using cutoff limits

For those not achieving the lower CD34+ dose cutoff of 3.5 10⁶/kg as calculated by IBW, the mean time to neutrophil engraftment was 13 days compared to 10.8 days for those who did achieve it (P<0.001). Platelet engraftment for those with CD34+ dose below 3.5 10⁶/kg by IBW averaged 18.3 days compared with 12.3 days for those with dose greater than 3.5 10⁶/kg (P<0.001). Using ABW, these differences were less marked; 12 vs 10.7 days for neutrophil engraftment (P=0.002) and 14.9 vs 12.3 days for platelet engraftment (P=0.005). There remains a significant difference in engraftment between those with CD34+doses above and below the higher cutoffs of 4 10⁶/kg and 5 10⁶/kg, although the P-value is the same whichever calculation method is used (Table 4).

Table 4 - A summary of engraftment times by stem cell dose cutoffs.

Full table

The patients were also divided into three groups for analysis dependent on whether they achieved the target CD34+ dose of 4 10⁶/kg by IBW or ABW. Group 1 did not achieve the target dose by either calculation method, group 2 achieved the target by IBW only, while group 3 achieved target dose by both methods. Neutrophil and platelet engraftment averaged 12.5 and 16.9 days, respectively, for group 1, 11.2 and 12.2 days for group 2 and 10.7 and 12.3 days for group 3 (Table 5). When these groups are compared using Wilcoxon's rank sum test the differences between all groups reach significance for days to neutrophil engraftment but there was no significant difference (P=0.27) in platelet engraftment between groups 2 and 3. When these analyses were performed on the myeloma group and the non-myeloma group markedly different results were obtained. In the Myeloma group, there was a significant difference in engraftment between groups 2 and 3 for both neutrophils and platelets, while no difference was seen between groups 1 and 2. Conversely in the non-myeloma group, the significant difference was between groups 1 and 2 with no difference between groups 2 and 3. Thus, for the non-myeloma group, the use of IBW allows better prediction of engraftment.

Table 5 - Comparison of engraftment times by achievement of target dose.

Full table

Discussion

The ratio of IBW to ABW we saw in our study was remarkably similar but the stem cell doses infused were approximately 25% greater than those used by Ali et al.³ Possibly because of this, despite larger numbers of patients, we were not able to show such close inverse correlations to engraftment by either stem cell dose calculation method. Our patient group also differs from that described by Ali et al.³ in that, there is a preponderance of myeloma patients among autografts performed at our centre.

It may be that IBW more closely reflects a patient's marrow volume than ABW and is a more accurate method of determining stem cell requirements. This is suggested by the closer correlation between engraftment and the anticipated inverse curve using IBW to calculate dose. Assessing this correlation is difficult as it is likely that the relationship between stem cell dose and neutrophil engraftment is initially steep then plateaus beyond a stem cell dose of around 3–5 10⁶/kg. Our data contained few patients with stem cell doses below 2 10⁶/kg and probably under-represents the steep part of the curve. In an attempt to overcome this problem, we included platelet engraftment in the analysis. As platelets generally take slightly longer to engraft, we felt that we may be able to demonstrate more of the steep part of their engraftment curve. The greater difference in r² between the IBW and ABW calculations when applied to platelet engraftment may reflect this.

The changing demographics of our patients are illustrated by the recently published Scottish Health Survey 2003, which shows a steady increase in body mass index (BMI) for adults in Scotland.⁹ Average male BMI has risen from 26.0 kg/m² in 1995 to 26.9 kg/m² in 2003. For women, there was an even greater rise over the same period from 25.7 kg/m² to 26.9 kg/m². This has resulted in the proportion of adults who were overweight or obese (BMI >25 kg/m²) rising from 55.6 to 64.0% for men and 47.2 to 57.3% for women. This increasing difference between IBW and ABW also increases the average stem cell dose required when calculated by ABW. If IBW was used to calculate stem cell dose then the actual number of stem cells harvested could be reduced by 20% on average to achieve the same dose/kg. This would undoubtedly save many patients additional apheresis procedures and courses of conditioning chemotherapy and would also remove the need to recalculate doses following changes in weight.

Should we change practice to use IBW instead of ABW, we need to be confident that no patients will receive inadequate stem cell doses as a result. In our clinical practice using a target stem cell dose of 4 10⁶/kg, we have shown that those patients treated for diseases other than myeloma who would have failed to reach the target dose by ABW but reach it by IBW achieve engraftment not significantly different than those reaching the target dose by ABW for both neutrophils (P=0.28) and platelets (P=0.8) (Table 5). This suggests that achieving our target dose by IBW is as likely to result in satisfactory engraftment as achieving it by ABW for these patients. The analysis of the myeloma group is markedly different with the significant difference in engraftment in this group being between groups 2 and 3. The difference in the outcome of this analysis between these two patient groups is we think explained by a general overestimate of CD34+ dose by IBW in myeloma patients due to disease-related loss of height and therefore underestimation of IBW.

Height is the key to determining IBW; therefore, it is important that the figure used in its calculation is representative of the patient's true height unaffected by disease. The 2 cm difference we have noted between all patients and myeloma patients corresponds with a recent study investigating the role of oral pamidronate in 300 patients with myeloma. This described a 1.5 cm loss in height (167.5 to 166 cm) in those receiving pamidronate and a 3 cm (166.8 to 163.8 cm) drop in those receiving placebo.¹⁰ The majority of patients attending our unit have received intravenous pamidronate. We did investigate the effect on our results of adding 2 cm to each myeloma patient, but observed little difference from our initial findings. This theoretical exercise may not be informative as the height loss experienced by myeloma patients will not be uniform. To further explore this concept, knowledge of patients' pre-morbid height will be needed for comparison.

In conclusion, the use of IBW to calculate stem cell dose for PBSC autograft predicts engraftment better than the use of ABW. In addition, for non-myeloma patients, the time to neutrophil and platelet engraftment when a target dose of 4 10⁶ CD34+ cells is achieved by IBW is no greater than if this was achieved by ABW and with a likely reduction in harvesting procedures. Analysis of a large subgroup of patients with myeloma has highlighted the importance of height in the calculation of IBW and we would suggest using pre-disease height or if in doubt reverting to the use of ABW in these patients. With this reservation, we suggest that the use of IBW to calculate stem cell dose is superior to the use of ABW in the setting of PBSC autograft.

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