The Goldilocks conundrum: how much granulocyte colony-stimulating factor following autologous stem cell transplant is ‘just right’?

It is tempting to assume that faster granulocyte recovery following high dose chemotherapy and autologous stem cell transplant (ASCT) will result in enhanced patient outcomes of fewer infections, less antibiotic usage, more rapid resolution of mucositis, and faster discharge from hospital, with all of the cost savings that would naturally follow from such outcomes.

The use of granulocyte colony-stimulating factor (G-CSF) following ASCT does indeed result in faster neutrophil recovery of approximately 2 days in many reported series, as reviewed by Ojeda et al. [1]. However, despite this, studies have been inconsistent in showing that routine use of G-CSF provides advantages such as reductions in antibiotic use and hospitalization days and improved cost-effectiveness. Acknowledging the obligatory period of neutropenia prior to the engraftment of granulocytic precursors in ASCT, some investigators have studied the use of delayed G-CSF administration post-transplant, and have shown that despite later commencement and less total G-CSF use there was no erosion of clinical advantage [2–5]. Despite the variation observed in clinical outcome in these studies there remains some confusion regarding the value of routine use of G-CSF post-ASCT, a situation reflected in the positive recommendation for routine G-CSF use post-ASCT by the American Society of Clinical Oncology (ASCO) guidelines [6], but a lower recommendation in the European Society for Medical Oncology (ESMO) guidelines [7].

In recent years, the availability of a pegylated preparation of G-CSF has logically led to the investigation of its utility for the support of neutrophil engraftment following ASCT. In this issue of Leukemia and Lymphoma, Wanneson and colleagues report their experiences of post-ASCT outcomes in relatively uniformly treated populations of patients undergoing ASCT for either myeloma or lymphoma, comparing pateints treated with pegylated (Peg)-G-CSF to a matched cohort of patients who received standard-of-care G-CSF on either day +5 or day +7 [8].

Their results indicate that Peg-G-CSF administration did indeed result in more rapid neutrophil recovery, by approximately 1.5 days, 2 days less antibiotic use, and a shortening of duration of in-hospital stay by 1 day. The size and retrospective nature of this cohort analysis precluded performing a meaningful cost–benefit analysis, although it is unlikely that, at current drug costs, an overall cost saving would probably have been observed. Whilst the clinical improvements were assumed to reflect faster neutrophil engraftment, it remains possible that the improved outcomes were a result of a Peg-G-CSF induced increase in the pre-nadir neutrophil numbers, resulting in an overall shorter time with severe neutropenia. Overall, the findings from Wanneson et al. suggest that the biological effect of a single dose of Peg-G-CSF from day +1 post-ASCT is similar or slightly enhanced to that delivered by daily G-CSF. This is a finding in line with that observed in other studies of Peg-G-CSF administration following ASCT [9,10].

One important finding from the Wanneson analysis is that patients undergoing ASCT for different indications (myeloma vs. lymphoma) may experience different levels of advantage from post-ASCT G-CSF administration. Patients with multiple myeloma receiving day +1 Peg-G-SCF post-ASCT experienced improved neutrophil recovery kinetics without translating to outcome improvements in duration of hospital stay and intravenous (IV) antibiotic use. This was in contrast to patients having ASCT for lymphoma who experienced benefits in terms of neutrophil engraftment and duration of neutropenia as well as IV antibiotics and hospitalization. This is a particularly important finding that may have reduced the apparent impact of G-CSF administration in previous analyses of unselected recipients of ASCT. Similarly, in an as yet unpublished analysis of G-CSF administration post-ASCT in 100 patients, we have also observed a disease-specific differential benefit of routine day +1 G-CSF in patients with multiple myeloma, who had shorter periods of neutropenia but no other clinical benefit, and those undergoing ASCT for relapsed lymphoma, who had no shortening of neutropenia or other clinical benefit. These observations should encourage future investigators to report outcomes based on the disease indication for ASCT and caution against the extrapolation of outcomes across patient cohorts.

A potential advantage of the routine use of Peg-G-CSF is that a single dose of Peg-G-CSF may make the delivery of outpatient ASCT more feasible. Whilst this may provide a pragmatic solution to G-CSF administration in that particular setting, it is likely that the routine use of Peg-G-CSF following a standard inpatient ASCT is a case of ‘too much,’ whereas the universal omission of any G-CSF post-ASCT across all patients is probably ‘too little.’ There seems to be an appropriate middle ground of G-CSF administration based on a pre-ASCT risk analysis of underlying disease, age, stem cell dose, and history of prior sepsis that will result in a G-CSF schedule for each patient that is ‘just right.’

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.