I was interested to read the article in the January 10 issue about specific strategies that can mobilize millions of stem cells. Strategies mentioned included (1) avoid radiation, multiple cycles of chemotherapy, and myelotoxic drugs, (2) collect early in treatment, (3) use higher doses of filgrastim or pegfilgrastim, (4) utilize chemomobilization plus colony-stimulating factor, and (5) use plerixafor to augment filgrastim.
The diseases noted were lymphoma and multiple myeloma. These are different diseases with different treatment strategies, and the opportunity to mobilize after induction will depend on the treatment used during induction. The definition of “early treatment” is therefore likely meant as early during treatment in cycles 1 or 2 of treatment. Can this safely be realized in lymphoma and multiple myeloma?
In the early ’90s I was heavily involved in the definition of optimal timing of leukapheresis for collection of hematopoietic progenitor cells. At the time we performed a study and mobilized by chemotherapy and granulocyte colony-stimulating factor (G-CSF) and assessed the opportunity to do so in cycle one and four of the treatment.
For collection, white blood cell count and circulating CD34+ cells were measured and colony-forming cells and long-term culture initiating cells were assessed in cultures.1,2 The results of these studies showed that mobilization of CD34+ cells, colony-forming cells, and long-term culture-initiating cells was far better during the first than the fourth cycle of chemotherapy and G-CSF. Moreover these studies showed that the mobilizing capacity rapidly decreased and was far less after one treatment of just four cycles of therapy.
The concern of collection in the first cycle of chemotherapy is that tumor cells may also be mobilized. It has been shown that myeloma cells do not mobilize, but it has not been extensively examined early during treatment; in lymphoma it appears that circulating lymphoma cells are rapidly eliminated by anti-CD20 if anti-CD20 is part of the therapy. To circumvent the high drug costs of plerixafor, use of leukapheresis should be considered during the first or second cycle of therapy.
The question then arises when to start leukapheresis; we kept as optimal when the white blood cell count increased from nadir to 4 x 10e9/L and performed leukapheresis on that particular day; this strategy made it possible to collect more than 2 x10e6 CD34+ cells/kg during one 12-liter leukapheresis in most patients. Moreover it appeared predictable that this would occur on day 11 or 12 of cycle one when G-CSF was started on day 2 of the cycle. Our data are consistent with the recommendations made in the study reported in the article.
With CHOP-R being the standard treatment for patients with diffuse large B-cell lymphoma, the addition of G-CSF makes it possible to collect during cycle one on day 11 or 12 when the white blood cell count increases to 4 x 10e9/L. Moreover it is likely that by day 11 and 12 of the first cycle that lymphoma cells are no longer circulating in the peripheral blood.
For early collection of peripheral blood progenitor cells in multiple myeloma, cyclophosphamide might need to be included in the first cycle(s) of treatment and G-CSF. However as not all agents are given on day 1 of treatment, research will need to show when the white blood cell count rises to 4 x 10e9/L.
The question remains whether there is a role in this regard of anti-CD20 in multiple myeloma; although it has not been examined in first line therapy, use of anti-CD20 in the 20 percent of multiple myeloma patients who do express CD20 might have another rationale – to eliminate potentially circulating multiple myeloma cells.
Marlies Van Hoef, MD, PhD, MBA
Amsterdam, The Netherlands
1. Ann Oncol 1994;5:217.
2. Ann Oncol 1996;5:1052.