autologous blood and marrow transplantation - Blog Science ...

542 Chapter 10: Graft Manipulation
which the benefit of purging could be clearly demonstrated, in a reasonable time, and
within a reasonably sized patient population, has often proven too much for even
ardent purging advocates. Third, it is recognized that no single purging technology is
regarded as the gold standard. This has made it difficult to decide whether the
primary purpose of a purging trial should be proof of principle of a depletion
technology, of the generic value of purging, or of the efficacy of a particular product.
This has been further complicated in the United States by the Food and Drug
Administration's evolving regulatory strategy for stem cell products, 6
which has seen
purging and positive selection transition from classification as minimal manipulation,
to extensive manipulation, and back again. The final status has still to be determined.
These impediments to traditional methods to demonstrate that purging is both safe
and effective by randomized trials have resulted in the use of other surrogate
measurements to demonstrate its potential benefits.
Pros and cons
Some of the most convincing evidence has come from gene marking
experiments in which autologous cells have been transfected with a marker gene in
the hope that it would be incorporated into any tumor cells within the graft. The
graft is then infused and the patient monitored for signs of relapse. At that time,
samples of blood and marrow are taken to determine whether gene-marked cancer
cells are present. Since they can only have originated from the graft, their presence
suggests that relapse is associated with reinfusion of tumor cells. 37
It cannot be
definitively shown that these cells caused relapse, and it has been argued that they
may simply home to sites of relapse and may not contribute substantially to its
etiology. This theory is based on the relative numbers of tumor cells that may be
present in the infused graft vs. those that escape the high-dose therapy. Depending
on the bulk of the disease at the time of treatment, it would be anticipated that there
might be several orders of magnitude more cells remaining in the patient than
would be returned with the graft. This fact would tip the balance irrevocably in
favor of chemotherapy-resistant cells acting as the origin of relapse. An argument
against the theory is that metastatic tumor within the marrow or mobilized into the
blood may differ markedly in its potential to cause relapse than cells at other sites
of disease. Their removal from the graft could, therefore, have more clinical impact
than would be anticipated solely based on their numbers. This possibility has yet to
be convincingly demonstrated.
Other evidence in favor of purging has come from transplants in which some
grafts were found to be ineffectively purged when examined by highly sensitive
molecular methods, such as the polymerase chain reaction (PCR). 48
Patients
receiving these grafts were found to have decreased disease-free survival in
comparison with those who were given grafts purged to PCR negativity. It has been