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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 381-383
INTRODUCTION: FOCUS ON HEMATOLOGY
Choosing the Source of Stem Cells for Allogeneic Transplantation:
No Longer a Peripheral Issue
By
Frederick R. Appelbaum
From the Fred Hutchinson Cancer Research Center and the University of
Washington School of Medicine, Seattle, WA.
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ARTICLE |
THE PREFERRED SOURCE OF stem cells for
allogeneic transplantation has become a central question among the
transplant community. In the early 1990s, it was found that granulocyte
colony-stimulating factor (G-CSF)- or granulocyte-macrophage
colony-stimulating factor (GM-CSF)-mobilized peripheral blood stem
cells (PBSCs) led to speedier granulocyte and platelet recovery after
autologous transplantation than seen with marrow; given the practical
and economic benefits of more rapid recovery, use of PBSCs quickly
became the community norm, despite the lack of randomized trials
measuring the impact of PBSC use on survival in specific disease
states. However, there was hesitation in applying this technology to
the allogeneic setting, because unmodified growth factor-mobilized PBSC
collections contain, on average, 1 log more T cells than a standard
marrow collection and murine studies have demonstrated a close
relationship between the number of T cells in a graft and the
development of acute graft-versus-host disease (GVHD). In 1995, 3 pilot
studies were published in a single issue of Blood, each
demonstrating in a small number of patients that use of PBSCs for
matched sibling transplantation resulted in the same rapid recovery
seen in the autologous setting and, surprisingly, no dramatic increase
in acute GVHD over that seen with allogeneic marrow.1-3
These pilots were followed by several larger phase II studies that
likewise demonstrated accelerated granulocyte and platelet recovery
with PBSCs and no apparent increase in acute GVHD.4,5
However, several of these studies have suggested an increase in chronic GVHD.6 A recent summary of registry data is consistent with these phase II studies and, in addition, suggests a survival advantage during the early posttransplant period with the use of PBSCs compared with marrow, particularly for high-risk patients.7 These
data all come from nonrandomized studies, but several large randomized trials of PBSCs versus bone marrow for matched sibling transplantation are well underway and should be nearing completion soon.
The report by the Essen group in this issue of Blood is the
first to suggest that use of PBSCs may influence relapse rates, at
least in the case of chronic myelogenous leukemia
(CML).8 In a nonrandomized comparison between
29 patients with CML transplanted using PBSCs and 62 recipients of bone
marrow, the incidence of molecular and cytogenetic relapse
posttransplant was far greater in the marrow recipients. At this stage
in an introduction, it is customary for the author to tell the reader
about the weaknesses of the cited study and, to be sure, there are some
in the Essen report. The study involves only a limited number of
patients, and they were not randomized according to stem cell source.
Most significantly, there was a higher degree of HLA-mismatching among PBSC recipients, with 45% of them being mismatched for a single class
I or II antigen with their family member donor compared with 18% of
bone marrow recipients. Nonetheless, the data appear to be convincing.
The magnitude of the difference in relapse rates is substantial (44%
with bone marrow compared with 7% with PBSC) and is similar in
recipients of HLA-identical and single antigen mismatched grafts. The
difference persists after statistical analyses accounting for all known
confounding factors. And finally, the findings make sense.
The investigators offer 2 explanations for these findings. The first
explanation they offer is that their observations are "consistent
with a stem cell competition effect by which a rapidly expanding normal
progenitor cell compartment can inhibit or displace residual clonogenic
leukemia cells" and cite as further evidence the finding of improved
survival in unrelated donor transplants if high bone marrow cell doses
are used. However, in the unrelated donor study they cite, the
increased cell dose was associated with a decrease in nonrelapse
mortality, but had no effect on relapse rates.9
Furthermore, although it might be possible and, in fact, interesting to
study the question, there are few, if any, convincing animal models
supportive of a nonimmunologically based stem cell competition effect
capable of eradicating established leukemia. It is much more likely
that the important observation of the Essen group is yet another
example of the potent effect of donor T cells against CML. Although the
investigators argue that neither acute nor chronic GHVD had a
significant influence on residual molecular or cytogenetic disease in
the study, the data would argue otherwise. The incidence of molecular
relapse was more than twice as high (38%) in those without acute GVHD as those with (15%), and a similar magnitude of difference was seen
with and without chronic GVHD. That the P values were not significant in the statistical analysis (P = .2 for acute
GVHD and P = .052 for chronic GVHD) speaks more to the size
of the study than a new biologic principle. Further, a
graft-versus-leukemia effect can be operative without clinically
evident GVHD. As the clearest example, CML relapse rates are much
higher in recipients of T-depleted transplants than in recipients of
nonmodified allogeneic marrow who do not develop clinically evident GVHD.
The study raises 3 large questions (at least). First, why is there not
more acute GVHD with the use of PBSCs containing so many more T cells
than marrow? Although in murine models there is a dose-response
relationship between the number of T cells infused and the incidence of
acute GVHD, it is possible that, in the clinic, once more than
approximately 1 × 105 CD3+ cells/kg are
transplanted, a critical threshold has been exceeded and further
increases do not necessarily translate into more acute GVHD. It is also
possible that the faster engraftment achieved with PBSCs may decrease
the incidence and severity of infection, which, in turn, may have a
protective effect on GVHD. Prior studies in mice and humans have shown
that transplantation in protected environments can diminish the
incidence of GVHD.10,11 Several studies have shown that
G-CSF treatment may cause a shift in the population of T cells in the
periphery towards CD4+ Th2 cells, a change expected to
diminish acute GVHD.12,13 Finally, it has recently been
demonstrated that administration of G-CSF favors mobilization of type
II dendritic cells, which, in turn, should favor the development of Th2
T cells.14 If this last explanation is correct, then a
study of the continued administration of G-CSF in the posttransplant
period to further diminish the incidence of acute GVHD would seem to be warranted.
A second major question again raised by this study concerns why CML is
so susceptible to an allogeneic reaction. A better understanding of
this question would suggest where else to expect an advantage of PBSCs
over bone marrow and, in those cases in which an effect is less
apparent, possibly how to create it. The power of an allogeneic effect
in CML may relate, in part, to the tumor's growth rate. The number of
leukemic cells eliminated by an allogeneic reaction is likely to be
rate-limited and may be outstripped by a fast growing tumor. In fact,
donor lymphocyte infusions have been more successful in chronic phase
CML than in accelerated phase or blast crisis and more successful in
other slower growing hematologic malignancies (chronic lymphocytic
leukemia, multiple myeloma, and myelodysplasia) than in very rapidly
growing ones.15 Other aspects of the target cell may
determine the impact of an allogeneic effect. CML cells constitutively
express high levels of class I antigens as opposed to acute
lymphoblastic leukemia (ALL) blasts, a setting in which donor
lymphocyte infusions are less effective. There may be
other molecules expressed on the cell surface or secreted into the
immediate microenvironment around CML cells (interleukin-12?) that
favor an immunologic effect; and the reverse may also be true, ie,
there may be molecules that suppress such an effect in those diseases
in which an allogeneic impact is less apparent. The anatomic location
of the tumor may also be important. CML is largely limited to blood,
marrow, and spleen and rarely involves immunologically privileged
sites. The spleen is an ideal place for donor T cells to encounter
antigen. It would be of interest to know if the success of donor
lymphocyte infusions is diminished in CML patients who have had a prior splenectomy.
The final question is whether the findings presented here by Elmaagacli
et al8 should change our standard approach to
transplantation. The answer, I would argue, is not yet. It is still
unknown if the benefits of PBSCs, including more rapid engraftment,
perhaps a diminution in early nonrelapse mortality (at least in
high-risk patients), and now a potential reduction in posttransplant
relapse (at least in CML), are worth the price of more chronic GVHD.
There are, after all, relatively effective ways of dealing with
molecular or cytogenetic posttransplant recurrence of CML, including
the addition of  -interferon, withdrawal of immunosuppression, and use of donor lymphocyte infusions, and chronic GVHD can be a difficult disease. The results of the large randomized studies being performed will help better define this balance. There will also almost certainly be improvements in the PBSC product. In the studies cited above, no
effort was made to limit the total number of T cells in the collections, and it may be that some limitation could preserve the
improved antileukemic effect without an increase in chronic GVHD. The
long-term goals of the allogeneic transplant community include
providing a better definition of the populations of stem cells and
immune effector cells contained in the transplant product and
manipulating those cells to provide faster engraftment, more protection
against infections and disease recurrence, and less GVHD. Recent
advances with the use of growth factor-mobilized stem cell products
have helped move this goal from the periphery to center stage.
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FOOTNOTES |
Address reprint requests to Frederick R. Appelbaum, MD, Fred Hutchinson
Cancer Research Center, 1100 Fairview Ave N, D5-310, PO Box 19024, Seattle, WA 98104; e-mail: fappelba{at}fhcrc.org.
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