Randomized trials are defining the role of autologous stem-cell
transplantation in aggressive non-Hodgkins lymphoma (NHL), but
there is less experience with this treatment in follicular lymphomas.
Approximately 40% to 50% of patients with follicular NHL are in
remission 4 to 5 years following autologous stem-cell
transplantation. Results from phase II studies and retrospective
analyses are remarkably similar, despite differences in patient
populations, preparative regimens, use of purging, and source of stem
cells. Nevertheless, there is little evidence of a plateau in
disease-free survival curves, and we do not know whether patients are
cured or overall survival is prolonged. Relapses 9 years following
transplantation have been described.
In their review, Freedman et al do not make recommendations about the
timing of transplantation. Retrospective analyses show that results
are better in patients with sensitive disease who have not been
heavily pretreated. However, these patients are most likely to
respond to any treatment modality. Decisions on timing have become
more difficult since the introduction of rituximab (Rituxan), and
likely will be further complicated when the iodine-131labeled
anti-CD20 antibody (tositumomab [Bexxar]) soon becomes available.
The authors also discuss the role of autologous transplantation in
patients whose disease has undergone histologic transformation. They
report that prolonged disease-free survival is possible for these
patients but that no survival plateau has been achieved. A
European Bone Marrow Transplant Registry (EBMTR) analysis estimated
the 5-year progression-free survival rate to be 33% for patients with
transformed lymphoma. Results were similar to patients without
transformation, and the authors came to the same conclusion as do
Freedman et al; namely, that autologous stem-cell transplantation is
a reasonable approach, at least for patients with sensitive disease.
Transplantation During First Remission
The apparent lack of a plateau in disease-free survival following
autologous transplantation for relapsed follicular NHL has led to
trials of transplantation during first remission. Unfortunately,
results from the Dana-Farber group and others have failed to document
a survival plateau in these patients.[4,5] The groups projected
3-year overall survival rate of 89% does offer the hope that
autologous transplantation may prolong overall survival, however.
Investigators at Stanford performed autologous stem-cell
transplantation in 37 patients with follicular NHL in first
remission. The actuarial 5-year overall survival rate was 87%. The
outcome of these patients will be compared with historical controls
before more transplants are performed. Caution is warranted because
most trials of early transplantation have reported outcomes only for
transplanted patients, and not for the entire denominator
of all patients at the time of diagnosis. The long natural history of
low-grade lymphoma makes it difficult to demonstrate overall survival
advantages with any treatment. The authors discuss the use of
surrogate end points, such as the absence of polymerase chain
reaction (PCR)detectable lymphoma cells in bone marrow
Role of Purging
The role of purging in autologous stem-cell transplantation for NHL
is controversial. The authors review their own studies demonstrating
that patients who receive contaminated autologous grafts are more
likely to relapse than are patients who receive uncontaminated marrow.
A recent French analysis demonstrated that relapse was less likely in
NHL patients whose marrow was purged more aggressively. An EBMTR
analysis showed improved overall survival (but no difference in
progression-free survival) in low-grade NHL patients who received
purged autografts. These trials provide additional indirect
evidence for the value of purging, although prospective trials are needed.
A European trial attempted to address this issue. Patients with
relapsed follicular lymphoma received three cycles of salvage
chemotherapy. Responders were randomized to three more cycles of
chemotherapy, unpurged autologous stem-cell transplantation, or
purged autologous stem-cell transplantation. This trial closed early
due to poor patient accrual.
A preliminary analysis showed that patients treated with chemotherapy
have a significantly higher relapse rate than transplanted patients,
although no differences between purged and unpurged transplants have
been noted.[personal communication, H. Schouten, August 1999] In the
absence of firm data, many believe that it is reasonable to attempt
purging or transplantation with purified CD34+ progenitor cells as
long as it is not associated with other toxicity.
Compared with autologous stem-cell transplantation, allogeneic
transplantation has the potential advantages of uncontaminated marrow
and a graft-vs-lymphoma effect. Freedman et al note lower relapse
rates after allogeneic transplantation for NHL than after autologous
grafting. These reports support the existence of a graft-vs-lymphoma
effect. Further support comes from reports of lymphoma regression
after withdrawal of immunosuppression in patients who relapse after
The International Bone Marrow Transplant Registry results of
allogeneic transplantation for low-grade lymphoma suggest the
presence of a survival plateau. However, nonrelapse mortality has
been 30% to 40% in most series. A French registry analysis revealed
an actuarial relapse rate of 12% at 5 years following allogeneic
transplantation, as compared with a rate of 55% following autologous
stem-cell transplantation (P < .001). Event-free survival at 4
years was estimated to be 53% with allogeneic transplantation vs 45%
with autologous transplantation. No events were observed later than
15 months after allogeneic transplantation, whereas a continuous
pattern of progression was observed after autologous grafting. These
results suggest that it may take several years before any survival
advantage of allogeneic transplantation can be detected.
An EBMTR analysis also compared the results of autologous vs
allogeneic transplantation for low-grade NHL. Despite a higher
relapse rate, overall survival at 4 years was significantly higher
following autologous stem-cell transplantation, because of the high
mortality associated with allogeneic transplantation.
The low relapse rate following allogeneic transplantation provides
strong support for the use of immunotherapy for low-grade lymphoma.
Freedman et al mention the use of low-intensity allogeneic
transplantation. This approach may be able to exploit a
graft-vs-lymphoma effect with lower mortality than does
conventional allogeneic transplantation. There is intense
interest and enthusiasm for low-intensity allogeneic
transplantation. However, a therapy rarely provides
something for nothing, and mature data are needed to sort
out the benefits vs risks of this approach.
Conclusions and Future Directions
Despite the increasing use of transplantation in patients with
follicular lymphoma, its role remains undefined. Ultimately,
randomized trials may be the only way to determine whether the
emperor is wearing any clothes.
Freedman et al discuss the use of various post-transplant treatments
to improve results. Several ongoing trials are evaluating the use of
rituximab either combined with or following autologous stem-cell
transplantation for follicular NHL. The use of vaccination after
autologous transplantation is also discussed; preliminary reports
suggest that cellular and humoral immune responses can be generated
soon after autologous stem-cell transplantation for lymphoma.
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