High-Dose Therapy for Follicular Lymphoma
High-Dose Therapy for Follicular Lymphoma
Patients with advanced-stage indolent
follicular non-Hodgkins lymphomas (NHLs) are generally not
cured with conventional therapy. Although many of these patients
often achieve a complete remission with standard treatment, the
median duration of the first complete remission is often short
(ranging from 12 to 36 months).
More importantly, many patients with advanced-stage disease
ultimately relapse, with a disease-free survival rate of only 25% at
5 years. Although follicular lymphomas remain responsive following
relapse, the duration of subsequent remissions decreases
progressively. Moreover in 15% to 70% of patients, the follicular
lymphoma eventually undergoes histologic conversion to a more
aggressive histology, which is generally associated with a poor prognosis.
The rationale for the use of high-dose therapy in NHL is based on the
observation that lymphomas have a steep dose-response curve to
chemotherapy and radiation in animal models and humans. High-dose
therapy has been shown to be a potentially curative modality in
patients with relapsed diffuse aggressive NHL. In contrast, there
is relatively limited evidence for a benefit of dose escalation in
indolent NHL. More intensive conventional regimens have been shown to
produce a higher complete remission rate and shorter time to complete
remission in selected studies but had no impact on overall survival.
In recent years, the use of high-dose therapy and autologous
stem-cell transplantation in relapsed indolent follicular lymphoma
has received increasing attention.[6-14] These studies suggest that a
subset of patients with follicular NHL may benefit from high-dose therapy.
The selection of patients with indolent lymphomas for autologous
stem-cell transplantation has been affected by the very long natural
history of these diseases. Since patients with follicular NHLs can
survive for many years with minimal therapy, excessive
treatment-related toxicities associated with ag-gressive therapy are
not acceptable. Performance status has been shown to be a major
determinant of treatment-related mortality following autologous
transplantation; therefore, younger patients with good performance
status and normal end-organ function generally have been selected for
Timing of Transplantation
A major question has been the timing of transplants in patients with
follicular lymphoma. Analogous to autologous stem-cell
transplantation in aggressive NHLs, patients with follicular lymphoma
who have not responded to multiple regimens and have developed
resistant disease are less likely to benefit from autologous bone
marrow transplantation than are patients with sensitive disease who
can achieve clinical complete remission or very good partial remissions.
Most published series have included patients in second or subsequent
remission. It is generally accepted that patients who have had
numerous relapses have a low likelihood of benefiting from autologous
transplantation. The question as to whether patients with advanced
follicular lymphoma should be considered for autologous stem-cell
transplantation during first remission remains investigational.
Following histologic transformation from a follicular to a diffuse
aggressive NHL, patients often have a poor prognosis with
conventional treatment. Approximately 40% of patients who achieve a
complete remission with aggressive chemotherapy experience long-term
remission following transformation.[15-17] Although selected patients
have undergone autologous stem-cell transplantation following
transformation, the outcomes have varied.[6,7,10]
Contamination of Stem Cells
Another major obstacle of autologous bone marrow transplantation in
follicular lymphoma relates to tumor contamination of the stem cell
product. In a study from the Dana-Farber Cancer Institute, all
patients with relapsed follicular lymphoma had bone marrow
involvement (by virtue of the presence of bcl-2 translocation
detected by the polymerase chain reaction [PCR]) at the time of bone
marrow harvest, even if the bone marrow appeared to be histologically
negative. This technique can detect 1 lymphoma cell in a
background of 105 to 106 normal cells. Other
centers have reported similar evidence for the presence of
PCR-detectable occult disease in the presence of histologically
Considering the studies of genetic-ally marked autologous marrow
cells, which suggest that reinfused tumor cells contribute to relapse
in a disease such as follicular NHL,[22,23] several approaches have
been taken to provide a tumor-free stem-cell preparation. These
include immunologic techniques (eg, monoclonal antibodies and
complement or magnetic beads) or pharmacologic agents
(4-hydroxycyclophosphamide) designed to purge malignant cells from
the graft, as well as steps to enrich the stem-cell preparation with
normal hematopoietic progenitors (eg, CD34-positive selection).
Some centers have restricted the use of high-dose therapy to patients
who have a histologically negative bone marrow or peripheral stem
cells, which may obviate the use of infiltrated bone marrow.
However, there is no evidence that these are tumor cellfree
sources of hematopoietic stem cells.
A limited number of patients with follicular lymphoma who received an
allogeneic or syngeneic bone marrow transplant have been reported in
the literature.[24-28] An obvious benefit of allogeneic or syngeneic
grafts in this setting is the use of a marrow that is not involved
with lymphoma and has not been exposed to chemotherapy. Furthermore,
a potential graft-vs-lymphoma effect may account for the decreased
relapse rate reported with allogeneic bone marrow transplantation in NHL.[29-31]
The major drawbacks are the lack of a suitable donor for most
patients and the higher treatment-related mortality associated with
an allogeneic bone marrow transplant. As the treatment-related
mortality of allogeneic bone marrow transplantation decreases, it may
be more widely used in patients with follicular lymphoma.
An emerging late complication of high-dose therapy in patients with
NHL is the development of secondary myelodysplasia, which has a very
poor prognosis.[32-34] The risk of the myelodysplastic syndrome
increases with extensive exposure to chemotherapy, pretransplant
radiation, and a prolonged period between diagnosis and transplantation.
The actuarial rates of myelodysplasia 5 years after autologous bone
marrow transplant for NHL are approximately 15% in several series. It
remains unclear whether the myelodysplastic syndrome arises from the
reinfused stem cells exposed to chemotherapy for years prior to
autologous stem-cell transplantation and/or represents a complication
of the high-dose chemoradiation, which leads to damaged stem cells
that were not ablated.
In Relapsed Lymphoma
A large number of patients who received purged autologous bone marrow
following high-dose therapy for follicular lymphoma have been
reported (Table 1). Between 1985
and 1995, investigators at the Dana-Farber Cancer Institute treated
153 patients (median age, 43 years) with a history of follicular NHL
in sensitive relapse or incomplete first remission with
cyclophosphamide (Cytoxan, Neosar)/total-body irradiation
conditioning and antiB-cell monoclonal antibodytreated
autologous bone marrow transplantation. At diagnosis, 90% of
patients had stage IV disease, 28% had B symptoms, and 30% had
extranodal disease exclusive of the bone marrow. At bone marrow
harvest, only 30% of patients were in complete remission. Overt bone
marrow infiltration was present in 47% of patients at marrow harvest.
As of March 1999, 63 patients have relapsed, the majority in prior
sites of disease, and 34 patients are alive after relapse (median
follow-up, 80 months). At a median follow-up of 61 months (range, 24
to 156 months), 79 patients remain alive and in complete remission.
The disease-free survival and overall survival rates at 8 years
following autologous bone marrow transplantation are 42% and 66%,
respectively. The survival rate from diagnosis for the entire group
of patients is 69% at 12 years. Nine patients have died without
recurrence of disease, including six from myelodysplasia/secondary
acute myelogenous leukemia.
Investigators at St. Bartholomews Hospital have also treated 64
relapsed indolent lymphoma patients with an anti-B1 monoclonal
antibodypurged autologous bone marrow transplant. These
patients received the same cyclophosphamide/total-body irradiation
conditioning regimen as was used at the Dana-Farber Cancer Institute.
At autologous bone marrow transplant, 34 patients were in complete
remission, with 7 having bone marrow involvement at harvest.
Treatment-related mortality following high-dose therapy has been very
low, and 35 patients remain in clinical complete remission from 1+ to
These researchers performed a retrospective analysis of patients who
underwent autologous bone marrow transplantation in second remission,
and compared them to patients treated with conventional therapy. The
patients who received an autologous bone marrow transplant had a
significantly better disease-free survival than those treated with
standard therapy. However, overall survival did not differ between
the two groups of patients.
Since bone marrow involvement is so common in patients with these
diseases, the number of patients receiving unpurged bone marrow is
limited. Investigators at the University of Nebraska have reported on
patients with low-grade follicular lymphoma undergoing autologous
bone marrow transplant with unmanipulated marrow.[6,13] The 4-year
failure-free and overall survival rates in these patients were 62%
and 76%, respectively.
An alternative to marrow purging for tumor-involved marrow in
patients with indolent NHL has been the use of peripheral stem cells.
University of Nebraska researchers described 100 patients (including
26 treated with one prior regimen) who received peripheral stem
cells, with 4-year failure-free and overall survival rates of 44% and
65%, respectively. In this series, there was no statistically
significant difference in outcomes between patients given unpurged
marrow and those who received peripheral stem cells.
Bastion and coworkers in France have reported the results of 60
patients who received autologous peripheral stem cells following
high-dose therapy. This study included 12 patients in first
partial remission, 34 in second partial or complete remission, and 14
in third or higher remission. The majority of patients (77%) received
a total-body irradiationbased conditioning regimen.
Failure-free survival and overall survival rates were 53% and 86% at
2 years. Patients treated during first partial remission or second
partial or complete remission had a more favorable outcome than
patients transplanted in subsequent remissions.
These studies with current follow-up suggest that high-dose therapy
supported by autologous peripheral stem cells yields similar results
to autologous marrow transplantation.