ABSTRACT: Most patients with advanced-stage
follicular non-Hodgkins lymphoma (NHL) are not cured with
conventional therapy. The use of high-dose therapy and autologous
stem-cell transplantation in patients with relapsed follicular NHL
has received increasing attention. Several large studies suggest a
disease-free survival rate of approximately 40% among patients
transplanted during sensitive relapse, although the role of
autologous transplantation in first remission remains controversial.
Patients with histologic transformation from low-grade to diffuse
large B-cell lymphoma whose disease remains sensitive to conventional
therapy have a similar disease-free survival rate. Allogeneic
transplantation has achieved relapse, overall survival, and
treatment-related death rates of approximately 15%, 50%, and 40%,
respectively, in patients with follicular NHL. Studies of minimal
residual disease suggest that the presence of lymphoma cells in the
autologous graft and within the patient before clinically apparent
relapse is predictive of later recurrence. Therefore, treatment of
minimal residual disease may improve the outcome of high-dose
therapy. Use of a tumor-free stem-cell product through improved
purging or allogeneic stem cells is one approach, although the
morbidity and mortality of allogeneic transplantation remain high.
Immunomodulatory strategies with monoclonal antibodies, vaccines, or
adoptive immunotherapy may be particularly well suited to patients at
high risk for relapse following high-dose therapy. [ONCOLOGY 14(3):321-331,
Patients with advanced-stage indolent follicular non-Hodgkin’s 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 this modality.
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 normal marrow.[10,19-21]
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 cell–free 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 anti–B-cell monoclonal antibody–treated 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. Bartholomew’s Hospital have also treated 64 relapsed indolent lymphoma patients with an anti-B1 monoclonal antibody–purged 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 8+ years.
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 irradiation–based 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.
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