High-Dose Therapy for Follicular Lymphoma

ABSTRACT: Most patients with advanced-stage follicular non-Hodgkin’s 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, 2000]

Introduction

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).[1]

More importantly, many patients with advanced-stage disease ultimately relapse, with a disease-free survival rate of only 25% at 5 years.[2] Although follicular lymphomas remain responsive following relapse, the duration of subsequent remissions decreases progressively.[3] 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.[4] 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.[5]

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.

Problems With High-Dose Therapy in Follicular NHL

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.[13]

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.[18] 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.[13] 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.

Secondary Myelodysplasia

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.

Autologous Transplantation in Follicular Lymphomas

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.[35] 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.[8] 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.[13] 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.[10] 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.

Following Histologic Transformation

Between 15% and 70% of patients with indolent NHL eventually undergo histologic conversion to a higher-grade histology; such transformation has been associated with a poor prognosis. Several groups have reported the results of high-dose therapy and autologous stem-cell transplantation in patients with a history of indolent lymphoma who underwent histologic transformation to a higher-grade lymphoma.[6,7,10,36]

Researchers at the University of Nebraska described a series of nine patients with a history of follicular lymphoma who progressed to a more aggressive histology and whose response to conventional therapy was poor. The outcomes in this study were unfavorable, with seven acute treatment-related deaths, one relapse, and only one patient in complete remission at 3+ months.

Bastion et al have reported on 16 patients transplanted following histologic transformation.[10] Two patients died of treatment-related toxicity, while eight relapsed with predominantly follicular pathology at a median of 14 months following transplantation. At the time of publication, six patients remained in remission from 2 to 34+ months following autologous stem-cell transplantation. The rate of freedom from recurrence following transplantation was lower among the patients whose disease transformed than among the patients who still had follicular lymphoma.

More recent results of autologous stem-cell transplantation in patients with chemosensitive disease and a good performance status after histologic transformation have been more favorable. At St. Bartholomew’s Hospital, 19 patients in a minimal disease state received an anti–B-cell purged autologous bone marrow transplant within 1 year of histologic transformation.[36] The median survival duration was 4.4 years, with three patients in remission at over 4 years of follow-up. Eight patients have relapsed; of six patients who underwent a biopsy at the time of relapse, five had documented recurrent transformed lymphoma.

In the series from Dana-Farber, 21 patients underwent anti–B-cell purged autologous bone marrow transplantation for transformed follicular lymphoma. No acute in-hospital deaths occurred, and the Kaplan-Meier estimate of the percentage of patients alive and disease-free at 5 years is 46%, with follow-up ranging from 12 to 120+ months.[37]

Patients in this series whose disease underwent histologic transformation within 18 months of diagnosis of follicular lymphoma had a significantly better overall survival than did patients whose disease transformed later. This difference was independent of prior therapy. All of the patients in whom pathology at relapse was available recurred with large-cell lymphoma.

A subset of patients with histologic transformation of low-grade lymphoma have a relatively favorable prognosis with conventional therapy. Aggressive therapy with autologous stem-cell transplantation is a reasonable treatment option for selected patients, particularly those whose disease remains chemosensitive and those whose disease transforms earlier.

For Low-Grade NHL in First Remission

One approach to treating previously untreated patients with follicular NHL would be to use high-dose therapy and autologous stem-cell transplantation during first remission. At Dana-Farber Cancer Institute, 83 previously untreated patients with advanced-stage follicular lymphoma were considered for induction therapy with CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone), followed by anti–B-cell monoclonal antibody–purged autologous bone marrow transplantation during first remission.[38] The median age of these patients was 43 years. Most patients (83%) had stage IV disease by virtue of bone marrow involvement. Extranodal disease, bulky masses > 5 cm, and B symptoms were present in 25%, 62%, and 25% of patients, respectively.

Marrow was harvested in 77 patients; only 36% of patients were in clinical complete remission at the time of marrow harvest, and 47% had histologic marrow involvement. Following autologous bone marrow transplantation, two patients died acutely and four patients died of non–lymphoma-related causes. Among the remaining 71 patients (as of November 1995), there were 28 relapses. At a median follow-up of 45 months (range, 14 to 82 months), 43 patients remained in clinical complete remission The Kaplan-Meier estimate of the percentage of patients alive and disease free at 3 years was 63%. Estimated overall survival at 3 years was 89%.

Three other groups have recently described the earlier use of autologous stem-cell transplantation. Bierman et al achieved 4-year failure-free and overall survival rates of approximately 70% and 85%, respectively, in patients transplanted after only one prior chemotherapy regimen.[13]

Fouillard et al reported very similar event-free and overall survival rates in patients transplanted during first complete or partial remission.[14] However, at the time of analysis, they found no significant differences in either event-free or overall survival between low-grade NHL patients transplanted during first complete remission, first partial remission, or second complete remission.

Horning and co-workers described 37 patients who underwent autologous bone marrow transplantation following induction chemotherapy with CVP (cyclophosphamide, vincristine, and prednisone), 26 of whom had a high tumor burden prior to initial treatment.[39] Rates of 5-year overall and progression-free survival were 87% and 73%, respectively, which compared favorably with survival rates achieved with conventional therapy in a population of patients with high tumor burden.

It is possible that, with longer follow-up, earlier autologous stem-cell transplantation may lead to a more favorable outcome. Whether this is, in fact, the case is unknown at present.

Impact of Minimal Residual Disease Detection and Purging

A major issue associated with the use of autologous bone marrow or peripheral stem cells in patients with low-grade lymphoma is whether reinfused tumor cells may contribute to relapse. Several studies have examined the impact of the presence of residual neoplastic cells in the autologous graft on disease-free survival. Minimal residual disease in subsequent bone marrow samples has been monitored to determine whether this could be a suitable surrogate end point for assessing the efficacy of autologous bone marrow transplant in a disease with a very long natural history. These studies have taken advantage of the presence of rearrangements of the bcl-2 gene seen on PCR in over 85% of patients with follicular NHL.[18]

In studies from Dana-Farber Cancer Institute, of 153 patients undergoing autologous bone marrow transplantation during second or greater remission, 112 with a known bcl-2/immunoglobulin H (IgH) rearrangement had prelysis and postlysis bone marrow samples available for analysis. Among the 47 patients who were PCR negative after purging, there have been 6 relapses. In contrast, 49 relapses have occurred among the 65 patients who were PCR positive after purging. The 8-year rate of freedom from relapse was 83% for the patients who were PCR negative postlysis, as compared with 19% for the PCR positive patients (P = .0001). Similar findings have been reported for patients transplanted during first remission.[38]

The impact of minimal residual disease following autologous stem-cell transplantation also has been examined. At the Dana-Farber Cancer Institute, bone marrow samples have assessed for minimal residual disease following autologous bone marrow transplantation. Three groups of patients were observed: patients with no evidence of PCR-detectable lymphoma in the bone marrow at any time point after autologous transplantation; patients with all samples having PCR-detectable disease after transplantation; and patients with a mixture of positive and negative PCR results following transplantation. In the patients with all negative PCR samples, very few relapses have been observed, whereas the majority of patients with persistent PCR-positive samples have relapsed.

Similar findings have been reported for patients who received peripheral stem-cell transplants. Patients who had PCR-detectable cells in the bone marrow or peripheral blood at mobilization had a higher likelihood of relapse and remained PCR positive in the bone marrow and peripheral blood samples after transplantation.[11,40] These studies suggest that the presence of PCR-detectable lymphoma cells in the reinfused stem-cell product and in follow-up bone marrow samples post-transplantation is associated with disease recurrence.

Other investigators have examined the effect of purging on outcome in low-grade NHL. Fouillard et al have described a relationship between the degree of purging (as measured by the residual number of colony-forming units–granulocyte-macrophage [CFU-GM] reinfused after mafosfamide marrow purging) and the incidence of relapse, further suggesting a role for ex vivo purging.[14]

The European Blood and Marrow Transplant Registry (EMBTR) has reported a higher 5-year overall survival rate in patients who received purged (monoclonal antibody or mafosphamide) marrow than in those given untreated bone marrow (84% vs 48%).[12] However, there was no difference in progression-free survival rates between the two groups (48% vs 44%).

These survival data suggest a benefit for purging. However, the number of patients treated with total-body irradiation was greater in the unpurged group, as was the number treated in small transplant centers. These factors leave the impact of purging uncertain.

Since the majority of relapses following high-dose therapy and autologous bone marrow transplantation occur in prior sites of bulk disease, and few “new” sites of relapse are seen, most relapses appear to be due to a failure of the ablative regimen to eradicate residual disease in the patient. If reinfused tumor cells do contribute to relapse, new sites of relapse should be observed more frequently. However, reinfused tumor cells clearly migrate to and probably proliferate more optimally in prior sites of bulk disease since this may be an ideal microenvironment to support neoplastic cell growth. Improvements in ex vivo purging, with the goal of rendering the majority of patients PCR negative, will help answer this question.

Allogeneic Marrow Transplantation

A limited number of studies have explored the role of allogeneic bone marrow transplantation in patients with low-grade lymphoma. The concern over mortality from transplant-related complications and graft-vs-host disease (GVHD) has limited this approach to patients with disease that is refractory to chemotherapy and has extensive marrow involvement.

Following allogeneic transplantation, the relapse rate is low but treatment-related mortality remains high (Table 2). Studies from M. D. Anderson Cancer Center and University Hospital Utrecht have found that the complete remission rate is high in generally refractory patients; however, in contrast to autologous stem-cell transplantation, the treatment-related mortality of allogeneic transplantation approaches 30%.[24,26] The relapse-free and overall survival rates in these studies are quite similar, approxi-mately 80%, and the relapse rate is exceedingly low.

The International Bone Marrow Transplant Registry recently published the results of allogeneic transplantation in 113 patients with low-grade lymphoma, the majority of whom had chemosensitive disease at the time of transplant.[41] Numerous conditioning regimens were used in these patients, and median follow-up was 25 months. Kaplan-Meier estimates of relapse and overall survival rates at 3 years were 16% and 49%, respectively. Of 33 patients followed for more than 2 years after allogeneic transplantation, only 1 patient experienced a recurrence of lymphoma, suggesting a possible graft-vs-lymphoma effect. Pulmonary toxicity was a major cause of treatment-related mortality.

T-Cell Depletion

In an attempt to decrease transplant-related morbidity and mortality, investigators at the Medical College of Wisconsin used T-cell depletion as a means of GVHD prophylaxis in allogeneic grafts transplanted in 16 patients with indolent lymphoma. At 5 years, the disease-free survival rate was 62%, with a relapse rate of 13%.[27] However, four patients in clinical remission with informative PCR for bcl-2/IgH translocation remained PCR positive following allogeneic bone marrow transplantation.

At Dana-Farber Cancer Institute, a very low treatment-related mortality has been observed following T-cell depletion in patients with relapsed indolent lymphoma, and the disease-free survival rate was 50%.[28] Longer follow-up is needed to determine whether or not T-cell depletion will interfere with a putative graft-vs-lymphoma effect in indolent NHL.

Nonmyeloablative Conditioning Regimens

Another strategy to decrease transplant-related mortality involves the use of nonmyeloablative conditioning regimens. A total of 15 patients, including 4 patients low-grade lymphoma, were treated at M. D. Anderson Cancer Center with fludarabine (Fludara) and cyclophosphamide followed by allogeneic peripheral stem-cell transplantation.[42] Mixed chimerism was achieved in the majority of patients, with prompt hematologic recovery, and there was only one transplant-related death.

Four patients subsequently received donor lymphocyte infusions in an attempt to augment a graft-vs-lymphoma effect. One patient later developed severe GVHD. Eight patients achieved a complete remission, with an overall survival rate of 50% at 1 year.

Ongoing studies are underway to define appropriate patients to consider for this approach.

Conclusions and Future Directions

High-dose therapy with autologous stem-cell transplantation has been shown to be a potentially curative modality for patients with relapsed diffuse aggressive NHL. Compared to the large numbers of patients with aggressive lymphoma who have undergone autologous transplantation, relatively few patients with relapsed indolent histologies have been treated with this approach. These studies demonstrate that selected patients with disease that is sensitive to conventional treatment can experience prolonged disease-free survival following high-dose therapy.

The observation that the presence of minimal residual disease at the time of autologous bone marrow transplantation and during follow-up is predictive of relapse has stimulated the development of novel approaches to eradicating residual disease. In vitro studies have demonstrated the potential for generating endogenous immune responses against follicular lymphoma cells. Amplification of effector cells with cyto-kines, such as interleukin-2 (Proleukin) or interferon-alfa (Intron A, Roferon-A), is one such approach that is currently being studied following autologous transplantation.[43,44] Other ways to enhance and induce host immunity against the patients’ tumor cells include tumor cell vaccination using engineered cells that express costimulatory molecules cells or granulocyte-macrophage colony-stimulating factor (GM-CSF).[45]

Another approach that has been used following conventional therapy is idiotypic peptides derived from the patients’ lymphoma cells with or without GM-CSF.[46-48] One problem with this strategy is the marked suppressive effect on T-cell subsets and antigen presenting cells (APCs) that occurs after autologous transplantation.[49]

Monoclonal antibodies, either unconjugated or conjugated to toxins, are also being given after autologous stem-cell transplantation to target tumor cells.[50] The anti–B-cell immunotoxin anti-B4–blocked ricin has been used in the adjuvant setting following autologous bone marrow transplantation but showed no benefit in a phase III trial.[51] Unconjugated monoclonal antibodies, such as rituximab (Rituxan), which are cytotoxic in the absence of effector cells,[52] will continue to be investigated as an attractive alternative for eradicating minimal residual disease. These immunomodulatory and targeted therapies may be particularly well suited to patients who are at high risk for relapse following high-dose therapy.

Improvements in induction and ablative regimens also will likely have an impact on the success of autologous stem-cell transplantation. One approach is the use of radioimmunoconjugates to target lymphoma cells.[53-55] Radioimmunoconjugates have been directly incorporated into ablative therapy. At the Fred Hutchinson Cancer Research Center, 29 patients, including 17 with follicular lymphoma, received iodine-131 conjugated to the anti-CD20 antibody anti-B1 as a conditioning regimen; this was followed by purged autologous stem-cell rescue.[55] All 29 patients had relapsed NHL that had failed to respond to conventional therapy.

Toxicities of labeled antibody included expected myelosuppression, transient renal insufficiency, and rare severe cardiac toxicity. At a median follow-up of 42 months since autologous bone marrow transplantation, 22 patients are alive and 14 are progression free. In both myeloablative and nonmyeloablative doses, radioimmunotherapy is showing very promising results with high response rates in patients with follicular lymphoma.

Allogeneic stem-cell transplantation may have a greater role in the treatment of follicular NHL as transplant-related mortality continues to fall and better strategies for controlling GVHD emerge. Longer follow-up will be necessary to confirm the apparent decrease in relapse and risk of myelodysplastic syndrome with allogeneic transplantation, as compared with autologous grafting.

Nonmyeloablative conditioning regimens that employ adoptive immunotherapy are also under investigation. Ongoing and future studies in these and other areas may provide novel adjuncts to therapies that currently only benefit a minority of patients.

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