Medscape: Continuing Medical Education Online
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Learning Objectives
Upon completion of this activity, participants will be able to:
- • Describe overall and progression-free survival associated with treatment of follicular lymphoma
- • Compare the benefits of in vitro graft purging vs no purging when using hematopoietic cell transplantation (HCT) for treating follicular lymphoma
- • Identify causes of failure of HCT in follicular lymphoma
- • Identify patients who are most and least likely to benefit from autologous HCT
Follicular lymphoma is an indolent disease and rarely curable with conventional chemotherapy. Although most patients experience a remission with initial chemotherapy, subsequent attempts to reinduce remissions using conventional chemotherapy are associated with decreased durability.1,2 Before the introduction of rituximab, overall survival with follicular lymphoma had not significantly changed for many years.3 With the addition of rituximab to chemotherapy regimens, several studies have shown an improvement in survival.4 However, no consensus has been reached regarding the optimal first-line or subsequent therapy. Because of the indolent biology of the disease and failure of durable responses to conventional chemotherapy, autologous and allogeneic hematopoietic cell transplantation (HCT) have been evaluated as alternative approaches. Before the rituximab era, high-dose chemotherapy with autologous HCT yielded higher response rates and improved progression-free survival in advanced-stage disease than standard chemotherapy.5 Initial reports with myeloablative allogeneic HCT show an improvement in relapse/progression compared with autologous HCT, but this improvement is associated with intolerable nonrelapse mortality (NRM). To reduce toxicities associated with high NRM, nonmyeloablative or reduced-intensity regimens have been studied and early results indicate promising efficacy. This article summarizes the current strategies and new developments in autologous and allogeneic HCT, including novel concepts such as radioimmunotherapy and in vivo purging strategies using B-cell–specific monoclonal antibodies.
Autologous HCT
Relapsed Follicular Lymphoma
The benefit of autologous HCT was first shown in patients experiencing relapsed follicular lymphoma. Several studies have shown autologous HCT to be associated with improved progression-free and overall survival rates in these patients compared with standard therapy. A series of historically controlled, nonrandomized trials in patients experiencing relapsed follicular lymphoma reported 5- to 10-year progression-free survival of 31% to 55% and overall survival of 52% to 75%.6–8
The European Blood and Marrow Transplantation (EBMT) group registry reported the long-term outcomes on 693 patients with relapsed follicular lymphoma undergoing an autologous HCT.8 With a median follow-up of 10.3 years, the 10-year progression-free and overall survival rates were 31% and 52%, respectively. At a median of 7 years, 9% of patients developed a second malignancy.
Vose et al.6 reviewed the effects of histologic grade and Follicular Lymphoma International Prognostic Index (FLIPI) on autologous HST for 250 patients with follicular lymphoma. The data suggested that a histologic grade of FL3, a high-risk FLIPI, or 3 or more prior chemotherapy regimens were factors predictive of a worse outcome. The only randomized trial conducted was a European trial that prospectively addressed the role of autologous HCT in this patient population (the Chemotherapy vs. Unpurged HCT vs. Purged HCT trial [CUP]).5 This trial registered 140 patients with relapsed, chemosensitive follicular non-Hodgkin’s lymphoma to undergo chemotherapy alone, autologous HCT with a purged autograft, or autologous HCT with an unpurged autograft. However, only 89 of these patients proceeded to randomization. The 2-year progression-free survival rates were 26%, 58%, and 55%, respectively, whereas 4-year overall survival rates for the chemotherapy, unpurged autologous HCT, and purged autologous HCT arms were 46%, 71%, and 77%, respectively. No difference in progression-free or overall survival was seen between the autologous HCT groups. However, a significant reduction in hazard rates for both progression-free and overall survival was observed in the combined groups of patients undergoing autologous HCT compared with the chemotherapy group. Even though the discrepancy between registered and randomized patients may limit the study’s impact, these results were the first to show an overall survival benefit of autologous HCT for patients with relapsed follicular lymphoma.5
One concern in many of these early trials is the high percentage of patients who developed a treatment-related myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML).8,9 Longer follow-up could potentially abolish any differences in survival based on the development of hazards associated with autologous HCT.
First Remission
Several phase II clinical trials have shown long-term remissions after consolidating autologous HCT in first remission of advanced-stage follicular lymphoma.10,11 The long-term beneficial effect was tested in 3 prospective, randomized trials. The German Low Grade Lymphoma Study Group (GLSG) conducted a randomized trial involving 240 patients with advanced-stage follicular lymphoma.12 Patients initially received 2 cycles of an anthracycline-based regimen and then were randomized to either autologous HCT or interferon maintenance therapy until disease progression. Myeloablation was achieved with total body irradiation (TBI) and cyclophosphamide before reinfusion of unpurged peripheral stem cells. The largest benefit was seen in patients who were in partial remission after initial cytoreductive chemotherapy. Although the 5-year progression-free survival favored the transplantation group, a significantly increased risk for secondary MDS or AML was observed. Subgroup analysis showed that this risk was higher in patients receiving MCP (melphalan, chlorambucil, and prednisone) than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial chemotherapy.
The French Group Ouest-der Leucemies et Autres Maladies du Sang (GOELAMS) group randomized 172 patients with newly diagnosed follicular lymphoma to either immunochemotherapy or autologous HCT with an ex vivo purged graft, with all patients experiencing at least a partial remission to induction chemotherapy.13 As in the GLSG trial, myeloablation was achieved with TBI and cyclophosphamide. After a median follow-up of 5 years, median progression-free survival was 45 months in the chemotherapy group but was not reached in the autologous HCT group. Unfortunately, an excessive 18.6% risk for secondary malignancies nullified any translation into a superior overall survival for the transplantation group. Subset analysis stratified by the FLIPI identified superior progression-free survival among poor-risk patients, whereas the good- and intermediate-risk patients in both treatment groups had comparable progression-free survival outcomes. This finding suggested that patients with poor prognostic factors at diagnosis may benefit from early intensive therapy. On longer follow-up, the authors concluded that first-line consolidation should not be standard care and that progression-free survival was marginally statistically significant.14
The third, and largest, randomized trial of the Groupe d’Etude des Lymphomes de l’Adulte (GELA) study group randomized 401 previously untreated patients with high tumor burden follicular lymphoma to chemotherapy or chemotherapy followed by autologous HCT (cyclophosphamide, etoposide, TBI myeloablation).15,16 The 7-year progression-free and overall survival rates favored the transplantation arm, and even more so when only patients with ongoing, continuous response of more than 6 months were considered. However, longer follow-up did not show transplantation to be superior in terms of progression-free or overall survival.16
All 3 studies showed that myeloablative therapy followed by autologous HCT is associated with superior disease-free survival, but whether autologous HCT improves overall survival remains unanswered. Reports have shown the incidence of secondary MDS and AML to be high17,18 and to negate the survival advantages in the GLSG and GOELAMS trials. Collective interpretation of these 3 trials may suggest that the risk for secondary MDS and AML depends on the pretreatment status of the patients, with a higher incidence in more heavily pretreated patients. Autologous HCT may therefore be a reasonable approach to consolidate untreated patients with late-stage, high tumor burden follicular lymphoma in first remission, but unlikely to benefit similar heavily pretreated patients.
Notably, these 3 trials did not include patients pretreated with rituximab, which may make these studies less generalizable to current practice. To address these concerns, 4 studies were published on autologous HCT in patients treated with rituximab.19–22 The first study showed that the combination of a salvage regimen containing rituximab, with or without autologous HCT, led to a dramatic improvement of long-term outcome.19
In the second study, the difference between R-CHOP (CHOP with rituximab) followed by interferon maintenance or autologous HCT was not yet significant; however, results strongly suggested a beneficial effect of autologous HCT in the era of R-CHOP front-line therapy, particularly for intermediate- or high-risk patients with advanced-stage follicular lymphoma.20
The third study made strong arguments that molecular response is critical for effective disease control, regardless of the treatment used. Although rituximab with autologous HCT (R-Au-HCT) ensured superior disease control and molecular outcome than R-CHOP, no improvement in overall survival was seen. R-CHOP failures had a good outcome after salvage R-Au-HCT, suggesting that relapsed/refractory follicular lymphoma could be the most appropriate setting for R-Au-HCT–like treatments.21
The fourth study showed that R-CHOP was associated with higher response rates, significantly longer time to treatment failure, longer response duration), and improved overall survival. R-CHOP significantly prolonged time to treatment failure in all risk groups compared with CHOP. The superiority of R-CHOP versus CHOP could be documented in the patient group not treated with autologous HCT: the response duration was significantly prolonged by the immunochemotherapy. This could not be seen in the group of younger patients consolidated with autologous HCT, but the number of events was too low to draw final conclusions.22 Although some of these early results seem to contradict the pre-rituximab studies, long-term follow-up is certainly needed before any definitive comparisons can be made. As a result, the GELA, GOELAMS, and GLSG trials offer the best available long-term data to support current treatment approaches.
Graft Purging
Prospective randomized trials supporting the use of purging are absent in the literature, but several studies contain data that may suggest clinical benefit. As in all autologous HCT strategies, contamination of the hematopoietic stem cell graft by residual or minimal tumor cells may contribute to relapse after autologous HCT. The International Bone Marrow Transplantation Registry (IBMTR) retrospectively analyzed 904 patients with follicular lymphoma who underwent stem cell purging that was being observed as an independent predictor of relapse and overall survival through multivariate analysis.23 In a second study, the Dana-Farber group reported the success of in vitro purging, showing an 8-year relapse-free interval of 83% in patients who received polymerase chain reaction (PCR)–negative grafts versus 19% in patients who received PCR-positive grafts.24 A third multicenter study by Gruppo Italiano Trapianto Midollo Osseo administered high-dose therapy at diagnosis to harvest stem cells after in vivo chemotherapeutic debulking.25 Progression-free and overall survival rates were 67% and 85%, respectively, but an encouraging higher progression-free survival rate of 85% was observed in patients who experienced a molecular remission.
Because in vitro purging methods can be financial and technically burdensome, rituximab has been evaluated as a potential in vivo purging agent when given concurrently with chemotherapy. Three studies have evaluated the role of rituximab for in vivo purging during administration of mobilization chemotherapy.26–28 Collectively, these reports show that in vivo rituximab may be useful to obtain stem cell harvests without minimal residual disease in the graft. However, until a definitive improvement in disease-free or overall survival rates can be shown in prospective randomized clinical trials, the benefit of in vivo purging on clinical outcome remains unknown.
Myeloablative Allogeneic HCT
Relapsed Follicular Lymphoma
Although, allogeneic HCT represents a promising modality that may cure select patients, its use for treating patients with early-stage follicular lymphoma, or those experiencing first remission or first relapse of disease is generally not an accepted practice. Furthermore, the only evidence of curative potential is overall survival plateaus in studies of allogeneic HCT that have a median follow-up of 5 years, without knowing if a substantial proportion of patients experiencing remission would have late relapses beyond 5 years. Allogeneic HCT is indicated for patients with recurrent follicular lymphoma to either reduce lymphoma cell contamination from an autologous harvest or to take advantage of a graft-versus-lymphoma effect.
As in other settings of allogeneic HCT, the benefit of lower relapse rates is associated with nullifying NRM, especially with myeloablative conditioning regimens. The IBMTR compared 904 patients with follicular lymphoma who underwent myeloablative allogeneic HCT, purged autologous HCT, or unpurged autologous HCT. The risk for relapse was significantly lower for the 176 allogeneic recipients, with minimal relapses occurring after 1 year. This is in comparison to a higher risk for relapse in the autologous recipients, who also experienced continuous treatment failure. The improvement in risk for relapse was negated by NRM of 24% at 1 year and 30% at 5 years after allogeneic HCT, which resulted in comparable 5-year overall survival.23 The use of TBI and receipt of a purged graft were associated with a lower risk for recurrence by multivariate analysis. The EBMT studied a total of 1185 patients with non-Hodgkin’s lymphoma, including 231 with low-grade disease. The patients treated with myeloablative allogeneic HCT were compared with 14,687 patients treated with autologous HCT.29 As seen with the IBMTR analysis, overall survival was not superior because of a 38% treatment-related mortality, which again negated a significantly lower relapse risk. These data are in accordance with previous data from several smaller series that all show a high NRM but a low recurrence rate.30,31 Myeloablative allogeneic HCT was also studied in the setting of chemoresistant follicular lymphoma by Toze et al.32 and the M. D. Anderson group,33 with both groups showing long-term disease-free survival in patients with chemoresistant disease.
Nonmyeloablative Allogeneic HCT
Relapsed Follicular Lymphoma
To reduce NRM, nonmyeloablative allogeneic HCT in follicular lymphoma has been studied. Khouri et al.34 initially studied 18 patients with relapsed follicular lymphoma, all undergoing a conditioning regimen of fludarabine and cyclophosphamide with or without rituximab. Progression-free and overall survival rates at 2 years were approximately 84%, with a 100% complete response after allogeneic HCT and only 1 treatment-related mortality. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 20%, and the cumulative incidence of chronic GVHD was 64%.34
Kusumi et al.35 studied 45 patients with indolent NHL, including patients with chemoresistant disease. Patients received a fludarabine-based regimen versus low-dose TBI. The efficacy of reduced-intensity conditioning was demonstrated by a 3-year overall survival rate of 79% and 3-year progression-free survival rates of 83% and 64% for the chemosensitive and chemoresistant patients, respectively. The cost of this approach was lower than for myeloablative regimens, and the NRM was only 18%. Although NRM is reduced with nonmyeloablative HCT from likely lower occurrence of acute GVHD, GVHD still remains a leading cause of mortality. Furthermore, retrospective studies have suggested higher relapse rates with nonmyeloablative or reduced-intensity regimens.36 However, longer follow-up by Khouri et al.37 showed that the long-term activity and toxicity of nonmyeloablative transplantation regimens for follicular lymphoma where beneficial, because patients experienced long-term survival with remission and none had died of recurrent lymphoma.
Because GVHD is a leading cause of morbidity and mortality, alemtuzumab has been studied for its ability to deplete donor T cells in the allogeneic grafts. In one study, 28 patients with low-grade non-Hodgkin’s lymphomas received a BEAM (carmustine, cytarabine, etoposide, melphalan)/alemtuzumab conditioning regimen. Grade III and IV acute GVHD were completely eliminated, estimated 1-year treatment-related mortality was only 8%, and relapse/progression was the major cause of treatment failure.38 A second series from the United Kingdom reported only a 15% incidence of grade II to IV acute GVHD when they used an alemtuzumab-containing regimen.39
These studies show remarkably lower acute GVHD rates than previously reported clinical trials. The EBMT described the use of reduced-intensity conditioning for 52 patients with follicular lymphoma, with most patients receiving a fludarabine-based preparative regimen. The 2-year progression-free and overall survival rates were 54% and 65%, respectively, with a 21% progression rate. However, approximately 10% of the patients were treated with the more intensive preparative regimen, BEAM, which likely translated to a higher NRM of 31%.40
If a patient experiences a relapse after allogeneic HCT, donor lymphocyte infusions can induce remissions, suggesting the importance of graft-versus-lymphoma effect for disease eradication.41,42 Collectively, the data from myeloablative and nonmyeloablative conditioning regimens indicate that allogeneic HCT after either conventional or dose-reduced conditioning is effective but associated with substantial mortality and morbidity. Because of these circumstances and small numbers of subjects in these various studies, the role and type of allogeneic HCT for follicular lymphoma can certainly be better defined by future clinical trials. A current Bone Marrow Transplant Clinical Trials Network trial is evaluating the cytoxan/fludarabine/high-dose rituximab regimen followed by an allogeneic stem cell transplant in patients with relapsed follicular lymphoma to try to reproduce the M. D. Anderson results, because it was a single-center study with potential selection bias.
New Strategies
The incorporation of yttrium-90 (90Y)–labeled ibritumomab or iodine-131 (131I)–labeled tositumomab radioimmunoconjugates into conditioning regimens to deliver targeted radiotherapy seems promising. The feasibility of myeloablative radioimmunotherapy was successfully shown in 125 patients with refractory or relapsed follicular lymphoma.43 Patients were treated with either myeloablative radioimmunotherapy or conventional TBI myeloablative radiochemotherapy followed by autologous HCT. Patients experienced an overall response rate of 93% and complete remission rate of 85% with a single myeloablative infusion of 131I-tositumomab. After conventional autologous stem cell transplant, 5-year overall and progression-free survival rates were estimated to be 67% and 48% versus only 53% and 29%, respectively. The risk for secondary MDS or AML did not differ between the treatment strategies.
A phase I/II study evaluated high-dose 131I-tositumomab followed by etoposide and cyclophosphamide and autologous stem cell transplant in 34 patients with grade I/II follicular lymphoma. Because this study also included other low-grade lymphomas, the estimated overall and progression-free survival rates were 83% and 68%, respectively, for all patients. These 2-year results compared favorably with a historical control group treated with TBI, etoposide, and cyclophosphamide.44 To expand the feasibility of this approach, 131I-tositumomab was given in combination with standard BEAM followed by autologous stem cell transplant in patients with mostly refractory lymphoma. The treatment was well tolerated without significant additional toxicity compared with historical controls treated with BEAM alone.45 Other trials have also used either standard or dose-intense 90Y-ibritumomab tiuxetan along with a standard transplant regimen.46
Because relapse of the original lymphoma is still the major cause of failure from an autologous HCT, additional modifications to the transplant regimen to reduce the relapse rate, such as maintenance in the post-transplant setting, are also being evaluated. Options include rituximab maintenance post-transplant or other agents, such as lenalidomide, histone deacetylase inhibitors, and other novel agents.
Conclusions
For patients with relapsed follicular lymphoma, autologous HCT appears to produce long-term disease-free survival in selected patients. The patients that seem to benefit most are those who undergo transplantation after receiving fewer than 3 chemotherapy regimens and have a lower FLIPI at relapse. For patients who experience multiple relapses of follicular lymphoma, autologous HCT does not produce a favorable risk–benefit ratio. However, for patients experiencing first remission, the incidence of secondary malignancies, especially MDS and AML, complicates autologous HCT and must be considered for patients with long expected life spans. Most centers now use autologous HCT for selected patients experiencing first or second relapse who have a shortened disease-free interval or other indications of a poor outcome with standard therapy. With the recent incorporation of radioimmunoconjugates and monoclonal antibodies into the mobilization, conditioning, or maintenance regimens, the role and efficacy of autologous HCT may continue to improve over time for patients with follicular lymphoma.
Allogeneic transplantation can be performed after either conventional myeloablative or reduced-intensity conditioning. The latter approach is an encouraging development because it has substantially reduced treatment-related morbidity and mortality, consisting mainly of acute and chronic GVHD and infectious complications, without a major increase in relapse risk. Although relapse and progression occur less often after myeloablative allogeneic HCT, this modality should be used cautiously because of its prohibitive NRM. Most currently published trials were initiated in the pre-rituximab era. Therefore, the role of autologous and allogeneic HCT must be reevaluated in the setting of initial therapy with rituximab-containing regimens, and prospective studies are urgently needed to validate these strategies.
The authors recommend that patients with follicular lymphoma who are physiologic candidates for autologous or allogeneic HCT be referred for a formal transplantation evaluation when the first regimen fails to produce a complete response, or at first or second relapse. This is particularly true for patients who experience relapse within 2 years of the first therapy, while still receiving rituximab maintenance (rituximab resistant), or within a radiation field. The choice between autologous and allogeneic HCT is not straightforward, and both should be discussed with patients who are physiologically able to receive both types. Autologous HCT prolongs the disease-free interval of patients with follicular lymphoma; however, the relapse rate seems to be much lower in patients who receive an allogeneic HCT. Because of the much higher NRM of allogeneic HCT, the risk–benefit ratio must be discussed individually. The choice between a fully ablative allogeneic HCT and a nonmyeloablative allogeneic HCT must also be decided on an individual basis, because the NRM is higher with fully ablative allogeneic HCT but the relapse rate seems to be slightly higher with nonmyeloablative allogeneic HCT. For patients who are older than the physiologic age at which an allogeneic HCT is considered a safe option, autologous HCT would be the best option if they are appropriate for this type of transplant. Individual patient evaluation and treatment planning should be considered.
CME AUTHOR
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