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Is there a role for autotransplants in patients with follicular lymphoma in the rituximab era?
Transfusion and Apheresis Science, 1, 49, pages 24 - 26
Patients with low grad follicular lymphoma were shown to be able to achieve long-term disease-free survival when transplanted after relapse in the era before the wide spread use of rituximab. It appears that the availability of rituximab has not diminished the value of transplantation (i.e., either autologous or allogeneic) in the care of these patients. A similar overall survival and less treatment related toxicity make autologous transplantation the better choice for most patients transplanted at first treatment failure.
Follicular lymphoma represents a histological spectrum, from tumors with predominately small cells to those with a high proportion of large cells (i.e. follicular lymphomas grades 1, 2, and 3) and those that are 100% follicular to those with a significant diffuse component. The focus of this manuscript will be low grade follicular lymphoma (i.e. follicular lymphoma grades 1 and 2). While the issue is controversial, it seems clear that some patients with high grade follicular lymphoma (i.e. follicular lymphoma grade 3) respond to anthracycline containing regimens in combination with rituximab in a manner similar to what is seen in diffuse large B-cell lymphoma. This manuscript will address the place of autotransplants in low grade follicular lymphoma before the development of rituximab, and then review the data for autotransplant patients who receive rituximab as part of their initial therapy for low grade follicular lymphoma.
2. Was there a place for autotransplantation in low grade follicular lymphoma before the use of rituximab?
Results using high dose therapy and autologous hematopoietic stem cell transplantation has been widely reported for patients with follicular lymphoma. Most studies have reported the results of transplantation in patients with recurrent or refractory follicular lymphoma, and there have been several studies of autologous hematopoietic stem cell transplantation as part of the primary therapy for patients with these disorders. Rohatiner et al. reported 64 patients with follicular lymphoma who received autologous hematopoietic stem cell transplantation after high-dose cyclophosphamide and total body radiotherapy  . The marrow was treated in vitro to try to eliminate tumor cells. The projected 5 year survival after the transplant was approximately 70% with approximately 50% of patients still in remission.
Liu et al. reported 29 patients treated with myeloablative doses of radioiodine delivered by monoclonal antibody  . At the time of the report, approximately 50 patients remained in unmaintained remission with a median follow-up of 42 months with an overall survival of 68%.
Brice et al. described patients from the GELF86 trial for follicular lymphoma who progressed  . Eighty-three patients underwent autologous hematopoietic stem cell transplantation. The majority of patients received a total body radiotherapy containing regimen, while the BEAM regimen was the second most common high dose therapy. Five year freedom from second failure was 42% for the patients undergoing transplantation versus 15% for the patients in the study who were not transplanted, and the five-year overall survival was 58% versus 38% favoring patients who were transplanted.
Laudi et al. described 67 patients with relapsed or refractory low-grade lymphoma who underwent autologous hematopoietic stem cell transplantation with high dose regimens involving total body radiotherapy in the majority of patients, or CBV in those not felt to be candidates for total body radiotherapy  . The overall survival at 10 years post transplant was 50% and the progression free survival 28%. Approximately 20% of patients remained in complete remission on an apparent plateau as long as 18 years post transplant.
Corradini et al. described long term follow up of patients with low grade lymphoma (40 with follicular lymphoma) who underwent autologous hematopoietic stem cell transplantation  . They found that patients who achieved a “molecular remission” were less likely to relapse. Patients with follicular lymphoma did better than patients with other types of indolent lymphoma. Twenty patients with follicular lymphoma had long term remissions.
Vose et al. reported 248 patients with recurrent follicular lymphoma who underwent high dose therapy and autologous hematopoietic stem cell transplantation  . The high dose therapy regimen in 99 patients included total body radiotherapy and the remainder received a chemotherapy only regimen, sometimes in combination with a monoclonal antibody. The 5 year overall survival for all patients was 63% and the 5 year progression free survival was 44%. Adverse risk factors in this study included grade 3 follicular lymphoma, high FLIPI score at the time of the transplant, and having received three or more previous chemotherapy regimens. Patients with none of these factors had a 5 year overall survival of 82%.
Perhaps the study that most convincingly showed a positive effect of autologous hematopoietic stem cell transplantation on patients with relapsed or refractory follicular lymphoma was the CUP trial performed in Europe. Although the study included only 89 patients, the results showed a significant advantage to transplantation. After demonstrating chemotherapy sensitivity, patients were randomized to receive further standard chemotherapy, high dose therapy with unpurged stem cells, or high dose therapy with purged stem cells. The results in the latter two categories did not differ and were pooled. With a 69 month median follow up, the 5 year progression free survival for patients in the chemotherapy arm was approximately 10% in contrast to approximately 55% in the 2 transplant arms. The overall survival at 5 years was approximately 45% in the chemotherapy only arm and approximately 75% in the 2 transplant arms. Both of these differences were statistically significant. This is the only randomized trial measuring the benefit of autologous hematopoietic stem cell transplantation for relapsed follicular lymphoma, and is likely to remain the only trial. Despite the small numbers, it showed a significant advantage to transplantation.
Based on these results, it is apparent that autologous hematopoietic stem cell transplantation can yield prolonged, failure free survival in some patients with recurrent/refractory low grade follicular lymphoma. The results seem to be better when patients are transplanted at the time of first treatment failure rather than waiting for multiple relapses. The results from patients transplanted at the University of Nebraska Medical Center with low grade follicular lymphoma transplanted at first treatment failure are presented in Fig. 1 . Of the 126 patients, approximately 45% are predicted to continue without relapse at 10 years.
3. Autotransplantation for low grade follicular lymphoma in first complete remission
A number of series have reported the results of using autologous transplantation as an adjuvant to initial chemotherapy in patients with follicular lymphoma in first response , , , , , , , and . In general, these studies show an advantage in failure free survival, but a clear overall survival advantage is lacking. In the United States, high dose therapy and autologous hematopoietic stem cell transplantation is not a standard treatment for patients with low grade follicular lymphoma who achieve a complete remission with initial chemotherapy regimens. This is in part related to the risk of myelodysplastic syndrome/acute myeloid leukemia that can occur in some of these patients. While the risk appears to be higher in patients who receive total body radiotherapy as their preparative regimen  and , it can be seen in patients with other preparative regimens.
4. Does rituximab improve results with autotransplantation through in vivo “Purging” or when used as maintenance therapy after transplant?
Rituximab had a major impact on treatment outcome for patients with low grade follicular lymphoma when it was incorporated into the initial treatment regimen—yielding an improved overall survival. It makes sense that the incorporation of rituximab into the transplant process might reduce the risk of relapse by reducing the number of tumor cells that could be “harvested” while collecting the cells necessary for the reinfusion and reestablishment of bone marrow function, and might reduce the risk of late relapse by reducing the tumor burden when the drug is included in the preparative regimen. It appears that this might be the case. Vose et al. found a reduced risk of relapse for patients who received rituximab as part of the transplant process  . Arcaini et al. found a high response rate for patients who received rituximab for “in vivo” purging and during the transplant process  . They found a 5 year progression free survival of 59%. Sebban et al. found a 5 year survival after relapse in patients treated with high dose therapy and rituximab of more than 90%  .
Hicks et al. and Brugger et al. administered rituximab after autologous hematopoietic stem cell transplantation in patients with follicular lymphoma  and . In both cases, the authors felt that there was evidence to support prolonged remission in the patients who received post transplant rituximab. However, one study found prolonged hypogammaglobulinemia in treated patients  . Kang et al. and Gouill et al. reported a series of patients who had received prior rituximab therapy, relapsed, and then underwent autologous hematopoietic stem cell transplantation  and . They found a possible poorer outcome in the patients who had received prior rituximab before coming to transplantation.
Both autologous and allogeneic hematopoietic stem cell transplantation provide a potentially curative option for patients with recurrent, low grade follicular lymphoma. At the present time no other treatment provides the same chance for prolonged disease-free survival. It appears that allogeneic hematopoietic stem cell transplantation is associated with a lower relapse rate  and . However, allogeneic transplantation has a higher treatment related mortality and is difficult to apply in older patients. For most patients with relapsed/primarily refractory low grade follicular lymphoma, autotransplantation remains the best salvage therapy. The availability of rituximab as part of the initial treatment for these patients has not eliminated the utility of this approach.
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University of Nebraska Medical Center, Omaha, NE, United States
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