Commentary (Schouten): High-Dose Therapy for Follicular Lymphoma

Freedman et al provide an extensive overview of the literature on high-dose therapy and transplantation in follicular non-Hodgkin’s lymphoma (NHL). They conclude that this approach can achieve responses in a high proportion of patients, resulting in relatively long disease-free or progression-free survival. Although Freedman et al do not cite all of the papers that have been published in this area, most of the omitted studies (several of which are from Europe and/or are registry reports) reach the same conclusions as the studies that are cited.[1-6]

From this overview, we learn that high-dose therapy is feasible and results in more or less prolonged intervals of progression-free disease in patients with follicular lymphoma. However, should this treatment modality be applied to all patients with follicular NHL? If not, how do we select patients for high-dose therapy, and in what stage of the disease should they be treated? In short: Is there a place for high-dose therapy in the standard clinical care of patients with follicular lymphoma? Or stated differently: Does high-dose therapy for follicular NHL constitute evidence-based medicine?

Randomized Clinical Trials: Preliminary Results

A randomized clinical trial holds the only possible answers to these questions. However, it is unlikely that a sufficiently powered, randomized trial will be conducted because of the difficulty of recruiting patients with the availability of lower morbidity peripheral stem-cell transplants. In Europe, we designed and initiated a three-arm study in patients with relapsed follicular NHL in the early 1990s.[7] In this trial, we posed two questions: Is high-dose therapy beneficial, and should purging of the graft be part of this procedure?

The general feeling at that time was that this procedure was too toxic for patients with a relatively long survival, which characterizes most patients with follicular lymphoma. However, after the introduction of peripheral blood stem cells (which has reduced the morbidity and mortality of the procedure), many transplanters decided to use this therapy in patients with follicular NHL. Unfortunately, due to insufficient patient accrual, the European three-arm study had to be stopped after the enrollment of about 140 patients.

Despite this, the data are being collected, and preliminary findings were presented during the recent International Conference on Malignant Lymphoma in Lugano, Switzerland. Of the 140 enrollees, 89 patients were randomized, 24 to chemotherapy, 33 to unpurged transplant, and 32 to purged transplant. At a median of 26 months from randomization, 16 (66%) of the patients treated with chemotherapy had progressed or relapsed, as compared with 13 (39%) of the patients who received an unpurged transplant and 12 (37%) of those who underwent a purged transplant (P = .002). At the time of the meeting, the data were too premature to present overall survival results. Because of the nature of the disease, further maturation of the data is needed.

Shortcomings of Published Studies

One of the shortcomings of the published literature on high-dose therapy in follicular NHL involves patient selection. In several studies, patients were selected based on good prognostic criteria, such as responsiveness to chemotherapy or maybe even complete remission. In other studies, patients were chosen based on characteristics indicative of poor prognoses, such as short remission duration.[7] Although it is known that the International Prognostic Index (IPI) criteria developed for patients with aggressive lymphoma can also be applied to patients with follicular NHL, these criteria are not frequently used to describe transplanted patient populations. Therefore, in the absence of results from a randomized clinical trial, all of the existing data on transplantation in follicular lymphoma is very difficult to interpret.

Published studies on follicular NHL may also be subject to a center effect or publication bias: Published data from very experienced centers are generally better than data from smaller centers. The latter are less likely to be published, resulting in the publication of papers reporting better results. This problem may be circumvented by the use of registry studies. Although one has to keep in mind the drawbacks of registry studies, they may be more likely to report poor results. Although difficult to compare with the studies cited by Freedman et all, registry results seem to be inferior.[1,2] Therefore, do we know how to treat a patient with relapsed follicular lymphoma in the year 2000? To be honest, the answer is still no.

Should High-Dose Therapy and Transplantation Be Used in Follicular NHL?

Should we use high-dose therapy and transplantation in patients with follicular NHL? The answer to this question may depend on the likelihood that such therapy may harm the patient-ie, the balance between therapeutic benefit and side effects. This is related more or less to the probability of morbidity and mortality. Unfortunately, these data are not extensively reported by Freedman et al.

Treatment-related mortality can be estimated at between 2% to 5%.[3,8] However, sound mortality data (excluding highly selected patients) do not exist. In the view of transplanters, some morbidity is acceptable; however, essential data, such as quality of life in transplanted patients with follicular lymphoma, are unavailable. Also, the risk of secondary myelodysplasia should not be ignored. Clearly, if one wishes to successfully apply transplantation in this disease, it is essential to use good clinical judgment in selecting patients who are most likely to benefit.

Should transplantation be considered standard care in follicular NHL, however, and are the results so favorable that they preclude the need for further clinical research or improved results? Although it may be true that a randomized trial analyzing the value of high-dose therapy can no longer be performed, many questions remain to be answered: What is the role of allogeneic transplantation in these patients? What about allogeneic grafting after nonmyeloablative therapy? Would the addition of monoclonal antibodies (with or without radiolabels) to standard conditioning and standard autologous transplantation offer an improvement over standard autologous transplantation alone? Is there a role for idiotypic vaccination after transplantation? What about purging? These are just a few of the many open questions.

The Future of High-Dose Therapy

Although one may justify the use of high-dose therapy in individual patients in order to improve their prognosis, given the significant number of research questions, it is difficult to consider high-dose therapy part of standard evidence-based care in follicular NHL. In the interest of future patients, however, we are obliged to try to tackle these topics using the tool of good clinical research. International cooperation may also be of value in resolving contentious issues. In the meantime, we should report the results of high-dose therapy in follicular NHL patients of any risk profile. This may help us interpret outcomes and facilitate further progress in the management of this enigmatic disease.

References:

1. Schouten HC, Colombat P, Verdonck LF, et al: Autologous bone marrow transplantation for low-grade non-Hodgkin’s lymphoma: The European Bone Marrow Transplant Group (EBMT) experience, in Dicke KA, Keating A, Nichols C, et al (eds): Autologous Bone Marrow Transplantation: Proceedings of the Sixth International Symposium, Arlington, Texas, pp 71-74. Cancer Treatment Research Education Fund, 1993.

2. Schouten HC, Colombat P, Verdonck LF, et al: Autologous bone marrow transplantation for low-grade non-Hodgkin’s lymphoma: The European Transplant Group Experience: EBMT Working Party for Lymphoma. Ann Oncol 5(suppl 2):147-149, 1994.

3. Schouten HC, Raemaekers JJ, Kluin-Nelemans HC, et al: High-dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin’s lymphoma: Dutch HOVON Group. Ann Hematol 73(6):373-277, 1996.

4. Colombat P, Binet C, Linassier C, et al: High dose chemotherapy with autologous marrow transplantation in follicular lymphomas. Leuk Lymphoma 7(suppl)3-6, 1992.

5. Colombat P, Donadio D, Fouillard L, et al: Value of autologous bone marrow transplantation in follicular lymphoma: A France Autogreffe retrospective study of 42 patients. Bone Marrow Transplant 13(2): 157-162, 1994.

6. Linassier C, Fouillard L, Milpied N, et al: Value of autologous bone marrow transplantation (ABMT) in 42 patients with follicular lymphomas responsive to conventional chemotherapy: A “France Autogreffe” study. Cancer Detect Prev 20(10:1-9, 1996.

7. Schouten HC, Sydes M, Kvalheim G, et al: The European CUP/UP trial: A preliminary analysis of autologous transplantation for relapsed follicular non-Hodgkin’s lymphoma, in Dicke KA, Keating A (eds): Autologous Bone Marrow and Blood Transplantation: Proceedings of the Ninth International Symposium, Arlington, Texas, pp 161-165. Charlottesville, Virginia, Carden Jennings Publishing, 1999.

8. Rohatiner A, Johnson P, Price C, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 12:1177-1185, 1994.