Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

We have seen major advances in our understanding of the biology of malignant lymphoma in recent years. These advances have been reflected in the development of the Revised European- American (REAL)/World Health Organization (WHO) classification of lymphoid malignancies, which incorporates data from immunophenotype, cytogenetic, and molecular genetic studies as well as morphologic appearance and clinical behavior. The description of DNA microarray studies in diffuse large B-cell non-Hodgkin's lymphoma (NHL) has already generated useful prognostic data and identified many potential therapeutic targets.[1] Future studies may provide pharmacogenomic data, which could predict response to therapy in individual patients, and thus allow a more tailored treatment approach. Researchers have developed new treatment modalities including unlabeled and radiolabeled monoclonal antibodies, antisense oligonucleotides, DNA vaccination strategies, and proteasome inhibitors. The potential for these new agents to affect outcome in patients with NHL is underscored by early experience with rituximab(Drug information on rituximab) (Rituxan), which has proven active as a single agent in lowgrade follicular lymphoma and has been shown to improve survival when combined with chemotherapy for certain patients with aggressive NHL.[2] The role of hematopoietic stem cell transplantation in NHL therefore needs to be addressed in the context of emerging knowledge and new therapies. The article by Holmberg and Stewart provides insight into the use of hematopoietic stem cell transplantation in various NHL subtypes, seen from a "transplanter's" perspective. It addresses important issues including the potential role of in vitro or in vivo purging for patients receiving autologous transplants and the exploitation of graft-vs-tumor effects in the setting of full and nonmyeloablative allogeneic transplantation. The article is less informative in placing the role of transplantation in the context of other therapies for NHL and fails to emphasize the potential effect of patient selection upon the reported outcomes in transplant studies. Some of the authors' specific observations deserve further comment. Autologous Transplantation for Indolent Lymphoma
Most of the data reviewed in this section relates to studies in low-grade follicular lymphoma. It is important to distinguish between this entity and small lymphocytic lymphoma/chronic lymphocytic leukemia, which the authors do not discuss in detail. Results of transplantation are not placed in the context of results of emerging therapies. High clinical and molecular response rates have been reported for patients with low-grade lymphoma receiving chemotherapy regimens such as CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)) with rituximab, and rituximab alone.[3,4] The molecular response rates observed in these studies are comparable to those reported in transplant series, and if molecular response is a predictive end point in these diseases, these results may imply that autologous transplantation has little to add to combined chemoimmunotherapy in this disease. The phenomenon of in vivo purging with monoclonal antibodies could therefore become a redundant issue. Ex vivo stem cell manipulation is also discussed, but two important studies are not cited. The European Chemotherapy/Unpurged/Purged (CUP) study is the only prospective randomized study that has attempted to explore the impact of purging on progression-free and overall survival.[ 5] Although patient numbers in this study are small, no apparent benefit from purging has been observed so far. Conversely, a large retrospective study from the joint databases of the Autologous Blood and Marrow Transplant Registry (ABMTR) and European Group for Blood and Marrow Transplantation (EBMT) has recently shown a lower relapse rate and higher overall survival for patients with low-grade disease undergoing ex vivo manipulation of their autologous stem cell product, suggesting that stem cell contamination may contribute to relapse.[6] Overall, the impact of ex vivo manipulation is unclear. The use of autologous stem cell transplantation (ASCT) as a component of first-line therapy is also discussed, but important data from Stanford University are not mentioned.[ 7] Although results of early transplantation are superficially encouraging, patient selection may be a major factor in the excellent results reported to date. The non-Hodgkin's lymphoma study group has reported very long progression-free survival rates in patients with low-grade follicular lymphoma with good-risk disease according to the International Prognostic Index. Autologous Transplantation for Aggressive NHL
The role of ASCT as a salvage therapy for patients with relapsed diffuse large B-cell (and probably aggressive peripheral T-cell) NHL is now well established. However, its use as postremission therapy for poorrisk patients after CHOP or similar chemotherapy regimens is unproven. Many randomized studies, some of which are included in this review, have explored the use of early highdose therapy in poor-risk aggressive NHL. To date, none of these studies has shown a survival advantage for early ASCT in poor-risk patients defined by the International Prognostic Index. A meta-analysis of all of these studies is currently in progress. Again, these data must be reviewed in the context of new treatment results. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) randomized comparison of CHOP with CHOP/rituximab has shown an apparent survival advantage to the combined-modality therapy.[2] If this is confirmed in other randomized studies-especially in younger patient groups-then early transplantation will need to be evaluated in comparison with CHOP/rituximab. Mantle Cell Lymphoma
The authors' comments that consolidation of first remission with transplantation in mantle cell lymphoma is "well accepted" should be interpreted cautiously. Although results of the published series are superficially encouraging, the median ages of the patients in these series is much younger than the entire population of patients with this disease, suggesting that patient selection may be a factor in these favorable results. First-remission transplant in this disease should be regarded as experimental. Results with the use of hyperCVAD (hyperfractionated cyclophosphamide(Drug information on cyclophosphamide), vincristine, doxorubicin [Adriamycin], dexamethasone(Drug information on dexamethasone)) and rituximab[8] have been at least as encouraging as the use of transplantation in this disease and represent an alternative first-line approach currently being evaluated by the Southwest Oncology Group. Allogeneic Transplantation in NHL
The review contains a thorough account of the potential use of full and nonmyeloablative transplantation in NHL. This is a potentially important new approach, especially in indolent NHL. However, it is important to recognize that, at present, the limited comparative data for allogeneic and autologous transplantation in NHL have failed to show a survival advantage for patients receiving allogeneic transplants, because the lower relapse rate associated with allogeneic transplants is offset by the higher regimen-related mortality. Whether the lower mortality of reduced-intensity conditioning will have an impact on this will depend on the magnitude of the graft-vs-lymphoma effect. Although there are many clinical observations of this effect, its impact on survival is unclear. In the retrospective ABMTR/ EBMT analysis mentioned above, no evidence of a graft-vs-lymphoma effect was seen.[6] Conclusions
Despite almost 20 years of clinical research, the role of stem cell transplantation is poorly defined. New studies of this approach will be required to compare transplantation with emerging therapies. It will be essential that these studies include homogeneous patient populations, with clearly defined histologic subtypes of NHL, and clearly defined prognostic factors at the clinical and molecular level.