Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma
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. Future
studies may provide pharmacogenomic
data, which could predict
response to therapy in individual patients,
and thus allow a more tailored
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 (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.
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.
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 HCl, vincristine [Oncovin], 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. 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. 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, vincristine, doxorubicin [Adriamycin], dexamethasone) and rituximab 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. 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.
2. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 346:235- 242, 2002.
3. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268- 276, 1999.
4. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non- Hodgkin’s lymphoma. J Clin Oncol 20:4261- 4267, 2002.
5. Schouten HC, Qian W, Sydes MR, et al: High dose therapy improves progression free survival in relapsed follicular non-Hodgkin’s lymphoma (NHL): Results from the randomized European CUP trial (abstract). Ann Oncol 13(suppl 2):26, 2002.
6. Bierman PJ, Sweetenham J, Loberiza F, et al: Syngeneic hematopoietic stem cell transplantation for non-Hodgkin’s lymphoma (NHL): Comparison with allogeneic and autologous transplants suggests a role for purging (abstract 15). Proc Am Soc Clin Oncol 20:5a, 2001.
7. Horning SJ, Negrin RS, Hoppe RT, et al: High dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: Results of a phase II clinical trial. Blood 97:404-409, 2001.
8. Romaguera JE, Dang NH, Hagemeister FB, et al: Preliminary report of rituximab with intensive chemotherapy for untreated aggressive mantle cell lymphoma (MCL) (abstract 3170). Blood 96:733a, 2000.