High-Dose Therapy With Stem-Cell Transplantation in the Malignant Lymphomas
High-Dose Therapy With Stem-Cell Transplantation in the Malignant Lymphomas
ABSTRACT: High-dose therapy with hematopoietic progenitor-cell transplantation plays a key role in the treatment of Hodgkin’s disease and the non-Hodgkin’s lymphomas. First and foremost, transplantation is used as a salvage treatment for those who relapse or do not achieve a complete remission with first-line chemotherapy. Carefully selected patients with poor prognostic features may benefit from the incorporation of high-dose therapy and transplant into their initial treatment programs. Despite a myriad of trials, many pivotal questions regarding the appropriate application of high-dose therapy with transplantation to the lymphoid malignancies remain unsettled, including the role of allogeneic transplantation and the optimal timing of transplant for patients with poor prognostic indicators. Phase III studies are required to address these issues; these trials will demand the active commitment of concerned transplanters and referring hematologists and oncologists. Although autologous transplantation has been the preferred approach for the majority of patient subgroups, new approaches to allogeneic transplantation that have diminished toxicity may pave the way for a greater role for allogeneic grafting in the lymphoid diseases. [ONCOLOGY 13(12):1635-1645, 1999]
Exquisitely sensitive to chemotherapy or irradiation, malignant lymphomas are characterized by steep dose-response curves that make them prime candidates for the use of dose-intensive therapies. High-dose treatment with hematopoietic progenitor-cell transplantation, therefore, plays a central but ever-changing role in the treatment of these neoplasms.
Therapeutic paradigms for malignant lymphomas continue to evolve. For example, the use of mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP) for the initial treatment of advanced Hodgkin’s disease has given way to combinations of MOPP and Adriamycin, bleomycin, and vinblastine, with or without dacarbazine (ABV[D]), and, most recently, to ABVD alone. Changes in the approach to initial treatment, the diminishing morbidity and mortality for high-dose therapy, and the recognition of long-term complications, such as myelodysplasia, have caused experts to continually rethink the optimal role of high-dose therapy with transplantation in the treatment of malignant lymphomas.
The lymphoid malignancies represent a heterogeneous group of diseases; high cure rates with standard regimens are the rule for some patients, while a pattern of repeated relapses is the expected outcome for others. Consistent with the clinical, morphologic, and biological heterogeneity of these diseases, success rates with high-dose therapy plus hematopoietic progenitor-cell transplantation vary.
The establishment of the International Prognostic Index for the non-Hodgkin’s lymphomas and a similar panel of clinical prognostic indicators for Hodgkin’s disease has helped identify patients destined to be unresponsive to conventional therapies, who may benefit from alternative approaches, including high-dose therapy with hematopoietic progenitor-cell grafting.[1,2] Similarly, many groups have tried to determine parameters that are predictive of outcome with transplantation. These tools help identify subgroups of patients within larger series for whom the expected results of therapy differ.
Disease status is one of the more important prognostic indicators. As a result, patients who respond completely to initial therapy (complete remitters), those who have only a partial response (partial remitters), and those who have primary refractory disease or relapsed disease should be considered separately whenever possible. Given the differences in biological behavior, the individual pathologic entities are best discussed individually, with subset analysis according to prognostic features when feasible.
For patients who suffer a relapse after first achieving a complete remission, the prognosis with conventional salvage therapy is directly related to the duration of the initial remission. The outcome for patients whose remission lasted less than 1 year is dismal with standard-dose second-line treatment, and most experts concur that these patients are best treated with high-dose therapy plus hematopoietic progenitor-cell transplantation. Approximately 40% to 50% of patients with Hodgkin’s disease who suffer a relapse within 1 year may be effectively treated with transplantation.[5-10]
For patients whose first remission lasts for more than 1 year, conventional-dose chemotherapy may provide a durable second remission. This is the case regardless of whether the primary therapy was MOPP, ABVD, or MOPP/ABVD. Deaths due to second malignancies and other cumulative toxicities of the treatment limit survival, which ranges from 28% to 47%, depending on the series and length of follow-up.[4,5]
Investigators at Stanford matched patients who underwent high-dose therapy and transplantation for relapsed or refractory Hodgkin’s disease to a group of patients with similar characteristics who were treated conventionally. For patients with an initial remission lasting more than 12 months, a statistically significant advantage to transplantation could not be demonstrated. Overall, the most significant predictor of outcome in this analysis was response to cytoreductive therapy.
These findings contrast with results reported by the Vancouver group; their multivariate analysis showed that the length of complete remission was predictive of progression-free survival. Longer follow-up may allow a difference in survival to emerge in the Stanford data.
Neither of the two randomized trials comparing high-dose therapy with autologous transplantation to conventional salvage chemotherapy in patients with relapsed Hodgkin’s disease demon-
strated a difference in overall survival among patients undergoing transplantation.[11,12] In the first of these studies, Linch and colleagues compared high-dose BEAM (BCNU, etoposide, ara-C, and melphalan) therapy with hemato-
poietic progenitor-cell transplantation to mini-BEAM salvage therapy in a small number of patients with relapsed or resistant Hodgkin’s disease. Accrual was terminated prematurely because patients refused to undergo randomization and, instead, requested high-dose therapy with transplantation. Notably, patients who underwent autologous transplantation had statistically greater event-free and progression-free survival rates. Overall survival rates were the same in the two groups.
A subsequent trial, conducted by the German Hodgkin’s Disease Study Group and the European Group for Blood and Marrow Transplantation (EBMT) and reported in abstract form, randomized a larger number of patients with relapsed but chemosensitive disease to receive either additional standard-dose therapy or high-dose therapy with hematopoietic progenitor-cell transplantation. Time to treatment failure was significantly longer with autologous transplantation (P = .04), regardless of the interval to relapse, but again, overall survival was not improved.
Summary—Given the apparent preference of patients and physicians for autologous transplantation when conventional therapy has failed, it is extremely difficult to accrue patients to randomized trials. As transplant-related morbidity and mortality decline, an advantage may emerge for the high-dose approach in all patients who relapse, regardless of the duration of remission.
Currently, ABVD is preferred over MOPP or a MOPP-like regimen for the initial treatment of Hodgkin’s disease. Although the occurrence of secondary myelodysplasia following transplantation may become less common with the use of the ABVD regimen for first-line treatment, cardiopulmonary complications may occurr more frequently. At present, each patient must be evaluated on an individual basis, and the immediate and long-term risks and benefits of both high-dose therapy with transplantation and salvage chemotherapy must be weighed judiciously.
Patients with refractory Hodgkin’s disease, unlike those with refractory non-Hodgkin’s lymphoma, may achieve durable complete remissions with high-dose therapy and hematopoietic progenitor-cell transplantation.[13-15] Numerous series, including that from the Autologous Blood and Marrow Transplant Registry (ABMTR), demonstrate that high-dose treatment, either chemotherapy alone or combined with radiotherapy, can overcome drug resistance in Hodgkin’s disease.
In the ABMTR analysis, patients were considered to have primary refractory Hodgkin’s disease if they never achieved a complete remission; evidence of progression on radiologic studies or tissue confirmation of disease was required. Following transplantation, the probability of 3-year progression-free survival was 38%, with an overall survival rate of 50%. Survival following transplant was inversely related to the presence of B-symptoms at diagnosis and Karnofsky performance status (< 90%) at the time of transplant.
Results from the EBMT were similar to those from the ABMTR. The European group reported an actuarial 5-year disease-free survival rate of 30% and an overall survival rate of 34%.
Summary—Overall, patients with refractory Hodgkin’s disease benefit from high-dose therapy with progenitor (stem)-cell transplant. Pathologic documentation of residual disease is strongly recommended prior to transplantation, as diagnostic errors are often uncovered when patients do not have the expected response to treatment.
Autologous Transplantation as Part of Initial Therapy
In an attempt to increase overall cure rates for patients with Hodgkin’s disease, some centers have begun using autologous transplantation as part of the initial treatment plan for selected patients believed to have a poor prognosis. The results of pilot studies of this approach have been excellent, perhaps reflecting the inclusion of patients with relatively favorable prognoses.[16-19]
Recently, an international effort sought to identify prognostic factors among untreated patients with Hodgkin’s disease. This project, which included data on nearly 5,000 patients, has identified seven key prognostic factors (albumin, hemoglobin, gender, age, stage, leukocytosis, and lymphocytopenia). Patients with three or more of these factors are believed to be at high risk of relapse (with a 5-year freedom from progression rate of 55% to 60%).
This prognostic index will be used to establish eligibility for an intergroup trial that is soon to be launched in the United States. This trial will randomize patients who respond to ABVD induction therapy to either (1) continued conventional-dose treatment or (2) high-dose therapy with hematopoietic progenitor-cell transplantation (Figure 1).
The results of an ongoing European trial comparing autologous transplantation and conventional therapy in responding patients with advanced Hodgkin’s disease will also be of interest, although this study is using different prognostic indicators (high lactic dehydrogenase, mediastinal mass > 45%, more than one extranodal site, low hematocrit, and inguinal involvement) to determine eligibility.
Patients with adverse prognostic indicators at the time of diagnosis constitute a small fraction of all patients with Hodgkin’s disease, making it even more important that all eligible patients be enrolled in the randomized trials.
Allogeneic transplantation appears to offer little benefit at the cost of great toxicity in the majority of patients with relapsed or refractory Hodgkin’s disease.[21-23] Most patients who have undergone allogeneic transplantation have been heavily pretreated.
In the Seattle series, relapse rates were lower in patients treated with allogeneic transplantation than in those who underwent autologous transplantation (45% vs 76% at 5 years; P = .05), suggesting the presence of a graft-vs-lymphoma effect. Nonetheless, survival, event-free survival, and mortality due to factors other than relapse did not differ significantly between the two groups.
In the International Bone Marrow Transplant Registry (IBMTR) series, the 3-year probability of relapse was comparatively high (65%), perhaps reflecting the particular patient population selected for allogeneic transplantation. The disease-free survival rate at 3 years was only 15%.
In a case-matched study reported by the EBMT, allogeneic transplantation from a human leukocyte antigen (HLA)–identical sibling donor was also associated with high relapse rates, except in patients with grade 2 or higher acute graft-vs host disease. Although the graft-vs-host reaction appeared to have a suppressive effect on relapse rates, its potential benefits were more than offset by toxicity.
Summary—Allogeneic transplantation seems to be of little benefit in most patients with relapsed or refractory Hodgkin’s disease. There remains a small group of individuals with myelodysplasia, however, for whom allogeneic transplantation may be the only alternative. Otherwise, autologous transplantation remains the preferred approach. New approaches to reducing the toxicity associated with allogeneic transplantation and its application earlier in the clinical course may prompt a reconsideration of this recommendation in the future.