It was not until 1995 that a phase III randomized trial demonstrated that autologous stem cell transplants (ASCT) improve the progression-free and overall survival of patients with relapsed refractory diffuse aggressive non-Hodgkin’s lymphoma. Investigators are now focusing on improving the clinical benefit of transplants. The relative contributions made by more intensive preparative regimens, purging, concomitant immunotherapy, and the timing of transplants are under study. Also, as transplant trials shift from relapsed disease to initial therapy, anticipated benefits must be balanced against both short-term and long-term toxicities.[ONCOLOGY 12(Suppl 8):56-62, 1998]
ABSTRACT: It was not until 1995 that a phase III randomized trial demonstrated that autologous stem cell transplants (ASCT) improve the progression-free and overall survival of patients with relapsed refractory diffuse aggressive non-Hodgkin’s lymphoma. Investigators are now focusing on improving the clinical benefit of transplants. The relative contributions made by more intensive preparative regimens, purging, concomitant immunotherapy, and the timing of transplants are under study. Also, as transplant trials shift from relapsed disease to initial therapy, anticipated benefits must be balanced against both short-term and long-term toxicities.[ONCOLOGY 12(Suppl 8):56-62, 1998]
Trials exploring high-dose chemotherapy for non-Hodgkins lymphoma first began in the mid-1970s. It was not until 1995, however, that autologous stem-cell transplants (ASCT) were shown to improve the progression-free survival and overall survival of patients with relapsed/refractory diffuse aggressive non-Hodgkins lymphoma in a phase III randomized trial. The benefits of transplant therapy may extend to selected patients with indolent non-Hodgkins lymphoma, with recent reports suggesting a role for transplants when incorporated into the initial therapy of patients with poor prognosis lymphoma.[1A]
Building on this theory, investigators are now focusing on four important areas of clinical research. They include: 1) improving cytoreduction with more intensive or targeted preparative regimens, 2) investigating the role of ex vivo purging, 3) re-exploring the benefit of allogeneic transplants, and 4) clearly defining the incidence of and risk factors for late complications after transplantation in myelodysplastic syndrome and acute nonlymphocytic leukemia (MDS/ANLL).
These four areas will become more important as transplant trials shift from relapsed disease to initial therapy, with anticipated benefits balanced against both short-term and long-term toxicities. This article focuses on these areas and reviews the current status of transplantation for both relapsed, diffuse aggressive, and indolent non-Hodgkins lymphoma.
For the initial management of advanced, diffuse aggressive non-Hodgkins lymphoma, CHOP chemotherapy (cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone) remains the best conventional regimen. Despite a high remission rate, however, the 3 to 5 year progression-free survival is only 40% to 50%. For those who fail or relapse after a remission, conventional salvage chemotherapy produces remissions in the 50% to 70% range, but long-term remissions are seen in £ 10% of patients.[3,4]
In early trials, ASCT for patients who failed initial therapy produced a 3 to 5 year survival rate of 15% to 50%, with outcome primarily related to prognostic factors present at the time of the transplant.[1,5-10] Among the most important prognostic factors was chemosensitivity immediately prior to transplant. For patients in this group failing induction therapy, 3 to 5 year survival was 0% compared to those patients with minimal chemosensitive disease in whom 3 to 5 year survival was 35% to 50%. The major cause for failure was relapse, with rates of 54% to 84%[1,5-7,9,10] and in those with chemosensitive first relapse (the best subpopulation), relapse rates were 35% to 54%.[8,11]
The PARMA Trial
To further define the benefit of transplant for patients with chemosensitive relapse, an international randomized trial (PARMA) was conducted. Patients who relapsed after a complete remission (CR), but who had no evidence of marrow involvement were randomized (if they responded to two cycles of DHAP chemotherapy [decedron, high-dose ara-C [Cytarabine], and cisplatinum]) to one of these two treatment groups: 1) continue DHAP for another four cycles with involved field radiotherapy for bulk disease, or 2) undergo autologous transplant using high-dose BEAM (BCNU, etoposide [Carmustine], ara-C, and melphalan [Chlorambucil]), plus involved field radiotherapy for bulk disease.
Patients who were randomized to transplant had a significantly higher response rate (84% vs 44%), and event-free (46% vs 12 %) and overall (53% vs 32%) survivals at 5 years. Because those randomized to chemotherapy had the opportunity to undergo a transplant after their second relapse, the improvement in survival suggests that transplants should be performed after first relapse to be maximally beneficial.
A recent update and analysis of outcome using the age-adjusted international prognostic factor index (IPI), demonstrated that for patients treated with chemotherapy alone, there is a progressive decline in disease-free survival with increasing IPI stage. Patients in risk group 0 had a 36% 8-year survival rate, whereas those in risk groups > 0 had a survival rate of 20%. In contrast, no difference in survival based on IPI was seen in the transplant group; patients in risk group 0 had an 8-year survival of 47% vs 49% in risk groups > 0. The data also suggest that for the 0 risk group, either transplant or chemotherapy is acceptable, although these data should be considered preliminary because the number of patients in the two groups is small.
Transplants in Chemotherapy-Resistant Disease
While it is clear that ASCTs are of value for those with chemosensitive relapse, the percent of patients with chemotherapy-resistant disease who survive long-term is only 10% to 20%. Outcomes for patients failing induction therapy have been reported to be even worse with essentially no survivors beyond 1 year. However, with improved conventional second-line chemotherapy, this appears not always to be the case.
In particular, we recently reported that a subgroup of patients failing induction therapy may have a significant long-term survival if they respond to first salvage therapy. In this retrospective analysis, responding patients transplanted with less than 1 cm of residual disease had a 2-year survival of 86% vs 7% for those with residual disease greater than 1 cm. Thus, it appears appropriate to treat induction failures with aggressive chemotherapy at the time of failure. If a significant response is seen, a transplant should be offered; if not, investigational approaches should be tested.
For patients who relapse but do not respond to salvage chemotherapy (resistant relapse), transplants may be of benefit to some.[1,5-7,9] However, when treated with conventional preparative regimens, less than 20% will survive long-term.[5,6,7,9] Low tumor bulk does not appear to improve prognosis for these patients, and those with aggressive disease, ie, those who respond then regrow tumors between cycles of salvage chemotherapy, are unlikely to benefit. As discussed further, more intensive preparative regimens may be of value for this patient group.
Follicular low-grade non-Hodgkins lymphoma accounts for 15% to 30% of all lymphomas. While the median survival for this patient group is approximately 7 years, for the vast majority of patients this tumor type is incurable with conventional chemotherapy.[14,15] In fact, given that the overall survival for this group has changed little over the past 15 to 20 years, it is probable that modern chemotherapy regimens administered early in the course of the disease only improve disease-free survival but not survival, as compared to observation.
Because of its long natural history, most trials of ASCT have been performed in patients who relapsed following conventional chemotherapy and while there have been no randomized comparative trials such as the PARMA trial in indolent non-Hodgkins lymphoma, some conclusions can be reached.[16-18] Compared to conventional salvage chemotherapy, there appears to be a significant difference in progression-free survival after transplant with 40% to 45% of patients progression free at 5 to 8 years for transplant vs 20% for chemotherapy. While the differences in progression-free survival appear real, the differences in overall survival are less impressive, at least for the typically short follow-up of most trials. The majority of transplant studies report a median overall survival of approximately 5 years, but show no evidence of a plateau for as far as 8 years following transplant.
While the data do suggest an improvement in survival when compared to survival with conventional approaches (2 to 3 year median survival), the median age for most transplant studies is significantly lower than that of unselected patients. At some centers, only patients with minimal bulk and marrow involvement are eligible for studies. In fact, in patient groups that include only a few patients transplanted with minimal residual disease, the majority will relapse within 2 years after transplant. When compared retrospectively to patients who were age and remission controlled, there did not seem to be a survival advantage for transplant vs best conventional therapy as reported by Rohatiner et al.
Transplants in Those Failing Initial Chemotherapy
However, the data from Dana-Farber showing an estimated survival of 70% at 12 years following transplant does suggest a role for ASCT for patients in whom initial chemotherapy fails (when patients are followed beyond 8 years). Their median follow-up is longer than that reported by Rohatiner et al, and in fact, the survival curves for the two treatment options in the Rohatiner comparison may diverge beyond 8 years post-transplant as well.
Prognostic factors for poor outcome following ASCT for indolent non-Hodgkins lymphoma include chemoresistant disease and the number of prior chemotherapy regimens. Also, some centers report the presence of the bcl-2 translocation as a measure of residual disease in the marrow to be an important prognostic factor for progression-free survival. The likelihood of a negative assay is greater early in the course of the disease when long remissions are sometimes seen with conventional therapy, although purging involved marrows to negativity also appears to be of prognostic significance.
Like diffuse aggressive non-Hodgkins lymphoma, the optimal time to consider an ASCT for indolent non-Hodgkins lymphoma is at the time of first relapse when there is minimal bulk disease, and bcl-2 negativity prior to transplant.
While data from several sources indicate no difference in transplant outcome with total body irradiation (TBI) vs selective irradiation with standard preparative regimens, several reports have suggested that intensification of the preparative regimen might decrease the number of relapses seen following transplant.[19-23] In particular, in patients with chemosensitive disease, the addition of etoposide to the standard preparative regimen of cyclophosphamide and TBI has, in several reports, been associated with a lower relapse rate of 3% to 30% compared to 35% to 54%.[19-22] In these reports, however, it is not clear whether the improvements were due to the preparative regimen, better supportive care, or more optimal patient selection. To further evaluate this strategy, the Southwest Oncology Group (SWOG) conducted a prospective phase II trial of a cyclophosphamide, etoposide (VePesid), and TBI preparative regimen in patients with persistent or recurrent intermediate and high-grade non-Hodgkins lymphoma.
This regimen, which had previously been tested in several variations by Gulati, Horning, and Weaver et al, formed the basis for the SWOG trial.[19,21,22] Survival improvements seemed to be the result of a decrease in the number of relapses, with the lowest relapse rate (7%) associated with an augmented regimen as reported by Gulati et al. In their series of unselected patients with recurrent non-Hodgkins lymphoma who received concomitant etoposide and cyclophosphamide after TBI, a 57% disease-free survival was achieved at a median follow-up of 42 months. The toxic death rate was 30%, however, due in large part to pulmonary complication that developed and appeared to be correlated to pretransplant boost RT to the mediastinum in a substantial number of these poor risk patients.
Horning et al initially reported a 76%, 2-year event-free survival for the same regimen as the one used in the SWOG trial, which appeared superior to retrospective controls. A recent follow-up at 3 years showed a progression-free survival of 53%.
Finally, in an early study of 101 unselected patients with lymphoma, the Seattle group reported an 11% 5-year progression-free survival using a standard preparative regimen. They recently achieved a 2-year event-free survival of 45% in 53 unselected patients treated with a TBI, and a cyclophosphamide and etoposide regimen. The relapse rate was only 30%. Their chemosensitive disease subgroup had better results with a 2-year event-free survival of 61% and a relapse rate of 34% (compared to an event-free survival of 35% for those treated in the earlier trial). The chemoresistant group also fared bettertheir event-free survival rose from the 17% reported in the earlier trial to 31%.
The SWOG Trial
As in the PARMA trial, all patients entering the SWOG trial who relapsed after a remission were required to undergo salvage chemotherapy to determine chemosensitivity prior to transplantation. For patients with a contraindication to TBI, a similar regimen that substituted high-dose BCNU (Carmustine) for the TBI was used. The median 3-year progression-free survival and survival rates for the chemosensitive group were 42% and 55%, respectively, and for patients with resistant disease, the progression-free survival and survival rates were 22% and 29%. The results of this multi-institutional trial are similar to those seen in the pilot studies, with the best improvements compared to historical controls in patients with chemoresistant disease.
Despite the added toxicity, as manifested in particular by a high rate of severe mucositis, the overall death rate in this study of 10.3% was low considering the use of autologous bone marrow as the transplant source and the fact that this was a multicenter trial. In fact, the number of treatment-related deaths in this study was similar to the 9% death rate seen in the earlier multicenter SWOG trial of cyclophosphamide and TBI only. The results for those patients with chemoresistant disease and particularly for those who failed induction chemotherapy are among the best reported to date, including the previous SWOG trial in which the 3-year progression-free survival was only 8% for chemoresistant disease.
Seattle Sequential Pilot Series
Without a randomized comparison, the survival improvement could be due to either the preparative regimen as documented by a lower relapse rate, or to better supportive care that was available during the early 1990s when this trial was being performed. However, a lower relapse rate was seen with the more aggressive regimen in patients with chemoresistant disease treated in the sequential pilot series from Seattle.[6,22] In these studies, patients with resistant disease had an early mortality rate of 22% in the earlier trial and a 25% rate in the cyclophosphamide/TBI plus etoposide trial, but had a near doubling of event-free survival to 31%identical to that seen in the SWOG trial.
Better supportive care was also likely a factor in patients with chemosensitive disease in these trials. A regimen-related mortality rate of 19% was seen in the earlier study with only an 8.3% mortality rate for the cyclophosphamide/TBI plus etoposide regimen, which explains at least some of the improvement in the 2-year event-free survival from 35% to 61%.
One possible explanation for the apparent improvements in chemoresistant disease but not in chemosensitive disease with the more aggressive regimens may be the significant changes in the salvage therapy for patients with diffuse aggressive non-Hodgkins lymphoma. Over the past 5 to 7 years, the availability of hematopoietic growth factors and newer, and more aggressive therapies have resulted in a minimal residual disease state prior to transplant. Thus, a greater percentage of patients may now be designated as "chemosensitive" at the time of transplant compared to the percentage thus designated among those treated earlier, yet significant populations of drug-resistant cells may still remain. Transplantation of this group with a standard regimen now may not yield the same results as those achieved in the earlier trials of sensitive disease. An augmented regimen, however, may yield the same results, but a true assessment of the usefulness of these augmented preparative regimens can only come from a randomized, clinical trial.
Augmented Regimens Too Toxic?
Given the toxicity of these augmented regimens, it is unlikely that a more effective TBI-based or chemotherapy-only preparative regimen will be developed that will reduce relapses following transplantation. While the use of mobilized peripheral blood stem cells has proven to reduce the pancytopenic period following autotransplants, the acute or toxic death rates have not been reduced in trials using this strategy. The fact that in this multicenter trial the acute death rate due to infectious causes was only 6.3% would support this fact.
To address this issue of relapses following autotransplants, SWOG is currently performing a phase II trial using the same cyclophosphamide/TBI plus etoposide preparative regimen, followed by a randomization to either observation or a 19-day course of intensive interleukin 2 (IL2) therapy. Use of IL2 is based on its preclinical activity in stimulating the production of activated lymphocytes against lymphoma cells, and the demonstration of its modest activity when infused into patients with lymphoma and leukemia. Fefer and colleagues treated 17 patients with non-Hodgkins lymphoma with either IL2 or IL2 plus lymphokine activated killer cells in an initial pilot trial. Nine were in complete response at a median follow-up of 29 months. Despite the fact that the majority had resistant disease.
Another promising method that may reduce both the toxicity of the preparative regimens currently used and decrease relapses is the use of ablative doses of I131 labelled anti-CD20 (B1) antibodies.[28-31] In the recently published phase II trial of this therapy, Press et al report a 62% progression-free survival rate for a group of 22 patients at a median follow-up of 2 years.
The importance of infusing tumor cell-free grafts into patients with non-Hodgkins lymphoma remains controversial. It appears that the infusion of tumor-free grafts as measured by either clonogeneic assays in diffuse aggressive non-Hodgkins lymphoma or by polymerase chain reaction (PCR) analysis of bcl-2 in indolent lymphoma is associated with an improved prognosis. Sharp et al described a unique clonogeneic assay to detect minimal residual disease in patients with intermediate or high-grade non-Hodgkins lymphoma. They reported that the disease-free survival at 3 years was only 5.5% for those with detectable cells compared to a 35.7% disease-free survival in these who were culture negative.
The assay is difficult to perform, and requires weeks to complete. It also requires human spleen-conditioned media samples whose potency varies from batch to batch. Yet these colonies have been verified as being malignant by PCR techniques after their culture. Whether the poor prognosis their detection reflects is due to re-inoculation after the preparative regimen or an epiphenomena remains undetermined.
Similar results have been achieved in studies examining minimal residual disease in patients with low-grade non-Hodgkins lymphoma, as detected by PCR for bcl-2. A recent analysis of patients undergoing ASCT using unpurged cells reported a better clinical outcome for those with negative grafts who had undergone transplant. This type of data led the Dana-Farber group to extensively evaluate purging using a combination of three anti-B cell monoclonal antibodies and complement in patients with indolent non-Hodgkins lymphoma.[16,31] Their results indicate that those who were purged to negativity had an improved progression-free survival.
To Purge or Not To Purge
Again the question remains whether the improvements in survival are due to the purging effects. Insufficient data are currently available to answer the question. Data indicating that purging may not be important come from several sources. Some patients treated by the Boston group and others reported elsewhere  indicate that prolonged survival with negative marrow exams for bcl-2 is possible even though patients are transplanted with contaminated grafts. These data suggest that in some patients the reinfused cells have limited survival capacity once infused after cryropreservation. In addition, several centers report survival results that appear to be similar to the results achieved in studies using purged cells, or cells purged but not to PCR negativity.
Recently, the European Blood and Marrow Transplant group analyzed a group of 224 patients who had undergone transplantation using bone marrow purged prior to transplant. These patients were compared to 224 patients who were matched for prognostic factors. The overall survival rate for the two groups at 5 years was equivalent (54% in purged patients vs 48.3% in unpurged), and there was also no difference in progression-free survival. However, the purging techniques used in this comparison for a large proportion of the patients were unlikely to purge more than two to three logs, (less than probably needed to return tumor-free grafts back to the patients, and less than routinely seen by the Dana Farber group using their monoclonal antibody cocktail). The true value of purging can only be determined in a randomized trial.
CD34 selection combined especially with a negative selection for lymphoid cells, is a potentially easier method of B-cell depletion in autografts that could produce tumor cell depletion similar to that achieved with monoclonal antibody cocktail with complement. If successful in eliminating minimal residual disease in the autografts, it would be of benefit to explore its efficacy in a randomized phase III trial.
Allogeneic transplants from matched sibling donors have been shown to occasionally produce a long-term disease-free survival in patients with either diffuse aggressive or indolent non-Hodgkins lymphoma who were in resistant relapse or who failed an ASCT.[34,35] The rationale for their use is the possibility of a significant graft vs lymphoma effect, which becomes the major antitumor component of the transplant. In the largest series to date, the Seattle group demonstrated a lower incidence of relapse after an allogeneic vs an autologous transplant. However, given the higher mortality rate due to graft-vs-host disease and opportunistic infections, the overall survival for those undergoing an allogeneic transplant was similar to that of those undergoing an autologous transplant (20%).
For patients with chemosensitive relapsed disease, a similar result was reported with lower rates of relapse again offset by higher rates of lethal complications. Reporting on 26 patients, for example, including 11 with high-grade lymphoma, Soffier found a 53% event-free survival at a median follow-up of 30 monthssimilar to the results of the PARMA trial. With improvements in the management of opportunistic infections and graft-vs-host disease, transplants using matched sibling donors in the under age 30 years group will likely be performed more frequently especially in those with chemotherapy resistant relapse. In otherwise healthy young patients with relapse after an ASCT, an allogeneic BMT is the only possibility for long-term disease-free survival.
Application of Allogeneic Transplantation
Given the high rates of bone marrow involvement in patients with indolent non-Hodgkins lymphoma, it would seem logical to use allogeneic transplantation more often for this group of patients. However, because of the high median age of this group, the number of transplants performed has been limited. To date, the same results and complications as those seen in intermediate- and high-grade non-Hodgkins lymphoma are observed in this patient group.[37-39] Based on the encouraging results in 10 patients with low-grade non-Hodgkins lymphoma treated at M. D. Anderson, an analysis of the 68 patients reported to the International Bone Marrow Transplantation Registry (IBMTR) was done.
The treatment-related mortality for the group was 42%. However, considering the poor prognostic features of these patients, the relapse rate was low at 24% and the 3-year disease-free survival was 44%. Unlike with ASCT, of the 18 patients surviving disease-free for > 2 years, only one relapsed. Additionally, the EBMT reported on 37 allogeneic transplantations for chemosensitive relapse, comparing them to 504 patients undergoing ASCT. The overall survival was better for the autologous group; however, for high-grade non-Hodgkins lymphoma there was no difference in survival. Thus, the recommendations for allogeneic transplantation for indolent non-Hodgkins lymphoma are similar to those for intermediate-grade non-Hodgkins lymphoma. Prior therapy with fludarabine is suggested to lower the incidence of graft-vs-host disease and thus make allogeneic transplants an attractive alternative for those with gross contamination of the marrow, those with disease > 2 cm, or those who have had multiple relapses.
Along with the increased use of transplantation therapy for relapsed and refractory non-Hodgkins lymphoma has come an increased awareness of late hematopoietic stem-cell damage including MDS/ANLL. As transplants are being increasingly performed in high-risk patients as part of initial therapy, it is clear that the factors associated with these conditions need to be elucidated. Several recent reports document an incidence of MDS/ANLL from 4% to 7.6%. However, the actuarial risk increases significantly over time to as high as 18% at 6 years.[40-41] Not unexpectedly, most of the chromosomal abnormalities seen involve chromosomes 5 and 7.
The question that remains unanswered is what influence the amount of pretransplant therapy and the preparative regimen have on the incidence of these disorders. Prognostic factors for the development of MDS/ANLL include older age, prior pelvic radiotherapy, the total amount of prior chemotherapy, and thrombocytopenia pretransplant, which suggest pre-existing stem-cell damage as the major cause. Indeed, patients with non-Hodgkins lymphoma are at risk of developing MDS/ANLL without transplant in a similar percentage to that of long-term survivors. The incidence of MDS/ANLL is rare after allogeneic transplants using TBI-containing regimens. In addition, using the Human Androgen Receptor Assay (HUMARA), an X-inactivation base clonality assay, Mach-Pascual et al found evidence of clonal hematopoiesis pretransplant in 3 out of 104 cases.
Several studies have, however, implicated the use of TBI-based preparative regimens, and patients have been described who developed their MDS/ANLL following treatment with this type of preparative regimen in an ASCT used to consolidate first remissions. However, the number of cases is still too small to draw final conclusions. For example, in the Nebraska series, where only patients over the age of 40 who received TBI at the time of their transplant were at a potentially higher risk of MDS/ANLL (P = .06), only 6 cases of MDS/ANLL were seen in 262 patients with non-Hodgkins lymphoma; no such effect was seen in patients under the age of 40. Nevertheless, damage to endogenous stem cells or the marrow microenvironment that may survive TBI could be important cofactors in the genesis of post-transplant MDS/ANLL.
The possible link between the preparative regimen and the development of MDS/ANLL must be balanced against any possible benefit to TBI containing regimens. In the Nebraska series, the failure-free survival appears to be slightly better for those with indolent lymphoma who received the TBI-containing regimen than of to those who received non-TBI-containing ones (P = .07).
Since patients transplanted with histologically normal marrow in whom an occult clonal abnormality is seen do develop MDS/ANLL, it is appropriate for at least high-risk patients (ie, over the age of 40) with thrombocytopenia or prior involved-field radiotherapy to undergo chromosomal analyses on pretransplant screening marrows. However, given the increasing use of this therapy for patients in early stages of their disease, efforts at determining the role of the preparative regimen (which as noted above may be less critical for chemosensitive disease), is critical. The HUMARA assay may be one such assay and has in a single-institutional study been predictive of the development of MDS/ANLL.
Efforts for improving the clinical benefits of transplant in non-Hodgkins lymphoma are in progress on many fronts. The relative contributions of more intensive preparative regimens, purging, concomitant immunotherapy, and the timing of transplants are currently being investigated. With improvements in allogeneic transplantation, including the availability of unrelated marrow or cord blood transplants, there will probably be an increase in the number of this type of transplant, particularly in young patients with chemoresistant disease. The risk of MDS/ANLL should not be a significant issue for patients with recurrent disease, however, it may be a major concern if MDS/ANLL occurs at similar rates in patients who receive early transplants.
Studies that include transplants as part of initial therapy or those that compare transplant regimens will need to prospectively determine the relative contributions of the pretransplant and the transplant therapy on the genesis of these disorders. Assays of clonality such as the HUMARA assay performed longitudinally will also likely be of value. As before, lessons learned from these studies of patients with non-Hodgkins lymphoma will translate into benefits for patients undergoing transplants for other hematologic and non-hematologic disorders.
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