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(Drug information on doxorubicin) [Adriamycin], vincristine [Oncovin], and prednisone(Drug information on 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(Drug information on etoposide) [Carmustine], ara-C, and melphalan(Drug information on 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.