SAN DIEGO--With the incidence of non-Hodgkins lymphoma (NHL) increasing throughout the United States, researchers have been searching for better ways to decrease the mortality rate of this cancer, which claims approximately 23,800 Americans each year.
Trials involving high-dose therapy and autologous stem cell transplant (HDT/ASCT) have shown promising results in these patients, said Arturo Molina, MD, of the City of Hope National Medical Center, Duarte, California.
"The results of most studies of high-dose therapy and stem cell transplantation in poor-risk NHL in first complete remission have been very encouraging, particularly in patients with high-intermediate and high-risk diffuse aggressive NHL," Dr. Molina said at the Sixth In-ternational Symposium on Recent Ad-vances in Hematopoietic Stem Cell Transplantation, sponsored by the University of California, San Diego.
The results of single-institution studies have produced excellent overall and event-free survival rates, ranging from 60% to more than 80% in first-remission patients with poor-risk features, he said. In contrast, survival for conventional anthracycline-containing regimens for the same type of patients is less than 50%.
So far, these results have come from several small pilot trials of HDT/ASCT in patients who have achieved complete remission.
Dr. Molina said that the International Prognostic Index (IPI) and the age-adjusted IPI can be used to identify patients with poor-prognosis aggressive lymphoma. This bad prognosis is due to an increased risk of death from both a lower complete response rate and a higher risk of relapse after a complete response.
Unfortunately, Dr. Molina said, most of the handful of randomized trials that have compared conventional chemotherapy with up-front HDT/transplant have not selected patients based on these poor-prognostic factors. Groups that have been pursuing research in this field include the Groupe dEtude Lymphomes de lAdulte (GELA) in France and researchers at Dr. Molinas own institution, the City of Hope.
The City of Hope recently reported the results of HDT/ASCT in 42 poor-risk patients with intermediate- and high-grade NHL in complete remission, who were classified into the IPI high and high-intermediate risk groups. Another 10 patients with poor-risk small noncleaved cell lymphoma also participated.
In the subset of patients with intermediate-grade and immunoblastic lymph-oma, the 3-year disease-free survival rates were 89% for all patients, 87% for high-risk patients, and 92% for high-intermediate risk patients. Based on these results, Dr. Molina said, "we are participating in a randomized cooperative group study, sponsored by the Southwest Oncology Group (SWOG), that will compare standard CHOP chemotherapy with the early use of HDT/ASCT as initial therapy for diffuse aggressive lymphoma."
Dr. Molina also discussed another important study in Europe that focused on relapsed non-Hodgkins lymphoma patients. The multicenter prospective PARMA trial showed a quite dramatic outcome difference between patients treated with a conventional salvage regimen vs HDT with autologous bone marrow transplant (BMT).
The 215 study patients had intermediate- or high-grade NHL and were in relapse after an initial remission with a doxorubicin(Drug information on doxorubicin)-containing regimen. Patients who responded to two cycles of DHAP (dexamethasone, cytarabine(Drug information on cytarabine), cisplatin) chemotherapy were then randomized into two groups. One received four more cycles of DHAP, while the other patients underwent high-dose therapy using the BEAC regimen (BCNU, cytarabine, cyclophosphamide(Drug information on cyclophosphamide)) with transplantation using unpurged bone marrow.
With a median follow-up of 63 months, event-free survival and overall survival were 46% and 53%, respectively, among patients receiving HDT/BMT, compared with just 12% and 32%, respectively, in the DHAP group.
This represented the first randomized trial in which high-dose therapy was shown to improve disease-free and overall survival, compared with a conventional salvage regimen, Dr. Molina said.
Mantle Cell Lymphoma
Not all the studies, however, have clearly favored transplantation and high-dose therapy. For instance, most of the phase II studies using HDT/ASCT in mantle cell lymphoma have produced inconclusive or mixed results.
One such study of 13 patients--9 were in either first complete remission or partial remission--has had a median follow-up of just 18 months. During that time, 10 patients were disease free.
The City of Hopes experience with the same type of patients has been similar, but longer follow-up is necessary to determine if there is a plateau in the disease-free-survival curve.
At the Dana-Farber Cancer Institute, a retrospective review of results of high-dose therapy with antibody-purged autologous BMT in 28 patients with mantle cell lymphoma found no evidence of long-term remission.
Small Noncleaved Cell Lymphomas
There also are few data on using transplants and high-dose therapy in patients with small noncleaved cell lymphomas. Because small noncleaved cell lymphomas and lymphoblastic lymphomas are rare in adults, Dr. Molina said that it will be very difficult to develop randomized studies to address unresolved treatment issues in these diseases.
In general, he recommends that high-dose therapy and stem cell transplantation--autologous or allogeneic--be offered to patients in their first complete response if they exhibit poor-prognostic features that put them at a high risk of relapse after treatment with conventional regimens.