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Transplant in First Remission Holds Off Progression in Non-Hodgkin's Lymphoma


 

FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

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