Early autologous stem cell transplantation might improve survival in high-risk lymphoma patients during their first remission.
The 2-year overall survival rate was 82% in the highest-risk patients who received "up-front" transplantation, according toresearch published in the October 31 issue of the New England Journal of Medicine.
Early autologous stem cell transplantation improved progression-free survival in patients with high-intermediate-risk and high-risk diffuse large B-cell lymphoma. However, overall survival improved only in the high-risk group.
For the high-intermediate-risk and high-risk populations combined, there was no benefit to early transplantation, said lead author Patrick J. Stiff, MD, in an audio file released by his institution. When a retrospective analysis of the 2 populations was conducted separately, there was still no benefit for the high-intermediate-risk patients.
Those with the highest International Prognostic Index (IPI) score or the poorest prognosis had, "at the end of the day, an 18% improvement in survival at 2 years," said Dr. Stiff, who is Coleman professor of oncology and director of the cancer center at Loyola University Medical Center in Maywood, Illinois.
"This needs to be carefully considered because it was not a prospectively determined analysis," he explained. "But the difference is there, and patients were stratified based on their risk category, giving a little more credibility to the results. We feel that the 18% difference in survival will trigger discussions between patients and their physicians as to the feasibility of doing a transplant in first remission or waiting until they relapse."
It has been established that autologous stem cell transplantation can improve both progression-free and overall survival in patients with diffuse, aggressive non-Hodgkin's lymphoma who are in second remission. Dr. Stiff explained that the idea of evaluating transplantation in first remission "came from the notion" that they improved the survival of patients who had gone into remission but ultimately relapsed. Survival was better in patients who underwent second-line autologous transplantation than in those who received chemotherapy.
"Only about 60% of patients with diffuse aggressive lymphomas are cured with therapy," Dr. Stiff said. "So why wait for them to relapse? If autologous transplantation is effective, why not use it as first line?"
In a previous analysis, no survival advantage was found with transplantation, but a retrospective subgroup analysis showed improved progression-free and overall survival in patients with high-intermediate-risk or high-risk disease (J Clin Oncol. 2000;18:3025-3030).
Remains Unresolved
At least 3 other randomized trials have shown no obvious benefit with early myeloablative treatment, notes Noel Milpied, MD, from the Department of Hematology and Cell Therapy, University Hospital and University of Bordeaux, France, in an accompanying editorial. However, the designs used in those studies were different than that used by Dr. Stiff and colleagues.
"The value of this treatment for aggressive, diffuse large B-cell lymphoma therefore remains unresolved," he writes. "It is clear only that such treatment is feasible — but at the price of greater toxicity than that associated with the current standard treatment."
In the future, "it should be possible to better select patients for enrollment in trials of early myeloablative therapy, and that selection should not be based simply on the IPI risk category," he says. "We must identify patients at highest risk for nonresponse to standard treatment (about 15% of patients) and those at highest risk for relapse (about 25% of patients), so that they can be given alternative treatments; we must also give patients without these risk factors an excellent chance of cure with easier-to-administer and less toxic chemotherapeutic agents."
Dr. Milpied adds that an increased understanding of the biologic complexity of these lymphomas has revealed the diverse range of oncogenic driver mutations and signaling pathways that are essential for the growth and survival of malignant cells, opening the door to possible treatment with new targeted agents.
But it remains to be proven if these new therapies will "challenge myeloablative therapies for the aforementioned patients with a poor prognosis, and obtaining proof will necessitate clinical trials in which patients should be encouraged to participate," he concludes. "Until these questions are answered, early myeloablative therapy, a 20th-century therapeutic innovation, remains an option for patients carefully selected with the use of 21st-century risk criteria."
Study Details
In their study, Dr. Stiff and colleagues treated 397 patients who had high-risk or high-intermediate-risk diffuse large B-cell lymphoma with 5 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or with CHOP plus rituximab. Those who responded were randomized to receive 3 additional cycles of induction chemotherapy (control group) or 1 additional cycle of induction chemotherapy followed by autologous stem cell transplantation.
The primary efficacy end points were 2-year progression-free and overall survival.
Overall, 46 of the 125 patients in the transplantation group and 68 of the 128 patients in the control group had disease progression or died.
Estimated 2-year progression-free survival was better in the transplantation group than in the control group (69% vs 55%). The hazard ratio for progression or death was 1.72 in the control group (P = .005).
Median progression-free survival from initial registration was not reached in the transplantation group and was 2.8 years in the control group.
At a median follow-up of 6.3 years, 37 patients in the transplantation group and 47 in the control group had died. Estimated 2-year overall survival rate was similar in the 2 groups (74% vs 71%; hazard ratio, 1.26; P = .30). Median overall survival from initial registration was not reached in either group.
Treatment after Relapse
Of the 62 (48%) patients in the control group who had a relapse, 29 (47%) underwent salvage chemotherapy and transplantation. A total of 18 (29%) patients in the control group who had a relapse survived without disease.
In the transplantation group, of the 28 patients who had a relapse (median time to relapse, 6 months), 23 (82%) died, usually after salvage chemoimmunotherapy failed to induce a second remission.
Toxicities
In the control group, there were 11 second cancers in 10 patients. In the transplantation group, there were 12 second cancers in 11 patients. As anticipated, there was a markedly greater number of grade 3 and grade 4 toxic effects in the transplantation group. Six patients (5%) died from toxic effects — 3 from lung damage, 1 from hemorrhage, 1 from renal failure, 1 from infection, and 1 from multiorgan failure. In the control group, 3 patients (2%) died — 1 from cardiovascular events, 1 from infection, and 1 from unknown factors.
The study was funded by grants from the National Cancer Institute, grants from the Canadian Cancer Society Research Institute, and in part by Bristol-Myers Squibb. Several of the study authors and Dr. Milpied have reported financial relationships, as detailed in the paper.
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