The strategy of autologous stem-cell transplantation as consolidation in high-intermediate– or high-risk diffuse aggressive non-Hodgkin lymphoma (NHL) has not been specifically examined in the rituximab (Rituxan) era. In the phase III Southwest Oncology Group (SWOG)-led intergroup 9704 trial reported in The New England Journal of Medicine, Patrick J. Stiff, MD, of Loyola University Medical Center, Maywood, Illinois, and colleagues compared three additional cycles of induction chemotherapy vs one additional cycle plus autologous stem cell transplantation in patients with response to induction CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab plus CHOP (R-CHOP).¹ The study showed that early autologous transplantation resulted in greater progression-free survival but not overall survival, although an overall survival benefit was observed among patients with high–International Prognostic Index (IPI) disease.

Study Details

In the trial, 370 eligible patients with NHL in Working Formulation groups D through H and J and age-adjusted IPI classification of high risk or high-intermediate risk received five cycles of CHOP or R-CHOP. Those with response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary endpoints were 2-year progression-free survival and overall survival.

Among the 370 patients, median age was 51 years, 59% were male, 89% had B-cell lymphoma (diffuse large B-cell lymphoma–not otherwise specified in 67%), 11% had T-cell lymphoma, 31% had stage III disease, and 63% had stage IV disease. In addition, 36% had Eastern Cooperative Oncology Group performance status ≥ 2, 84% had elevated lactate dehydrogenase, 22% had bone marrow involvement, 66% had ≥ 1 extranodal site (≥ 2 in 26%), 62% had B symptoms, 32% had IPI high-risk disease, and 47% of those with B-cell lymphoma (156/330) received R-CHOP.

Of the 370 patients, 117 did not enter the randomized phase, primarily due to disease progression (56%) and patient decision (20%). The remaining 253 patients were randomly assigned to the transplantation group (n = 125) or control group (n = 128). There were no significant differences between groups in age, sex, risk group, initial stage, lactate dehydrogenase level, number of extranodal sites, or B symptoms. Of patients with B-cell lymphoma, 60% had received R-CHOP induction, indicating a higher dropout rate among those receiving CHOP induction.

Key Findings

Two-year progression-free survival rates were 55% in the control group vs 69% in the transplantation group (hazard ratio [HR] in multivariate analysis adjusting for risk score = 1.72, P = .005). Median progression-free survival was not reached in the transplantation group vs 2.8 years in the control group.

Two-year overall survival rates were 71% in the control group vs 74% in the transplantation group (adjusted HR = 1.26, P = .30). Median overall survival was not reached in either group. Nine transplantation group patients who did not receive transplantation had a 2-year progression-free survival rate of 56% and overall survival rate of 78%.

Treatment of Relapse

Of 62 control group patients with relapse (48% of group), 29 (47%) received salvage chemotherapy and transplantation; of these, 11 (38%) survived without disease progression and another 7 patients survived without progression after alternative salvage therapy. Thus, a total of 18 (29%) of the control group patients with relapse survived without disease.

Of the 28 patients in the transplantation group with relapse, 23 (82%) died, most after salvage chemoimmunotherapy. Allogeneic stem-cell transplantation was performed in three patients, with two dying from toxic effects and one having a subsequent relapse but surviving.

Subgroup Analyses

No differential treatment effect was found between the subgroup of patients with B-cell lymphoma and the subgroup with T-cell lymphoma for either progression-free survival (P = .46 for interaction) or overall survival (P = .56 for interaction). Among patients with B-cell lymphoma, the hazard ratios for control vs transplantation group were 1.84 (P = .004) for progression-free survival and 1.36 (P = .21) for overall survival.

There was also no differential effect between patients with B-cell lymphoma treated with R-CHOP vs CHOP for either progression-free survival (P = .33 for interaction) or overall survival (P = .31 for interaction). Among those receiving R-CHOP, 2-year progression-free survival rates were 63% in the control group vs 73% in the transplantation group (HR = 1.56, P = .10) and 2-year overall survival rates were 73% vs 77% (HR = 1.09, P = .79).

Benefit in High-Risk Patients

A significant treatment effect was observed according to risk category for both progression-free survival (P = .04 for interaction) and overall survival (P = .01 for interaction). Among randomized patients, 36% of those with B-cell lymphoma receiving R-CHOP, 32% of those with B-cell lymphoma receiving CHOP, and 36% of those with T-cell lymphoma were in the high-risk category. Among all 165 high-intermediate-risk patients, 2-year progression-free survival was 66% in transplantation patients vs 63% in control patients (P = .32), whereas rates were 75% vs 41% (P = .001) among all 88 high-risk patients.

Two-year overall survival was 70% in the transplantation group vs 75% in the control group (P = .48) among those at intermediate-high risk and 82% vs 64% (P = .01) among those at high risk. Similar differential effects were found among patients with B-cell lymphoma for both progression-free survival (P = .05 for interaction) and overall survival (P = .03 for interaction).

Toxicities

During the first five cycles of CHOP or R-CHOP, four patients died, three due to neutropenic infection and one due to hemorrhage. Among patients randomized to the transplantation group or the control group, grade 3 or 4 adverse events were more frequent in the transplantation group. These  included infection (50% vs 13%), gastrointestinal effects (26% vs 5%), metabolic effects (13% vs 1%), lung effects (11% vs 2%), cardiovascular effects (10% vs 4%), neurologic effects (7% vs 5%), dyspnea (7% vs 2%), hyperglycemia (6% vs 0%), hypoxia (4% vs 0%), and hepatic effects (3% vs 0%).

Six patients in the transplantation group (5%) died from toxic effects, consisting of lung damage in three and hemorrhage and renal failure, infection, and multiorgan failure in one each. Three control group patients died (2%), due to cardiovascular toxic effects, infection, and unknown factors in one each.

The investigators concluded:

[A]lthough we found that progression-free survival was superior with early transplantation among patients with high-intermediate-risk or high-risk non-Hodgkin’s lymphoma who had a response to induction therapy, we could not validate a benefit of consolidative transplantation with respect to overall survival. Thus, early transplantation and late transplantation achieve roughly equivalent overall survival in the combined risk groups. Early transplantation appears to be beneficial for the small group of patients presenting with high-risk disease. ■

Disclosure: The study was supported by NCI grants, Canadian Cancer Society Research Institute grants, and Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013.