Myeloablation for lymphoma--question answered?

The value of early myeloablative treatment of aggressive lymphoma in adults has been the subject of argument for many years. Before the addition of rituximab to the four-drug regimen known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), a meta-analysis of randomized trials showed similar survival among patients undergoing up-front autologous stem-cell transplantation and those undergoing standard chemotherapy.1 At that time, outside clinical trials, high-dose chemotherapy with autologous stem-cell support was recommended only for patients with primary refractory or relapsed aggressive lymphoma. The widespread use of CHOP plus rituximab (R-CHOP) chemotherapy has considerably improved overall survival rates among patients with diffuse large-B-cell lymphoma; however, the survival rate among patients in an International Prognostic Index (IPI) risk category of high-intermediate or high remains about 60%. Thus, early myeloablative treatment in these patients with the highest risk of relapse is worth investigating. In this issue of the Journal, Stiff et al.2 report the findings of an 8-year study of high-intermediate-risk and highrisk patients who began treatment before R-CHOP became standard induction therapy, so that fewer than half the 370 adults younger than 66 years of age eligible for inclusion in their study cohort received it. Stiff et al. randomly assigned 253 patients who had a response to induction therapy either to continued chemotherapy (control group) or to autologous stem-cell transplantation after an additional round of induction chemotherapy plus a preparative regimen of total-body irradiation or high-dose chemotherapy (transplantation group). They found that progression-free survival in the control group was similar to that in the transplantation group for the 165 high-intermediate-risk patients; however, for the 88 high-risk patients, survival was significantly shorter in the control group. The results of their study certainly bring hope for high-risk patients, but they merit discussion as to whether they can be applied broadly, in view of what we have learned in the years since this study was initiated. At least three other randomized trials have not shown an obvious benefit of early myeloablative treatment, but their study designs differed from that of Stiff et al. (i.e., the other studies involved only patients with diffuse largeB-cell lymphoma treated with rituximab, and regimens used to treat the chemotherapy-only groups were more dose intense).3-5 The value of this treatment for aggressive, diffuse large-B-cell lymphoma therefore remains unresolved. It is clear only that such treatment is feasible — but at the price of greater toxicity than that associated with the current standard treatment. Going forward, it should be possible to better select patients for enrollment in trials of early myeloablative therapy, and the selection should not be based simply on the IPI risk category. 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. Several means can be envisioned; for example, choosing patients according to cell of origin of the lymphoma —