Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL).

INTRODUCTION: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. METHODS: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. RESULTS: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48). CONCLUSION: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.