Prospective international cohort study demonstrates inability of interim PET to predict treatment failure in diffuse large B-cell lymphoma

The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET).Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2-3 cycles of chemotherapy and at the end of chemotherapy scored visually.Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79\% (95\% confidence interval [CI], 74\%-83\%) for event-free survival (EFS) and 86\% (95\% CI, 81\%-89\%) for overall survival (OS). Two hundred ten patients (64\%) were I-PET-negative, and 117 (36\%) were I-PET-positive. Two-year EFS was 90\% (95\% CI, 85\%-93\%) for I-PET-negative and 58\% (95\% CI, 48\%-66\%) for I-PET-positive, with a hazard ratio of 5.31 (95\% CI, 3.29-8.56). Two-year OS was 93\% (95\% CI, 88\%-96\%) for I-PET-negative and 72\% (95\% CI, 63\%-80\%) for I-PET-positive, with a hazard ratio of 3.86 (95\% CI, 2.12-7.03). On sequential monitoring, 192 of 312 (62\%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97\% (95\% CI, 92\%-98\%); 110 of these with favorable clinical indicators had an EFS of 98\% (95\% CI, 92\%-100\%). In contrast, the 107 I-PET-positive cases segregated into 2 groups: 58 (54\%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86\%; 95\% CI, 73\%-93\%); 46\% remained PET-positive (EFS, 35\%; 95\% CI, 22\%-48\%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET.This large international cohort delivers 3 novel findings: treatment response assessed by I-PET is comparable across disparate healthcare systems, secondly a negative I-PET findings together with good clinical status identifies a group with an EFS of 98\%, and thirdly a single I-PET scan does not differentiate chemoresistant lymphoma from complete response and cannot be used to guide risk-adapted therapy.