Response-guided first-line therapy and treatment of relapse in aggressive lymphoma: 10-year follow-up of the PETAL trial

Abstract

The PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas) trial investigated whether treatment intensification after 2 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; plus rituximab [R] for CD20⁺ lymphomas) improved survival in aggressive non-Hodgkin lymphoma. A total of 754 patients (87.5%) had a negative and 108 (12.5%) had a positive interim positron emission tomography (iPET) scan. iPET-positive patients were randomly assigned to receive another 6 (R-)CHOP cycles or 6 blocks of a more intensive protocol. Interim PET-negative patients received another 4 cycles of R-CHOP with or without 2 additional doses of R. After a median follow-up of 4 years, treatment intensification had not improved outcome. These results were confirmed after 10.3 years of follow-up. The present analysis also describes the management of relapse that was part of the study. Among 240 relapsing patients, 94 of 133 autologous transplantation-eligible patients (70.7%) and 16 of 107 ineligible patients (15.0%) received the salvage treatments recommended in the study protocol. Adherence to recommendations had no impact on outcome. Best results were seen after allogeneic transplantation, followed by autologous transplantation and treatment without transplantation (5-year overall survival rate, 64.3% vs 45.5% vs 22.6%), but patients undergoing allogeneic transplantation were significantly younger and their disease was well controlled at the time of transplantation. Early outcome prediction by iPET, alone or in combination with other methods, is a powerful tool to investigate the value of immunological treatment options for patients with a poor response to chemotherapy. This trial was registered at ClinicalTrials.gov as #NCT00554164.

Graphical abstract

Figure 1.

Outcome by lymphoma subtype. Progression-free survival (top) and OS (bottom) from the day of iPET for patients with various types of B-cell non-Hodgkin lymphoma (DLBCL, primary mediastinal B-cell lymphoma [PMBCL], follicular lymphoma [FL] grade 3; left) or T-cell non-Hodgkin lymphoma (ALK⁺ ALCL, ALK⁻ peripheral T-cell lymphoma [PTCL]; right). Of 623 patients with DLBCL, 574 had DLBCL alone, and 49 had DLBCL combined with an indolent lymphoma. Of 54 patients with FL grade 3, 25 had FL grade 3a, 17 had FL grade 3b, and 12 had FL grade 3 combined with FL grade 1 or 2. Of 55 patients with ALK⁻ PTCL, 13 had ALK⁻ ALCL, 18 had angioimmunoblastic T-cell lymphoma, 20 had PTCL not otherwise specified, and 4 had unclassified T-cell lymphoma. Because the subgroups within the DLBCL, FL grade 3, and ALK⁻ PTCL cohorts had similar outcomes (supplemental Figure 1), they were combined in this analysis. No., number; p, log-rank test.

Figure 2.

Outcome by iPET response. Time to progression from the day of iPET in relation to the iPET result for all patients and for the subgroups of patients with DLBCL, PMBCL, FL grade 3, ALK⁺ ALCL, and ALK⁻ PTCL. The numbers in parentheses represent 95% CIs. The negative predictive values (NPVs) and positive predictive values (PPVs; categorization irrespective of follow-up time) of the iPET result for progression or relapse are also indicated. Similar results were obtained for event-free survival, progression-free survival, and OS (data not shown). No., number; p, log-rank test.

Figure 3.

Outcome by randomly assigned treatment arm. Event-free survival (EFS, top), progression-free survival (PFS, middle), and OS (bottom) from the day of random assignment for all patients undergoing randomization (left) and for the DLBCL subgroup (right). The top 2 curves in each panel represent iPET-negative patients with CD20⁺ lymphomas, randomly assigned to a total of 6 cycles of R-CHOP with or without 2 additional doses of R. The bottom 2 curves represent iPET-positive patients randomly assigned to a total of 8 cycles of R-CHOP or 2 cycles of R-CHOP followed by 6 blocks of the Burkitt protocol. Baseline stratification factors included age, sex, lymphoma subtype, risk group of the International Prognostic Index, and type of treatment institution. The numbers in parentheses represent 95% CIs. No., number; p, log-rank test.

Figure 4.

Outcome after relapse by time to relapse, stage at relapse, and type of salvage therapy. OS from the day of first relapse for all relapsing patients (left) and for the DLBCL subgroup (right) in relation to the time to first relapse from iPET evaluation (top), the Ann Arbor stage at first relapse (middle), and the type of salvage therapy. The type of salvage therapy was defined on the basis of the entire disease course (up to 7 lines of salvage therapy), including (1) supportive care alone; (2) chemotherapy, immunotherapy, and/or radiotherapy with or without supportive care, but without transplantation; (3) high-dose chemotherapy with auto-SCT with or without chemotherapy, immunotherapy, radiotherapy or supportive care, but without allogeneic transplantation; and (4) allogeneic transplantation with or without autologous transplantation, chemotherapy, immunotherapy, radiotherapy, or supportive care. Chemotherapy/immunotherapy alone, radiotherapy alone, and chemotherapy/immunotherapy consolidated by radiotherapy were combined in 1 group, because outcome after first relapse did not significantly differ among these modalities (supplemental Figure 5). Pairwise comparisons of treatment types were statistically significant (P < .001 to P = .049), except for autologous vs allogeneic transplantation (P = .225 for all relapsing patients, P = .791 for the DLBCL subgroup). The numbers in parentheses represent 95% CIs. No., number; p, log-rank test.

Figure 5.

Forest plot showing multivariable Cox regression analysis of factors determining the OS from the day of first progression or relapse in patients participating in the PETAL trial. The analysis was restricted to 199 progressing or relapsing patients with a well-defined diagnosis (DLBCL, 146; PMBCL, 4; FL grade 3, 15; ALK⁺ ALCL, 4; ALK⁻ PTCL, 30) fulfilling the study inclusion criteria and receiving antineoplastic treatment for relapse or progression (chemotherapy, immunotherapy, and/or radiotherapy without transplantation, 109; auto-SCT without allogeneic transplantation, 65; and allogeneic transplantation, 25). Overall, 112 patients relapsed within the first year after iPET evaluation, and 87 relapsed later. At the time of first relapse, 21 patients had stage I relapse, 178 had stage II to IV (including 41 patients with unknown stage whose disease course was indistinguishable from that of patients with stage IV disease [Figure 4]), 91 were aged ≤60 years, and 108 were older. Age also failed to reach statistical significance when it was included as a continuous variable into the model (HR, 1.016 per year; 95% CI, 0.999-1.034; P = .068). There were 135 events (deaths) among 199 patients.