Patients

Table 1. Table 1. Patient Demographic and Clinical Characteristics at Baseline (Intention-to-Treat Population).

From November 19, 2012, through January 13, 2016, a total of 1334 patients at 218 sites in 21 countries were randomly assigned to receive A+AVD (664 patients) or ABVD (670 patients) (intention-to-treat population) (Fig. S1 in the Supplementary Appendix). Overall, 58% of the patients were men, 64% had stage IV disease, 62% had extranodal involvement at diagnosis, 59% had B symptoms (i.e., weight loss, night sweats, and fever), and the median age was 36 years (34% of patients were ≥45 years of age). Baseline characteristics were generally well balanced between the two groups (Table 1, and Table S3 in the Supplementary Appendix).

Efficacy

Figure 1. Figure 1. Modified Progression-free Survival in the Intention-to-Treat Population. Panel A shows Kaplan–Meier estimates of modified progression-free survival, by treatment group, according to the independent review committee. The hazard ratio for treatment with A+AVD versus ABVD and the 95% confidence intervals (CIs) were based on a stratified Cox proportional-hazards regression model, with treatment as the explanatory variable. Stratification factors included region and International Prognostic Score risk group at baseline. Panel B shows Kaplan–Meier estimates of modified progression-free survival, by treatment group, according to investigators. In Panels A and B, circles indicate censored data. A+AVD denotes brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, and ABVD doxorubicin, bleomycin, vinblastine, and dacarbazine.

Table 2. Table 2. Summary of Modified Progression-free Survival According to the Independent Review Committee and Concordance with Events Noted by Trial Investigators (Intention-to-Treat Population).

Table 3. Table 3. Summary of Responses in the Intention-to-Treat Population.

After a median follow-up of 24.6 months (range, 0 to 49.0), the rate of the primary end point of independently determined modified progression-free survival was significantly higher in the A+AVD group than in the ABVD group (2-year modified progression-free survival rate, 82.1% [95% confidence interval {CI}, 78.8 to 85.0] vs. 77.2% [95% CI, 73.7 to 80.4]; hazard ratio for progression, death, or modified progression, 0.77 [95% CI, 0.60 to 0.98]; P=0.04), corresponding to a 23% risk reduction (Figure 1A). Events of progression, death, or modified progression occurred in 117 patients in the A+AVD group and in 146 patients in the ABVD group; disease progression occurred in 90 and 102 patients, respectively; death from any cause in 18 and 22 patients, respectively, and receipt of subsequent anticancer therapy after failure to achieve a complete response at the completion of frontline therapy (modified progression) in 9 and 22 patients, respectively (Table 2). The majority (71%) of these subsequent anticancer therapies consisted of salvage chemotherapy (7 of 9 patients in the A+AVD group and 15 of 22 patients in the ABVD group), with radiotherapy given to the remainder of patients in both groups (Table S4 in the Supplementary Appendix). Modified progression events assigned because of an end-of-treatment PET scan and subsequent treatment were predominantly associated with a Deauville score of 4 or 5 (a score of 3 was recorded in 7 of 31 patients [23%], a score of 4 in 10 of 31 patients [32%], and a score of 5 in 14 of 31 patients [45%]); these events also met the criteria for a progression event according to investigator assessment. Of note, only 7 of the 21 patients with a Deauville score of 3 on the end-of-treatment PET scan went on to receive additional therapy and were therefore determined to have had a modified progression event (2 patients in the A+AVD group and 5 patients in the ABVD group; Table 2 and Table 3).

According to investigator assessment, the 2-year modified progression-free survival rate was 81.0% (95% CI, 77.6 to 83.9) with the A+AVD regimen versus 74.4% (95% CI, 70.7 to 77.7) with the ABVD regimen, corresponding to a 28% lower overall risk of an event among patients treated with A+AVD than among those treated with ABVD (hazard ratio for progression, death, or modified progression, 0.72; 95% CI, 0.57 to 0.91; P=0.006) (Figure 1B). There was 91% concordance between independent review and investigator determination of a modified progression-free survival event.

Figure 2. Figure 2. Forest-Plot Analysis of Modified Progression-free Survival. This forest plot shows modified progression-free survival according to the independent review committee in key prespecified subgroups. The hazard ratio for treatment with A+AVD versus ABVD and the 95% confidence intervals (CIs) were based on an unstratified Cox proportional-hazards regression model, with treatment as the explanatory variable. The intention-to-treat population included all the patients who underwent randomization. The International Prognostic Score (IPS) ranges from 0 to 7, with higher scores indicating increased risk of treatment failure: low risk, 0 or 1; intermediate risk, 2 or 3; and high risk, 4 to 7. The Ann Arbor staging system ranges from I to IV, with higher stages indicating more widespread disease. B symptoms consist of night sweats, unexplained fever (temperature >38°C), or loss of more than 10% of body weight. Values for the Eastern Cooperative Oncology Group (ECOG) performance status range from 0 to 5, with higher scores indicating greater disability.

Prespecified subgroup analyses of modified progression-free survival showed a hazard ratio of less than 1 for the A+AVD regimen versus the ABVD regimen in the majority of subgroups (Figure 2). Certain subgroups of patients appeared to benefit more with A+AVD than with ABVD. These subgroups included patients from North America, patients with involvement of more than one extranodal site, patients with an IPS indicating a high risk of treatment failure (scores of 4 to 7), men, patients with stage IV disease, and patients younger than 60 years of age. The rates of negativity at PET2 (Deauville score, 1 to 3) were 89% with A+AVD versus 86% with ABVD.

There were 28 deaths in the A+AVD group (9 during treatment [within 30 days after the last dose of frontline therapy] and 19 during follow-up [31 days or more after the last dose of frontline therapy]) and 39 deaths in the ABVD group (13 during treatment and 26 during follow-up). The interim 2-year overall survival rate for the A+AVD group was 96.6% (95% CI, 94.8 to 97.7) and that for the ABVD group was 94.2% (95% CI, 92.0 to 95.9), which corresponded to a reduction in the risk of death of 27% in favor of the A+AVD regimen (hazard ratio, 0.73; 95% CI, 0.45 to 1.18; P=0.20) (Fig. S2 in the Supplementary Appendix). Results for other secondary end points are shown in Table 3. Only 15 of 662 patients who received A+AVD and 9 of 659 patients who received ABVD switched to alternative chemotherapy during frontline therapy for reasons other than progressive disease (a Deauville score of 5 in 1 of 15 and 4 of 9 patients, respectively; adverse events in 12 of 15 and 1 of 9 patients, respectively; and other reasons in 2 of 15 and 4 of 9 patients, respectively) (Table S5 in the Supplementary Appendix).

Overall, fewer patients in the A+AVD group than in the ABVD group received subsequent anticancer therapies. Recipients of these therapies in the A+AVD group versus the ABVD group were as follows: radiation (in 52 patients in each group), chemotherapy (66 vs. 99), high-dose chemotherapy plus transplantation (36 vs. 54), immunotherapy (10 vs. 16), and chemotherapy plus radiation (2 vs. 3).

Safety

The median duration of treatment and the number of completed cycles were similar in the two groups (Table S6 in the Supplementary Appendix). The proportions of patients who received the regimens as intended, without dose modification such as delays, holds, or reductions, are shown in Table S6 in the Supplementary Appendix.

Table 4. Table 4. Summary of Adverse Events in the Safety Population.

The safety profiles for both groups are summarized in Table 4, and in Table S7 in the Supplementary Appendix. Overall, neutropenia was reported in 58% of the patients receiving A+AVD and in 45% of the patients receiving ABVD, and febrile neutropenia was reported in 19% and 8%, respectively. In both groups, the incidence of febrile neutropenia was higher among patients 60 years of age or older than among those younger than 60 years of age (37% vs. 17% in the A+AVD group and 17% vs. 6% in the ABVD group). The incidence of febrile neutropenia was also higher in earlier rather than later cycles of therapy in both groups (9% in cycle 1 vs. 1 to 6% in cycles 2 through 6 in the A+AVD group and 4% in cycle 1 vs. ≤1% in cycles 2 through 6 in the ABVD group). The incidence of discontinuation of any trial drug due to neutropenia or febrile neutropenia was 1% or less in both groups.

Table 5. Table 5. Summary of Adverse Events in Patients Who Did and Those Who Did Not Receive Primary Prophylaxis with Granulocyte Colony-Stimulating Factor.

The rate of infections (determined in accordance with the MedDRA primary system organ-class term of “infections and infestations”) in the A+AVD group was 55% (361 of 662 patients) and the rate in the ABVD group was 50% (331 of 659 patients); rates of infection of grade 3 or higher were 18% (116 of 662 patients) and 10% (66 of 659 patients), respectively. Discussion with the independent data and safety monitoring committee (after 75% of enrollment was complete) led to the recommendation of primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) for patients who were yet to be enrolled and who would receive the A+AVD regimen, owing to the higher incidence of febrile neutropenia in that group. In the A+AVD group, the incidence of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with G-CSF (defined as use of G-CSF by day 5 of treatment) than among those who did not (11% [9 of 83] vs. 21% [119 of 579]) (Table 5). The occurrence of infections and infestations of grade 3 or higher was also lower among the patients who received G-CSF than among those who did not (11% [9 of 83 patients] vs. 18% [107 of 579 patients]).

Peripheral neuropathy (determined on the basis of a standardized MedDRA query; see Table S8 in the Supplementary Appendix) occurred in 67% of the patients (442 of 662) receiving A+AVD and 43% of the patients (286 of 659) receiving ABVD. Grade 2 peripheral neuropathy occurred in 20% of the patients (130 of 662) in the A+AVD group versus 9% of the patients (57 of 659) in the ABVD group, and peripheral neuropathy of grade 3 or higher occurred in 11% of the patients (70 of 662) in the former group (with grade 4 occurring in 1 patient) versus 2% of the patients (11 of 659) in the latter. Among patients with peripheral neuropathy, a trial drug was discontinued in 10% in the A+AVD group (44 of 442) versus 4% in the ABVD group (11 of 286). Two thirds of the patients in the A+AVD group (295 of 442) who had peripheral neuropathy had resolution (43%, 191 of 442) or improvement by at least one grade (24%, 104 of 442) in terms of events related to peripheral neuropathy at the time of the last follow-up visit; at that time, 92% of ongoing events related to peripheral neuropathy were grade 1 (64%) or grade 2 (29%) in the A+AVD group. Pulmonary toxicity, defined as events related to interstitial lung disease (in accordance with a standardized MedDRA query), was reported in 2% of the patients (12 of 662) in the A+AVD group versus 7% (44 of 659) in the ABVD group; events of grade 3 or higher were reported in less than 1% of the patients (5 of 662) in the former group and 3% of the patients (21 of 659) in the latter.

During treatment, there were 9 deaths in the A+AVD group and 13 deaths in the ABVD group. In the A+AVD group, 7 deaths were associated with neutropenia (all occurred in patients who had not received primary prophylaxis with G-CSF before the onset of neutropenia, with the exception of 1 patient who entered the trial with preexisting neutropenia) and 2 deaths were due to myocardial infarction. In the ABVD group, 11 deaths were due to or associated with pulmonary-related toxicity and 1 death was due to cardiopulmonary failure. The cause of 1 death was unknown. Among the patients enrolled in the trial, 37% (242 of 662) in the A+AVD group and 28% (186 of 659) in the ABVD group were hospitalized during the trial.

Fertility was not formally assessed; however, similar numbers of pregnancies were reported in each treatment group, which suggests that there was no significant difference in the effect on fertility. At the time of this analysis, a total of 78 pregnancies were reported among trial participants and their partners (42 in the A+AVD group and 36 in the ABVD group).