Among the 324 patients enrolled in the four, phase 2 studies, 260 met the criteria for inclusion in analyses of long-term outcomes. A total of 215 patients were identified as ineligible for ASCT, for whom inaccessibility to remission after salvage chemotherapy was the most common reason (n = 184), followed by co-existing comorbidity (n = 12), older age (n = 10), and failure to collect stem cells or being unable to perform stem cell collection (n = 9). Baseline demographic and disease characteristics for responders enrolled in each of the studies and the consolidated responder dataset are detailed in Table 1. Of the whole cohort, 140 patients achieved CR and 120 achieved partial remission (PR) as best response to anti-PD-1 therapy. The median age for the cohort was 32 years with a male/female ratio of 1.3:1. The median number of prior lines of chemotherapy was 3 (range, 2–11). Approximately one-third of patients received prior radiotherapy, 45 underwent ASCT and 9 had prior treatment with BV. Of the cohort, 184 (70.8%) patients had refractory disease at baseline. The median duration of anti-PD-1 therapy was 24.2 months (range, 2.8–55.8 months). A total of 105 patients discontinued anti-PD-1 therapy within 24 months, for whom disease progression was the most common reason (n = 93), followed by adverse events (n = 7), and withdrawal of consent (n = 5).
A total of 116 (44.6%) responders experienced disease progression after a median follow-up period of 31.1 months. More patients who achieved a PR experienced disease progression than those with CR (62.0% vs. 27.7%; P < 0.001). Correspondingly, the 3-year PFS rate for PR patients was 29.5% compared with 72.3% for patients who achieved CR (Fig. 1a). The 3-year PFS was inferior for responders to anti-PD-1 therapy with refractory disease at baseline compared with those with non-refractory disease (49.1% vs. 66.5%, P < 0.001, Fig. 2a). Anti-PD-1 treatment for ≥24 months correlated with better disease control compared with <24 months as evidenced by 3-year PFS rates of 74.5% and 28.6%, respectively (P < 0.001). For those patients with CR, the median maintenance duration of anti-PD-1 therapy from CR was 23.8 months (range, 0.4–53.0 months). In the subset, those patients who continued anti-PD-1 therapy for ≥24 months had more favorable 3-year PFS rate compared with those who were treated for <24 months (81.3% vs. 47.1%, P < 0.001). Those patients who maintained CR for ≥24 months (n = 76) had more favorable 3-year PFS (93.0% vs. 30.2%, P < 0.001) compared with those who maintained CR for <24 months (n = 64).
Progression-free survival (a) and overall survival (b) according to best response achieved to anti-PD-1 therapy. CR complete remission, OS overall survival, PFS progression-free survival, PR partial remission
Progression-free survival (a) and overall survival (b) according to presence/absence of refractory disease at baseline. OS overall survival, PFS progression-free survival
Eighteen (6.9%) responders (6 with CR, 12 with PR) died. The most common cause of death was lymphoma progression (n = 11). The 3-year OS rate was 89.7% for responders overall. The trends of OS generally mirrored those observed in PFS. Patients with PR had inferior OS compared with those with CR (81.5% vs. 94.4% at 3 years, P = 0.017, Fig. 1b). However, the difference in the OS rate between patients with and without refractory disease had no statistical significance (Fig. 2b). In terms of duration of treatment, the 3-year OS rates were 71.6% and 98.5% for patients with a duration of treatment of <24 and ≥24 months, respectively (P < 0.001). Among patients with CR, a longer duration of treatment (≥24 months) brought a positive impact on the survival outcome (3-year OS, 98.1% vs. 82.9%, P < 0.001). Those patients who maintained CR for ≥24 months had more favorable 3-year OS (98.0% vs. 88.9% P = 0.011) compared with those who maintained CR for <24 months. The median time from disease progression to death or last follow-up were 16.7 months for patients who continued anti-PD-1 (n = 68) and 10.2 months for those who transitioned to other therapies post-progression (n = 48), respectively.
Univariate Cox regression analysis identified male gender, presence of B symptoms, refractory disease, PR as best response, and time to response >3 months as risk factors for PFS. In the multivariate analysis, refractory disease (hazard ratio [HR] = 1.9) and PR (HR = 3.6) were independent risk factors for progression (Table 2). According to the above two risk factors, the cohort was divided into four risk groups (Table 3). As shown in Fig. 3, the 3-year PFS rates were 27.6% for patients who had PR with refractory disease (n = 92), 40.5% for patients who had PR with non-refractory disease (n = 28), 67.5% for patients who had CR with refractory disease (n = 92), and 80.9% for patients who had CR with non-refractory disease (n = 48), respectively.
Progression-free survival according to presence/absence of refractory disease at baseline and best response achieved to anti-PD-1 therapy. CR complete remission, PFS progression-free survival, PR partial remission