Salvage Checkpoint Inhibitors Reduce Peri-ASCT Progression in R/R Hodgkin Lymphoma

Checkpoint inhibitor–based salvage regimens significantly reduced the likelihood that patients with relapsed/refractory classic Hodgkin lymphoma undergoing autologous stem cell transplant (ASCT) would need further salvage therapy compared with conventional salvage regimens, according to findings from a multicenter observational cohort study that were presented at the 2023 Transplantation & Cellular Therapy Meetings.¹

The 2-year event-free survival (EFS) rate in patients who received checkpoint inhibitor–based first salvage therapy was 79.7% (95% CI, 70.5%-90.2%) vs 62.3% (95% CI, 51.2%-75.9%), 36.9% (95% CI, 30.1%-40.1%), and 49.6% (95% CI, 46.1%-53.5%) in those who received first salvage regimens with brentuximab vedotin (Adcetris) plus chemotherapy, brentuximab vedotin alone, or chemotherapy alone, respectively. The EFS difference between checkpoint inhibitor–based therapy and brentuximab vedotin plus chemotherapy was statistically significant, with a P value of .03.

“In patients bridged to transplant after 1 salvage therapy, checkpoint inhibitors are associated with reduced likelihood of post-transplant progression,” Sanjal H. Desai, MD, of Mayo Clinic in Rochester, Minnesota, said in a presentation of the data.

Checkpoint inhibitors as salvage therapy in relapsed/refractory classic Hodgkin lymphoma have previously been evaluated in studies such as a phase 1/2 trial (NCT02572167) investigating the checkpoint inhibitor nivolumab (Opdivo) plus brentuximab vedotin. In this single-arm trial, the combination produced an overall response rate of 85% and a complete response rate of 67%. Additionally, at a median follow-up of 34.3 months, the estimated 3-year progression-free survival (PFS) rate was 77%.²

At the meeting, Desai presented the final results of a 14-center study of peri-transplant outcomes in patients with relapsed/refractory classic Hodgkin lymphoma who received novel vs conventional salvage regimens.¹

This study enrolled 936 adult patients who had progressed on anthracycline-based frontline therapies such as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). During the study, all patients received salvage therapy and ASCT.

The primary end point of this trial was EFS, defined as time from relapse to the requirement of second salvage therapy, progression before or after ASCT, or death in the entire population. Other end points included PFS and overall survival (OS) in patients who underwent ASCT after 1 or 2 lines of salvage therapy.

Most patients received conventional chemotherapy as their first salvage regimen (n = 728), including ICE (ifosfamide, carboplatin, and etoposide; n = 630), GVD (gemcitabine, vinorelbine, and doxorubicin; n = 37), DHAP (dexamethasone, cytarabine, and cisplatin)/ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin; n = 32), GDP (gemcitabine, dexamethasone, and cisplatin; n = 15), and IGEV (ifosfamide, gemcitabine, and vinorelbine; n = 14). Additionally, 65 patients received salvage regimens with checkpoint inhibitors, including brentuximab vedotin plus nivolumab (n = 49), brentuximab vedotin plus nivolumab and ipilimumab (Yervoy; n = 12), and nivolumab or pembrolizumab (Keytruda) monotherapy (n = 3). Furthermore, 73 patients received brentuximab vedotin with either bendamustine (n = 72) or ICE (n = 1). In addition, 70 patients received brentuximab vedotin alone.

Patients who received brentuximab vedotin alone had a higher median age of 41 years (range, 31-55), vs 33 years (range, 26-44), 31 years (range, 24-43), and 31 years (range, 23-40) in the chemotherapy alone, brentuximab vedotin plus chemotherapy, and checkpoint inhibitor populations, respectively (P < .001). Patients who received checkpoint inhibitors or brentuximab vedotin alone had a higher likelihood of having bulky disease, at 40% (n = 26) and 35% (n = 24), respectively, vs 30% (n = 209) and 19% (n = 14) in the chemotherapy alone and brentuximab vedotin plus chemotherapy populations, respectively (P = .046). Additionally, patients who received novel salvage regimens were more likely to receive subsequent brentuximab vedotin consolidation, at 38% (n = 28), 28% (n = 18), and 23% (n = 16) in the brentuximab vedotin plus chemotherapy, checkpoint inhibitor, and brentuximab vedotin alone populations, respectively, compared with 18% (n = 132) in patients who received salvage chemotherapy (P < .001).

In patients who received salvage chemotherapy, the 2-year EFS rates were similar, at 49.9% (95% CI, 46.0%-54.0%) with ICE, 42.4% (95% CI, 28.1%-64.0%) with DHAP/ESHAP, 55.3% (95% CI, 41.0%-74.5%) with GVD, and 50.9% (95% CI, 35.5%-73.1%) with other gemcitabine-based regimens.

A univariable analysis of EFS found that, in addition to type of first salvage, bulky disease, B symptoms, and primary refractory disease were associated with significantly lower EFS, with respective HRs of 1.28 (95% CI, 1.06-1.540; P = .01), 1.28 (95% CI, 1.08-1.53; P = .005), and 1.76 (95% CI, 1.42-2.19; P < 1e-04). When adjusted for these adverse disease features, a multivariable analysis of EFS found no EFS difference between patients who received brentuximab vedotin plus chemotherapy compared with conventional chemotherapy, with an HR of 0.6900 (95% CI, 0.48-1.01; P = 0.0539). Checkpoint inhibitor–based regimens were still associated with higher EFS (HR, 0.3100; 95% CI, 0.18-0.52; P < 1e-04), and brentuximab vedotin alone was associated with a significantly lower EFS (HR, 1.4800; 95% CI, 1.09-2.00; P = .0110).

“The efficacy of checkpoint inhibitors in improving EFS was persistent in the subgroup of patients with primary refractory disease and early relapse,” Desai noted. In patients with primary refractory disease, the 2-year EFS rates with first salvage therapy were 76.5% (95% CI, 62.7%-93.3%) with checkpoint inhibitor–based therapies, 59.6% (95% CI, 41.7%-65.2%) with brentuximab vedotin plus chemotherapy, 42.1% (95% CI, 36.6%-48.4%) with chemotherapy alone, and 26.9% (95% CI, 13.1%-51.9%) with brentuximab vedotin alone.

In the subgroup of patients with early relapse, defined as relapse within 1 year of receiving their frontline regimen, the 2-year EFS rates with first salvage therapy were 78.8% (95% CI, 67.7%-91.3%) with checkpoint inhibitor–based therapies, 58.8% (95% CI, 45.6%-76.1%) with brentuximab vedotin plus chemotherapy, 43.4% (95% CI, 39.5%-48.4%) with chemotherapy alone, and 35.9% (95% CI, 24.4%-52.7%) with brentuximab vedotin alone.

The 2-year PFS rates in patients who were successfully bridged to ASCT after 1 line of salvage therapy were 98% (95% CI, 94.1%-100%) with checkpoint inhibitor–based therapies, 84.1% (95% CI, 72.2%-90.9%) with brentuximab vedotin alone, 76.8% (95% CI, 65.5%-90.1%) with brentuximab vedotin plus chemotherapy, and 68.8% (95% CI, 64.8%-73.2%) with chemotherapy alone.

A univariable PFS analysis showed that primary refractory disease and early relapse were associated with a lower likelihood of post-transplant PFS, with respective HRs of 1.6900 (95% CI, 1.20-2.37; P = .0026) and 1.2100 (95% CI, 0.84-1.74; P = .3050). Conversely, brentuximab vedotin consolidation was associated with higher post-transplant PFS (HR, 0.6300; 95% CI, 0.43-0.93; P = .0193). When adjusted for these features, a multivariable PFS analysis showed that checkpoint inhibitor­­–based regimens were still associated with higher PFS (HR, 0.1100; 95% CI, 0.0300-0.4500; P = .0021). Additionally, brentuximab vedotin plus chemotherapy was not associated with a PFS difference compared with conventional chemotherapy (HR, 0.7900; 95% CI, 0.4300-1.4400; P = .4475).

OS was not significantly different between the types of first salvage therapy. The 2-year OS rates in patients undergoing ASCT after 1 line of salvage therapy were 93.1% (95% CI, 90.8%-95.5%) with chemotherapy alone, 97.5% (95% CI, 92.9%-100%) with brentuximab vedotin plus chemotherapy, 98.3% (95% CI, 94.3%-100%) with checkpoint inhibitor–based regimens, and 93.7% (95% CI, 85.7%-100%) with brentuximab vedotin alone.

In patients who received at least 2 lines of salvage therapy, checkpoint inhibitor–based second salvage was not associated with significantly higher EFS vs chemotherapy-based or brentuximab vedotin–based second salvage. The 2-year EFS rates were 56.1% (95% CI, 41.7%-75.5%) with checkpoint inhibitor–based therapy, 47.9% (95% CI, 38.4%-59.8%) with brentuximab vedotin alone, 47.4% (95% CI, 39.7%-56.6%) with chemotherapy alone, and 44.1% (95% CI, 26.6%-73.2%) with brentuximab vedotin plus chemotherapy.

In patients with at least 2 lines of salvage therapy who were successfully bridged to ASCT, checkpoint inhibitor–based second salvage trended toward higher PFS vs chemotherapy-based second salvage, although this difference was not statistically significant. The 2-year PFS rates were 79.6% (95% CI, 64.8%-97.7%) with checkpoint inhibitor–based therapy, 64.2% (95% CI, 55.5%-74.2%) with chemotherapy alone, 51.8% (95% CI, 32.4%-82.9%) with brentuximab vedotin plus chemotherapy, and 59.4% (95% CI, 48.8%-72.3%) with brentuximab vedotin alone.

“Earlier use of checkpoint inhibitor–based salvage regimens is necessary to improve outcomes of relapsed/refractory classic Hodgkin lymphoma,” Desai concluded.

References

1. Desai SH, Spinner MA, David K, et al. Checkpoint inhibitors based salvage regimens lead to higher survival in relapsed refractory classic Hodgkin lymphoma undergoing autologous stem cell transplant. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 39.
2. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. 2021;138(6):427-438. doi:10.1182/blood.2020009178