At the 2020 Debates and Didactics in Hematology and Oncology Virtual Conference, sponsored by Emory University School of Medicine and Winship Cancer Institute, Pamela Allen, MD, Assistant Professor of Medicine at Emory, described recent trials on therapeutic approaches that are informative on this topic.1
PET-Directed Therapy With ABVD
Therapy directed by the results of positron-emission tomography (PET) has become frequently used for advanced-stage Hodgkin lymphoma. Interim PET imaging allows for the omission of bleomycin in patients with PET-negative disease and escalation to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in patients with PET-positive disease.
Pamela Allen, MD
In the phase II SWOG 0816 study, 371 patients with stage II to IV classical Hodgkin lymphoma received ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for two cycles and then PET imaging. The 271 patients (82%) who had PET-negative disease received another four cycles of ABVD, whereas the 66 (18%) who had PET-positive disease (Deauville score of 4 or 5) were escalated to BEACOPP for six cycles.
Recently updated results2 showed the 5-year progression-free survival rate to be 76% in the PET-negative group and 66% in the PET-positive group, with an overall survival rate of 94%, albeit with more toxicity including second malignancies (14% vs 2%). “This underscores the salvageability of this disease,” Dr. Allen said.
In the RATHL trial, 1,214 patients with stage IIb to IV disease (or IIa with risk factors) received two cycles of ABVD followed by PET imaging.3 The 1,119 patients with PET-negative disease were randomly assigned to four cycles of ABVD or AVD, a de-escalated regimen that omitted bleomycin. The 182 patients with PET-positive disease were escalated to one of four different BEACOPP schedules.
At a median follow-up of 41 months, outcomes were similar with ABVD and AVD: approximately 85% progression-free survival at 3 years and 97% overall survival, reflecting no negative impact of omitting bleomycin when PET is negative. Outcomes were somewhat worse, however, for the patients with PET-positive disease treated with BEACOPP—approximately 67% and 88%, respectively. ABVD was associated with more pulmonary toxicity and, when all six cycles were given, more hematologic toxicity and febrile neutropenia.
Incorporating Brentuximab Vedotin: ECHELON-1
ECHELON-1 attempted to improve upon these outcomes by incorporating the novel antibody-drug conjugate brentuximab vedotin into the AVD backbone.4 The 1,334 patients with stage III or IV disease were randomly assigned to two cycles of AVD plus brentuximab or ABVD, followed by PET imaging; patients continued the assigned treatment for another four cycles (This was not a PET-directed protocol, and no changes were made based on PET findings.) The primary endpoint was modified progression-free survival, which included disease progression, death, and modified disease progression (defined as evidence of noncomplete response after front-line therapy, followed by subsequent anticancer therapy such as radiotherapy or stem cell transplantation).
The updated results of the study showed an absolute difference of 7.1% in 3-year progression-free survival in patients with PET-negative disease (hazard ratio [HR] = 0.70; P = .005) and, “most strikingly,” a 16% difference among patients with PET-positive disease (HR = 0.59; P = .077) with this approach vs ABVD. The benefit was greatest for patients younger than age 65.
“The results suggest the regimen of brentuximab and AVD is most beneficial in high-risk patients who are inevitably going to have a positive PET scan,” Dr. Allen said. “Patients treated with brentuximab had significantly fewer subsequent therapies than those treated with ABVD, including one-third fewer instances of salvage chemotherapy or need for transplant.” There was no difference in overall survival.
Of note, however, brentuximab plus AVD was associated with more peripheral neuropathy and more febrile neutropenia, though the latter was ameliorated by the use of growth factors. Pulmonary toxicity was greater with ABVD.
The take-home message from ECHELON-1 is that brentuximab vedotin, added to AVD, improves modified progression-free survival, reduces the need for subsequent therapy, and is associated with less pulmonary toxicity than ABVD for six cycles. However, noted Dr. Allen, this comes at the increased risk for cytopenias and neuropathy.
“I would consider this regimen in patients with advanced-stage Hodgkin lymphoma who are younger than age 65, especially those who are at risk for bleomycin toxicity and those with high-risk baseline disease features,” Dr. Allen commented.
Front-Line Immunotherapy
Trials that incorporate immunotherapies for Hodgkin lymphoma have been encouraging. In a phase II study of nivolumab plus AVD in 51 patients, nivolumab alone was given for four cycles, followed by PET assessment, and then by nivolumab plus AVD for six cycles.5 Tolerability was reported to be good overall, with some grade 1 or 2 infusion reactions (35%), hypothyroidism (16%), and rash (6%) observed. However, four serious adverse events were deemed related to the combination treatment, as was one death in an elderly patient, Dr. Allen noted.
There was a 9-month progression-free survival rate of 92% and an overall survival rate of 98%. “By the end of therapy, most patients achieved complete remission,” she noted.
“The modified progression-free survival in this study is similar to what we would expect with ABVD in newly diagnosed patients,” Dr. Allen observed. “Unfortunately, only 18% responded [with a complete response] to single-agent nivolumab, which is nearly identical to what we see in the relapsed setting.”
Early-Stage Unfavorable Disease
The combination of anti–PD-1 agents plus AVD is also a promising approach in early-stage unfavorable disease, given sequentially or concurrently. In a German trial of 110 patients, the sequential arm received four doses of nivolumab, then two cycles of nivolumab plus AVD, followed by two cycles of AVD; the concurrent arm received four cycles of nivolumab and AVD.6 After treatment, complete responses were observed in 94% of the sequential arm and 90% of the concomitant arm; 1-year progression-free survival was 98% and 100%, respectively. Both strategies combining nivolumab and AVD appeared to be feasible and may result in high remission rates.
Dr. Allen is leading an Emory study of sequential pembrolizumab plus AVD in newly diagnosed patients with either advanced disease or early unfavorable characteristics.7 Patients will receive three doses of pembrolizumab, then undergo PET assessment, followed by AVD alone for four to six cycles. To date, the complete metabolic response rate to single-agent pembrolizumab is 37%, increasing to 100% after two cycles of AVD and remaining at 100% at the end of treatment. All patients are alive at a median follow-up of 12.6 months.
Another novel regimen for early unfavorable disease is brentuximab vedotin plus AVD in addition to site-directed radiotherapy. In a study of 30 patients, this trimodality treatment resulted in a 1-year progression-free survival of 93%.8
Novel Approaches in the Elderly
Elderly patients tend to have poor responses and tolerability to current treatments. Brentuximab plus nivolumab is a chemotherapy-free approach that may lend itself well to this population, according to an interim analysis of 18 older patients; the response rate was 100%, the complete response rate was 72%, and the median duration of response was not reached after almost 7 months of follow-up.9 Grade ≥ 3 neuropathy was seen in 52%, presumably related to 16 cycles of brentuximab, suggested Dr. Allen. Immune-related adverse events were relatively rare, and just 14% of patients required steroids for them.
The combination of brentuximab plus chemotherapy is also being studied in elderly patients with Hodgkin lymphoma, given either concurrently or sequentially. The 2-year progression-free survival has been encouraging in early studies that have used brentuximab first, followed by AVD (70%) or dacarbazine (50%), although peripheral neuropathy remains problematic for some patients. The brentuximab/dacarbazine regimen may be worth considering in older patients who have no contraindications to multiagent chemotherapy, Dr. Allen maintained.
Also Being Evaluated
In the relapsed or refractory setting, other novel approaches being studied are pembrolizumab plus ifosfamide, carboplatin, and etoposide in transplant-eligible patients. In the post-transplant or transplant-ineligible population, under investigation is nivolumab in combination with lenalidomide, brentuximab, or gemcitabine/bendamustine.
DISCLOSURE: Dr. Allen has served on the advisory boards or speakers bureaus of Bayer, Imbrium Therapeutics, Research to Practice, and Clinical Care Options.
REFERENCES
1. Allen P: Current and Future Frontline Approaches in Hodgkin Lymphoma. 2020 Debates and Didactics in Hematology and Oncology Virtual Conference. Presented July 18, 2020.
2. Stephens DM, Li H, Schöder H, et al: Five-year follow-up of SWOG S0816: Limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood 134:1238-1246, 2019.
3. Johnson P, Federico M, Kirkwood A, et al: Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374:2419-2429, 2016.
4. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378:331-344, 2018.
5. Ramchandren R, Domingo-Domènech E, Rueda A, et al: Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: Safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol 37:1997-2007, 2019.
6. Bröckelmann PJ, Goergen H, Keller U, et al: Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma: The randomized phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol 6:872-880, 2020.
7. Allen P, Savas H, Evens AM, et al: Brief pembrolizumab monotherapy results in complete and near complete responses in the majority of untreated patients with classical Hodgkin lymphoma: A multicenter phase 2 PET-adapted study of sequential PEM and AVD. 2019 ASH Annual Meeting & Exposition. Abstract 235. Presented December 7, 2019.
8. Kumar A, Casulo C, Yahalom J, et al: Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood 128:1458-1464, 2016.
9. Yasenchak CA, Bordoni R, Yazbeck V, et al: Phase 2 study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin lymphoma aged ≥ 60 years. 2019 ASH Annual Meeting & Exposition. Abstract 237. Presented December 7, 2019.
