Updates in Classical Hodgkin Lymphoma Treatment and Research

Brentuximab Vedotin (BV) is effective and safe in patients with advanced staged Hodgkin’s Lymphoma according to the presentation by Brianne Dixon, PharmD, a lymphoma clinical pharmacist for Memorial Sloan Kettering Cancer Center, at 2019 Hematology/Oncology Pharmacy Association Annual Conference in Fort Worth, TX.

Classic Hodgkin’s Lymphoma (cHL) is a cancer of the lymphatic system predominantly diagnosed in those between 15 to 30 years old, and 55 years and older. About 2.5 per 100,000 people are newly diagnosed per year and present with the classic painless swelling of lymph nodes, fatigue, night sweats, and unexplained weight loss. Diagnosis is based on the presence of the characteristic Reed-Sternberg cells and immunohistochemistry (including CD30 positivity). The overall five-year survival for cHL is encouraging at 86.6%, but 0.3 per 100,000 people are projected to die per year due to cHL.

Pharmacologic treatment options for advanced stage cHL (stage III and IV) has been previously restricted to the combinations of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) and doxorubicin, etoposide, cyclophosphamide, bleomycin, vincristine, procarbazine, and prednisone (BEACOPP). New evidence suggests a potential role for brentuximab vedotin (BV) in the treatment of stage III and IV cHL.

According to Dixon, there are three mechanism of action for BV. It acts as a monomethyl auristatin E (MMAE) microtubule disrupting agent, a protease-cleavable linker, and as an anti-CD30 monoclonal antibody. BV is currently FDA approved as a front-line option for treatment of patients with cHL. The Echelon-1 study results secured this FDA approval. In the Echelon-1 study, patients were 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and had adequate blood counts, renal, and liver function. Patients with prior chemotherapy, nodular-lymphocytic predominant Hodgkin’s, or peripheral neuropathy were excluded from the trial.

The combination of BV with adriamycin, vinblastine, and decarbazine (AAVD) was juxtaposed to ABVD, resulting in statistically and clinically significant improvements in progression-free survival (PFS). Despite the increased efficacy, there were more reports of febrile neutropenia and peripheral neuropathy noted in the patient group treated with AAVD.

The effect of BV in relapsed/refractory cHL was then investigated in the AETHERA trial. This study was a global phase III, randomized, placebo-controlled trial which included 329 patients with advanced cHL. Patients must be 12 years or older with a measurable disease defined as greater or equal to 1.5 cm, and previous auto-stem cell transplant before randomization. The patients must also have demonstrated a high risk of relapse. Anyone with prior BV therapy was excluded from this study. BV was compared to a placebo with the results measured in terms of PFS. There was resolved or improved neuropathy shown in 90% of patients within a median time interval of 37.6 weeks with the administration of BV. The results also indicated that patients with three or more risk factors noted greater improvement with BV.

Other immunotherapeutic agents have been studied and FDA-approved in the treatment of relapsed/refractory cHL, particularly nivolumab and pembrolizumab. Nivolumab is a monoclonal antibody directed against programmed cell death protein 1 (PD1). In the CheckMate 205 Trial, the effect of nivolumab administration was juxtaposed in three different cohorts (BV naive, post-autologous stem cell transplant [auto-SCT], and treatment with BV before and/or after auto SCT treatment failure). This study was a single-arm, multicenter, phase II trial comprised of 276 patients with relapsed/refractory advanced cHL after treatment with auto-SCT. In this study, patients were 18 years or older without a diagnosed autoimmune disease, radiotherapy within twenty-one days, or auto-SCT in 90 days. Effect of nivolumab was measured in terms of the overall response rate (ORR), complete response (CR), median duration of response (DOR), and PFS. There was an overall positive effect of treatment of nivolumab with favorable safety profile.

Pembrolizumab is also a monoclonal antibody directed against PD1. Keynote-087 Trial is a single-arm, multicenter, phase II trial which examined the effect of Pembrolizumab in relapsed/refractory cHL. A total of 210 patients (18 years and older) with adequate organ function and performance status of 0 to 1, were recruited for the study. Those with diseases associated with immunosuppression, immunosuppressants within seven days, or allogeneic transplant within five years were excluded from the study. Pembrolizumab exhibited substantial clinical activity in those heavily pre-treated, however the overall survival (OS) and PFS were only estimations.

Overall, the three immunological agents (BV, nivolumab, and pembrolizumab) are shown to be effective in the treatment of relapsed/refractory cHL, and pembrolizumab appears particularly useful in those who have been heavily treated beforehand. This is still an area of active research, some of which the Dixon said, “are combining checkpoint inhibition with every chemo backbone.”

Dixon B. Classical Hodgkin Lymphoma Treatment Updates. Presented at the Hematology/Oncology Pharmacy Association Annual Conference; April 3-6, 2019; Fort Worth, TX.