SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 8,540 new cases of Hodgkin lymphoma will be diagnosed and about 920 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).
For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.
Response-adapted therapy involves the administration of 2 cycles of chemotherapy with ABVD regimen, followed by an interim PET scan, which serves as the basis for either intensifying or de-escalating therapy. If PET negative after the second cycle, patients receive 4 additional cycles of AVD omitting Bleomycin from the ABVD regimen. Radiotherapy is not recommended for patients with negative findings on interim PET scans. This response-adapted therapy resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy (NEJM 2016; 374:2419-2429).
ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In a previously published Phase I study, ADCETRIS® in combination with AVD (A+AVD) resulted in a Complete Response rate of 96% and a 5 year Overall Survival rate of 100%. Based on these finding, ECHELON-1 study was conducted, which is an international, open-label, randomized, multicenter, Phase III trial, comparing A+AVD with ABVD, as frontline therapy in patients with Stage III or IV Classical Hodgkin lymphoma. The goal of this study was to maintain the high probability of cure, while reducing the incidence of toxic effects.
ECHELON-1 study included 1334 previously untreated patients with Stage III or IV Classical Hodgkin lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously, on days 1 and 15 of each 28-day cycle, for up to 6 cycles. Both treatment groups were well balanced and approximately 14% of the patients in the trial were 60 years of age or older. The use of Granulocyte Colony Stimulating Factor (G-CSF), which was initially permitted according to institutional guidelines, was subsequently recommended after an increased incidence of febrile neutropenia with A+AVD therapy during an interim safety analysis. The Primary end point was “modified” Progression Free Survival (mPFS), which, in addition to disease progression or death, included less than Complete Response after the completion of frontline chemotherapy, based on independently assessed PET results. PET scan interpretation was based on Deauville score (The Deauville score is a 5-point scale on which higher scores indicate greater uptake of FDG glucose at involved sites on PET). Patients were stratified according to International Prognostic Score (IPS) risk group (Low risk versus Intermediate risk versus High risk). A PET scan was performed at the end of the second cycle of treatment (PET2) and patients were offered alternative frontline therapy at the discretion of the treating physician, for patients with a PET Deauville score of 5. Secondary end points included Overall Survival.
At a median follow up of 73.0 months, the analysis of Overall Survival significantly favored A+AVD over ABVD across various subgroups (HR for death=0.59; P=0.009). The 6-year Overall Survival estimates were 93.9% in the A+AVD group and 89.4% in the ABVD group. Progression Free Survival (PFS) outcomes also favored A+AVD over ABVD and the 6-year PFS estimates were 82.3% with A+AVD and 74.5% with ABVD (HR for disease progression or death=0.68). The PFS estimates again favored A+AVD over ABVD across various subgroups, including subgroups defined according to disease Stage (III or IV) and PET2-negative status. Further, fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation. Fewer second cancers were reported with A+AVD, but more patients had peripheral neuropathy with A+AVD than with ABVD. However, majority of patients in both treatment groups had resolution or amelioration of neuropathy by the last follow up.
It was concluded from the ECHELON-1 study that, after a median follow up of 6 years, treatment with ADCETRIS® in combination with Doxorubicin, Vinblastine and Dacarbazine (A+AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival.
Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma. Ansell SM, Radford J, Connors JM, et al. for the ECHELON-1 Study Group. N Engl J Med 2022; 387:310-320.
