Game of Thrones: The New King in Advanced-Stage Hodgkin Lymphoma

No malignancy has likely epitomized the promise of “modern” advancement in medicine more than Hodgkin lymphoma (HL). The medical discovery of HL has been credited to Dr. Thomas Hodgkin, who gave a gross description of abnormal adenopathy¹  and would later be credited by Dr. Samuel Wilks with the discovery of HL lymphoma.²  Years later, with the aid of the microscope, pathologists identified the malignant cells of HL, now known as Reed-Sternberg cells. The next evolution in HL occurred with the discovery of radiotherapy (RT) and its benefits, particularly in early-stage HL,^3-4  with the notion of a “cure” first becoming associated with the disease. During the same era in which the role of RT in HL was being established, researchers began exploring the benefits of chemotherapy based on observations of the effects of chemical warfare in World War II, with the first clinical trials of nitrogen mustard in patients with hematologic cancers conducted in 1942.^5-6  It would be another two decades before combination regimens were studied in this patient population.^7-8 

The most impactful chemotherapy-based study of subsequent years, conducted by Vincent DeVita Jr., MD, and colleagues, involved the use of nitrogen mustard, vincristine, prednisone, and procarbazine (MOPP).⁹  This seminal study was the first to demonstrate the curative potential of chemotherapy specific to advanced-stage HL. While this regimen was far more successful than others for HL, there was still a modest percentage of patients who failed to obtain remission or whose period of improvement was short-lived. Given the success of MOPP, researchers began exploring and developing other combination regimens that were not cross-resistant to the agents used in MOPP. One of the most successful of these regimens involved six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).¹⁰  While ABVD was not developed to take the place of MOPP, it demonstrated similar efficacy and improved safety. The reduction in infertility rates and secondary cancers associated with ABVD was of particular note, given that HL has a higher prevalence in younger patients than most other cancers. This eventually led to the establishment of ABVD as the standard of care (SOC) for advanced-stage HL in the United States.^11-19 

Despite improvements in safety, however, there remained some unique toxicities associated with ABVD’s dosing schedule (each biweekly cycle consists of two treatments with all four drugs), particularly in older patients. No toxicity has likely been more concerning for this regimen than bleomycin-induced pneumonitis.²⁰  This insidious and potentially fatal side effect was a key driver behind the development of the brentuximab vedotin plus AVD (A+AVD) regimen,²¹  which was compared to ABVD in the ECHELON-1 study.²²  While the results of this trial were positive, adoption of the regimen was slow given the study’s primary endpoint of progression-free survival (PFS) after second-line therapy. The novelty of this endpoint versus traditional PFS led to some consternation among clinicians about the role of this regimen, especially with recent data suggesting durable efficacy in advanced-stage HL with the removal of bleomycin after the second cycle and the continuation of AVD for the remaining four cycles of therapy in patients who obtained complete remission (CR). Additionally, this regimen did not eliminate toxicity concerns related to the treatment of older patients, despite not containing bleomycin.

In time, further follow-up data indicated a PFS benefit²³  (and, eventually, a survival benefit) of A+AVD compared to ABVD in patients with advanced-stage HL.²⁴  Yet while the reign of ABVD extended for several decades, A+AVD looks to have been replaced within a scant few years.

Research conducted by Alex F. Herrera, MD, and colleagues²⁵  demonstrates that, even with short follow-up time, addition of the checkpoint inhibitor nivolumab to the AVD backbone is superior to A+AVD. This remarkable study enrolled and randomized 994 pediatric and adult patients (aged 12 years or older) with stage III or IV HL to either A+AVD or nivolumab plus AVD (N+AVD), with 970 patients included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved PFS as compared with A+AVD (hazard ratio [HR] for disease progression or death = 0.48; 99% CI 0.27-0.87; two-sided p=0.001). With a median follow-up of 2.1 years (range, 0 to 4.2 years), the two-year PFS was 92% (95% CI 89-94) for N+AVD, compared to 83% (95% CI 79-86) for A+AVD (HR for disease progression or death = 0.45; 95% CI 0.30-0.65). Importantly, the HR for patients over age 60 was 0.30 (range, 0.12-0.72) in favor of N+AVD. Historically, there have been differences between how pediatric and adult hematologists have managed HL, particularly regarding the use of RT. Therefore, it is also notable that the use of RT was less than 1% in the N+AVD arm of this study, saving patients from the long-term risks associated with such treatment. The authors rightfully concluded (in so many words) that N+AVD should be considered the new SOC in advanced-stage HL in the U.S.

With the wonderful results of this study, longer follow-up is eagerly awaited to determine longer-term benefits and survival associated with N+AVD. Additionally, clarity is hoped for regarding the long-term consequences of checkpoint inhibitors (CPIs), given that the introduction of nivolumab into the frontline regimen (albeit with a shorter duration) will result in a much greater number of patients being exposed to CPI as compared to those in the relapsed/refractory population. Further study should also look to determine resistance mechanisms for those who fail or relapse after recent treatment with the N+AVD regimen.

We can continue to expect advancements in the treatment of patients with HL per the rapid changes to the SOC for HL over the last few years. The results of this magnificent study suggest that the reign of N+AVD will last for some time, putting an end to what has been a remarkable “game of thrones” over the last five years.