The use of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in treatment of Hodgkin lymphoma (HL) was originally described in 1975 with subsequent comparisons to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), resulting in the incorporation of ABVD as the standard of care in untreated advanced-stage HL for the subsequent 30 years. The efficacy of ABVD and salvage therapy, if required, has allowed significant attention to be turned to minimizing therapy related toxicities in HL. The recent presentation and publication of the ECHELON-1 study comparing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) versus ABVD continues to improve therapeutic efficacy in HL while offering a differing toxicity profile.
Balancing Survival & Toxicity With ABVD
In patients with advanced stage (stage III/IV) disease, at least 75 percent of patients treated with ABVD will be cured (J Clin Oncol 1987;5:27-37, J Clin Oncol 2009;27:5390-5396, J Clin Oncol 2009;27:805-811). And of those who require salvage therapy, based on risk factors present at the time of relapse, between 30 percent and 80 percent will achieve long-term disease remission and potentially be cured (J Clin Oncol 2002;20:221-230).
One of the most dangerous complications of ABVD is pulmonary toxicity associated with bleomycin, which has been reported to occur in 18 percent of patients in one large series (J Clin Oncol 2005;23:7614-7620), with higher rates up to 43 percent in older patients (Br J Haematol 2015;170:179-184, Br J Haematol 2013;161:76-86). When using ABVD, patients should be assessed for possible risk factors for bleomycin-associated lung toxicity including older age, cumulative dose of more than 400 mg, smoking history, renal insufficiency, and radiation to the lung fields (J Clin Oncol 2005;23:7614-7620), with risk reduction pursued as able with measures such a smoking cessation and limitation of radiation fields.
NCCN guidelines also recommend baseline pulmonary function testing with measurement of the diffusing capacity of the lungs for carbon monoxide (pulmonary function tests (PFTs) with diffusing capacity of carbon monoxide (DLCO)), and they recommend against the routine use of granulocyte-colony stimulating factor (G-CSF) (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Guideline Hodgkin Lymphoma Version 1). Close monitoring for new or worsening respiratory symptoms such as cough, dyspnea, or decrease in O2 saturation by pulse oximetry is essential with follow-up imaging and repeat PFTs indicated if symptoms are present. If a patient has suspected pulmonary toxicity, bleomycin should be discontinued and the patient should not be re-challenged. High-dose corticosteroids (prednisone 60-100 mg/day) are commonly used to treat bleomycin associated lung toxicity, although there is no randomized data supporting their use (Chest 2001;120:617-624).
Most recently, in ECHELON-1, the ABVD arm experienced lower pulmonary toxicity rates with 7 percent of patients experiencing toxicity and only 3 percent of patients having grade 3 or higher toxicity. This lower rate compared to older series was likely due a combination of younger age of patients (85% were less than 60 years) and contemporary effort to minimize use of G-CSF with bleomycin (only 6% of the ABVD arm received primary G-CSF ppx), as well as close monitoring on trial keeping rates of high-grade toxicity low.
Reduction of the cumulative dose of bleomycin can also decrease rates of lung toxicity and has been incorporated into NCCN guidelines based on results of the RATHL trial (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Guideline Hodgkin Lymphoma Version 1, N Engl J Med 2016;374:2419-2429). In this trial, patients with a response to treatment (defined as a PET/CT Deauville score of 3 or less) after two cycles of ABVD were randomized to receive four more cycles of ABVD, or four cycles of AVD without bleomycin. Severe (grade 3/4) respiratory events were seen in 3 percent of the patients in the ABVD arm versus 1 percent of the patients in the AVD arm, and patients in the AVD arm were less likely to experience a decrease in DLCO. Notably, survival was similar between the AVD and ABVD groups with 3-year PFS being 84.4 percent versus 85.7 percent, respectively, and 3-year overall survival reported as 97.6 percent versus 97.2 percent. Given the survival data, this approach may be particularly appealing to those patients in whom concerns about treatment-related toxicity exceeds concerns regarding a small increased risk of relapse (e.g., elderly and those with pre-existing lung disease).
Neutropenia & Neuropathy in A+AVD
Brentuximab vedotin is an antibody-drug conjugate against the cell surface marker CD30, which is expressed on the malignant lymphocytes of HL. It was initially approved for HL in the relapsed/refractory setting, with researchers describing an ORR of 75 percent (34% CR) in this population with limited therapeutic alternatives (J Clin Oncol 2012;30:2183-2189). It was subsequently approved as consolidation therapy after ASCT based on the AETHERA trial showing a benefit in patients that are at high-risk of post-transplant relapse (Lancet 2015;385:1853-1862).
ECHELON-1 was an international, open-label, randomized, multicenter phase III trial with enrollment of over 1,300 patients with stage III/IV untreated Hodgkin lymphoma comparing the current standard of care ABVD versus the investigational regimen A+AVD. The primary endpoint in this study was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of incomplete response followed by subsequent therapy. In ECHELON-1, improved efficacy was seen with a 2-year modified PFS of 82.1 percent (95% CI: 78,7%-85.0%) in the A+AVD arm versus 77.2 percent (73.7 percent-80.4%) in the ABVD arm with a hazard ratio for an event of progression, death, or modified progression of 0.77 (0.60-0.98; p=0.03).
While A+AVD was proven to be more efficacious, there were differing toxicity profiles seen between A+AVD and ABVD. In the non-bleomycin containing A+AVD regimen, lower rates of pulmonary toxicity were seen with grade 3+ pulmonary toxicity only seen in 1 percent of the A+AVD group versus 3 percent of the ABVD group. Among deaths during treatment, 11 of 13 in the ABVD group were attributed to pulmonary toxicity.
However, the A+AVD group did experience higher rates of peripheral neuropathy and febrile neutropenia. Sixty-seven percent of patients in the A+AVD group experienced peripheral neuropathy as compared to 43 percent in the ABVD group. It is notable that the neuropathy was largely reversible in the A+AVD arm with 43 percent experiencing complete resolution and additional 24 percent experiencing improvement by at least one grade at time of last follow-up. Of the patients with ongoing peripheral neuropathy, 92 percent were grade 1 (64%) or grade 2 (29%) events. Per trial protocol, patients who experienced moderately symptomatic neuropathy, as defined by limiting instrumental activities of daily living, were required to undergo a brentuximab vedotin dose reduction from 1.2mg/kg to 0.9mg/kg, while drug-hold was required for patients with severe symptoms limiting activities of daily living or requiring assistive devices.
Unexpectedly high rates of febrile neutropenia were initially seen with the use of A+AVD. However, outcomes were improved after primary G-CSF prophylaxis with A+AVD was instituted, after which rates dropped from 21 percent to 11 percent; this is in comparison to an 8 percent rate of febrile neutropenia in the ABVD group. Of the deaths during treatment in the A+AVD arm, seven of nine were associated with neutropenia (and presumably due to infection, although not specified), with none of those seven receiving primary G-CSF prophylaxis. Of those patients in the A+AVD arm who received primary G-CSF prophylaxis, only one death was associated with neutropenia—a patient who was enrolled with pre-existing neutropenia.
As with ABVD, given the curative intent of frontline therapy in HL, an attempt was made to minimize any dose reductions due to toxicities from A+AVD as seen in the recommended dose modifications for treatment-associated toxicities due to A+AVD. Notably, 96 percent of patients in ECHELON-1 had an ECOG performance status of 0 or 1, and the number of patients over 60 years of age was small.
Factors for Choosing an Upfront Regimen
Brentuximab vedotin is currently undergoing priority review by the FDA for use in untreated Hodgkin lymphoma as part of the A+AVD regimen. If approved, clinicians will have two very effective regimens to choose from. While A+AVD may provide a slightly improved efficacy rate as defined by modified PFS, it has a differing toxicity profile, and several factors should be considered.
Elderly patients were not a significant proportion of patients on ECHELON-1, and how they will tolerate increased rates of neutropenia seen with A+AVD—even with primary G-CSF prophylaxis—is unclear, with 37 percent of elderly patients in the A+AVD arm experiencing febrile neutropenia as compared to 17 percent in the ABVD arm. This is compared to the well-described rates of toxicity in patients over 60 years of age who undergo treatment with ABVD in which the German Hodgkin Study Group described 10 percent of patients experiencing serious infections, 5 percent experiencing serious respiratory complications, and 5 percent experiencing treatment-related mortality (J Clin Oncol 2013;31:1522-1529).
However, we also must consider that the elderly experience higher rates of pulmonary toxicity with exposure to bleomycin in the ABVD regimen, and consider this in the context of additional risk factors for pulmonary toxicity such as previous known pulmonary dysfunction, a significant smoking history, or significant concern of needing G-CSF prophylaxis while on treatment.
Consideration of existing peripheral neuropathy or a diagnosis of diabetes must also be considered when choosing regimens. Patients receiving A+AVD did experience higher rates of peripheral neuropathy, with the majority of patients experiencing resolution of neuropathy by the final study visit. However, patients with any underlying sensory or motor peripheral neuropathy—a common complication of diabetes—were excluded from enrolling in ECHELON-1.
Additional considerations are that ECHELON-1 only enrolled stage III and IV patients, and the use of A+AVD regimen in earlier stage patients in combination with radiation has been less well-described. Initial economic costs with A+AVD will be higher than with ABVD. However, presumably a portion of those costs would be saved in the form of less use of salvage stem cell transplant and therapies such as PD-1 inhibitors. Finally, while we have decades of experience with the ABVD regimen, long-term follow-up for toxicities and efficacy with A+AVD is still pending. Fortunately, both regimens offer high rates of treatment efficacy, with manageable toxicity profiles to help patients diagnosed with HL.
I. BRIAN GREENWELL, MD, is a Fellow of Hematology and Medical Oncology at Winship Cancer Institute, Emory University, Atlanta. JONATHON B. COHEN, MD, MS, is Assistant Professor, Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta.