Partial omission of bleomycin for early‐stage Hodgkin lymphoma patients treated with combined modality therapy: Does incomplete ABVD lead to inferior outcomes?

Abstract Classical Hodgkin lymphoma (HL) patients achieve excellent outcomes; therefore, treatment de‐escalation strategies to spare toxicity have been prioritized. In a large randomized trial of early‐stage HL patients, omission of chemotherapeutic agents including bleomycin from the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen was not found to be noninferior; however, the effect of partial omission is unknown. We investigated the effect of bleomycin omission on outcome for 150 early‐stage HL patients. At 8 years, freedom from relapse was 99% for both patients who received complete or incomplete bleomycin, which is reassuring for patients requiring bleomycin omission due to toxicity.


INTRODUCTION
Given the excellent prognosis of classical Hodgkin lymphoma (HL) patients, therapy has been progressively de-escalated to minimize treatment-related toxicity. Large HL-randomized trials have explored bleomycin omission from all cycles [1] or later cycles [2] of the standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, but noninferiority could not be clearly established. For patients planned for combined modality therapy (CMT) with chemotherapy and radiation therapy (RT), oncologists may omit bleomycin from later cycles due to concern for increased risk of pulmonary toxicity. We aimed to explore the effect of full or partial omission of bleomycin on outcomes for earlystage HL (ESHL) patients treated with CMT.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. The five-point scale (FPS) [3] was not routinely used in assessment of PET-CT imaging. Therefore, patients were considered to have a negative interim PETCT if language such as "complete metabolic remission" or "complete resolution of FDG avidity" was used. All other interim PETCTs were reviewed independently by two radiation oncologists (JRG, CCP) and an FPS score was assigned. FPS scores of 1-3 were considered negative.
We compared characteristics and treatment-related variables for the CB and IB administration groups using Fisher's exact test and Wilcoxon rank sum. All statistical analyses were performed using JMP version 14 (SAS Institute, Cary, NC, USA). Overall survival (OS) and freedom from relapse (FFR) were estimated using Kaplan-Meier analysis.

DISCUSSION
In this study, we investigated the effect of full or partial bleomycin omission from the standard ABVD regimen for ESHL patients receiving CMT. We found that patients who received regimens with CB or IB both achieved excellent outcomes in terms of FFR and OS.
The pulmonary toxicity of bleomycin is well established [5,6], and this concern has motivated the randomized trials that examined the full or partial omission of the agent from the ABVD backbone. A large randomized trial of ESHL patients examined the effect of omitting dacarbazine, bleomycin, or both from standard ABVD therapy [1].
Five-year freedom from treatment failure was clearly inferior when In our study, provider rationales for omitting bleomycin varied, but several common themes emerged. Most often, providers chose to discontinue bleomycin due to symptoms or signs suggestive of pulmonary toxicity which included cough, shortness of breath, radiographic pulmonary changes, and/or worsening pulmonary function tests. Bleomycin administration was also terminated prematurely for many patients who were planned to receive consolidation RT. There may be less concern regarding inferior outcomes with bleomycin omission from initial chemotherapy for patients planned to receive CMT.
There is also possible theoretical concern for increased pulmonary toxicity in patients where the radiation treatment field would necessitate partial lung treatment. However, among HL patients that experience bleomycin toxicity, prior studies do not support an increased risk of radiation pneumonitis after mediastinal RT [5,7].
Finally, age or comorbid conditions often influenced the decision to omit bleomycin from all or part of the ABVD regimen. The median age of the IB group was slightly higher than the CB group, suggesting that providers may be more inclined to omit bleomycin in older patients. Studies have investigated the toxicity of the ABVD regimen in elderly patients, with focus on bleomycin-induced lung toxicity [8,9]. One study analyzed patients 60 years or older who were treated on the HD10 and HD13 trials and compared those who received two cycles of ABVD or AVD with those who received four cycles of ABVD, all followed by RT. Grade III-IV adverse events and bleomycin-induced lung toxicity were higher in those patients receiving four cycles of therapy. The authors conclude that more than two cycles of bleomycin led to a high risk of severe toxicity for older HL patients. Another study reported outcomes and toxicity for 147 patients aged 60 or above who received ABVD treatment for HL. As 14% of deaths were related to lung toxicity, the authors recommend bleomycin dose reduction or removal [9]. A phase I trial attempted to replace bleomycin with lenalidomide for Hodgkin lymphoma patients aged 60 years or above, and concluded that this approach was feasible and highly effective [10].
Although the toxicity concerns are valid, thus far published randomized data do not support the noninferiority of full bleomycin of chemotherapy that patients in the IB and CB groups received, suggesting that providers had concern for increased pulmonary toxicity with the administration of a full six cycles of bleomycin. However, it is also possible that, for patients requiring early bleomycin omission, providers had concern for inferior outcomes and therefore decided to give additional cycles. Moreover, a significantly higher proportion of patients had interim PET-CTs read as negative in the IB compared to the CB group, suggesting that providers were more willing to omit bleomycin after having the assurance of a negative interim PETCT. It is also possible that patients who received IB had an overall more favorable prognosis (given the interim PETCT negativity) compared to the CB group; however, the large number of patients in the CB group without interim PETCT results complicates this comparison.