Advanced-stage Hodgkin lymphoma in an elderly patient: A case report highlighting the efficacy of brentuximab vedotin treatment
Hodgkin lymphoma (HL) is an aggressive hematological malignancy, with around 70 new cases being reported per year in Hong Kong.1 The incidence rate for HL among people aged 65 or above in Hong Kong is 1.6 per 100,000 persons.1 Survival rates are high during the early stages of disease, with an estimated 5-year overall survival (OS) of over 86% in the United States (US).2 However, outcomes are considered less favorable in patients with advanced‐stage disease (Stage III or IV) which is observed in 40% of patients at initial presentation.3 Dr. Liu, Sung-Yu Herman, Specialist in Hematology and Hematological Oncology, shared a case of an elderly patient, with advanced-stage HL, who was managed successfully with brentuximab vedotin.
The management of HL has seen a remarkable improvement over the last 50 years due to better understanding of the disease biology and the availability of effective and safer treatment options.3 The current standard of care for HL makes use of a regimen consisting of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD).3 This regimen, when used in the early stages of disease, has led to marked improvements in clinical outcomes as compared with the pre‐ABVD era.4,5 However, the survival rate of advanced-stage HL remains less favorable.3 Recently, brentuximab vedotin has been approved in the frontline therapy for stage IV HL and has replaced bleomycin from the ABVD regimen (A+AVD).6
Bleomycin-induced pulmonary toxicity is a major contributor to toxicity in most frontline therapies for advanced-stage HL.7 Replacement of bleomycin with brentuximab vedotin in the frontline regimens has reduced therapy-related lung toxicity and subsequently enhanced clinical outcomes.8 The increased tolerability of this new regimen could be beneficial in treating older age groups with advanced-stage HL.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and monomethyl auristatin E (MMAE).8 It remains stable in plasma, but once internalized in CD30-expressing cells and cleaved by a protease, it releases the MMAE agent, causing cell cycle arrest and apoptosis by disrupting microtubules.8 The efficacy of brentuximab vedotin as frontline therapy was evaluated in the ECHELON-1 trial. ECHELON-1 was an open-label, multicenter and randomized phase 3 trial involving patients with previously untreated stage III or IV classic HL, and was shown to improve PFS with A+AVD than ABVD alone.8 Dr. Herman Liu emphasized, “The patient is at an advanced age with advanced-stage HL and both of these factors are poor prognostic indicators.”
The patient described in this case is an 85-year-old man presented with high-grade fever (40°C), weight loss of 20lbs over 6 weeks, and night sweats. The patient had no relevant family history, but suffered from hypertension, diabetes mellitus and hyperlipidemia. He was previously a chronic smoker, having discontinued the habit 10 years ago, and suffers from chronic obstructive pulmonary disorder (COPD) as a result. Initially, he was treated by a Specialist in Respiratory Medicine due to lung infection; chest X-ray and computed tomography (CT) scan displayed multiple enlarged lymph nodes. A lymphoma was suspected, and the patient was referred to Dr. Liu. Under Dr. Liu’s care, the patient underwent a positron emission tomography (PET) scan and lymph node biopsy before reaching a diagnosis of stage IV HL. Dr. Liu commented, “It is not very common. The incidence is only 70 cases per year and usually presents as a bimodal distribution at the 30-35 age group or at extended age.” Due to the advanced age of the patient and advanced stage of the disease, initial outlook appeared dismal. Additionally, the patient was found to have pancytopenia. The treatment regimen being considered was a combination of chemotherapy and anti-CD30 therapy. Routine ABVD therapy was chosen, but bleomycin was replaced by brentuximab vedotin. Due to preexisting COPD, the removal of bleomycin was an advantage due to the possibility of lung toxicity.
The patient was then hospitalized for the treatment of lung infection and pancytopenia; intravenous antibiotics were administered. Concurrently, chemotherapy was initiated at day 1 and day 15 of each cycle, with cycles being 4 weeks apart. During the first cycle, chemotherapy dose was reduced to a third as the patient was too physically weak to tolerate the full dose. However, full dose of brentuximab vedotin was administered. The patients’ fever subsided within 2-3 days of therapy. PET scan after the second cycle (PET2) observed diminished lymphadenopathies, and the patient was discharged after recovering from pancytopenia. Later on, the patient completed the remaining four cycles of the therapy, and he only felt tired on the first day of treatment. By the day after treatment, he was even fit enough to go out for a short walk. “Without brentuximab vedotin, the patient may have to rely solely on chemotherapy. I am not sure how many cycles he could tolerate,” stated Dr. Liu, who pointed out that in the absence of brentuximab vedotin, any reduction in chemotherapy dosage due to intolerance could have resulted in partial remission of the disease. At the end of six cycles, the PET scan showed complete metabolic response and the patient currently remains in the disease remission for 9 months. Commenting on the role of brentuximab vedotin in the management of the patient, Dr. Liu highlighted, “It definitely made a huge difference in the life of this patient.”
The treatment outcome of advanced-stage HL is determined by several demographic and socioeconomic indicators.3 Age in particular has been identified as an imperative prognostic factor for survival.3 A study by Henderson et al. demonstrated that the ability to tolerate intensive therapy and biological differences in disease response to therapy changes with age.9 Newer regimens developed in combination with brentuximab vedotin, such as sequential A+AVD, have particularly improved clinical outcomes in older patients with HL.10 In addition, due to the pulmonary toxicity, the replacement of bleomycin from standard of care with brentuximab vedotin is an added advantage for elderly patients with respiratory deficiencies.7 For instance, the use of bleomycin in the case presented could have aggravated the underlying chronic obstructive pulmonary disorder.
A+AVD has demonstrated a good tolerability among elderly and it should be noted that additional geriatric-based measurements, such as Geriatric Comorbidity Score and International Prognostic Score, are strongly correlated with patient survival.10 Thus, when treating geriatric patients with advanced stage HL, as in this case presented, their related comorbidities and abilities to tolerate the prescribed dose should be considered.
In the ECHELON-1 study conducted on previously untreated stage III or IV classic HL, patients were assigned to receive A+AVD (n=664) or ABVD (n=670).8 After a median follow-up of 24.9 months, the 2-year modified PFS was significantly higher in the A+AVD group (82.1%) than in the ABVD group (77.2%), which corresponded to a 23% risk reduction (Modified progression=0.77, p=0.03).8
In the 3-year update of the ECHELON-1 study, the PFS benefits remained durable.11 After a median follow-up of 37.1 months, the 3-year PFS rates, irrespective of PET2 status, were 83.1% in the A+AVD arm and 76.0% in the ABVD arm (HR=0.704; 95% CI: 0.550-0.901; p=0.005) (Figure 1).11 Most importantly, a trend favoring A+AVD was also observed for 3-year PFS in the subset of patients aged ≥60 years.11
The consistent PFS benefit demonstrated by A+AVD therapy in the intent-to-treat population appeared independent of disease stage and prognostic risk factors such as age and international prognostic score.11 During follow-up, peripheral neuropathy continued to resolve and improve in both arms.11
Taken together, A+AVD therapy provides a sustainable PFS benefit with a predictable and manageable safety profile. Furthermore, these data support the advantages of A+AVD over ABVD as the frontline treatment of patients with advanced stage III or IV HL. Despite poor prognostic indicators, the patient tolerated and recovered well with brentuximab vedotin. The enhanced survival of this patient is an evidence to the clinical efficacy of brentuximab vedotin. “We have been using ABVD to treat HL for many years, but we have to bear in mind that if we treat patients with advanced stages, there are better treatment options available, such as brentuximab vedotin, for attaining optimal survival benefits,” Dr. Liu remarked.
Although the survival of patients with early-stage HL has continued to improve over time, the survival rates for advanced-stage HL remain inadequate. Furthermore, significant differences in survival, which is influenced by nonbiological factors, such as age, continue to exist, highlighting the need for novel therapies to address these discrepancies. Brentuximab vedotin has set a new benchmark as the frontline combination regimen in advanced HL, with substantial and robust survival benefits.
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