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A.M. Evens et al.
treatment in those receiving PET2-adapted therapy and for PET2-positive patients (who continue on more inten- sive therapy), must be considered. However, treatment intensification is not recommended for older patients because of poor tolerance of BEACOPP.29 In the random- ized HD9elderly study comparing baseline-BEACOPP regi- men with cyclophosphamide, vincristine, procarbazine, prednisone + ABVD (COPP-ABVD), the treatment-related mortality rates among 75 patients with advanced-stage HL aged 66–75 years were 21% and 8%, respectively.7 A modified regimen incorporating brentuximab vedotin, dacarbazine, and dexamethasone (BrECADD) in place of bleomycin, vincristine, procarbazine, and prednisone (as used in BEACOPP) is being investigated in a phase III trial (HD21; NCT02661503)30 after a phase II study found that this regimen was associated with a relatively favorable toxicity profile while maintaining a complete response rate of 88%.31
Microtubule inhibitors, such as the vinca alkaloids (e.g., vinblastine and vincristine) and the monomethyl auris- tatin E component of brentuximab vedotin are associated with occurrence of peripheral neuropathy.32-34 The inci- dence of any-grade peripheral neuropathy in older patients was higher with A+AVD than with ABVD (65% vs. 43%), especially grade 3/4 peripheral neuropathy (18% vs. 3%). Severe peripheral neuropathy was also more fre- quently seen in older than younger cHL patients treated with A+AVD. In the A+AVD arm, approximately four- fifths of older patients with peripheral neuropathy experi- enced improvement or resolution, a rate similar to that observed in the ABVD arm. With longer follow-up, resid- ual peripheral neuropathy continues to improve and resolve.21,35 These findings highlight the importance of appropriate screening, monitoring, and active clinical management of peripheral neuropathy in patients treated with A+AVD (including potential dose reductions particu- larly in older patients who frequently present with multi- ple comorbidities).
In the current analyses, the rates of neutropenia and febrile neutropenia were higher in the A+AVD arm overall and, moreover, higher in older than younger patients in both the A+AVD and ABVD arms. Although the use of primary prophylaxis with G-CSF was not mandated in ECHELON-1 and the cohort of older patients who received G-CSF primary prophylaxis was small (n=10), post-protocol amendment use of G-CSF primary prophy- laxis was associated with reduced rates of neutropenia and febrile neutropenia in patients treated with A+AVD. Similar effects of primary prophylaxis with G-CSF on rates of neutropenia and febrile neutropenia were observed in patients treated with A+AVD in the overall ECHELON-1 study population.36 Consequently, G-CSF primary prophylaxis is recommended for all patients who receive A+AVD.37 As the optimal dosing schedule has not been established, G-CSF should be administered with each cycle, starting at cycle 1, as recommended in the US prescribing information and EU Summary of Product Characteristics.
Taken together, these data showed overall similar effica- cy for A+AVD and ABVD in older patients with stage III/IV cHL. A+AVD was associated with increased neu- ropathy and neutropenia but with less pulmonary-related toxicity compared with ABVD. Thus, A+AVD represents a treatment option (with primary prophylaxis with G-CSF) for selected fit, older patients with cHL overall,
and especially for patients in whom pulmonary toxicity is a concern. Moreover, outcomes reported here set a new benchmark for older patients with untreated cHL when treated with A+AVD or ABVD. However, continued study of new therapeutic regimens is needed to improve out- comes and to decrease toxicity for older cHL patients. This includes continued examination of PET response- adapted strategies, which may be prognostic in brentux- imab vedotin-based treatment for older cHL patients,19,21 as well as analysis of timing of brentuximab vedotin rela- tive to chemotherapy (i.e., sequential vs. concurrent), inte- gration of other targeted therapeutic agents (e.g., NCT03907488), and via the incorporation of objective geriatric assessments for prediction of tolerable and indi- vidualized therapy.
Disclosures
AME reports consultancy with honoraria for MorphoSys, Miltenyi, Seagen, and Epizyme; membership on an advisory committee with honoraria for Pharmacyclics and Novartis, Inc.; and research funding from Tesaro. JMC reports research funding from Merck, Amgen, Roche Canada, NanoString Technologies, Seagen, Janssen, F. Hoffmann-La Roche, Bayer Healthcare, Cephalon, Bristol Myers-Squibb, Lilly, Genentech, and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; being a named inventor on a patent licensed to NanoString Technologies; and honoraria from Seagen. AY reports research funding from J&J, Bristol Myers-Squibb, Curis, Genentech, Pharmacyclics, Janssen, Novartis, Roche, Abbvie, and Astra Zeneca; and hono- raria from Celgene, Bristol Myers-Squibb, Sanofi, Abbvie, Merck, Bayer, Incyte, Seagen, Roche, and Takeda. SMA reports research funding from LAM Therapeutics, Regeneron, Pfizer, Bristol-Myers Squibb, Merck & Co, Trillium, Seagen, Celldex, Takeda, and Affimed. JR reports research funding from Celgene, ADC Therapeutics, Pfizer, and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; consultancy for ADC Therapeutics, Novartis, Takeda, Seagen, and Bristol Myers-Squibb; equity ownership in GlaxoSmithKline and AstraZeneca; and speakers bureau for Novartis, Takeda, Seagen, and Bristol Myers-Squibb. TF reports research funding from Seagen and Portola; and speakers bureau for Seagen, Janssen, Pharmacyclics, J&J, Celgene, and KITE. JT reports research funding from Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Genentech, Celgene, and Pharmacyclics; speakers bureau for Amgen, Seagen, and Celgene; and honoraria from Amgen, Seagen, and Celgene. KJS reports honoraria from and consulting for Seagen, Merck, Bristol Myers-Squibb, Abbvie, Astra Zeneca, Verastem, and Gilead Consulting Servier; and research funding from Seagen, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company, Merck, Bristol Myers- Squibb, Beigene, and Roche Canada. YO reports employment with Genentech and research funding from Seagen and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; honoraria from Takeda Millennium; and employment with Jazz Pharmaceuticals. AGri reports membership on an entity's Board of Directors or advisory committees for Roche, Gilead, Bristol Myers-Squibb, and Takeda. CP reports employment with Kent & Canterbury Hospital. MD-D reports consultancy for Servier and Roche. KF reports employment with and equity ownership in Seagen, Inc. AF-T reports employment with Seagen, Inc. RL, HJ, and AGau report employment with Millennium Pharmaceuticals,
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