Risk-Based Treatment of Hodgkin Lymphoma in the Era of Novel Therapies

Catherine Diefenbach, MD

The widely accepted standard of care for patients with early-stage Hodgkin lymphoma (HL) is the chemotherapy regimen ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin sulfate, vinblastine, dacarbazine) followed by involved-field radiation therapy (IFRT), or 4 cycles of ABVD with or without IFRT, according to Catherine Diefenbach, MD—and, for advanced-stage patients, 6 cycles of an ABVD backbone with either response-adapted approach or novel agents.¹ Despite complete remission rates of up to 90%, late toxicities, such as secondary malignancies and cardiovascular events, are key concerns in patients treated for early-stage HL.²

Diefenbach, director of hematology translational research and director of the clinical lymphoma program at NYU Langone Health’s Perlmutter Cancer Center, New York, New York, said in an interview with The SOHO Daily News ahead of the 11th Annual Meeting of the Society of Hematologic Oncology, “There’s been a large emphasis over the [past] 30 years in moving from treating all patients with extensive toxic chemotherapy and radiation to minimizing late toxicities in patients who are cured of their Hodgkin lymphoma but then go on to develop breast cancer or cardiac disease because of radiation to the chest.” To minimize unnecessary toxicities, new tools are needed to distinguish between early-stage patients with a high cure rate and those who could benefit from switching to another treatment. Diefenbach discussed balancing the risks and benefits of therapy in limited-stage HL in a presentation on Friday, September 8, 2023.

Interim PET scan is a prognostic tool used to identify patients needing de-escalated or escalated therapy. Patients with a negative early PET scan have the highest probability of cure (>90%) whereas those with a positive early PET scan have poorer outcomes.² The EORTC/LYSA/FIL H10 trial (NCT00433433) examined treatment adaptation based on early PET scan in patients with previously untreated early-stage HL who received 2 cycles of ABVD.2 Patients with a negative PET received only ABVD whereas those with a positive PET received 2 cycles of BEACOPP (bleomycin sulfate, etoposide phosphate, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate [Oncovin], procarbazine hydrochloride, prednisone) followed by radiotherapy.² Results showed that patients with positive PET results had progression-free survival (PFS) improve from 77.4% (95% CI, 70.4%-82.9%) to 90.6% (95% CI, 84.7%-94.3%) as compared with patients having negative PET results, although overall survival (OS) did not differ between the 2 groups.²

In the RAPID trial (NCT00943423), researchers investigated whether radiotherapy could be omitted in the treatment of patients with nonbulky early-stage HL when the interim PET was negative after 3 cycles of ABVD.³ Patients with negative PET results received either IFRT or no further treatment whereas those with positive PET results received 1 additional cycle of ABVD plus radiotherapy.³ The 3-year PFS was 90.8% (95% CI, 86.%-94.8%) for the PET-negative group with no further treatment, 94.6% (95% CI, 91.5%-97.7%) for the PET-negative group with IFRT, and 83% for the PET-positive group.³ The EORTC/LYSA/FIL H10 and RAPID trials also demonstrated that therapy escalation may improve outcomes for patients with advanced-stage HL with a suboptimal response to therapy.³

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One of the most notable clinical trials to propel the field in terms of risk-adapted therapy was the RATHL study (NCT00678327), during which patients with advanced-stage HL received 2 cycles of ABVD followed by chemotherapy and an interim PET scan.⁴ Patients whose PET results were negative were randomized to continue ABVD or receive AVD (no bleomycin), whereas those whose PET results were positive received BEACOPP.⁴ Patients in the BEACOPP group had a 3-year PFS of 67.5% (95% CI, 59.7%-74.2%) and an OS of 87.8%.⁴ The 3-year PFS and OS in the ABVD group were 85.7% (95% CI, 82.1%-88.6%) and 97.2% (95% CI, 95.1%-98.4%), respectively, compared with 84.4% (95% CI, 80.7%-87.5%) and 97.6% (95% CI, 95.6%-98.7%) in the AVD group.⁴ Patients who received ABVD experienced more severe respiratory adverse events than those who received AVD.⁴ “Bleomycin is really the primary chemotherapy related to toxicity in Hodgkin lymphoma. The ABVD regimen has pulmonary toxicity, which can be cumulative, but dropping the bleomycin improves tolerability and considerably lowers the risk of toxicity,” Diefenbach said.

Another noteworthy study is ECHELON-1 (NCT01712490), which did not use a response-adapted approach but demonstrated a survival advantage for first-line treatment with brentuximab vedotin (Adcetris; Seagen), an immunoconjugate directed to CD30, plus AVD (A+AVD).⁵ Patients with previously untreated advanced-stage HL were randomized to receive either 6 cycles of A+AVD or ABVD.⁵ The 6-year OS and PFS were 93.9% and 82.3% for the A+AVD group (95% CI, 91.6%-95.5%), respectively, compared with 89.4% and 74.5% in the ABVD group (95% CI, 86.6%-91.7%).⁵ A+AVD is now one of the preferred regimens for the primary treatment of advanced-stage HL.⁶

Recently, the phase 3 SWOG S1826 trial (NCT03907488) showed that in patients with advanced-stage HL, treatment with the PD-1 inhibitor nivolumab plus AVD was superior to A+AVD.⁷ Early results showed that the 1-year PFS was 94% in patients treated with nivolumab plus AVD compared with 86% in those who received A+AVD.⁷

“What’s needed next is to better understand how to tailor therapy according to risk and biology,” Diefenbach said. “Unfortunately, there are no biomarkers that help us to determine the ideal treatment plans for patients. In addition, there is a concern that as the most successful agents for relapsed patients move into earlier lines of therapy, how will patients be salvaged if they relapse?

“These next steps should certainly be explored using new tools we have at our disposal to create new risk stratification and de-escalation paradigms for patients with good-risk disease and continue to explore the optimal therapeutic platforms that can maximize cure and minimize toxicity for patients with advanced-stage and high-risk disease,” Diefenbach added.

In conclusion, there are multiple approaches for treating patients with HL, and emerging data from clinical trials has increased the number of treatment options and the complexity of choosing a regimen. For those with early-stage disease, the goal should be to maximize cure while minimizing toxicity. For patients with stage IIB disease, the data support a response-adapted approach, and for advanced-stage III or IV disease, integration of novel therapies into standard ABVD or risk-adapted approach remain treatment options. Particular attention should be paid to optimizing treatment for frail or older patients, and for tailoring therapeutic intensity to risk for all patients.

References

1.Aldin A, Umlauff L, Estcourt LJ, et al. Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies. Cochrane Database Syst Rev. 2020;1(1):CD012643. doi:10.1002/14651858.CD012643.pub3

2.Andre MPE, Girinsky T, Federico M, et al. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017;35(16):1786-1794. doi:10.1200/JCO.2016.68.6394

3.Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015;372(17):1598-1607. doi:10.1056/NEJMoa1408648

4.Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016;374(25):2419-2429. doi:10.1056/NEJMoa1510093

5.Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125

6.NCCN. Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2023. Accessed August 3, 2023. https://tinyurl.com/5dkp4awy

7.Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/JCO.2023.41.17_suppl.LBA4