Improving Risk/Benefit of Frontline Classical Hodgkin Lymphoma Treatment

Ranjana H. Advani, MD

The main goal of therapy for advanced-stage classic Hodgkin lymphoma (cHL) should be to increase efficacy and limit toxicity, according to a presentation at given by Ranjana H. Advani, MD, at the NCCN 2021 Virtual Congress: Hematologic Malignancies.¹

cHL accounts for approximately 10% of all lymphomas, with 9000 new cases in the United States. The early favorable cure rate is ≥ 90% and the cure rate for advanced-stage disease is between 75% and 85%.

“It's highly curable with frontline therapy, even in advanced stage disease. And at any given time, there are more cured survivors than patients with active disease,” said Advani, a medical oncologist, lymphoma specialist, and the Saul A. Rosenberg, MD, professor of Lymphoma at Stanford Health Care.

The last decade of clinical trials have focused on using interim positron emission tomography (PET) based modification of therapy, which allows for treatment escalation or de-escalation. Currently, there are 2 main strategies for initial therapy. The first is to start with 2 rounds of the chemotherapy regimen of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), then escalate or de-escalate therapy based on a second PET scan. The second strategy is similar, but uses 2 rounds of escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP esc) that is escalated or de-escalated based on a second PET scan.

Five-year follow-up data from the phase 2 SWOG 0816 study (NCT00822120) found that the ABVD strategy produced high overall survival rates, along with the values and limitations of a PET approach. During the study, 331 received a PET scan at baseline, after 2 cycles of ABVD therapy, and 6-8 weeks after the end of treatment. At the 5-year follow-up, the progression-free survival (PFS) in those who were negative at PET2 was 76%, compared to the 66% who were PET-positive. PET-positive patients received 6 cycles of BEACOPP esc. The overall survival (OS) for those who were PET-positive was 86% compared with 96% of those who were PET-negative. Second cancers were seen in 14% of patients who received BEACOPP esc, with a median onset of 4.2 years.²

“The overall survival was excellent and the patients in whom therapy was escalated because of being PET- positive, [they] also had a very good progression-free survival of 66%. But getting 6 cycles of escalated BEACOPP as too much because there was a very high rate of second cancers,” said Advani.

According to Advani, the SWOG 0816 study highlights several things. First, it shows that it’s important to remember that relapse and second cancers occur late in cHL patients, pointing to the importance of long-term follow-up reports. Secondly, early PET response and adapted ABVD-based therapy for CHL improves outcomes and results. However, a high rate of false negatives using this strategy have been reported. Additionally, 6 cycles of BEACOPP esc lead to an unacceptable risk for second malignancies, and does not offer a better disease control rate than 4 cycles of BEACOPP exc.

The phase 3 RATHL study (NCT00678327) found that female patients who received response-adapted ABVD-therapy experienced reduced recovery of ovarian function. Additionally, BEACOPP was found to potentially have high gonadotoxicity.³

Advani also discussed evidence supporting the use of upfront BEACOPP, with or without dose modifications and treatment adjustments after the second PET scan., most notably in the phase 3 AHL LYSA 2011 study (NCT01358747).

“This was done as an attempt to reduce the BEACOPP-related toxicity. We don't have data on that yet. But what we do have is data on gonadal function recovery in patients on the cHL trial, where you can see the standard group that got the 6 cycles have escalated BEACOPP, whereas the study group is the 1 in which therapy was de-escalated to ABVD,” said Advani.

The AHL LYSA 2011 study found that upfront BEACOPP with dose adjustments after a second PET scan is safe and can help mitigate toxicity without impairing disease control. At the median follow-up of 67.2 months, median survival has yet to be reached. Six cycles of BEACOPP was found to be more toxic than 2 cycles of BEACOPP plus 4 cycles of ABVD. Common grade ≥ 3 adverse events for those who received 6 cycles of BEACOPP versus 2 cycles of BEACOPP with 4 cycles of ABVD included (anemia (11% vs 2% ), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), respectively.⁴

Gonadal function recovery was found to increase with time in both study groups. At 60 months, nearly all patients had ovarian function recovery (HR, 2.52; 95% CI, 1.73-3.67; P <.0001).

_REFERENCES:

_{1.Advani R, Optimizing first-line therapy for advanced stage Classic Hodgkin Lymphoma. Presented at: NCCN 2021 Virtual Congress: Hematologic Malignancies. October 14-16, 2021.}

_{2.Stephens D, Li H, Schöder H, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood. 2019;134 (15):1238–1246. doi:10.1182/blood.2019000719}

_{3.Anderson R, Remedios R, Kirkwood A, et al. Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial. Lancet Oncol. 2018;19(10):1328-1337. doi: 10.1016/S1470-2045(18)30500-X}

_{4.Casasnovas O, Brice P, Bouabdallah R, et al. Randomized phase III study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma: Final analysis of the AHL2011 LYSA study. J Clin Oncol. 2018;36(15):7503. doi: 10.1200/JCO.2018.36.15_suppl.7503}