“It isn’t the mountains ahead to climb that wear you out; it’s the pebble in your shoe.”

—Muhammad Ali

Long-term survival in early-stage classic Hodgkin lymphoma (cHL) was first made possible by the introduction of the mantle and inverted Y fields of radiotherapy in the 1960s. The addition of adjuvant mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)-like chemotherapies improved progression-free survival rates. However, it was increasingly apparent that cure was bought at a high price of late toxic effects.

The recent history of cHL clinical research and therapy has focused on therapy de-escalation while maintaining cure rates to reduce toxicity. Therapy adaptation with positron-emission tomography (PET) scans, including reduction of chemotherapy cycles and omission of radiotherapy in patients with early favorable responses, is now commonly used. In moving toward the goal of maximizing cure while minimizing toxic effects, greater individualization of therapy is appealing and remains the focus of robust research in early-stage cHL.

GUEST EDITORS

Syed Ali Abutalib, MD

Alex Francisco Herrera, MD

Dr. Abutalib is Director of the Malignant Hematology and Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Herrera is Chief of the Division of Lymphoma at City of Hope Medical Center, Duarte, California, and Associate Professor of Hematology, Hematopoietic Cell Transplantation, and Cellular Therapy.

RAPID Trial: Stage IA or IIA Without Mediastinal Bulk

ABSTRACT 457: Involved-field radiotherapy (IFRT) vs no further treatment in patients (aged 16–75) with newly diagnosed stage 1A or 2A nonbulky cHL and a ‘negative’ PET scan (Deauville score [DS] = 1–2) after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; n = 420). Survival and cause of death after a median of 16 years’ follow-up in the RAPID noninferiority trial (ClinicalTrials.gov identifier NCT00943423).¹

Background: Interim PET is prognostic in cHL, with a high negative predictive value associated with early metabolic response. Therefore, this technique is used in guiding a response-adapted approach in early-stage cHL, whereby patients who have positive PET findings after chemotherapy receive radiotherapy, but those with negative PET findings undergo no further treatment.

In early-stage cHL, abbreviated chemotherapy followed by 30 Gy of IFRT is commonly employed,² but results of the RAPID trial showed that most patients achieving PET-‘negative’ status are probably cured by abbreviated chemotherapy alone.³ Patients taking part in RAPID trial received three cycles of ABVD followed by a centrally reviewed PET scan; those with a PET scan result of DS of 1 or 2 on a 5-point scale were randomly assigned 1:1 to IFRT or no further treatment. The late toxic effects of radiotherapy are avoided in patients cured by chemotherapy, and the 3-year progression-free survival rate was 94.6% (95% confidence interval [CI] = 91.5%–97.7%) in the radiotherapy group and 90.8% (95% CI = 86.9%–94.8%) in the group that received no further therapy, with an absolute risk difference of −3.8 percentage points (95% CI = −8.8 to 1.3). Here investigators report long-term (median, 16 years) survival and cause of death, obtained using data-linkage approaches.

Methods: In all, 602 patients with newly diagnosed, stage1A or 2A (disease above the diaphragm and patients without mediastinal bulk [bulky disease defined as maximal mediastinal diameter ≥ 33% of the internal thoracic diameter at T5–T6]) were eligible. Following three cycles of ABVD, 571 patients had a PET scan; 426 were classified as PET-‘negative’ (score 1, n = 301; score 2, n = 125), and 420 were randomly assigned to receive IFRT (n = 209) or no further treatment (n = 211). Although those with a ‘positive’ PET scan (score of > 2 on a 5-point scale) had a fourth cycle of ABVD and IFRT.

Results: Based on UK national death registration data for patients recruited to the RAPID trial, there was no evidence (after 16 years of median follow-up) of a difference in overall survival between patients in the IFRT arm and the no further treatment arm achieving PET-‘negative’ status following three cycles of ABVD. In the PET-‘positive’ group, there were seven deaths from HL, highlighting the known adverse prognostic significance of a positive PET scan after chemotherapy.

Clinical Implications: The results indicate that in newly diagnosed patients with nonbulky, early-stage cHL with a negative PET scan (DS of 1–2) after three cycles of ABVD chemotherapy, consolidation radiotherapy had no impact on long-term survival in the RAPID trial.

Retrospective Study: Omission of Bleomycin in PET2-Negative Disease

ABSTRACT 461: Omission of bleomycin in radioencompassable, limited-stage (IA, IB, IIA, nonbulky [< 10 cm] adenopathy, ± extranodal extension) cHL with a negative PET scan following two cycles of ABVD is associated with comparable outcomes and reduced pulmonary toxicity.⁴

Background: The RATHL study in advanced-stage cHL established that bleomycin may be omitted from subsequent cycles if the PET scan after ABVD × 2 (PET2) is negative to minimize bleomycin pulmonary toxicity without significantly lower efficacy.⁵

Methods: All patients received ABVD × 2, and those with a positive PET2 were switched to radiotherapy. If PET2-negative (DS of 1, 2, or DX [new area of uptake thought unlikely to be related to the cancer]), patients were recommended to receive a further ABVD × 2 (‘ABVD era’) or AVD × 2 after the policy change (‘AVD era’), for a total of four cycles. An era-to-era outcome comparison and a secondary analysis comparing outcomes in the as-treated PET2-negative groups (ABVD4 vs ABVD2/AVD2) were performed.

Results: In an as-treated analysis of PET2-negative patients who completed treatment with either ABVD × 2 (n = 65) or AVD × 2 (n = 96) in both eras, there was no difference in baseline clinical features. There further was no difference in progression-free survival (5-year: 91.2% vs 95.9%, P = .39) or overall survival (5-year: 98.4% vs 100%, P = .998) in the ABVD and AVD groups, respectively. In total, six patients (9%) in the PET2-negative ABVD group relapsed, four at the original disease site, and two patients (3%) died (one of cHL). Four patients (4%) in the PET2-negative AVD group relapsed, all at the original site, and one patient died of a cardiac cause.

Clinical Implications: Omission of bleomycin for cycles 3 and 4 in limited-stage, nonbulky cHL following a PET2-negative scan preserves excellent outcomes and may reduce the incidence of pulmonary toxicity.

SGN35-027 (Part C) Trial: Stage I or II cHL Without Bulky Disease

ABSTRACT 460: Updated analysis of brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for nonbulky, early-stage (I and II) cHL (NCT03646123).⁶

Background: Brentuximab vedotin is approved with doxorubicin, vinblastine, and dacarbazine (BV-AVD) for stage III to IV cHL but carries increased risks of peripheral neuropathy and neutropenic fever, likely because of the overlapping toxicity between brentuximab vedotin and vinblastine.⁷ A study in nonbulky, early-stage cHL showed preserved efficacy with improved safety when omitting vinblastine in the regimen of brentuximab vedotin plus doxorubicin and dacarbazine.⁸ Initial results from the phase II SGN35-027 (Part C) study, with a median follow-up of 16.5 months, showed promising efficacy and an acceptable safety profile for brentuximab vedotin and nivolumab plus doxorubicin and dacarbazine in patients with nonbulky, early-stage cHL. The updated results from this study after longer follow-up were reported.

Methods: Patients received four cycles of brentuximab vedotin and nivolumab plus doxorubicin and dacarbazine. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was not required. The primary endpoint was complete response rate at the end of treatment. Additional analyses included efficacy assessments for early-favorable and early-unfavorable subgroups, as defined by German Hodgkin Study Group (GHSG) criteria. The median duration of follow-up was 30.7 months (range, 24–45 months).

Results: At the data cutoff of May 30, 2024, 154 patients received at least one dose of brentuximab vedotin and nivolumab plus doxorubicin and dacarbazine (early favorable, 36%; early unfavorable, 64%).

Efficacy: The complete response rate was 92% (95% CI = 86%–95%). In the earl- favorable (n = 55) and early-unfavorable (n = 98) subgroups, complete response rate rates were 95% (95% CI = 85%–99%) and 91% (95% CI = 83%–96%), respectively. Of patients who achieved a complete response rate, the duration of complete response rate at 36 months was 95% (95% CI = 89%–98%). At a median progression-free survival follow-up of 26.3 months, six patients (4%) had progressive disease, all of whom had early-unfavorable disease at diagnosis. No progressive disease events were reported in patients with early-favorable patients. The 36-month progression-free survival rate was 95% (95% CI = 88%–98%). The planned treatment course of four cycles was completed by 98% of patients. Overall, 44% of patients received G-CSF at investigator discretion, mostly for primary prophylaxis.

Safety: Grade ≥ 3 treatment-emergent adverse events occurred in 44% of patients; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events with a potential immunologic cause were reported in 22% of patients. Grade ≥ 3 treatment-emergent immune-mediated adverse events occurred in 8% of patients. Serious treatment-emergent adverse events were reported in 19% of patients. Treatment-related serious treatment-emergent adverse events occurred in 12% of patients, with the most common being pyrexia (3%). There was one disease-related death reported after the safety reporting period.

Clinical Implications: The updated analysis demonstrated continued efficacy in early-stage nonbulky cHL, with a complete response rate of 92% and a 36-month progression-free survival rate of 95%. Long-term results from this study support further study of the use of brentuximab vedotin and nivolumab in combination with limited chemotherapy in patients with nonbulky, early-stage cHL.

Study Inclusive of All Types of Early-Stage cHL

ABSTRACT 459: Randomized phase II study incorporating nivolumab and brentuximab vedotin into radiation-free treatment of early-stage (IA, IB, IIA, and IIB) cHL.⁹

Background: The goal of early-stage cHL is to maximize treatment efficacy while minimizing late effects of therapy. Investigators of this study hypothesized improving progression-free survival with the addition of immunotherapy and minimizing toxicity by omitting radiotherapy in early-stage cHL.

Methods: The primary endpoint was 18-month progression-free survival. All patients underwent PET-CT after two cycles of ABVD (PET2).

• Patients with nonbulky (defined as < 7.5 cm), PET2-negative (DS of 1–3) disease were randomly assigned to two additional cycles of ABVD followed by 3 months of nivolumab consolidation (arm A; n = 45; administered every 2 weeks = six doses) vs three cycles of nivolumab and brentuximab vedotin administered every 3 weeks (arm B1; n = 36), in both cases without radiation. Patients were stratified for baseline factors of stage I vs II and A vs B symptoms.
• Patients with bulky, PET-2 negative disease received two additional cycles of ABVD followed by 3 months of nivolumab consolidation (arm B2; n = 35).

Results: According to GHSG, 54 (35%) were favorable and 95 (62%) unfavorable (3% missing information). In all, 52 patients (34%) had bulky disease, and 75% of patients were PET2-negative after two cycles of ABVD.

Efficacy: The 18-month progression-free survival rate for arm A and arm B1 (nonbulky, PET2-negative) was 100%; for arm B2 (bulky, PET- negative), it was 97% (95% CI = 81%–99.6%); and for arm B2 (bulky, PET2-negative), it was 81% (95% CI = 62%–91%). The 24-month progression-free survival for arm A and arm B1 was 100%; for arm B2, it was 86% (95% CI = 66%–94%); and for Arm C, it was 76% (95% CI = 55%–88%).

Safety: No deaths have been reported to date in any study arm. The most common adverse events of any grade in patients treated on arm A were maculopapular rash (40%), infusion-related reaction (24%), nausea (22%), and peripheral sensory neuropathy (20%). The most common adverse events reported in arm B1/B2 were neutropenia (48%), nausea (35%), fatigue (35%), constipation (24%), alanine aminotransferase elevation (21%), anemia (20%), and peripheral sensory neuropathy (20%). The most common adverse events in arm C were peripheral sensory neuropathy (70%), constipation (54%), nausea (49%), fatigue (49%), neutropenia (46%), anemia (38%), vomiting (35%), and diarrhea (32%). Febrile neutropenia was reported in 0% of arm A, 7% of arm B, and 8% of arm C. A total of four patients in arm A, seven patients in arm B, and one patient in arm C discontinued therapy for toxicity.

Clinical Implications:

• Nonbulky, PET2-negative disease: Incorporating nivolumab ± brentuximab vedotin without radiotherapy resulted in a 24-month progression-free survival rate of 100%, with reportedly manageable toxicity.
• Bulky, PET-2 negative disease: Patients experienced good disease control, although alternative approaches may be warranted.
• PET2-positive disease: Escalation to BV-AVD followed by nivolumab led to acceptable efficacy, though further improvement is needed, and radiation may be necessary for these patients.

DISCLOSURE: Dr. Abutalib reported a financial relationship with AstraZeneca. Dr. Herrera reported financial relationships with Bristol Myers Squibb, Genentech, Merck, Seattle Genetics, Kite Pharma, Gilead Sciences, AstraZeneca, Karyopharm Therapeutics, ADC Therapeutics, Takeda, Tubulis, Regeneron, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, AbbVie, and Allogene Therapeutics.

REFERENCES

1. Radford J, Williams J, Edwards D, et al: Involved field radiotherapy versus no further treatment in patients with newly diagnosed stage 1A or 2A Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Survival and cause of death after a median of 16 years’ follow-up in the UK RAPID trial. 2024 ASH Annual Meeting & Exposition. Abstract 457. Presented December 8, 2024.
2. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363:640-652, 2010.
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 372:1598-1607, 2015.
4. Yang J, Villa D, Gerri AS, et al: Omission of bleomycin in limited stage classic Hodgkin lymphoma patients with a negative PET scan following 2 cycles of ABVD is associated with comparable outcomes and reduced pulmonary toxicity. 2024 ASH Annual Meeting & Exposition. Abstract 461. Presented December 8, 2024.
5. 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 374:2419-2429, 2016.
6. Abramson JS, Straus DJ, Bartlett NL, et al: Updated analysis of brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for nonbulky, early-stage classical Hodgkin lymphoma. 2024 ASH Annual Meeting & Exposition. Abstract 460. Presented December 8, 2024.
7. 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 387:310-320, 2022.
8. Abramson JS, Bengston E, Redd R, et al: Brentuximab vedotin plus doxorubicin and dacarbazine in nonbulky limited-stage classical Hodgkin lymphoma. Blood Adv 7:1130-1136, 2023.
9. LaCasce AS, Jagadeesh D, Lee HJ, et al: A randomized phase 2 study incorporating nivolumab and brentuximab vedotin into radiation-free treatment of early stage classic Hodgkin lymphoma. 2024 ASH Annual Meeting & Exposition. Abstract 459. Presented December 8, 2024.