Adding Novel Agents to Established Chemotherapy Regimens Key to Expanding Frontline Treatment of Classic Hodgkin Lymphoma

Alison J. Moskowitz, MD

Treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus radiation is the established as the standard of care in the frontline setting for patients with classic Hodgkin lymphoma. Though some studies have shown the continued efficacy of chemotherapy alone and chemoradiotherapy for select patients, finding novel agents to combine with chemotherapy or chemoradiotherapy will be vital for developing new options, according to Alison J. Moskowitz, MD.

“Randomized studies are ongoing and will ultimately determine the role of these novel agents in untreated, early-stage Hodgkin lymphoma and potentially allow us to give shortened-course chemotherapy and avoid radiation therapy for the majority of patients,” Moskowitz said during a presentation at the 2022 Pan Pacific Lymphoma Conference.¹

Immunotherapy plus chemotherapy has displayed intriguing early efficacy in untreated patients with Hodgkin lymphoma, Moskowitz explained.

The phase 2 NIVAHL trial (NCT03004833) examined concurrent nivolumab (Opdivo) plus AVD before radiation and sequential single-agent nivolumab followed by nivolumab plus AVD, followed by AVD alone before radiation.² In the concurrent arm, the 12-month PFS rate was 100% and 98% (95% CI, 95%-100%) in the sequential arm. Moreover, 87% of patients in the concurrent arm and 51% in the sequential arm had complete response.

Sequential pembrolizumab (Keytruda) followed by AVD elicited similar efficacy in a phase 2 trial (NCT03226249) for patients with newly diagnosed classical Hodgkin lymphoma. Thirty patients with early unfavorable (n = 12) or advanced stage (n = 18) disease received 3 cycles of pembrolizumab followed by AVD for 4 to 6 cycles depending on stage and bulk.³

At a median follow-up of 33.1 months (range, 26-43), the combination produced a PFS rate of 100%. Furthermore, patients maintained responses at the end of treatment.

In another trial (NCT01868451), the addition of brentuximab vedotin (Adcetris) to AVD displayed a 2-year PFS rate of 94% (95% CI, 89.7%-98.3%) in all patients, and patients who did not receive radiation following treatment, the 2-year PFS rate was 96.6% (95% CI, 89.9%-100%).⁴ The combination is being further evaluated in the phase 3 RADAR trial (NCT04685616).

"These are the studies that we need in order to determine whether we truly can incorporate these drugs and change the standard of care for early-stage disease,” Moskowitz said.

Current Frontline Chemotherapy/Chemoradiation Options

The phase 3 GHSG HD10 trial (NCT00265018) evaluated the optimal number of cycles of ABVD and dosing of radiation for patients with favorable stage I or II Hodgkin lymphoma without risk factors, including bulky disease; extranodal involvement; an erythrocyte sedimentation rate (ESR) of more than 50 for stage A disease or more than 30 for stage B disease; or the involvement of 3 or more lymph node areas.5 Patients (n = 1190) were randomized between 4 treatment arms, where they received a combination of 2 or 4 cycles of ABVD plus 20 Gy or 30 Gy of radiation.

The 5-year rates of freedom from treatment failure were 91.1% (95%, 88.3%-93.2%) for patients who received 2 cycles of ABVD, compared with 93% (95% CI, 90.5%-94.8%) in patients administered 4 cycles of ABVD. The 2 chemotherapy regimens were not statistically different in freedom from treatment failure (P = .39) or overall survival (OS; P = .61). Similarly, the 2 radiation dosages did not have statistically significant differences in time to treatment failure (P = 1.00) or OS (P = .61).

Investigators in the phase 3 GHSG HD11 trial (NCT00264953) sought to find the optimal treatment for patients with early-stage, unfavorable or bulky Hodgkin lymphoma who had at least 1 of the risk factors. The trial, which also featured 4 randomized arms, examined the same 2 doses of radiation, combined with either 4 cycles of ABVD or 4 cycles of BEACOPP (bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone).⁶

Findings from this trial deemed 4 cycles of ABVD combined with 30 Gy of radiation as sufficient for the treatment of patients with early unfavorable disease. The phase 3 GHSG HD14 trial (NCT01712490) further tested this regimen against 2 cycles each of escalated BEACOPP and ABVD plus 30 Gy of radiation, which also established the latter as a viable treatment option for patients with early, unfavorable or bulky Hodgkin lymphoma.⁷

Trials examining early interim positron emission tomography (PET)–adapted therapies also opened the door for other options for patients with early favorable, unfavorable, and bulky disease, who may not need radiation to improve outcomes.

“I would say for the vast majority of the patients that I take care of with early-stage disease, I'm really not using radiation therapy. We learned through retrospective analyses and some prospective studies that interim PET is prognostic, not only an advanced-stage disease, but also an early-stage disease,” Moskowitz noted.

In the phase 3 RAPID trial (NCT00943423), patients between the ages of 16 and 75 years received 3 cycles of ABVD before undergoing a PET scan.8 Patients deemed PET positive with a Deauville score between 3-5 continued to another cycle of ABVD, followed by radiation. However, patients who were PET negative with a Deauville score of 1 or 2 were randomized to receive radiation or no further treatment.

Although patients who received radiation achieved a 3-year progression-free survival (PFS) of 97% (95% CI, 94.5%-99.6%) compared with 90.7% (95% CI, 86.7%-94.7%) in patients given no further treatment. Nonetheless, Moskowitz said that the high 3-year PFS rate among patients who did not receive radiation makes her feel comfortable offering that treatment option in patients who meet the RAPID criteria.

The phase 3 CALGB 50604 trial (NCT01132807) also established another treatment option for patients with favorable or unfavorable disease if they were PET negative after 2 cycles of ABVD (PET2-negative).⁹ All enrolled patients received 2 cycles of ABVD. Those who were PET2-negative continued with 2 more cycles of ABVD and those who were PET2-positive received 2 cycles of escalated BEACOPP plus radiation.

Patients in the PET2-negative cohort (n = 135) achieved a 3-year event-free survival (EFS) rate of 91% compared with 67% for patients in the PET-positive cohort.

Regarding patients with favorable or unfavorable disease who are PET2-positive, treatment options can vary based on Deauville score, Moskowitz explained. For patients with a Deauville score of 3, regimens should include 2 additional cycles of ABVD or 4 cycles of AVD.

In patients with a Deauville score of 4, physicians can consider an additional 4 cycles of ABVD plus radiotherapy if the patient is PET4-negative. Otherwise, options include 2 cycles of escalated BEACOPP plus radiotherapy, 4 cycles of escalated BEACOPP, or 4 cycles of escalated BEACOPP plus radiotherapy. Those same treatment options can be considered for a patient with Deauville score of 5, or a biopsy can be used to determine the best course of action.

Risk Stratification in Early Hodgkin Lymphoma

Though PET2-negative status has been an indicator of better outcomes, the system is far from perfect, Moskowitz noted. She pointed to data from the phase 3 EORTC/LYSA/FIL H10 trial (NCT00433433), where patients with favorable disease who were PET2-negative before receiving 2 additional cycles of ABVD had a lower 5-year PFS than patients with PET2-negative or -positive disease who received 1 extra cycle of ABVD plus radiation (87% vs 99%, respectively).¹⁰ Notably, patients with unfavorable disease were received 4 additional cycles of ABVD after being PET2-negative also had a higher 5-year PFS (89.6%) during the trial.

“Our risk stratification that we use to determine patients who are favorable or unfavorable is faulty, and we need better risk stratification,” she said. “Also, our reliance on PET2 is not perfect. Patients who are PET2-negative will fail [treatment], and patients who are PET2-positive will sometimes do well. We need better factors to help modify therapy.”

One area that continues to evolve in terms of risk stratification is the definition of bulk, Moskowitz continued. Investigators conducting a retrospective analysis found that patients with disease bulk of at least 7 cm experienced less favorable outcomes to chemotherapy alone. Data from that study also showed that 7 cm was the best cutoff for identifying which patients would benefit more from combined modality therapy.¹¹

Additionally, findings from RAPID showed that patients with a bulky disease of 5 cm or more who received chemotherapy alone did not perform as well. “Both of these studies indicate that for patients with slightly more bulky disease, we need to do something different. Maybe it [means] including radiation, or maybe these are the patients who really need novel therapies," Moskowitz said.

Total metabolic tumor volume (TMTV) can also serve as a prognostic factor for patients with Hodgkin lymphoma. In the EORTC/LYSA/FIL H10 trial, TMTV was found to be the only baseline factor that remained prognostic in a multivariate analysis.¹² The role of TMTV as a prognostic factor is under further investigation in the phase 2 RAFTING trial (NCT04866654).¹³

References

1. Moskowitz A. Early-stage classic Hodgkin lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI.
2. Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma: the randomized phase 2 German Hodgkin study group NIVAHL trial. JAMA Oncol. 2020;6(6):872-880. doi:10.1001/jamaoncol.2020.0750
3. Allan PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma. Blood. 2021;137(10):1318-1326. doi:10.1182/blood.2020007400
4. Kumar A, Casulo C, Advani RH, et al. Brentuximab vedotin combined with chemotherapy in patients with newly diagnosed early-stage, unfavorable-risk Hodgkin lymphoma. J Clin Oncol. 2021;39(20):2257-2265. doi:10.1200/JCO.21.00108
5. Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med. 2010;363(7):640-52. doi:10.1056/NEJMoa1000067
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7. von Tresckow B, Plütschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol . 2012;30(9):907-13. doi:10.1200/JCO.2011.38.5807
8. 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):1598-607. doi:10.1056/NEJMoa1408648
9. Straus DJ, Jung S-H, Pitcher B, et al. CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood. 2018;132(10):1013-1021. doi:10.1182/blood-2018-01-827246
10. 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
11. Kumar A, Burger IA, Zhang Z, et al. Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes. Haematologica. 2016;101(10):1237-1243. doi:10.3324/haematol.2016.141846
12. Cottereau A-S, Versari A, Loft A, et al. Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood. 2018;131(13):1456-1463. doi:10.1182/blood-2017-07-795476
13. Radiation Free Chemotherapy for Early Hodgkin Lymphoma (RAFTING). ClinicalTrials.gov. Updated August 12, 2021. Accessed July 20, 2022. https://clinicaltrials.gov/ct2/show/NCT04866654