Response-adapted therapy of stage III-IV Hodgkin lymphoma using PET imaging: a five-year follow-up of the SWOG S0816 trial

The standard of care for patients with newly-diagnosed, advanced-stage, Hodgkin lymphoma (HL), is treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). An alternative first-line regimen is escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP), which has been associated with improved efficacy but also increased toxicity when compared to ABVD.¹ Therefore, ABVD treatment is preferred but not all patients are responsive to this regimen. Positron emission tomography (PET) scan can be used to identify patients that are not responsive to ABVD treatment and can be switched to eBEACOPP. After two cycles of ABVD, PET-positive scans seem highly predictive of treatment failure with ABVD.

The phase II Southwest Oncology Group (SWOG) S0816 trial (NCT00822120) investigated the long-term outcomes in patients who received response-adapted therapy based on PET imaging. Patients were treated with two cycles of ABVD and then a PET scan (PET2) was performed to evaluate the efficacy of the treatment. Those achieving a complete response (CR) on PET2 continued with four additional cycles of ABVD, while those who didn’t were switched to eBEACOPP for six cycles.

Results of SWOG S0816 with a median of 3.3 years follow-up have been previously published by Oliver W. Press, Fred Hutchinson Cancer Research Center, Seattle, US and the University of Washington, Seattle, US, and colleagues. The primary endpoints were reached with a two-year progression-free survival (PFS) of 79% for all patients, 82% for PET2-negative patients and 64% for PET2-positive patients. The estimated two-year Overall Survival (OS) was 98%.² In a paper published in Blood on the 10^th of October 2019, Deborah M. Stephens, University of Utah, Salt Lake City, US, and colleagues presented a five-year follow-up of the SWOG S0816 trial.³

Study design

• The full study design has been published previously,² briefly 371 patients, aged 18–60 years with stage III-IV HL, were enrolled between July 2009 and December 2012. Out of them, 336 patients were eligible, evaluable, HIV-negative, and with no prior therapy for lymphoma. Of this group, 331 patients had a central review of the scans
• The median follow-up evaluation was 5.9 years (range, 0.2–3)
• PET was performed after two initial cycles of ABVD, and at 6–8 weeks after the end of protocol treatment
• Among the 331 patients with PET2 central review, 270 patients (82%) were PET2-negative and received an additional four cycles of ABVD, while 61 patients (18%) were PET2-positive, with 49 patients (80%) switching to eBEACOPP therapy for six cycles
• The primary analysis of this long-term follow-up was five-year PFS in the overall population and five-year PFS in PET2-negative and PET2-positive patients, respectively

Results

PFS

• Median follow up: 5.9 years (range, 0.2–8.3)
• In total, 85 patients (26%) experienced disease progression or died
• The estimated five-year PFS among all patients was 74% (95% confidence interval [CI], 69–79)
• Sixty-four of 270 (24%) PET2-negative patients experienced a progression event with a five-year PFS of 76% (95% CI, 70–81)
• Twenty of 61 (33%) PET2-positive patients experienced a progression event with a five-year PFS of 66% (95% CI, 52– 76)
• The estimated five-year PFS for PET2-positive patients receiving eBEACOPP was 63% (similar to the PET2-positive group)

OS

• Median follow up: 5.9 years (range, 0.2–8.3)
• The estimated 5-year OS (median follow-up: 5.9 years; range, 0.2–3) among all patients was 94% (95% CI, 91–96)
• Nine of 61 (15%) PET2 positive patients died with a five-year OS of 86% (95% CI, 74–3)
• Ten of 270 (4%) PET2-negative patients died with a five-year OS of 96% (95% CI, 93–98)
• The estimated five-year OS for PET2-positive patients receiving eBEACOPP was 85% (similar to the PET2-positive group)
• Causes of death:
  • The most common cause of death was HL, with 11 of 331 (3%) patients dying during follow-up (n= 6 PET2-negative; n= 5 PET2-positive)
  • Treatment-related toxicity (eBEACOPP, n = 1)
  • Bleomycin lung injury (eBEACOPP, n= 1; ABVD, n= 1)
  • Graft-versus-host disease (ABVD, n= 1)
  • Second primary cancers (eBEACOPP, n= 2)
  • Unknown causes (ABVD, n= 2)

Safety

• Post-therapy adverse events (AEs):
  • In patients who received ABVD, AEs included heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, and deep venous thrombosis
  • In patients who received eBEACOPP, AEs included osteonecrosis of hips/shoulders
• Thirteen cases of second cancers were reported, seven in patients treated with eBEACOPP (with a median time to development of 2.9 years) and six in patients treated with ABVD (with a median time to development of 4.2 years)

 Conclusions

• Although the long-term OS rate remains high, the PFS reduced from 79% after two years to 74% after five years
• Nearly one-quarter of the PET2-negative patients experienced relapse demonstrating that the ABVD regimen has limitations and that a negative PET2 has a predictive value
• PET2-positive patients that received eBEACOPP, had a favorable PFS but the treatment was associated with a high rate of secondary malignancies
• More efficacious and less toxic therapies are needed for patients with stage III-IV HL