Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy….

— Peter Johnson, MD, and colleagues

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In a phase III trial reported in The New England Journal of Medicine, Peter Johnson, MD, of the Cancer Research UK Centre, University of Southampton, and colleagues found similar efficacy with continued ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) vs omission of bleomycin (AVD) after negative interim PET-CT (positron-emission tomography–computed tomography) in patients with advanced Hodgkin lymphoma.¹

Study Details

In the trial, 1,203 patients with newly diagnosed advanced classical Hodgkin lymphoma were enrolled from 138 sites in the UK, Italy, Australia, New Zealand, Norway, Sweden, and Denmark between August 2008 and December 2012. Patients underwent baseline PET-CT and received two cycles of ABVD, followed by an interim PET-CT scan. Images were centrally reviewed using a 5-point scale, with negative PET findings defined as a score of 1 to 3. Patients with negative findings after two cycles were randomized to continue ABVD or to receive AVD without bleomycin in cycles three to six. Patients with positive PET findings after two cycles received ­BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative interim scans. The primary outcome measure was the difference in 3-year progression-free survival rate between the ABVD and AVD groups, using a noninferiority comparison to exclude a difference of ≥ 5 percentage points.

Overall, patients had a median age of 33 years (range = 18–79 years); 54.5% were male; 41.6% had stage II, 30.2% stage III, and 28.3% stage IV disease; 61.3% had B symptoms; and 32.1% had bulky disease.

Randomized Comparison

After 2 cycles of ABVD, 1,119 patients underwent interim PET-CT, with negative PET findings found in 937 (83.7%). Of them, 470 continued ABVD and 465 received AVD; 172 patients with positive PET findings received BEACOPP. Consolidation radiotherapy was given to 2.6% of patients in the ABVD group and 4.3% in the AVD group. Median follow-up was 41 months.

Three-year progression-free survival was 85.7% (95% confidence interval [CI] = 82.1%–88.6%) in the ABVD group vs 84.4% (95% CI = 80.7%–87.5%) in the AVD group (hazard ratio [HR] = 1.13, 95% CI = 0.81–1.57). The absolute difference in the 3-year progression-free survival was 1.6 percentage points, with a 95% confidence interval of −3.2% to 5.3%, which exceeded the noninferiority margin of 5%. Three-year overall survival was 97.2% (95% CI = 95.1%–98.4%) vs 97.6% (95% CI = 95.6%–98.7%; HR = 0.90, 95% CI = 0.47–1.74).

In subgroup analysis, there was no significant difference between groups in 3-year progression-free survival according to age, sex, disease stage, international prognostic score, presence or absence of bulky disease, or PET score; the hazard ratio favored the ABVD group in patients without B symptoms.

Outcome With BEACOPP

Among the 172 patients receiving BEACOPP, 74.4% had negative third PET-CT scans; 3-year progression-free survival was 67.5%, and 3-year overall survival was 87.8%. There was no significant difference in outcomes between the 94 patients receiving BEACOPP-14 and the 78 patients receiving escalated BEACOPP. Adverse events were generally similar between these treatments, except for more frequent thrombocytopenia and febrile neutropenia in those receiving escalated BEACOPP.

Overall, 62 patients died during the trial, including 24 from Hodgkin lymphoma, yielding 3-year progression-free survival of 82.6% and overall survival of 95.8% in the total population.

Adverse Events

Grade 3 or 4 adverse events occurred in 69% of the ABVD group and 65% of the AVD group, with the most common being neutropenia (59% in both) and any infection (15% vs 10%, including febrile neutropenia in 5% vs 2%). Grade 3 or 4 respiratory events were more common with ABVD, including any pulmonary or upper respiratory event (3% vs 1%), dyspnea (2% vs < 0.5%), and pneumonitis (1% vs < 0.5%). Longitudinal analysis showed an absolute difference in DL_CO (diffusing capacity of the lungs for carbon monoxide) between the ABVD group and AVD group of –7.4% (P < .001) at the end of therapy and −4.6% (P = .003) at 1 year.

The investigators concluded:

Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy…. [D]isease control of advanced Hodgkin lymphoma after interim-PET–adapted therapy showed overall outcomes at least as good as in our previous studies. Longer follow-up will be required to establish whether reduction in the use of bleomycin and consolidation radiotherapy may affect long-term morbidity and mortality. ■

Disclosure: The study was funded by Cancer Research UK, Leukaemia and Blood Cancer New Zealand, and Cancer Australia. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. 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.