Casasnovas RO, et al. - In patients with advanced Hodgkin lymphoma, whether PET monitoring during treatment could allow dose de-escalation by switching from a regimen containing bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP_escalated) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in early responders without loss of disease control vs standard treatment without PET monitoring was investigated. In this patient population, PET after two cycles of induction BEACOPP _escalated chemotherapy guided treatment safely and enabled ABVD to be used in early responders without impairing disease control and reduced toxicities. Accurate monitoring of treatment was permitted by PET staging and this could be considered as a strategy for the routine management of these patients.

Methods

• In 90 centers across Belgium and France, researchers performed a randomized, non-inferiority, phase 3 study (AHL2011), including patients aged 16–60 years who had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0.33 or greater than or extranodal localization, and had received no previous treatment for Hodgkin lymphoma.
• Using unmasked randomization, done centrally by the permuted block method, they assigned patients to standard treatment (BEACOPP_escalated given every 21 days for six cycles) or PET-driven treatment.
• Two cycles of upfront BEACOPP _escalated were administered to all patients, after which PET assessment was done (PET2).
• Regardless of PET2 findings, two additional cycles of BEACOPP _escalated induction therapy were given to PET2 patients in the standard treatment group.
• Further two cycles of BEACOPP _escalated were administered to patients with positive PET2 scans and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy, in the PET-driven treatment group.
• In both treatment groups, the decision to whether or not continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPP _escalated) was made using PET at the end of induction therapy.
• The regimen for BEACOPP_escalated included bleomycin 10 mg/m² and vincristine 1.4 mg/m² intravenously on day 8, etoposide 200 mg/m² intravenously on days 1–3, doxorubicin 35 mg/m² and cyclophosphamide 1,250 mg/m² intravenously on day 1, 100 mg/m² oral procarbazine on days 1–7, and 40 mg/m² oral prednisone on days 1–14.
• Every 28 days, ABVD was administered (doxorubicin 25 mg/m², bleomycin 10 mg/m², vinblastine 6 mg/m², and dacarbazine 375 mg/m² intravenously on days 1 and 15).
• Investigator-assessed progression-free survival was the primary endpoint.
• To demonstrate non-inferiority of PET-guided treatment vs standard care with 80% power and an alpha of 2.5% (one-sided), the study had a non-inferiority margin of 10%.

Results

• Enrollment of 823 patients—413 in the standard care group and 410 in the PET-driven group—was done between May 19, 2011 and April 29, 2014.
• Among 410 patients in the PET-driven treatment group, 346 (84%) received ABVD and 51 (12%) were continued on BEACOPP _escalated after PET2.
• A median follow-up of 50.4 months (IQR 42.9–59.3) was performed.
• In the standard treatment group vs in the PET-driven treatment group, the estimated 5-year progression-free survival by intention to treat was 86.2%, 95% CI 81.6–89.8 vs 85.7%, 81.4–89.1 (hazard ratio [HR] 1.084, 95% CI 0.737–1.596; p=0.65), respectively, and per protocol the values were 86.7%, 95% CI 81.9–90.3 and 85.4%, 80.7–89.0, respectively (HR 1.144, 0.758–1.726; p=0.74).
• Grade 3–4 adverse events that were most commonly experienced included leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]).
• Treatment-related serious adverse events were seen in 192 (47%) patients and 114 (28%) patients in the standard treatment group and in the PET-driven treatment group, respectively, and included infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]).
• As far as death from treatment-related causes was concerned, this was reported in 6 (1%) patients in the standard care group (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukemia), and in two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukemia).