Photo by Rhoda Baer
LUGANO—Long-awaited results of the Intergroup H10 trial in PET-positive Hodgkin lymphoma (HL) patients have shown that intensifying chemotherapy significantly increases 5-year progression-free survival (PFS) and produces a non-significant increase in overall survival (OS).
Switching patients who are PET-positive after 2 cycles of ABVD to escalated BEACOPP and involved-node radiotherapy increased 5-year PFS to 91% and 5-year OS to 96%.
The trial was a cooperative effort of the European Organisation for Research and Treatment of Cancer (EORTC), Lymphoma Study Association (LYSA), and Fondazione Italiana Linfomi (FIL).
The investigators already knew that early FDG-PET scans have prognostic impact. Patients with a negative PET scan after 2 cycles of chemotherapy have very good outcomes, while those with PET-positive interim scans have poor outcomes.
So the team designed the H10 trial to learn whether they could reduce long-term toxicity in the majority of patients and improve outcomes in the unfavorable subgroups.
Results of the primary endpoint—whether chemotherapy alone is as effective as, but less toxic than, combined-modality treatment in PET-negative patients after 2 cycles of ABVD—were published in the Journal of Clinical Oncology.
The secondary endpoint was an improvement in PFS with an early change from ABVD to escalated BEACOPP in stage I or II HL patients who are PET-positive after 2 cycles of ABVD.
John M. M. Raemaekers, MD, PhD, of Radboud University Medical Center in The Netherlands, presented details on the trial’s secondary endpoint at the 13th International Congress on Malignant Lymphoma (no abstract available).
H10 trial design
The investigators enrolled patients with favorable and unfavorable prognostic characteristics.
Unfavorable characteristics consisted of age 50 or older, more than 3 nodal areas, mediastinal-to-thorax ratio of 0.35 or higher, erythrocyte sedimentation rate of 50 mm or greater without B symptoms, or erythrocyte sedimentation rate of 30 mm or greater with B symptoms.
In the standard treatment arm, patients with favorable or unfavorable characteristics were treated similarly. After 2 cycles of ABVD, a PET scan was performed, and, irrespective of the result, patients received combined-modality treatment of ABVD followed by involved-node radiotherapy.
In the experimental arm, patients who were PET-negative had chemotherapy alone without involved-node radiotherapy. PET-negative patients were not discussed further in this presentation.
For the PET-positive patients in the experimental arm, the treatment for those with favorable and unfavorable characteristics was identical.
Patients who were PET-positive after 2 cycles were switched to 2 escalated BEACOPP cycles plus involved-node radiotherapy. Patients were considered PET-positive if they had a Deauville score of 3, 4, or 5.
The first patient was enrolled in November 2006 and the last in June 2011. Investigators randomized 1950 patients, 754 with favorable and 1196 with unfavorable characteristics. All patients had untreated, supradiaphragmatic, clinical stage I or II HL.
Nine hundred fifty-four patients were enrolled in the standard arm, 371 with favorable characteristics and 583 with unfavorable. Nine hundred seventy-one patients entered the experimental arm, 376 with favorable and 595 with unfavorable characteristics.
Twenty-five patients were excluded because they did not complete the first 2 cycles of ABVD or did not have a PET scan.
After 2 cycles of ABVD, 361 patients were PET-positive, 192 in the ABVD arm (54 favorable, 138 unfavorable), and 169 in the escalated BEACOPP arm (43 favorable, 126 unfavorable).
The median age was 30 years in both arms (range, 15 to 70), and the investigators followed patients for a median of 4.5 years.
The only grade 3-4 toxicities were hematologic events and infection.
“As expected, the neutropenia, thrombocytopenia, and anemia, grade 3-4, were more frequent in the experimental BEACOPP arm,” Dr Raemaekers said.
The incidence of grade 3-4 neutropenia was 30.3% (ABVD) and 53.5% (BEACOPP), thrombocytopenia was 0% (ABVD) and 19.7% (BEACOPP), and anemia was 0% (ABVD) and 4.9% (BEACOPP).
The incidence of grade 3-4 febrile neutropenia was 1.1% (ABVD) and 23.9% (BEACOPP), and infection without neutropenia was 1.1% (ABVD) and 11.2% (BEACOPP).
Progression or relapse occurred in 18.8% of patients in the ABVD arm and 7.7% in the BEACOPP arm.
There were 18 deaths in the ABVD arm and 7 deaths in the BEACOPP arm. Eleven deaths in the ABVD arm and 3 in the BEACOPP arm were due to progressive disease or relapse.
The investigators also tallied up the number of patients who progressed, relapsed, or died, whichever occurred first. Forty-one patients in the ABVD arm fulfilled one of these criteria, compared to 16 in the BEACOPP arm.
“Progression and relapse had to be established by conventional restaging, including physical exam, chest X-ray, and CT scan,” Dr Raemaekers pointed out. “And it was based on any new lesion or increase by 50% or more in size of previously involved sites.”
Patients in the BEACOPP arm experienced a significantly better PFS than the ABVD arm, with a hazard ratio of 0.42 (P=0.002). The 5-year PFS was 91% in the BEACOPP arm and 77% in the ABVD arm.
The 5-year OS was 89% in the ABVD arm and 96% in the BEACOPP arm, a difference that was not statistically significant.
“But [the trial] was also not powered for overall survival,” Dr Raemaekers said. “[T]here is a hint, at least, that, even in overall survival, the BEACOPP arm is superior to the ABVD arm.”
Based on these findings, the investigators concluded that, despite increased toxicity, physicians should consider intensifying chemotherapy in early PET-positive patients with stage I/II HL in the combined-modality setting.