Peter Johnson, MD
Interim PET-CT scanning was successfully used to adapt treatment regimens in patients with advanced classical Hodgkin lymphoma, according to the first analysis of data from the international RATHL study reported at the 13th International Conference on Malignant Lymphoma, in Lugano, Switzerland.
The results showed that treatment could be intensified or de-escalated based on the scans. Of particular note, it was demonstrated that pulmonary toxicity could be decreased without loss of efficacy by omitting bleomycin from ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) in patients with a negative interim PET.
“We expect that ABVD will cure 70% of patients with advanced Hodgkin lymphoma but it is desirable to de-escalate treatment in the best responders to avoid late toxicity,” according to Peter Johnson, MD, Cancer Research UK Centre, University of Southampton, UK. “This trial asked whether bleomycin can be eliminated from cycles 3 to 6 for the best responders without having an adverse effect on progression-free survival and whether the results in PET-positive patients can be improved by escalation to BEACOPP.”
Johnson headed an international team in conducting the prospective randomized RATHL study. Initially, 1214 adult patients with newly diagnosed Hodgkin lymphoma were enrolled and received baseline PET-CT scans. At study entry, 500 patients (41%) had Ann Arbor stage II disease, 372 patients (31%) had stage III, and 342 patients (28%) had stage IV disease. The international prognostic score (IS) was ≥3 for 445 patients (37%).
All patients received 2 cycles of ABVD and then underwent an interim PET-CT scan (PET2). PET2 scan results were negative in 954 patients (84%); of these, 469 patients with negative scans were randomized to ABVD and 466 to AVD for an additional 4 cycles, and 33 patients (4%) also received consolidation radiotherapy. Two patients elected to continue ABVD and seven patients withdrew from the study.
Patients with positive scans proceeded to intensification with either 4 BEACOPP-14 (n = 96) or 3 escalated BEACOPP (n = 78) and received a third scan (PET3), after which patients with negative PET3 completed a further 2 BEACOPP-14 or 1 escalated BEACOPP. Patients with a positive PET3 scan received off-study salvage regimens. Radiotherapy was not advised for patients with an interim negative scan, regardless of bulk or residual masses.
The primary endpoint was progression-free survival (PFS) for PET-negative randomized patients (first randomization) and the endpoint for the second randomization was response rate following BEACOPP.
The overall 3-year PFS rate was 83% (range, 80%-85%) and the 3-year overall survival (OS) rate was 95% (range, 94%-97%) for patients in all treatment groups.
The patients with positive PET2 were given intensified therapy and 74% of this cohort achieved a negative PET3. No difference was observed between the nonrandomized comparison of escalated BEACOPP and BEACOPP-14 treatment.
“Escalated therapy for interim PET-positive patients gives good subsequent response rates and promising PFS results,” said Johnson.
At a medium follow-up of 36 months, results were comparable with either ABVD or AVD in patients with a negative interim PET. Three-year PFS rates were 85.4% (95% CI, 81.6-88.5) with ABVD compared to 84.4% (95% CI, 80.7-87.6) with AVD.
OS rates in PET-negative patients showed no difference between the two treatments; 3-year OS rates, were 97.1% (95% CI, 94.7-98.4) with ABVD and 97.4% (95% CI, 95.0-98.6) with AVD.
The initial disease stage (P
= .01) and the International Prognostic Score (P
= .05) emerged as prognostic factors for treatment failure after negative PET2; however, tumor bulk, B symptoms or the PET2 score were not associated with treatment failure in this analysis.
“There was a higher false-negative rate for interim PET among patients with advanced stage disease,” said Johnson.
Toxicity in the PET-positive patients was higher in the escalated BEACOPP cohort than the BEACOPP-14, with thrombocytopenia occurring in 18.8% and 42.3% of BEACOPP-14 and escalated BEACOPP patients, respectively (P
= .001). Neutropenic fever was reported in 10.4% versus 25.6% of patients in the respective BEACOPP arms (P
= .08). There 53 deaths during the study, 19 that were disease related.
More cases of pulmonary toxicity were observed with ABVD than with AVD. At least 6 cycles of treatment were delivered to 98% of patients in both the ABVD and AVD arms and 14 deaths occurred in each arm.
Discussant Andreas Engert MD, University Hospital, Cologne, Germany who was not involved in the RATHL study, remarked, “bleomycin is a drug many people are not impressed with; in this setting it is safe to omit bleomycin from the backbone.”