Photo by Jens Maus
LUGANO—Results of the RATHL trial indicate that bleomycin can be omitted from ABVD therapy following a negative interim FDG-PET scan in patients with Hodgkin lymphoma.
Progression-free survival (PFS) and overall survival (OS) were the same at 3 years for patients who were PET-negative after 2 cycles of ABVD and then continued therapy with or without bleomycin.
These results were presented at the 13th International Conference on Malignant Lymphoma (13-ICML).
Investigators based the RATHL study on the principles that it’s desirable to de-escalate treatment in the best responders to avoid late toxicity and that PET scans after 2 cycles of ABVD are highly predictive.
The team enrolled 1214 patients from 6 countries, 861 of whom were in the UK. Patients received a PET scan at staging, 2 cycles of ABVD, and then a second PET scan (PET2).
If patients were negative after PET2, they were randomized to receive 4 more cycles of ABVD or AVD and no radiotherapy.
If they were positive after PET2, patients received 4 cycles of BEACOPP-14 or 3 cycles of escalated BEACOPP. These patients then received a third PET scan, and the positive patients went on to receive radiotherapy or a salvage regimen.
The PET3-negative patients received 2 more cycles of BEACOPP-14 or one of escalated BEACOPP without radiotherapy.
Peter W. Johnson, MD, of the University of Southampton in the UK, presented the results of these treatment regimens during the plenary session of 13-ICML as abstract 008.
Patient characteristics
Patients were a median age of 33 (range, 18-79), and 55% were male. They had disease stages of II (41%), III (31%), or IV (28%).
Seventy-four percent of patients had a performance status of 0. Almost half (49%) had an IPS score of 2 to 3, and 18% had an IPS score of 4 or more. Thirty-two percent had bulky disease.
Investigators followed the patients for a median of 34.7 months (range, 1 day to 68.2 months).
Results after PET2
Seventy-seven patients were missing a second PET scan, mostly due to PET protocol violations of having to use the same scanner for the baseline and second scan and the same acquisition time.
“We were very strict on our quality control,” Dr Johnson said, “because we wished to make sure this was reproducible data.”
So the results after 2 cycles of ABVD treatment were based on 1137 patients.
PET-negative patients
More than 80% of patients were PET-negative after 2 cycles. Four hundred and sixty-nine patients were randomized to receive ABVD and 466 to AVD.
The groups were well-balanced in terms of median age, performance status, stage, B symptoms, bulky disease, and IPS score.
There was a significant excess of neutropenic fever (P=0.032) and infection (P=0.040) in those patients continuing on ABVD compared to AVD. And any hematologic toxicity was highly significantly different between the 2 arms (P<0.001).
“So we have demonstrated that continuing with bleomycin beyond cycle 2 is accompanied by significantly more toxicity,” Dr Johnson said.
Ninety-eight percent of patients in both cohorts received at least 6 cycles of therapy post-randomization.
At a median follow-up of 36.3 months, 65% of patients in the ABVD arm and 69% in the AVD arm achieved a complete remission (CR) or unconfirmed CR (CRu).
Fourteen patients died in each of the arms. Seven patients died of their disease in the AVD arm, compared with 1 in the ABVD arm. Slightly more patients died from toxicity in the ABVD arm.
The primary endpoint of PFS showed very little difference between the 2 arms. The 3-year PFS in the intent-to-treat analysis was 85.4% for patients in the ABVD arm and 84.4% for those in the AVD arm.
The investigators observed that the PFS of 85% was somewhat lower than the 95% PFS observed in the literature. So they looked at the association between baseline factors and PFS after negative PET2.
“And what stands out from this is that if you have high-stage disease at presentation, there is a slightly higher chance of treatment failure following a negative PET scan,” Dr Johnson said. “And you can see the trend here, from early stage disease up to advanced-stage disease, the PET scan becomes a less reliable indicator of result.”
The investigators also conducted a subgroup analysis of the PET2-negative patients and found there was no difference in outcome between treatment arms in patients with more advanced disease, with bulky disease, with a high IPS score, or according to the PET score.
“So we have not succeeded in finding any subgroup where it appears to be beneficial to continue bleomycin,” Dr Johnson said.
The OS rate was also the same between the 2 arms, at 97%.
PET2-positive patients
One hundred and seventy-four patients who were positive after the second PET scan received either BEACOPP for 14 days or escalated BEACOPP.
The percentage of patients who experienced grade 3-4 toxicities was largely similar between the 2 regimens, although the patients receiving escalated BEACOPP had more neutropenia (P=0.057), thrombocytopenia (P=0.001), and neutropenic fever (P=0.08).
In terms of efficacy, two-thirds of patients became PET-negative by the third PET scan, and 48% of patients achieved a CR or CRu.
Twenty-one patients died, 8 due to Hodgkin lymphoma.
The PFS was 66.0% in the BEACOPP-14 group and 71.1% in the escalated-BEACOPP group. The 3-year OS was 89.6% in the BEACOPP-14 group and 82.8% in the escalated-BEACOPP group.
For the entire group of 1214 patients, the 3-year PFS was 82.5%, and the OS was 95.4%.
Based on these results, the investigators concluded that it is safe to omit bleomycin and consolidation radiotherapy from subsequent ABVD therapy after a negative interim PET scan. And doing so reduces toxicity, especially dyspnea, thromboembolism, and neutropenic fever.
“[B]y using more selective chemotherapy and much less radiotherapy than we have previously used in our studies, where we’re giving less than 3% of patients consolidation radiotherapy, the results appear to be favorable and an improvement over what we have seen previously,” Dr Johnson said.
Details on lung toxicity in this study were presented separately at 13-ICML as abstract 041.
