Addition of Rituximab to BEACOPP_escalated to Improve the Outcome of Early Interim PET Positive Advanced Stage Hodgkin Lymphoma Patients: Second Planned Interim Analysis of the HD18 Study.

Introduction: Positron emission tomography (PET) assessment early during treatment of advanced stage Hodgkin lymphoma (HL) patients might be suited to determine the individual risk for treatment failure. In the HD18 study, PET was performed after induction therapy with two courses of BEACOPP_escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine). Depending on this PET-2 result, patients were either classified as high-risk or low-risk patients and escalation or de-escalation treatment strategies were tested, respectively. To improve the presumably poor progression free survival (PFS) of PET-2 positive patients, we introduced the anti-CD20 antibody rituximab into the BEACOPP_escalated regimen (R- BEACOPP_escalated). Here, we report the results of the second planned interim analysis for the PET-2 positive patient cohort.

Methods: HD18 is an open-label, multicenter, prospective, randomized, phase III study (ClinicalTrials.gov ID: NCT00515554) for patients with newly diagnosed advanced stage HL aged 18–60 years. Patients with PET positive disease (standard uptake value above mediastinal background) after two courses of BEACOPP_escalated were randomly assigned to receive additional six courses of BEACOPP_escalated (BEACOPP group), or rituximab in conjunction with six cycles of BEACOPP_escalated (R-BEACOPP group). We centrally performed a 1:1 randomization by stratified minimization. Primary endpoint was progression free survival (PFS) using an adaptive study design with three interim analyses. Sample size was determined to ensure that an improvement by at least 15 percentage points could be detected by the addition of rituximab to BEACOPP_escalated assuming a 5-year PFS rate of 68% for PET-2 positive patients with BEACOPP_escalated.

Results: Between May 2008 and May 2011, 1,100 patients were enrolled into the HD18 trial, of whom 440 were PET-2 positive and randomized (BEACOPP n=220; R-BEACOPP n=220), corresponding to 43% of all randomized patients. One patient in the BEACOPP_escalated group was excluded from intention-to-treat analysis because HL was not confirmed by reference histology. Median age was 30 years (range 18-60), 177 were female (40%). One patient had stage IIA disease, 103 patients (23%) had Ann Arbor stage IIB disease with the risk factors large mediastinal mass or extranodal involvement, the remaining patients had stage III/IV disease. IPS risk groups were distributed as follows: 120 patients 0-1 (28%), 241 2-3 (55%), and 75 4-6 (17%). Overall, grade 4 toxicity occurred in 197/218 (90.4%) and 206/220 (93.6%) of the documented patients in the BEACOPP and R-BEACOPP group, respectively. Grade 4 leukopenia was documented in 193 (88.5%) and 201 (91.4%) patients, grade 4 thrombocytopenia in 112 (51.4%) and 123 (55.9%) patients, anemia in 27 (12.4%) and 31 (14.1%) patients, and grade 4 infections in 9 (4.1%) and 13 (5.9%) patients. Other grade 4 toxicities had a frequency of less than 2%. Treatment related mortality occurred in 1 (0.5%) and 3 patients (1.4%), respectively. Overall, 16 patients died, 6 in the BEACOPP_escalated group and 10 in the R-BEACOPP_escalated group. With a median follow-up of 35 months, Kaplan-Meier PFS estimates were largely overlapping (log rank p=0.99) with an estimated 3 year PFS of 91.4% for BEACOPP (95% CI: 87.0% – 95.7%) and 93% for R-BEACOPP (95% CI: 89.4% – 96.6%). Accordingly, overall survival was not different (96.5% versus 94.4% at 3 years for BEACOPP versus R-BEACOPP, p=0.31). The data monitoring committee (DMC) recommended publication of this second interim analysis, since a futility analysis indicated a low likelihood of the trial to become successful.

Conclusion: Importantly, the definition of PET positivity used in the HD18 study failed to determine a high-risk patient group. PFS in PET-2 positive patients receiving standard treatment with BEACOPP_escalated was much better than expected. Accordingly, the chance to improve the overall excellent PFS of these patients with rituximab was low. In fact, we did not observe any benefit. Future analyses of the PET-2 negative patient cohort will show if PET guided risk group allocation allows treatment reduction in advanced stage HL patients.