A multicenter real-world analysis of combined chemotherapy followed by consolidative radiation versus chemotherapy alone in the management of early-stage Hodgkin lymphoma – the HODGKIN25 study

Abstract Intro Early-stage classical Hodgkin lymphoma (cHL) is a highly curable malignancy. Traditionally, patients (pts) have been treated with combined modality therapy (CMT) using A(B)VD +/- consolidative radiotherapy (RT). Given potential toxicities of RT, trials have investigated excluding RT but have failed to show noninferiority. The optimal treatment (tx) paradigm remains controversial, and practice patterns vary across institutions. Methods HODGKIN25 is a retrospective, multi-institution cohort study across 8 academic centers in the U.S. including adult pts with Stage I/II cHL diagnosed between Jan 2012-2022. Primary endpoints include PFS and OS for CMT and chemo alone with subgroup analyses to identify groups that benefit from CMT. Pts whose final therapy differed from initial intention were excluded from subgroup analyses to avoid biases including progression on chemo before radiation or unplanned salvage radiation. Bulky/unfavorable disease were defined per NCCN. Results 810 pts met criteria for analysis. Median age was 33 yrs (18-84). Majority were female (436, 53.6%) and White race (644, 79.5%). Nodular sclerosing histology was most common (624, 77.0%), 13.0% (105) were Stage I, 78.5% (636) Stage II, and 8.5% (69) Stage IIBX; 27.0% (219) had bulky disease and 75.6% (612) unfavorable disease. Frontline, 88.3% (716) received A(B)VD with 63.0% (510) intended for chemo alone and 37.0% (300) for CMT. For actual tx, 65.7% (536) received chemo alone and 36% (191) of these pts received 4 cycles of A(B)VD. In 34.3% (280) pts who underwent CMT, 61.1% (171) were treated with £30Gy of RT; 30.7%(86) were treated with protons. 36.5% (80) with bulky disease received CMT. 14.7% (119) had interim (i) PET2+ disease (DS ) of whom 25% (30/119) received escalated chemo. Median follow up was 64.7 months (range 0.7-154.6). For the entire cohort, 2 and 5 yr OS were 99.0% (95% CI 0.98-0.99) and 97.8% (95% CI 0.96-0.99), and 2-and 5 yr PFS 85.4% (95% CI 0.83-0.88) and 82.8% (95% CI 0.80-0.85), respectively (resp). 713 pts were included in the subgroup analyses. There was no significant (sig) difference in OS (p=0.36) or PFS (p=0.16) between CMT vs chemo alone. Subgroups without sig differences in outcome based on tx modality included age, gender, histology, stage, extranodal disease, number of lymph node groups, B symptoms or favorable/unfavorable disease. In pts with DS ≤3 at the end of chemo, there was no difference in PFS or OS with CMT versus 6 cycles of A(B)VD alone. However, pts who received CMT with 2-4 cycles of A(B)VD had improved outcomes compared to 4 cycles of A(B)VD alone with 5 yr PFS of 90.6% (95% CI 0.85-0.94) and 86.8% (95%CI 0.81-0.91; p=0.05), resp. In pts with favorable disease, there was no difference in outcome between CMT with 2 cycles of A(B)VD vs ≥3 cycles of A(B)VD alone. In pts with unfavorable disease, there was no sig difference in outcome between CMT with 4 cycles A(B)VD vs 6 cycles of A(B)VD alone. There were higher rates of neuropathy with longer courses of chemo (p=0.04) and hypothyroidism with CMT (p<0.001). There were no differences in cardiac toxicity based on TTE. Pts with bulky disease had improved local disease control with CMT compared to chemo alone with 5 yr PFS 93.1% (95% CI 0.83-0.97) compared to 86.8% (95% CI 0.78-0.92; p=0.008). Hazard ratio (HR) for local progression at bulky site in the chemo alone group was 3.38 (95% CI 1.30-8.86; p=0.013). There was also a decreased risk of progression in pts with iPET+ disease who received CMT versus chemo alone with 5 yr PFS of 73.6% (95% CI 0.52-0.87) and 52.4% (95% CI 0.39-0.64; p=0.012), resp. HR for progression in pts who received chemo alone was 2.75 (95% CI 1.21-6.24; p=0.016). With RT, rates of pneumonitis and esophagitis were 3.2% (9) and 35% (98), resp. Late toxicities included any second malignancy 5.4% (44), myocardial infarction/stroke 2% (16), interstitial lung disease 1.3% (11), and endocrinopathy 9.2% (75). Pts who received CMT were more likely to develop hypothyroidism (p<0.001) and second malignancy (p=0.022), and less likely to develop pulmonary fibrosis (p=0.07). Conclusion Our large, multi-institution study indicates that while there is no sig difference in survival between CMT vs chemo alone in pts with limited stage cHL, CMT benefited pts who received <4 cycles of A(B)VD for unfavorable, iPET+ or bulky disease. This largest real-world analysis may provide additional guidance when selecting frontline therapy for cHL pts.