Radiation-free therapy for the initial treatment of good prognosis early non-bulky HL, defined by a low metabolic tumor volume and a negative interim PET after 2 chemotherapy cycles. a phase II prospective rafting trial

Abstract

Abstract Patients (pts) with early-stage favorable Hodgkin Lymphoma (efHL) have a heterogeneous prognosis: most (70%) are cured with chemotherapy (CT) alone, 20–30% by combined modality therapy (CMT: CT + Involved-node radiotherapy (INRT)), whereas 5-10% fail CMT. Moreover, treatment-related morbidity and mortality (TRM), including late complications (malignancies and cardiovascular events), still remains a concern. Previous studies (RAPID, H10, HD16) aimed to assess the safety of radiation-free treatment (RFT) in efHL failed to confirm the non-inferiority of RFT to CMT. Nonetheless, about 70% of pts can be cured with CT alone, most of them with a negative interim PET after 2 CT cycles (PET-2), while ~25% of pts with a positive PET-2 fail standard CMT (H10 trial). So far, PET-2 is considered the strongest predictor of Treatment Failure (TF) both in early and advanced classical HL (cHL). A large nodal mass (NM) (LNM: defined as a NM with the largest diameter >5 cm) proved the strongest predictor of TF in efHL treated with CT alone (Illidge, 2020). Moreover, baseline total metabolic tumor volume (TMTV) showed a great prognostic relevance both in early and advanced cHL. Finally, H10 study showed ~50% of PET-2 negative pts relapsing mostly in initially involved nodes were effectively salvaged by INRT alone. The anti PD-1 MoAb Nivolumab (Nivo) proved very efficacious in pre-treated and untreated cHL. The latter, adimistered after INRT could improve the long-term disease control in this high-risk pts. The RAFTING(NCT04866654, EudraCT 2020-002382-33) is a prospective, multicenter, international (Poland, Italy, Spain), single-arm, non-inferiority, phase 2 study. Eligibility criteria include untreated, stage I–IIA cHL, age 18–70, absence of bulky mass (>10 cm), B-symptoms or extranodal disease. Different from low risk (LR) pts, high-risk (HR) pts are defined by presence of high TMTV >84ml at baseline and/or a positive PET-2. LR pts are treated with CT alone, while HR pts receive “triple therapy”, consisting in 4 ABVD cycles, INRT 20/30 Gy and Nivo (240 mg q2w, up to 24 doses). The cutoff value of 84ml was extrapolated from the French cohort of standard arm of the H10 study in which baseline PET images were available fitting the inclusion criteria in RAFTING (unpublished observation). LR pts are in turn stratified into very low-risk (VLR) or low-risk (LR), in the absence or presence, respectively, of at least one of the modified EORTC (mEORTC) risk factors (RF), in which classical bulky is replaced by a LNM, defined as NM >5 and <10 cm. VLR and LR pts are treated with 2 or 4 ABVD cycles, respectively, and, upon CR entry, they are monitored for the presence of circulating tumor (ct) DNA in the plasma by blood sampling every 3 months for 2 years. CtDNA assay is performed with the CAPP sequencing method (Spina, 2018) in core laboratory in Bellinzona (CH). The PET images of enrolled pts performed at baseline, PET-2 and end of treatment are centrally reviewed by 3 expert Nuclear Medicine doctors in a Blinded Independent Central Review (BICR) method. TMTV is calculated with a 41% SUVmax threshold. During the follow-up PET is repeated only upon the suspect of relapse. VLR/LR pts with limited relapse (LimRel: 3 nodal areas) are rescued with INRT (36Gy)+Nivo. Pts with extended relapse (ExtRel) are addressed to salvage and are off study. The primary endpoint is 3-year PFS of VLR/LR pts, defined as time from registration to any type of progression or death compared to an expected value of a 3-year PFS of 90% with the lower inferiority margin of 87%, calculated from data of efHL pts treated with CT alone fitting the same inclusion as in the RAFTING trial. The non-inferiority margin has been set as 7% less than the results expected for PET-2 negative pts from the standard arm of the RAPID study (3-year PFS of 94.6%). The main secondary end-point is 3-year event free survival, defined as a time form registration to any progression after completing planned treatment or to ExtRel occurring at any time during the study or to death. The planned treatment for VLR/LR pts consist of CT alone and in case of LimRel salvage with INRT+Nivo, whereas for HR “triple therapy”. The other secondary endpoints include 3-year OS and accuracy of ctDNA for relapse detection in VLR/LR pts.The RAFTING trial is approved by IRB of Medical University of Gdańsk, Poland (NKBBN/74/2021) and is funded by the Medical Research Agency, Poland (Project 2019/ABM/01/00060).