Treatments for advanced-staged Hodgkin lymphoma (HL) include non-intensified ABVD, ABVD-based escalation with BEACOPP in case of a positive interim PET-CT (ABVDesc), BEACOPP-based de-escalation in case of a negative interim PET-CT (BEACOPPdesc) and AVD+brentuximab vedotin (A-AVD). Since a clinical trial comparing all these strategies is unlikely to be performed, alternative statistical methods should be employed.
We included data from the HD0607, RATHL, HD18, AHL2011, S0816 and ECHELON1 trials and compared the 3-year progression free survival (PFS) and overall survival (OS) of young patients. We used Liu’s method (BMC Med Res Methodol 2021) to reconstruct individual patient data (IPD) from Kaplan-Meier survival curves. Comparisons of adverse events were performed Among the 6 included trials, the ECHELON-1 was the only one that enrolled patients>60yr and excluded stage II patients. Since we focused on patient<=60yr, we excluded the RATHL trial as survival curves of patients<=60yr were not published. Among the 5,034 included patients, 11% received not-intensified ABVD, 12% A-AVD, 22% ABVDesc (S0816 and HD0607), 55% BEACOPPdesc (AHL2011 to ABVD and HD18 to less treatment cycles). The extrapolated 3-yr PFS increased from 79% with ABVD alone, to 81% with ABVDesc, 85% with A-AVD and 92% with BEACOPPdesc (Fig.1,p<0.0001).
Of note, the difference between the ABVD without or with intensification was not statistically significant (HR1.03, 95%CI 0.83-1.29, p=0.5398). Whereas a significant difference was identified between A-AVD vs ABVDesc (HR1.56,95%CI 1.25-1.95,p=0.0055) and BEACOPPesc (HR0.62,95%CI 0.44-0.76,p<0.0001). The strategy of non-intensified ABVD lead to a lower OS that the other strategies. The 3-yr OS was 95% with ABVD, 97% ABVDesc, A-AVD and BEACOPPdesc (Fig.1,p<0.0025). In particular, no difference was observed between A-AVD vs BEACOPPdesc (HR1.04,95%CI0.67-1.61,p=0.9943) or ABVDesc (HR1.57,95%CI 0.99-2.29,p=0.0515) Regarding safety, grade>=3 cytopenia and febrile neutropenia were more common with BEACOPPdesc 90% and 27% > ABVDesc 67%-76% and 10%-32% > A-AVD 54% and 8% > ABVD 46% and 3% (p<0.001). While grade 3 neuropathy was more common with A-AVD 11% > BEACOPPdesc 2-7%, ABVDesc 2% > ABVD 1% (p<0.001)
In conclusion, by using indirect clinical trials comparisons with IPD extraction we demonstrated the superiority and the safety of A-AVD therapy over ABVDesc while the superimposable OS with BEACOPPesc suggest the reliability of salvage therapies after A
Andrea Visentin, Alessandro Cellini, Francesco Angotzi, Valeria Ruocco, Andrea Serafin, Nicolò Danesin, Arianna Bevilacqua, Chiara Adele Cavarretta, Francesco Piazza, Livio Trentin