Phase 2 study of panobinostat +/- rituximab in relapsed diffuse large B cell lymphoma and biomarkers predictive of response
Mené sur 40 patients atteints d'un lymphome diffus à grandes cellules B récidivant ou réfractaire, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse, et la toxicité du panobinostat, combiné ou non avec le rituximab, en fonction de la présence de mutations du gène MEF2B dans l'ADN tumoral circulant
Panobinostat induces responses in 28% of patients with relapsed and refractory diffuse large B cell lymphoma that are typically durable off therapy.MEF2B mutations predicted for response whereas early increase in ctDNA abundance was a strong predictor of subsequent treatment failure. The majority of DLBCL tumors contain mutations in histone modifying enzymes (HME), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDI) and preclinical data suggest that HDI augment the effect of rituximab. In this randomized phase II study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI, administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n=27) or transformed (n=13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. 11/40 patients (28%) responded to panobinostat (95% CI: 14.6% - 43.9%) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI: 9.4 to "not reached"). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response (likelihood ratio 3.67, 95% CI: 1.46 - 9.19). We detected ctDNA in at least one plasma sample from 96% of tested patients. A significant increase in ctDNA at day-15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days following treatment initiation. This clinical trial was registered in www.clinicaltrials.gov (NCT01238692).