Sequential immunotherapy in a patient with primary refractory Hodgkin lymphoma and novel mutations.

Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab. During the following two years she responded to the anti-CTLA-4 mab ipilimumab, the Jak2 inhibitor ruxolitinib, and a combination of lenalidomide plus cyclophosphamide given in subsequent relapses. A thorough genomic analysis demonstrated seven genomic alterations with six of them not previously described in this disease (i.e. BRIP1 G212fs*62, KRAS L19F, KDM5A R1239W, MYC A59T, ARIDA1A E1683fs*15 and TP53 277Y). Three alterations were considered actionable and one of them drugable. The number of mutations increased over time and the BRIP1 mutation was found to be a germline mutation.