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

// Richard Greil 1, 2, 3 , Lisa Pleyer 1, 2, 3 , Bettina Jansko 1 , Carmen Feierabend 1 , Lukas Rettenbacher 4 , Olga Stiefel 5 , Christoph Rass 1 , Patrick Morre 1 , Daniel Neureiter 3, 6 and Sigrun Greil-Ressler 1 1 IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria 2 Salzburg Cancer Research Institute, A-5020 Salzburg, Austria 3 Cancer Cluster Salzburg, A-5020 Salzburg, Austria 4 Department of Nuclear Medicine, Paracelsus Medical University, A-5020 Salzburg, Austria 5 Ordensklinikum Linz, A-4010 Linz, Austria 6 Institute of Pathology, Paracelsus Medical University, A-5020 Salzburg, Austria Correspondence to: Richard Greil, email: r.greil@salk.at Keywords: immunotherapy; molecular targets; gene mutations; lymphoma Received: April 12, 2017      Accepted: March 15, 2018      Published: April 17, 2018 ABSTRACT 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.