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

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.

Case report: Composite mantle cell lymphoma and classical Hodgkin lymphoma

“…BRIP1 mutation is associated with an increased risk of epithelial ovarian cancer, and might be targeted by PARP inhibitors such as olaparib (22). BRIP1 mutation in cHL have been reported in only one study (22). In our current case, limited to experimental conditions, we did not do the microdissection.…”

“…However, the prognostic effect of the three mutations in cHL has not been reported, and their influence on the prognosis of CMLHL is uncertain. BRIP1 mutation is associated with an increased risk of epithelial ovarian cancer, and might be targeted by PARP inhibitors such as olaparib (22). BRIP1 mutation in cHL have been reported in only one study (22).…”

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

“…Sporadic mutations in the RAS-MAPK pathway genes were found, including NRAS, BRAF, MAP2K1 and NF1 [22,23,85,86]. A single case with KRAS L19F mutation was reported in the literature [24]. In a cHL case, KRAS mutation (G60D) was found in cells from clonal hematopoiesis but not in HRS cells; indeed, clonal hematopoiesis of indeterminate potential was shown to occur in a fraction (12.5%) of cHL cases, including in young patients [87].…”

Classical Hodgkin’s Lymphoma in the Era of Immune Checkpoint Inhibition

“…Data on CTLA-4 inhibitors use in cHL have been reported for patients after autologous stem cell transplantation [116]. Combined inhibition of PD1/PD-L1- and CTLA4-mediated suppression in cHL was hypothesed by the finding that CTLA4 significantly increased during treatment with nivolumab and ipilimumab, and remained so after the end of treatment with this drug [117]. Although now tested only in melanoma, dual blockade of PD-1 (with nivolumab) and CTLA-4 (with ipilimumab) resulted in higher response rate and longer survival than in patients treated with a single IC inhibitor [118].…”