XPO1 E571K

We found co-occurrence of inactivating events in A20 and XPO1 missense mutations impacting 15% of PMBCL evaluated cases, with consistent results seen across all studies (range: 13.8-20%). As expected, A20 mutations/del were more prevalent than XPO1 mutations across all studies (OR 2.46, 95% CI 0.84-7.18, p = 0.02). XPO1 mutated cases trended towards a greater likelihood of having co-occurring A20 mutations (OR 8.51, 95% CI 0.84-86.47, p = 0.08).

P2, N=36, Recruiting, Memorial Sloan Kettering Cancer Center

HSP110 is an essential protein for PMBL and cHL cell survival, through its interaction with STAT6 and its requirement for STAT6 phosphorylation. HSP110 is a cargo protein of XPO1 which is also required for STAT6 phosphorylation. HSP110 inhibitor and selinexor have a synergistic effect in reducing tumour growth, suggesting that this combination could be a promising new therapeutic strategy for PMBL and cHL.

A combination of the NGS (large-scale mutation screening) at the diagnosis with rapid and sensitive mutation monitoring using dPCR at the time of the treatment-tailoring or follow-up could improve decision-making accuracy in the routine care of Hodgkin lymphoma patients. Further analyses are needed to directly compare the sensitivity of the NGS and dPCR methods.

Correlation of mutational load with continuous PET examination would reduce the amount of false-positive results and enable us to use more precise and safe therapy de-escalation. DPCR proved to be sensitive fast and afordable technology for MRD testing.

Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

Although CNS involvement in NA-ATLL portends a poor prognosis, a sizable number of patients can be offered allogeneic grafting as a safe and potentially curative treatment.

Significance : We report that simultaneous disruption of essential regulators XPO1 and A20 in murine B cells encourages development of irregular B and T cell populations, and can stimulate a progressive CLL-like or T cell leukemia-like expansion. Continued investigation with these models can further our understanding of the relationship between overall immune function and these critical regulatory molecules, and can provide considerable insight to identifying pathways for selective targeting as a personalized therapy in several high-risk cancer types.

Also, some of these genetic aberrations like MAP2K1 and PAX5 were associated with worse prognosis. Our patient had little response despite standard therapy, hence we conclude that a poor prognosis could be associated with these genetic alterations.

We therefore hypothesized that combining selinexor and venetoclax would have potential synergy and could be used to target hematologic malignancies bearing XPO1 and SF3B1 mutations.We first determined whether XPO1 and SF3B1 mutant cell lines showed differential response to either selinexor or venetoclax monotherapy. This combination is highly promising as an all oral regimen for hematologic malignancies bearing these mutations. Further, preclinical testing in in vivo using XPO1 and SF3B1 mutant and wildtype mice is ongoing.