Detection and Prognostic Value of Recurrent XPO1 Mutations of Patients With Classical Hodgkin Lymphoma

A research team of Centre Henri Becquerel recently detected an unexpected recurrent point mutation of XPO1 (exportin 1) (also known as Chromosome Region Maintenance 1) located in exon 15 (c.1711G>A) leading to the Glu571Lys (p.E571K) missense substitution in relapsed/refractory (R/R) Primary Mediastinal Large B-cell Lymphoma (PMBL) patients included in the LYSA LNH03 trial program and in classical Hodgkin's Lymphoma patients. It was found recurrent XPO1 E571K mutations in a large cohort of 94 patients with classical Hodgkin's lymphoma. This observation is new and could add new information on driver events and tumorigenesis in this disease. In total, 24.2 % of the patients with classical Hodgkin's lymphoma harbored the XPO1 E571K mutation. It is remarkable that 29% of all XPO1 mutations were only found in the plasma but not in the tumor because of the well-known tumor cell sparsity in Hodgkin's lymphoma. In this particular disease, highly sensitive techniques like digital Polymerase Chain Reaction and targeted Next-Generation Sequencing are essential to highlight low frequency mutations. The research team of the Centre Henri Becquerel have identified a trend toward unfavorable prognostic impact in terms of progression-free survival in patients with detectable XPO1 E571K mutation in plasma cell-free DNA at the end of treatment, which could prove to be statistically significant in a larger cohort. It was observed that 57% of patients who ultimately relapsed were positive in the plasma after end of therapy. It remains to be established whether this mutation adds new relevant value as compared to Positron Emission Tomography-scan.

Inclusion criteria

• Age ≥18 years
• Pathologically confirmed, recent diagnosis of classical Hodgkin Lymphoma
• treatment planned with Adriamycin Bleamycin Vinblastine Dacarbazine (ABVD) or Bleomycin Etoposide Adriamycin Cyclophosphamide Vincristine Procarbazine Prednisone (BEACOPP) regimen (and radiotherapy if applicable)
• all stages (Ann Arbor I - IV)
• Written informed consent
• Patient affiliated or beneficiary of a benefit system
• untreated patient (no corticosteroids or chemotherapy)

Exclusion criteria

• No informed consent
• Treatment by ABVD or BEACOPP not indicated
• Previously treated Hodgkin lymphoma (including corticosteroids)
• Patients who are pregnant or lactating
• Active Hepatitis B or Hepatitis C infection
• Known human immunodeficiency virus (HIV) infection - Patient with no social protection
• Patient under tutorship or curatorship
• Patient not affiliated of beneficiary of a benefit system
• Medical contraindication to PET/CT