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

Sponsor

Centre Henri Becquerel (Other)

Overall Status

Unknown status

CT.gov ID

NCT02815137

Collaborator

(none)

130

Enrollment

Location

Arm

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the XPO1 E571K mutation could be used as molecular residual disease biomarker in classical Hodgkin's lymphoma. To determine the interest of the mutation assessment by digital Polymerase Chain Reaction, sensitivity and specificity after 2 courses of chemotherapy (C2) will be compared with the deltaSUVmax determined by Positron Emission Tomography after C2 and at end of treatment.

Condition or Disease	Intervention/Treatment	Phase
Classical Hodgkin Lymphoma	Other: Digital Polymerase Chain Reaction	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

130 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Prevalence, Kinetic and Prognostic Value of XPO1 E571K Mutation Detection in Plasma Cell-free DNA From Patients Xith Classical Hodgkin Lymphoma

Actual Study Start Date :

Jun 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2018

Anticipated Study Completion Date :

Jun 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: XPO1 E571K mutation detection Determination of mutation of XPO1571K in patient with classical hodgkin Lymphoma by digital PCR on blood samples and biopsy	Other: Digital Polymerase Chain Reaction Determination of mutation of XPO1 E571K by digital PCR in blod sample of patient with classical hodgkin lymphoma

Arm

Intervention/Treatment

Other: XPO1 E571K mutation detection

Determination of mutation of XPO1571K in patient with classical hodgkin Lymphoma by digital PCR on blood samples and biopsy

Other: Digital Polymerase Chain Reaction

Determination of mutation of XPO1 E571K by digital PCR in blod sample of patient with classical hodgkin lymphoma

Outcome Measures

Primary Outcome Measures

If the mutation can be used as a molecular minimal residual disease biomarker [56 days]
Comparison of the sensitivity and specificity of the detection of the mutation between delta Standard Uptake Value max (SUV max) determined by PET after two courses of chemotherapy

Secondary Outcome Measures

Kinetic of allele frequency decrease [224 days]
difference between the variant allele fraction at the end of treatment and at the diagnosis
Variation of Deauville scale [224 days]
Difference of metabolic parameter in TEP between the end of treatment and the diagnosis
Progression-free survival [2 years]
Time between the inclusion and the date of progression or death

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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