Prognostic Significance of ctDNA in HL

Prognostic Significance of Circulating Tumor DNA in Hodgkin Lymphoma

Specific somatic mutations using ctDNA will be analyzed in predefined subgroups of cHL (e.g., age <60 and ≥ 60 years, EBV). These mutations will be correlated with response to the treatment in the first line, in the relapse, during brentuximab vedotin and/or nivolumab treatment. Circulating tumor DNA will be correlated with the extent of tumor mass and chemo/radiotherapy.

Study Overview

• Status: Recruiting
• Conditions: Prognostic Cancer Model

Detailed Description

Samples of plasma from peripheral blood will be taken for investigational ctDNA examination during the specific timepoints: at diagnosis, after 2 cycles of initial chemotherapy, at the end of chemotherapy, 3 months after radiotherapy, at the diagnosis of the first relapse, after salvage chemotherapy before ASCT, 3 months after ASCT, at the diagnosis of second relapse and every 3 months during brentuximab vedotin treatment or during nivolumab treatment until progression. The buccal swab for germline DNA extraction will be performed at the time of enrollment into the study. Samples of peripheral blood for EBV-DNA analysis will be obtained from the EBV-positive cHL patients to measure EBV load at the same time-points as ctDNA. Microdissected HRS cells from fresh frozen biopsies at the diagnosis and at the relapse will be used for tumor cells next generation sequencing.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Heidi Mocikova, M.D., Ph.D.; Phone Number: +420267163554; Email: heidi.mocikova@fnkv.cz
• Study Contact Backup: Name: Ondrej Havranek, assoc. prof.; Phone Number: +420325873029; Email: ondrej.havranek@lf1.cuni.cz

Study Locations

• Czechia
  • Hradec Kralove, Czechia, 50005
    • Recruiting
    • University hospital Hradec Králové
    • Contact: Alice Sykorova, M.D., Ph.D.; Phone Number: +420495 832 866; Email: alice.sykorova@fnhk.cz
  • Olomouc, Czechia, 77520
    • Recruiting
    • University Hospital Olomouc
    • Contact: Vit Prochazka, prof. M.D.; Phone Number: +420588 442 878; Email: prochazv@fnol.cz
  • Praha, Czechia, 10034
    • Recruiting
    • University Hospital Královské Vinohrady
    • Contact: Heidi Mocikova, M.D., Ph.D.; Phone Number: +420267163554; Email: heidi.mocikova@fnkv.cz
    • Contact: Katerina Klaskova, Ing.; Phone Number: +420267162880; Email: katerina.klaskova@fnkv.cz
  • Praha, Czechia, 12108
    • Active, not recruiting
    • Charles University
  • Praha, Czechia, 12808
    • Recruiting
    • General University Hospital
    • Contact: Jan Koren, M.D.; Phone Number: +420224962541; Email: jan.koren@vfn.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

Patients ≥ 18 years with new HL, all patients will undergo standard diagnostic procedures and will be divided based by stages and risk factors. Patients below 60 years will be divided into 3 treatment risk groups and treated according to the standard recommendations explained as well as elderly patients (see study groups). Younger relapsed patients will be treated with salvage platinum-based chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). Relapses after ASCT in younger patients or after at least two lines of chemotherapy in elderly patients will be treated with brentuximab vedotin (up to 16 cycles) or nivolumab until progression.

Description

Inclusion Criteria:

• Patients ≥ 18 years with newly histologically confirmed classical Hodgkin lymphoma (cHL) will be enrolled
• signing the informed consent

Exclusion Criteria:

• Pacients without signing the informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort
Standard first line treatment, stages I or II without risk factors; Standard first-line treatment that includes 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and involved site radiotherapy of 20 Gy in early clinical stages I or II without risk factors.
Patients < 60 years, stages I or II and 1 risk factor; Patients below 60 years in intermediate clinical stages I or II with at least one risk factor are treated with 2 cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) escalated and 2 cycles of ABVD in PET-4 negative cases. Involved site radiotherapy of 30 Gy is indicated in PET-4 positive patients with intermediate stages after chemotherapy.
Patients < 60 years, stages III or IV with MMT and/or EN disease; Patients in advanced stages III or IV and patients in stage IIB with massive mediastinal tumor and/or extranodal disease are treated with 4 or 6 cycles of BEACOPP escalated based on PET-2 negativity or positivity.
Elderly patients ≥ 60 years and 1 risk factor; Elderly patients in intermediate stages are treated with 2 cycles of ABVD and 2 cycles of AVD without bleomycin and involved site radiotherapy of 30 Gy.
Elderly patients ≥ 60 years, stages III or IV; Elderly patients in advanced stages are treated with 2 cycles of ABVD and 4 cycles of AVD without bleomycin
Relapsed patients up to 65 years; The treatment for patients in relapse up to the age of 65 years is two cycles of platinum based salvage chemotherapy: cisplatin, cytarabine and dexamethasone (DHAP) or ifosfamide, carboplatin, etoposide (ICE) followed by high- dose chemotherapy and autologous stem cell transplantation (ASCT).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of tumor specific mutation profiles at dg. of HL based on ctDNA	Identification of tumor specific mutation profiles at diagnosis of classical Hodgkin: age at diagnosis < 60 years in comparison to patients with age at diagnosis 60 years and more; EBV negative versus EBV positive cases; correlation with the first line treatment outcome lymphoma based on ctDNA analysis with correlation to clinical and pathological characteristics	4 years
Quantitative analysis of ctDNA level during the first-line chemotherapy	Quantitative analysis of ctDNA level during the first-line chemotherapy: analysis in relation to the type of chemotherapy: BEACOPP escalated vs ABVD; dynamics of ctDNA decline in correlation with treatment response	4 years
Identification of tumor specific mutation profiles at relapse of classical HL	Identification of tumor specific mutation profiles at relapse of classical Hodgkin lymphoma: detection of newly developed mutations in comparison to the initial diagnosis; characteristics of mutations in HL tumors refractory to brentuximab vedotin; characteristics of mutations in HL tumors refractory to nivolumab	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In vitro functional characterization of identified DNA variants and/or mutations	In vitro functional characterization of identified DNA variants and/or mutations: variants with unknown impact on classical HL development; variants identified as associated with features analyzed in above mentioned goals	4 years

Collaborators and Investigators

• Sponsor: Interni hematologicka klinika FNKV
• Collaborators: Charles University, Czech Republic; University Hospital Olomouc; General University Hospital, Prague; University Hospital Hradec Kralove; University Hospital, Motol
• Investigators: Study Chair: Heidi Mocikova, M.D., Ph.D., Faculty Hospital Královské Vinohrady

Publications and helpful links

General Publications

• Dusek L, Majek O. Editorial. Klin Onkol. 2014;27 Suppl 2:3. No abstract available.
• Mocikova H, Sykorova A, Stepankova P, Markova J, Michalka J, Kral Z, Buresova L, Belada D. [Treatment and prognosis of relapsed or refractory Hodgkin lymphoma patients ineligible for stem cell transplantation]. Klin Onkol. 2014;27(6):424-8. doi: 10.14735/amko2014424. Czech.
• Sykorova A, Mocikova H, Lukasova M, Koren J, Stepankova P, Prochazka V, Belada D, Klaskova K, Gaherova L, Chroust K, Buresova L, Markova J; Czech Hodgkin's Lymphoma Study Group. Outcome of elderly patients with classical Hodgkin's lymphoma. Leuk Res. 2020 Mar;90:106311. doi: 10.1016/j.leukres.2020.106311. Epub 2020 Jan 24.

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: November 14, 2023
• First Submitted That Met QC Criteria: February 8, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hodgkin lymphoma; next generation sequencing; circulating tumor DNA
• Other Study ID Numbers: NU22-03-00182

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No