Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia

NCT ID: NCT02827617

Last Updated: 2025-11-18

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 56 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-06-01
• Study Completion Date: 2024-05-16

Brief Summary

The general aim of the project is the identification of dynamic molecular markers that can help the early and real time prediction of sustained benefit or no benefit from ibrutinib treatment in CLL harboring TP53 mutations. Specific aims of the project include: 1) Assess whether clearance of TP53 mutated clones translates into a predictive biomarker of long term benefit from ibrutinib treatment in CLL. 2) Assess whether plasma cell free DNA represents a sensitive tool that can early and dynamically inform on the development of ibrutinib resistant mutations in CLL.

Detailed Description

In the chemoimmunotherapy era, TP53 mutations defined a subgroup of high risk chronic lymphocytic leukemia (CLL) patients in whom allogeneic stem cell transplantation had to be strongly considered. As a result of the accumulating favorable outcome data reported for new biological drugs, including ibrutinib, in high risk CLL harboring TP53 mutations, there is concern about whether these patients should continue to be offered allogeneic stem cell transplantation. Despite their improved outcome, a proportion of high risk CLL harboring TP53 mutations is going to develop ibrutinib resistance, which in turns translate in a very poor survival. On these bases, in the setting of ibrutinib treatment, novel biomarkers are required to re-define high risk CLL patients candidate for consolidation strategies including allogeneic stem cell transplantation. Our working hypotheses are that: i) clearance of high risk TP53 mutated clones upon treatment with ibrutinib may associate with long progression free survival (PFS), while conversely, the persistence or increase of high risk TP53 mutated subclones under ibrutinib may associate with acquisition of resistance and disease progression; and ii) plasma cell free DNA represents an accessible source of tumor DNA for the early and sensitive identification of mutations causing resistance to ibrutinib. By using highly sensitive ultra-deep next generation sequencing strategies to monitor molecular biomarkers potentially relevant for ibrutinib in DNA coming from both cellular and the plasma fractions of peripheral blood, the project has the chance of identifying new dynamic molecular markers that can help the early and real time prediction of sustained benefit from ibrutinib treatment vs imminent progression in TP53 mutated CLL patients. In the end, the results of this study will provide the bases to refine the current approach for treatment tailoring in TP53 mutated patients by allowing the identification of cases who, though being in clinical response under ibrutinib, will conceivably benefit from immediate switch to alternative options (i.e. novel drugs, allogeneic stem cell transplantation, or CART).

Conditions

Chronic Lymphocytic Leukemia

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

TP53 mutated CLL

Ibrutinib

Intervention Type: DRUG

Treatment with ibrutinib 420 mg quaque die in the clinical practice

Interventions

Ibrutinib

Treatment with ibrutinib 420 mg quaque die in the clinical practice

Intervention Type: DRUG

Other Intervention Names

PCI-32765

Eligibility Criteria

Inclusion Criteria

• Male or female adults 18 years or older
• Documented diagnosis of CLL, according to iwCLL 2008 criteria
• Presence of TP53 mutation as demonstrated by sequencing at the local laboratory and/or presence of 17p deletion as demonstrated by fluorescence in situ hybridization (FISH) testing performed at the local laboratory
• CLL that warrants treatment
• Planned treatment with ibrutinib 420 mg quaque die
• Willing and able to comply with scheduled visits, laboratory tests, and study procedures
• Evidence of a signed informed consent

Exclusion Criteria

• Current or prior histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).
• Prior treatment with ibrutinib or idelalisib

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oncology Institute of Southern Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Davide Rossi, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Oncology Institute of Southern Switzerland

Locations

Onco Ematologia Clinico Sperimentale, I.R.C.C.S. Centro di Riferimento Oncologico

Aviano, , Italy

Ospedale San Raffaele

Milan, , Italy

Dipartimento di Ematologia, Niguarda Cancer Center, Ospedale Niguarda

Milan, , Italy

Department of Medical and Surgical Sciences, section of Hematology

Modena, , Italy

Divisione di Ematologia, Universita' del Piemonte Orientale

Novara, , Italy

Institute of Hematology, Catholic University S. Cuore

Roma, , Italy

Department of Haematology, Tor Vergata Hospital

Rome, , Italy

Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi"

Udine, , Italy

Ematologia, Ospedale di Circolo e Fondazione Macchi

Varese, , Italy

Oncology Institute of Southern Switzerland

Bellinzona, Switzerland, Switzerland

Division of Hematology, Department of Internal Medicine, Basel University Hospital

Basel, , Switzerland

Hematology, Luzern Kantonsspital

Lucerne, , Switzerland

Clinica Luganese Moncucco

Lugano, , Switzerland

Countries

Italy; Switzerland

Other Identifiers

IOSI-EMA-001

Identifier Type: -

Identifier Source: org_study_id