Discontinuation of TyrosIne Kinase Inhibitors (TKI) in Chronic Myeloid Leukemia (CML) and Impact on the Immune System

Discontinuation of TyrosIne Kinase Inhibitors (ITK) in Chronic Myeloid Leukemia (LMC) and Impact on the Immune System: a Randomized Comparative Study of Two Therapeutic Strategies

Tyrosine kinase inhibitors (TKI) have revolutionized the management and prognosis of chronic myeloid leukemia (CML). Daily treatment with TKI, which is necessary due to lack of cure, is frequently associated with moderate, chronic and sometimes severe adverse effects. The ability to permanently stop treatment with TKI has thus become a major goal in CML to prevent the occurrence of adverse events, improve quality of life and reduce the general cost of the treatment; we talk about Treatment Free Remission (TFR). It now remains to be demonstrated in a comparative prospective study that a strategy of de-escalation of the TKI treatment dose before treatment discontinuation optimizes TFR results. At the same time, it is possible to reduce adverse reactions and improve the quality of life of patients. In this context, the investigator propose to conduct a randomized clinical trial including CML patients, allowing to compare the results of TFR at 24 months between a sudden stop of treatment after a maintenance phase of dosage for 12 months and a de-escalation arm of dose (dosage reduced by 50%) for 12 months before stopping. A secondary immunological translational objective of this project will be to compare the quantitative and qualitative evolution of innate CD8 T cells between the 2 arms (abrupt cessation of ITK treatment versus progressive withdrawal) and look for a predictive innate CD8 T cells blood signature at the time of stopping treatment of a successful TFR in both arms.

Study Overview

• Status: Recruiting
• Conditions: Chronic Myeloid Leukemia; Tyrosine Kinase Inhibitors
• Intervention / Treatment: Drug: treatment of TKI in CML

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emilie Cayssials-Caylus, Dr; Phone Number: c; Email: emilie.cayssials@chu-poitiers.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • CHU Angers
    • Contact: Corentin ORVAIN, Dr
  • Bayonne, France
    • Recruiting
    • CH Bayonne
    • Contact: Fréderic BAUDUER, Dr
  • Brest, France
    • Recruiting
    • CHU Brest
    • Contact: Jean Christophe IANOTTO, Dr
  • Créteil, France
    • Recruiting
    • CHI Créteil
    • Contact: Lydia ROY, Dr
  • La Rochelle, France
    • Recruiting
    • CH La Rochelle
    • Contact: Emmanuel FLECK, Dr
  • Lille, France
    • Recruiting
    • CHU Lille
    • Contact: Valerie COITEUX, Dr
  • Limoges, France
    • Recruiting
    • CHU Limoges
    • Contact: Amélie PENOT, Dr
  • Lyon, France
    • Recruiting
    • Centre Leon Berard
    • Contact: Franck NICOLINI, Dr
  • Mont-de-Marsan, France
    • Recruiting
    • CH Mont de Marsan
    • Contact: Samia MADENE HAROUNE, DE
  • Nantes, France
    • Recruiting
    • CHU Nantes
    • Contact: Viviane DUBRUILLE, Dr
  • Poitiers, France
    • Recruiting
    • CHU Poitiers
    • Contact: José Miguel TORREGROSA DIAZ, DR
  • Périgueux, France
    • Recruiting
    • Ch Perigueux
    • Contact: Claire CALMETTE, Dr
  • Toulouse, France
    • Recruiting
    • Oncopole Toulouse
    • Contact: Francoise HUGUET, Dr
  • Tours, France
    • Recruiting
    • Chu Tours
    • Contact: Antoine MACHET, Dr
  • Versailles, France
    • Recruiting
    • CH Versailles
    • Contact: Philippe ROUSSELOT, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Patient ≥ 18 year-old.
• Diagnosis of chronic phase CML according to WHO 2016 criteria with a typical BCR::ABL1 rearrangement (e13a2 or e14a2)
• Duration of treatment by Imatinib ≥ 4 years / ITK2G ≥ 3 years and no change of TKI or decrease in dosage in the last 6 months prior to inclusion
• Deep Molecular Response (DMR) duration ≥ 1 year
• Absence of contraindication to the continuation of the same TKI for 12 months at the same dosage according to international recommendations nd the PCR of each TKI:

Imatinib (≥ 300 mg/j) Dasatinib (≥ 50 mg/j) Nilotinib (≥ 300 mg/j) Bosutinib (≥ 200 mg/j)

• Patient not participating in another interventional study for the duration of the interventional study
• Sexually active men should use effective contraception when taking Dasatinib
• Having an health insurance
• Having signed the consent form

Non-Inclusion Criteria:

• Patients with progressive severe pathology of poor prognosis immediately compromising participation in the entire study and/or with uncontrolled chronic pathology
• ECOG ≥ 3
• Prior resistance to TKI
• Patients who have already experienced an attempt of TKI cessation
• Patients with a malignant tumour that has been treated with chemotherapy within 2 months of inclusion or undergoing chemotherapy or that will be treated with post-inclusion chemotherapy
• Protected person
• Pregnant women or women of childbearing age without appropriate contraceptive measures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: continued treatment with TKI at 50% dose reduction; continued treatment with TKI at 50% dose reduction compared to dosing received at randomization and then stopped treatment 12 months after randomization	Drug: treatment of TKI in CML; continued treatment with TKI at randomization a then stopped treatment 12 months after randomization
Active Comparator: continuation of TKI treatment without dose change; continued treatment with TKI at same dose compared to dosing received at randomization and then stopped treatment 12 months after randomization	Drug: treatment of TKI in CML; continued treatment with TKI at randomization a then stopped treatment 12 months after randomization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients in treatment free Remission (TFR) 24 months after treatment discontinuation in patients.Treatment-Free Remission (TFR) is defined as patients with Major Molecular Response (MMR) or better (BCR-ABL level ≤ 0.1% IS).	Percentage of patients in treatment free Remission (TFR) 24 months after treatment discontinuation in patients is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL level ≤ 0.1% IS) on the total number of patients.	24 months after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference in proportions (%) at randomization and 12 months post randomization, of innate CD8 T cells among total CD8 T cells	12 months

Collaborators and Investigators

• Sponsor: Poitiers University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2023
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: February 9, 2023
• First Submitted That Met QC Criteria: February 21, 2023
• First Posted (Actual): March 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Characteristics of innate T cells
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: AITIK

Drug and device information, study documents

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