CML Pediatric ITK Response According to Molecular Identification at Diagnosis (CML Piramid)

CML Pediatric ITK Response According to Molecular Identification at Diagnosis (CML Piramid

Treatment of chronic myeloid leukemia (CML) has been revolutionized by tyrosine kinase inhibitor (TKI). Nevertheless, case of failure and suboptimal response are still observed even in children. Pediatric CML is a rare disease and differs from adult in terms of disease presentation and treatment response underlying a likely different CML biology. Molecular mechanisms that induce resistance to TKI are still poorly characterized except mutations in the tyrosine kinase domain of BCR::ABL1. We propose to search for a molecular signature to predict the response to TKI in the pediatric population.

Study Overview

• Status: Recruiting
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Biological: Next Generation Sequencing (DNA and RNA)

Detailed Description

Commonly mutated genes associated with myeloid malignancies have been described in acceleration phase and blastic phase but also at diagnostic in adult chronic phase-CML (CP-CML). The impact of these mutations on treatment response is still debated but several studies observed a worse outcome in adult patients with some mutations. In children only one study explored the molecular status of 30 genes in 21 children and young adults. They found a higher proportion of ASXL1 mutations in children than in adult They did not observed any significant difference in overall survival of ASXL1 mutated versus non-mutated patients but probably due the small size of the cohort. We propose here, to investigate retrospectively on DNA at diagnosis of 88 CP-CML children the mutation status of 64 genes by next generation sequencing and to see if there is an association with the response to TKI treatment. We will complete the molecular signature by analyzing the differentially genetic expression profile by RNA-seq on peripheral blood RNA of 8 patients with CCR at 12 months (and/or a BCR ::ABL1 IS ≤1%IS) and 8 patients with no CCR at 12 months.

• Study Type: Observational
• Enrollment (Estimated): 88

Contacts and Locations

• Study Contact: Name: Stéphanie DULUCQ; Phone Number: 05 57 82 14 98; Email: stephanie.dulucq@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • CHU de Bordeaux, service Hématologie Biologique
    • Contact: Stéphanie DULUCQ; Email: stephanie.dulucq@chu-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Pediatric CML patients

Description

Inclusion Criteria:

• Age at diagnosis less than or equal to 18 years
• Presence of a Philadelphia chromosome detected by cytogenetic analysis (conventional karyotype or Fluorescence In Situ Hybridization (FISH)) and a BCR ::ABL1 transcript e13a2 ou e14a2
• Diagnosis in chronic phase according to the European Leukemia Net (ELN) criteria
• First-line treatment with TKIs
• Possible pre-treatment with hydroxyurea
• DNA available at diagnosis
• RNA available for a sub-group patients (8 responders vs 8 no responders)

Exclusion Criteria:

• Age at diagnosis more than 18 years
• Diagnosis in accelerated phase or blastic phase
• First line treatment other than TKI

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Responders (with CCR at 1 year)	Biological: Next Generation Sequencing (DNA and RNA); Targeted Next Generation Sequencing (DNA and RNA)
No responders (without CCR at 1 year)	Biological: Next Generation Sequencing (DNA and RNA); Targeted Next Generation Sequencing (DNA and RNA)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete cytogenetic response (CCR)	We will analyse the impact of the presence of mutations on the obtention of CCR	At 12 months from TKI start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular response	We will analyse the impact of the presence of mutations on the obtention of molecular response (MR4, MMR)	At 3, 12, 18 and 24 months
Type of response according to ELN2020 criteria	We will analyse the impact of the presence of mutations on the type of response	At 3, 12, 18 and 24 months
Occurrence of secondary resistance	We will analyse the impact of the presence of mutations on the occurrence of loss of complete hematologic, and/or cytogenetic and/or molecular responses	At 3, 12, 18 and 24 months
Occurrence of TK domain mutation	We will analyse the impact of the presence of mutations on the occurrence of mutation in the TK domain ABL1	At 3, 12 18 and 24 months
Progression Free Survival (PFS)	Progression to accelerated phase or blast crisis and deaths will be analysis according to the mutational status	At 3, 12, 18 and 24 months
Overall Survival (OS)	We will analyse the impact of the presence of mutations on OS	At 3, 12, 18 and 24 months

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2023
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: October 12, 2022
• First Submitted That Met QC Criteria: October 28, 2022
• First Posted (Actual): November 4, 2022

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 26, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Children; Chronic Myeloid Leukemia; Molecular landscape; TKI response; Expression profile
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Chronic Disease; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CHUBX 2022/44

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No