CML Pediatric ITK Response According to Molecular Identification at Diagnosis

Chronic Myeloid Leukemia Clinical Trial

— CML Piramid  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05605379
• Other study ID #: CHUBX 2022/44
• Status: Recruiting
• Start date: February 27, 2023
• Est. completion date: March 2024

Study information

• Verified date: October 2023
• Source: University Hospital, Bordeaux
• Contact: Stéphanie DULUCQ
• Phone: 05 57 82 14 98
• Email: stephanie.dulucq[@]chu-bordeaux.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: March 2024
• Est. primary completion date: January 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Biological:
• Next Generation Sequencing (DNA and RNA)
Targeted Next Generation Sequencing (DNA and RNA)

Locations

Country	Name	City	State
France	CHU de Bordeaux, Service Hématologie Biologique	Bordeaux

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bordeaux

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall Survival (OS)	We will analyse the impact of the presence of mutations on OS	At 3, 12, 18 and 24 months