"Triple Negative" Adult B-cell Acute Lymphoblastic Leukemia - TRINEG-ALL

Recruiting

• Conditions: Leukemia, Lymphoblastic

• Registration Number: NCT06919393
• Lead Sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS

Brief Summary

It is a multicenter, non-interventional, non pharmacological, translational, prospective study. Any decision about drug administration is made by the physician based on his clinical judgment in the context of clinical practice, independently from the decision to include the patient in the study.

Detailed Description

Survival rates from Acute lymphoblastic leukemia (ALL) have improved dramatically over the past four decades but vary significantly with age. Children treated on modern protocols have survival rates exceeding 90%. Although the remarkable progress made in the treatment of B-Acute lymphoblastic leukemia (B-ALL) in children and, with less efficacy, in adults, several ALL subtypes continue to have a poor prognosis and in a proportion of long-term surviving patients, treatment is responsible for short and long-term toxicities. Consequently, there is a need in improving the molecular dissection of subtypes, identifying genetic alterations that predict the risk of treatment failure and developing novel and targeted therapies. B-ALL patients that doesn't have the most recurrent adult rearrangements (breakpoint cluster region (BCR) - Abelson murine leukemia viral oncogene homolog 1 (ABL1) t(9;22); Transcription Factor 3 (TCF3) - Pre-B-cell leukemia transcription factor 1(PBX1) t(1;19); mixed-lineage leukemia 1 (MLL) - ALL1-fused gene from chromosome 4 (AF4) t(4;11)) are collectively referred to as triple negative (Ph-/-/-) ALL (that represents 61% of adult B-ALL; Roberts KG, J Clinical Oncology 2016). Triple negative ALL is a heterogeneous group of patients; most of these patients have a poor prognosis and miss a target therapy. In the last few years the role of CRLF2 (cytokine receptor-like factor 2; a type I cytokine receptor) gene have become pivotal in ALL, both in adult and paediatric patients. In the last few years the role of CRLF2 (cytokine receptor-like factor 2; a type I cytokine receptor) gene have become pivotal in ALL, both in adult and paediatric patients. CRLF2 is frequently altered in adult B-ALL, especially in Ph-like pts (50-75% of cases) and in Down syndrome ALL (50% to 55%). Alterations that lead, in the majority of cases, to a CRLF2 overexpression. Adult pts with upregulated CRLF2 have poor outcome and novel strategies are needed to improve it.

It is a multicenter, non-interventional, non pharmacological, translational, prospective study. Any decision about drug administration is made by the physician based on his clinical judgment in the context of clinical practice, independently from the decision to include the patient in the study.

The primary objective is the biological characterization of Ph-/-/- ALL, considering CRLF2 overexpression event, in order to define cluster of patients and to assess biomarkers in this subgroup to test new drugs.

The secondary objective is to evaluate if the cytofluorimetric assay - developed on the basis of preliminary data - may be used to detect triple negative subgroups, to provide a rapid, simple and economically viable diagnostic tool to recognize these cases at presentation.

About 60 patients affected by primary or secondary ALL will be enrolled at diagnosis and/or relapse/s.

Patients will be asked to donate part of the Peripheral Blood and Bone Marrow samples, collected according to clinical practice for the management of their disease, for the purposes of this study. A saliva sample will be collected from each patients. Clinical data will be collected in a study dedicated database.

The total duration of the study is 36 months.

Study Timeline

• Study Start: 2019-10-23
• Study First Submitted: 2021-02-25
• Status Verified: 2025-04
• Study First Submitted QC: 2025-04-07
• Last Update Submitted: 2025-04-07
• Study First Posted: 2025-04-09
• Last Update Posted: 2025-04-09
• Primary Completion: 2026-01
• Study Completion: 2026-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Participant is willing and able to give informed consent for participation in the study;
• Patients with new diagnosis and/or relapse/s of primary or secondary B-ALL;
• Negative for BCR-ABL1 t(9;22); TCF3-PBX1 t(1;19); MLL-AF4 t(4;11) rearrangements;
• Participant is willing and able to give informed consent for participation in the study;
• Male or Female, aged >18 years;
• Availability of clinical data.

Exclusion Criteria

• Age < 18 years;
• B-ALL positive for BCR-ABL1 t(9;22); TCF3-PBX1 t(1;19); MLL-AF4 t(4;11) rearrangements.

Low blast percentage (<70%) samples could be excluded for molecular evaluations, not for cytofluorimetric analyses;

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Biological characterization for B-ALL Ph-/-/- subgroup identification	3 years	Biological characterization of Ph-/-/- ALL, considering CRLF2 overexpression event, to better define clusters preliminarily identified and to identify biomarkers in these subgroups. Each sample at diagnosis and/or relapse time-point will be sequenced with an RNA-seq capture approach. Through bioinformatic analysis we will identify upregulated CRLF2 samples and associated gene signature. Fusion, mutation identification will integrate expression data.

Secondary Outcome Measures

Name	Time	Method
Correlation, in terms of survival, between identified Ph-/-/- molecular subgroups and eventual novel associated molecular features.	3 years	To investigate the association of identified Ph-/-/- molecular subgroups and/or molecular features with the clinical outcome (OS, EFS). To assess if a Ph-/-/- molecular subgroups, identified thanks to our analyses, could be associated with poor prognosis.
Cytofluorimetric evaluation of Ph-/-/- ALL markers as CRLF2, CTGF and CD200.	3 years	To evaluate if the cytofluorimetric assay - developed on the basis of preliminary data - may be used to detect triple negative subgroups, to provide a rapid, simple and economically viable diagnostic tool to recognize these cases at presentation. On each enrolled fresh sample cells will be analysed through a B-ALL flow cytometer panel (e.g. CD45, CD19, CD34) to which markers of interest will be added (e.g. CRLF2, CTGF and CD200).; Their expression in flow cytometry will be compared with the expression obtained from RNA-seq data.
Discover new biomarkers identified Ph-/-/- molecular subgroups	3 years	To assess if some molecular feature could be associated to specific Ph-/-/- molecular subgroups. To explore if these biomarkers, detected in some of identified Ph-/-/- molecular subgroups, could be targeted by novel drugs. To evaluate the drug/s effects through sensitivity in vitro/ex vivo tests on B-ALL cell lins and on primary leukemic cells.

Trial Locations

Locations (3)

Irst Irccs; 🇮🇹 Meldola, FC, Italy

Ospedale S. Maria delle Croci RAVENNA; 🇮🇹 Ravenna, RA, Italy

Ospedale Infermi; 🇮🇹 Rimini, RN, Italy