CRLF2 expression and MRD kinetics outcomes across the age spectrum in Mexican patients with acute lymphoblastic leukemia: Prevalence and association with post-induction measurable residual disease Free

Introduction

CRLF2 gene rearrangements are the most common genetic alteration in Philadelphia chromosome-like (Ph-like) B-cell acute lymphoblastic leukemia (ALL), leading to overexpression of the CRLF2 receptor complex and activation of downstream signaling pathways. These abnormalities are more prevalent in Hispanic populations and correlate with inferior survival. While gene expression profiling remains the gold standard, flow cytometry and FISH offer more accessible alternatives. In Mexico, the prevalence of CRLF2 expression in ALL remains unclear. This study aims to determine its frequency in a cohort of pediatric and adult Mexican patients and evaluate its association with post-induction measurable residual disease (MRD) and outcomes.

Methods

This was a single center retrospective study that included consecutive patients of any age diagnosed with ALL between 2020 and May 2025. CRLF2 expression was assessed by flow cytometry in a FACS Canto II cytometer in addition to the standard Euroflow panel or fluorescence in situ hybridization (FISH). Clinical, demographic, and laboratory variables were collected. First-line treatment included standard risk-adapted combination chemotherapy and allogeneic hematopoietic cell transplantation according to international recommendations with limited access to first-line blinatumomab for children. The primary outcome was the proportion of patients with CRLF2 expression at diagnosis. Secondary outcomes were to compare treatment response, MRD status, overall and event-free survival between CRLF2-positive vs negative patients.

Results

A total of 85 patients with ALL were included in the study, comprising 46 pediatric (54.1%) and 39 adult (45.9%) cases. The overall prevalence of CRLF2 expression was 42.4% (n=36), with a higher frequency in adults (51.4%) compared to pediatric patients (36%). The median follow-up was 10.9 months (IQR: 2.9–18.9). CRLF2-positive patients exhibited significantly worse early treatment outcomes. Induction refractoriness, defined as ≥5% blasts at the end of the first chemotherapy cycle, was observed in 56.5% of CRLF2-positive patients versus 27.9% of CRLF2-negative patients. Post-induction mortality was also higher in the CRLF2-positive group (22.2% vs. 2.3%, p = 0.011). When stratified by age, induction refractoriness rates did not differ significantly. However, post-induction mortality was significantly higher among CRLF2-positive pediatric patients (25% vs. 0%, p = 0.018), while in adults the difference was not statistically significant (20% vs. 8.3%, p = 0.389). With respect to MRD kinetics, MRD ≥1% after induction was more frequent in CRLF2-positive adults (30%) than in CRLF2-negative adults (27.3%). In children, none of the CRLF2-positive patients had persistent MRD, compared to 6.7% in the CRLF2-negative group. Although individual comparisons did not reach statistical significance, a trend toward higher MRD positivity in CRLF2-positive patients was observed in the entire cohort. In the combined analysis (n=61), this trend approached statistical significance (p = 0.131). Event-free survival (EFS) was also inferior in CRLF2-positive patients. The median EFS in this group was 1.8 months (95% CI: 1.0–2.5), whereas the median EFS was not reached in CRLF2-negative patients. At 12 months, EFS was 65.8% in CRLF2-positive patients and 79.9% in CRLF2-negative patients.

Conclusions

CRLF2 overexpression was identified in nearly half of the Mexican patients with newly diagnosed ALL and was associated with early markers of poor prognosis, including higher rates of induction refractoriness, persistent MRD, and early mortality. These trends were particularly pronounced in adult patients, although pediatric patients also showed increased early mortality when CRLF2 was overexpressed. These findings highlight the prognostic relevance of CRLF2 assessment at diagnosis and support its integration into routine diagnostic and risk stratification strategies, particularly in Hispanic and underserved populations. Moreover, they emphasize the urgent need for broader access to targeted therapies such as blinatumomab in first-line treatment protocols for high-risk patients with CRLF2 overexpression.