Surface expression of Cytokine Receptor-Like Factor 2 increases risk of relapse in pediatric acute lymphoblastic leukemia patients harboring IKZF1 deletions

Abstract

We prospectively examined whether surface expression of Cytokine Receptor-Like Factor 2 (CRLF2) on leukemic blasts is associated with survival and induction treatment response in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Flow cytometric analysis of bone marrow-derived leukemia cells revealed that 7.51% (29/286) of 386 pediatric BCP-ALL patients were CRLF2-positive (CRLF2pos) at diagnosis. The median minimal residual disease (MRD) was lower in CRLF2pos than CRLF2-negative (CRLF2neg) patients on day 15 (MRD15) after induction therapy [0.01% (0.001-0.42%) vs. 0.45% (0.05-3.50%); p=0.001]. By contrast, the MRD15 was higher in Ikaros family Zinc Finger Protein 1 (IKZF1)-deleted BCP-ALL patients than in BCP-ALL patients without IKZF1 deletions [1.18% (0.06-12.0%) vs 0.33% (0.03-2.6%); p=0.003]. Subgroup analysis showed that MRD15 levels were lower in IKZF1Δ/CRLF2pos patients than in IKZF1Δ/CRLF2neg patients [0.1% (0.02-5.06%) vs. 2.9% (0.25-12%); p=0.005]. Furthermore, MRD15 levels were higher in IKZF1WT/CRLF2neg patients than in IKZF1WT/CRLF2pos patients [0.40% (0.04-2.7%) vs. 0.001% (0.001-0.01%)]. Despite the low MRD15 levels, IKZF1Δ/CRLF2pos patients showed poorer relapse-free survival (RFS) than other patient groups (p=0.003). These findings demonstrate that surface CRLF2 expression is associated with increased risk of relapse in pediatric BCP-ALL patients harboring IKZF1 deletions.

GATA3 germline variant is associated with CRLF2 expression and predicts outcome in pediatric B‐cell precursor acute lymphoblastic leukemia

“…CRLF2 protein level was successfully assessed in 10 available AA patients and 518 control patients. Bone marrow samples from all BCP‐ALL patients were analyzed using 8‐color FC according to the protocols of the EuroFlow Consortium in one reference center (Medical University of Silesia in Zabrze) as described earlier by Pastorczak et al The EuroFlow panel for BCP‐ALL diagnostics was extended by an additional tube combining anti‐CRLF2 antibody (TSLPR‐PE, clone 1D3, Biolegend, San Diego, California) with the panel backbone composed of CD19‐PE‐Cy7 (Beckman Coulter, Brea, California), CD34‐PerCP‐Cy5.5 (Becton Dickinson, San Diego, California), and CD45‐Pacific Orange (Thermo Fisher, Carlsbad, California) antibodies. The samples were processed according to a lyse/wash protocol with 1× FACS Lyse used for erythrocyte lysis (Becton Dickinson) and analyzed using FACS Canto II flow cytometer (Becton Dickinson) within 1‐48 hours from sample collection; at least 50 000 cells were acquired.…”

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

“…While some studies indicate that MRD-directed therapy can improve outcomes in these patients [10,24], other studies demonstrate otherwise [2,24,25,33]. Data from a limited number of patients derived from the HOVON study group clinical trials indicate that allogeneic stem cell transplant (ASCT) in the first complete remission may improve outcomes in Ph-like B-ALL.…”

“…CRLF2 overexpression, JAK mutations, and IKZF1 deletions orchestrate leukemogenesis and contribute to dismal prognosis with survival rates of 25-30%. CRLF2-overexpressing B-ALL-harboring IKZF1 deletion is associated with increased risk of relapse even with low MRD levels [33]. Therefore, risk adapted therapy using MRD alone may not be sufficient in reducing relapse in these patients, underscoring the need for novel targeted therapies [2].…”

“…Since multiple studies have demonstrated poor outcomes with pediatric and adult treatment regimens with and without allogeneic stem cell transplant in Ph-like ALL across all age groups [4, [9][10][11][12][13][15][16][17]21,25,27,28,30,32,33,41,62,67,72], there is an unmet need for novel therapies. The plethora of genomic and molecular alterations in Ph-like ALL opens up multiple avenues for targeted therapies.…”

Paediatric oncology and haematology in Poland: position paper

“…All of these molecular approaches are currently available in Oncolab. This is especially important for paediatric patients who have resistant of relapsed disease [7].…”