A surrogate molecular approach for the detection of Philadelphia chromosome–like B‐acute lymphoblastic leukemia

Abstract

Abstract Background Philadelphia chromosome (Ph)–like B‐acute lymphoblastic leukemia (B‐ALL) is a clinically significant, high‐risk genetic subtype of B‐ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph‐like ALL cases from low‐ and middle‐income countries. There is a pressing need to establish a well‐organized/cost‐effective approach for identifying Ph‐like ALL instances. Methods Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph‐like ALL cases among recurrent genetic abnormalities (RGA) neg B‐ALL cases. At the end of induction therapy, flow cytometry‐minimal residual disease (MRD) assay was used to quantify MRD positivity in Ph‐like ALL cases. Results Of 130 newly diagnosed B‐ALL cases, 25% ( BCR::ABL1 ), 4% ( ETV6::RUNX1 ), 5% ( TCF3::PBX1 ), 2% ( KM2TA::AFF1 ), and 65% RGA neg B‐ALL cases were revealed by multiplex reverse transcriptase polymerase chain reaction. Among RGA neg B‐ALL cases, 24% Ph‐like ALL cases using nCounter NanoString were identified, with 48% CRLF2 high cases with 45% CRLF2::P2RY8 and 18% CRLF2::IGH rearrangements(∼r) revealed by fluorescence in situ hybridization. In 52% of CRLF2 low cases, 17% ABL1 and JAK2∼r 8% EPOR::IGH & PDGRFB ∼r were identified. Ph‐like ALL cases had higher total leukocyte count ( p < .05), male preponderance ( p < .05), and high MRD‐positivity/induction failure compared with RGA neg B‐ALL cases. Furthermore, in Ph‐like ALL cases, 11 significant genes using quantitative polymerase chain reaction were identified and validated. CRLF2, IGJ, CEACAM6, MUC4, SPATS2L and NRXN3 genes were overexpressed and show statistical significance ( p < .05) in Ph‐like ALL cases. Conclusions This study showed the high incidence of Ph‐like ALL cases with kinase activating alterations and treatment outcomes from low‐ and middle‐income region. Furthermore, a surrogate cost‐effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph‐like ALL cases is proposed. Plain Language Summary Identification of recurrent gene abnormalities (RGA) neg B‐acute lymphoblastic leukemia (B‐ALL) cases using multiplex‐reverse transcriptase polymerase chain reaction. Identification and characterization of Philadelphia (Ph)–like ALL cases using nCounter NanoString gene expression profiling and fluorescence in situ hybridization. Furthermore, Ph‐like ALL cases were characterized according to CRLF2 expression and kinase‐activating genomic alterations. Minimal residual disease of Ph‐like ALL cases were quantified using flow cytometry‐minimal residual disease assay. A surrogate molecular approach was established to detect Ph‐like ALL cases from low‐ and middle‐income countries.

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