Characterization of Immunophenotypic Aberrancies with Respect to Common Fusion Transcripts in B-Cell Precursor Acute Lymphoblastic Leukemia: A Report of 986 Indian Patients

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BackgroundThe published literature on hematological, clinical, flowcytometric‐immunophenotyping, and minimal residual disease outcomes of the prognostically important genetic subtypes of acute lymphoblastic leukemia (ALL) is scarce from low‐income countries. For newer classifications such as BCR::ABL1‐like ALLs, the scarcity of patient‐level data is even more pronounced.MethodsThe authors performed comprehensive detection of recurrent gene fusions and BCR::ABL1‐like ALL cases followed by immunophenotypic profiling and obtained clinical outcome parameters for a large cohort (n = 1021) of patients from India. This cohort included a significant number of patients with BCR::ABL1‐like ALL subtype and other genetic subtypes of ALL.ResultsPatients with BCR::ABL1‐positive and BCR::ABL1‐like ALL were significantly older, had male preponderance, and expressed a higher white blood cell count than BCR::ABL1‐negative cases (p < .05). Logistic regression modeling of B‐lineage‐ALL (B‐ALL) subtypes revealed that cluster of differentiation (CD)36 is a strong statistically significant predictive marker of BCR::ABL1‐like ALL (p < .05). Furthermore, patients with BCR::ABL1‐like ALLs show a significantly higher frequency of CD36 expression compared to BCR::ABL1‐negative ALLs (p < .05). In terms of clinical symptoms, lymphadenopathy is a strong statistically significant predictive marker in BCR::ABL1‐like ALLs compared to BCR::ABL1‐negative ALL cases (p < .05). In terms of treatment outcomes, minimal residual disease (MRD) positivity in BCR::ABL1‐positive ALL cases were statistically significant (p < .05), and BCR::ABL1‐like ALL cases had high MRD‐positivity as compared to BCR::ABL1‐negative ALL cases but did not show statistical significance.ConclusionsThe findings evince the use of novel therapies and personalized treatment regimens to improve the overall survival of the newer incorporated entities in B‐ALLs. This is the first report characterizing the hematological, clinical, flowcytometric‐immunophenotyping, and minimal residual disease outcomes of the prognostically significant subtypes of ALLs in patients from India.Plain Language Summary Characterizing the hematological, clinical, flowcytometric‐immunophenotyping, and minimal residual disease outcomes of the prognostically significant subtypes (n = 1021) of acute lymphoblastic leukemia (ALLs) in patients from India. We have made two independent logistic regression models of cluster of differentiation (CD) markers and clinical symptoms to differentiate prognostically significant subtypes of ALLs. Logistic regression analysis of CD markers revealed CD36 as a strong predictor in BCR::ABL1‐like ALL cases compared to BCR::ABL1‐negative ALL cases. Logistic regression analysis of clinical symptoms revealed lymphadenopathy significantly predicts BCR::ABL1‐like ALLs (p < .05). In terms of treatment outcomes, BCR::ABL1‐positive ALL had statistically significant minimal residual disease (MRD) (p < .05), and BCR::ABL1‐like ALL cases had high MRD‐positivity but did not show statistical significance as compared to BCR::ABL1‐negative ALLs.

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Hematological, clinical, immunophenotypic characterization, and treatment outcomes of prognostically significant genetic subtypes of B‐lineage acute lymphoblastic leukemia: A report of 1021 patients from India

Gupta

Varma

Sharma

et al. 2023

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“…22 Furthermore, we studied the global proteome of five sets of pooled Ph-like and Ph-positive ALL cases (n = 5 samples, 1 set*5 = 5 sets in biological triplicates), using LC-MS/MS. For global 1218 -CHARACTERIZATION OF PH-LIKE ALL CASESproteome analysis, data for nine Ph-positive samples were taken from one of our recently published studies 23.…”

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Genomic and proteomic characterization of Philadelphia‐like B‐lineage acute lymphoblastic leukemia: A report of Indian patients

Gupta

Varma

Kumar

et al. 2023

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Background The gold standard for the identification of Philadelphia (Ph)‐like acute lymphoblastic leukemia (ALL) patients is gene expression profiling. Because of its diverse nature, its identification is extremely difficult and expensive. On the genomic and proteomic landscape of Ph‐like ALL patients, there is a paucity of published literature from developing countries. Methods The authors used digital barcoded nCounter NanoString gene expression profiling for its detection, followed by molecular and proteomic characterization using fluorescence in situ hybridization and liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results The authors found 32.05% Ph‐like ALL patients and their median age at presentation was considerably higher than Ph‐negative ALL cases (p = .0306). Furthermore, we identified 20% CRLF2 overexpressed cases having 8.33% CRLF2‐IGH translocation with concomitant R683S mutation and 8.33% CRLF2‐P2RY8 translocation. In 80% of CRLF2 downregulated cases, we identified 10% as having JAK2 rearrangement. Minimal residual disease‐positivity was more common in Ph‐like ALL cases (55.55% vs. 25% in Ph‐negative ALL cases). Immunoglobulin J chain (Jchain), small nuclear ribonucleoprotein SmD1 (SNRPD1), immunoglobulin κ constant (IGKC), NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 2 (NDUFA2), histone H2AX (H2AFX), charged multivesicular body protein 4b (CHMP4B), and carbonyl reductase (NADPH) (CBR1) proteins were identified to be substantially expressed in Ph‐like ALL patients, using LC–MS/MS. Gene enrichment analysis indicated that involvement of spliceosomal mediated messenger RNA splicing pathway and four microRNAs was statistically significant in Ph‐like ALL patients. Conclusions For the first time, we have described incidence, molecular, and proteomic characterization of Ph‐like ALL, in developing nations. Plain language summary In developing countries, detecting Philadelphia (Ph)‐like B‐lineage acute lymphoblastic leukemia is complicated and challenging due to its diverse genetic landscape. There is no well‐defined and cost‐effective methodology for its detection. The incidence of this high‐risk subtype is very high in adult cases, and there is an urgent need for its accurate detection. We have developed an online PHi‐RACE classifier for its rapid detection, followed by delineating the genomic and proteomic landscape of Ph‐like acute lymphoblastic leukemias for the first time in Indian patients.

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

Gupta,

Varma,

Abdulkadir

et al. 2023

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BackgroundPhiladelphia 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.MethodsMultiplex 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.ResultsOf 130 newly diagnosed B‐ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGAneg B‐ALL cases were revealed by multiplex reverse transcriptase polymerase chain reaction. Among RGAneg B‐ALL cases, 24% Ph‐like ALL cases using nCounter NanoString were identified, with 48% CRLF2high cases with 45% CRLF2::P2RY8 and 18% CRLF2::IGH rearrangements(∼r) revealed by fluorescence in situ hybridization. In 52% of CRLF2low 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 RGAneg 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.ConclusionsThis 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.