Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

Abstract

Minimal residual disease (MRD) monitoring is an essential tool for risk group stratification in current treatment protocols for childhood acute lymphoblastic leukaemia (ALL). Although quantitative detection of clonal immunoglobulin (Ig) and T-cell receptor (TCR ) gene rearrangements is currently considered to be the standard method, leukaemia fusion genes provide other possible targets for MRD follow-up, as already demonstrated in TEL/AML1-positive ALLs. We analysed and compared MRD levels quantified by BCR/ABL transcript detection and by the standard Ig/TCR-based method in 218 bone marrow specimens from 17 children with BCR/ABL-positive ALL. We found only a limited overall correlation of MRD levels as assessed by the two methods (correlation coefficient R 2 ¼ 0.64). The correlation varied among patients from excellent (R 2 ¼ 0.99) to very poor (R 2 ¼ 0.17). Despite identical sensitivity of the approaches, 20% of the samples were negative by the Ig/TCR approach whereas positive by the BCR/ABL method. We show that multilineage involvement is at least partly responsible for the discrepancy. Moreover, our data demonstrate that BCR/ABL monitoring enables better and earlier prediction of relapse compared to the standard Ig/TCR methodology. We conclude that BCR/ABLbased MRD monitoring of childhood ALL is a clinically relevant tool and should be performed in parallel with the standard Ig/ TCR follow-up.

Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008

“…Recent data comparing MRD levels obtained by quantitation of the BCR-ABL transcript and Ig/TCR rearrangements show that, in ALL, transcript monitoring might provide additional prognostic information compared with standard Ig/TCR follow-up. 57 Indeed, because these markers do not have the same role in oncogenesis, their distribution within the leukemia population may differ, leading to apparent discrepancies in MRD evaluation.…”

“…20,[48][49][50]57 Instead, FCM-based risk definition may be independently reliable and therefore has to be independently validated.…”

Clinical Significance of Wt1 mRNA Levels in Japanese Acute Lymphoblastic Leukemia Patients

“…While morphological examination can reveal a decrease in lymphoblasts in the bone marrow (BM) or peripheral blood (PB), indicating hematological remission, MRD cannot be detected by this method and therefore, molecular methods are employed. MRD in ALL patients has been measured and assessed using several techniques such as quantification of fusion gene transcripts [5][6][7][8], immunoreceptor (immunoglobulin/T-cell receptor (Ig/TCR)) gene rearrangements [9][10][11][12], and flow cytometry [8,[13][14][15]. However, fusion gene transcripts are expressed in approximately 25% of adult ALL patients and 3% of childhood ALL patients, even in minor BCR/ABL, which is thought to have the highest expression frequency [16].…”

Discovery of Dihydroartemisinin and Dasatinib Drug Combination to Cure Pooroutcome BCR-ABL+ Acute Lymphoblastic Leukemia

“…The leukemia cells in Ph+ ALL which display poor initial response and evade eradication by BCR-ABL-KIs [45][46][47] express cell surface markers of lymphoid B cell lineage [48]. No distinct population of LSCs has been characterized to drive drug-resistant populations, unlike CML [35][36]48].…”

“…The relative primary drug-resistance in human Ph+ ALL necessitates the addition of several chemotherapeutic agents and HSCT in combination with BCR-ABL-KIs [44]. Multi-modality BCR-ABL-KI-combined regimens, the current standard of clinical care in Ph+ ALL, improve the remission rates but relapses remain common [44][45][46][47] with an 18-to 24-month survival rate of 64% and an even lower relapse-free survival rate [44].…”