Early Response Assessment by Minimal Residual Disease in Adolescents with T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Abstract

Minimal residual disease has displaced almost every other prognostic variable in acute lymphoblastic leukaemia, but the timing that works for B-cell disease does not transfer to T-lineage disease. T-cell blasts clear more slowly, and an early measurement that would condemn a B-cell patient turns out to carry no information at all in T-ALL provided the later measurement is clear. Objectives: To review the published evidence on minimal residual disease as an early response measure in T-cell acute lymphoblastic leukaemia, with attention to adolescents: which timepoints carry prognostic weight, how the kinetics differ from B-cell disease, how the available assays compare, and what the measurement has been used to change. Material and Methods: Narrative review of cooperative group trials, methodological comparisons and response-adapted randomised studies indexed in PubMed and the major haematology journals. Studies were eligible if they reported the prognostic value of minimal residual disease in a defined acute lymphoblastic
leukaemia population, compared assay platforms, or tested treatment modification on the basis of residual disease. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators.
Results: Among 464 patients with T-ALL stratified within a large international trial, 16 per cent were residual disease negative at both timepoints, 63 per cent intermediate and 21 per cent had 10-3 or more at day 78. Their seven-year event-free survival was 91.1, 80.6 and 49.8 per cent respectively (p < 0.001). Only 16 per cent of T-ALL patients cleared at the first timepoint against 42 per cent of 3,184 patients with B-cell precursor disease. Critically, the 32 per cent of T-ALL patients who became negative only at the second timepoint did equally well, indicating that early residual disease level is irrelevant provided the later measurement is clear. Residual disease at or above 10-3 at day 78 was the single most important predictor of relapse. At day 29, hazard ratios for relapse were 3.55 by flow cytometry and 5.6 by polymerase chain reaction. Conclusion: In T-ALL the informative timepoint is late rather than early, which inverts the logic applied in B-cell disease. Applying B-cell timing to T-lineage patients would misclassify roughly a third of them as high risk when their outcome is excellent. Abbreviations: ALL – Acute Lymphoblastic Leukaemia, T-ALL – T-Cell Acute Lymphoblastic Leukaemia, BCP-ALL – B-Cell Precursor ALL, MRD – Minimal Residual Disease, TP1 – Time Point 1, TP2 – Time Point 2, FCM – Flow Cytometry, RQ-PCR – Real-Time Quantitative Polymerase Chain Reaction, Ig/TCR – Immunoglobulin and T-Cell Receptor, ETP – Early T-Cell Precursor, EFS – Event-Free Survival, HSCT – Haematopoietic Stem Cell Transplantation, AYA – Adolescent and Young Adult.