Cytogenetic-specific heterogeneity in the kinetics of minimal residual disease (MIRD) clearance in childhood lymphoblastic leukaemia (ALL)

Moorman, A.V., Richards, S.M., Hancock, J.P., Mitchell, C.D., Vora, A.J., Harrison, C.J. and Goulden, N.J. (2008) Cytogenetic-specific heterogeneity in the kinetics of minimal residual disease (MIRD) clearance in childhood lymphoblastic leukaemia (ALL). British Journal of Haematology, 141 (Supplement 1), pp. 2. (doi:10.1111/j.1365-2141.2008.07061.x).

Abstract

Although both MRD and karyotype are powerful determinants of outcome in childhood ALL, few studies have examined the kinetics of MRD clearance by cytogenetics. In ALL2003, patients are stratified by NCI criteria to a three or four drug induction. MRD is assessed at day 29 and week 11 using a standardised and quality controlled RQPCR of 21patient specific immunoglobulin or T-cell receptor rearrangements. MRD risk groups were defined as: (1) High risk MRD410-4 at day 29 (HR); (2) Low risk MRD negative or o10-4 at day 29 and negative at week 11 (LR); or (3) MRD indeterminate risk. Among 1000 patients entered into the trial, 98% were eligible for these analyses, 94% had a successful cytogenetics and 57% were assigned to a clinically relevant MRD groups. Among these latter 555 patients, 54% were MRD-HR whereas 45% were MRD-LR. Collectively, patients with high-risk cytogenetics ‘t(9;22), o40 chromosomes, 11q23/MLL, t(17;19) and iAMP21’ were more likely to be MRDHR ‘83% vs 52%, P50.003’. Patients with ETV6-RUNX1 fusion were less likely to be MRD-HR ‘28% vs 63%, Po0.001’ whereas high hyperdiploid patients were more likely ‘64% vs 49%, P50.002’. However, excluding ETV6-RUNX1 patients from the latter analysis revealed that high hyperdiploid patients were as likely to be MRDHR as other ETV6-RUNX1 negative patients. T-ALL patients were also more likely to be MRD-HR compared to BCP-ALL patients ‘70% vs 52%, P50.022’. In particular, 9/10 patients with t(5;14)/TLX3- BCL11B fusion and 6/6 patients with SIL-TAL1 fusion were MRD-HR. In conclusion, we have clearly demonstrated that MRD status varies by cytogenetic subgroup with ETV6-RUNX1 patients having the fastest MRD clearance rate. Despite the good prognosis associated with high hyperdiploidy, these patients were as likely to be MRD-HR as other standard risk patients. Longer follow-up is required to determine the clinical significance of this finding.

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