Cytogenetic-Specific Heterogeneity in the Kinetics of Minimal Residual Disease (MRD) Clearance in Childhood Acute Lymphoblastic Leukaemia (ALL).
Authors: Moorman Anthony V. , Richards Sue M. , Hancock Jerry P. , Mitchell Chris D. , Vora Ajay J. , Harrison Christine J. , Goulden Nick J. 
Published: April 2020

Although both MRD and karyotype are powerful determinants of outcome in childhood ALL, few studies have examined the kinetics of MRD clearance by cytogenetic subgroup. ALL2003 is an ongoing UK trial open to all patients aged 1–19 years with ALL, except those with mature-B ALL. At diagnosis, patients are stratified by NCI criteria to receive a three drug (Regimen A - age 1–9 years and white cell count (WCC) &lt;50×109/L) or four drug (Regimen B - age 10–18 years or WCC &gt;50×109/L) induction. MRD is assessed at day 29 and week 11 of therapy using a standardised and quality controlled RQ-PCR of at least two patient specific immunoglobulin or T cell receptor rearrangements. MRD risk groups were defined as:

MRD high risk (HR) MRD &gt;10−4 at day 29; MRD low risk (LR) MRD negative or &lt;10−4 at day 29 and negative at week 11; MRD indeterminate risk - all other patients.

Cytogenetic analysis was performed on pre-treatment samples and six abnormalities were defined as high risk: t(9;22)(q34;q11), near-haploidy (23–29 chromosomes), low hypodiploidy (30–39 chromosomes), 11q23/MLL translocations, t(17;19)(q22;p13) and intrachromosomal amplification of chromosome 21 (iAMP21). Among the first 1000 patients entered into the trial, 979 (98%) patients were eligible for these analyses. A total of 920 (94%) had a successful cytogenetic result and 555 (57%) were assigned to MRD high or low risk groups. Of these 555 patients, 298 (54%) were classified as MRD-HR whereas 257 (45%) were classified as MRD-LR. Collectively, patients with high risk cytogenetics were more likely to be classified as MRD-HR [20/24 (83%) v 261/501 (52%), p=0.003]. Patients with ETV6-RUNX1 (TEL-AML1) fusion were less likely to be classified as MRD-HR [40/145 (28%) v 241/380 (63%), p&lt;0.001]. In contrast, high hyperdiploid patients were more likely to be MRD-HR compared to all other patients [99/155 (64%) v 182/370 (49%), p=0.002]. However, this effect was driven by the low rate of MRD-HR among the ETV6-RUNX1 positive patients and excluding these patients from the analysis revealed that high hyperdiploid patients were as likely to be MRD-HR as other ETV6-RUNX1 negative patients [99/155 (64%) v 142/225 (63%), p=0.880]. There was no difference between high hyperdiploid patients with and without the triple trisomy of +4, +10 and +17 with respect to MRD status. T-ALL patients were also more likely to be classified as MRD-HR compared to B-cell precursor ALL patients [32/46 (70%) v 249/479 (52%), p=0.022]. In particular, 9/10 patients with t(5;14)/TLX3-BCL11B fusion and 6/6 patients with SIL-TAL1 fusion were classified as 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.