Children with ETV6-RUNX1 or high hyperdiploid (HeH, 51–65 chromosomes) acute lymphoblastic leukaemia (ALL) have an excellent prognosis when treated on modern protocols and achieve survival rates in excess of 90% at 5 years. They are prevalent aberrations and together account for nearly 60% cases at diagnosis. Approximately 10–15% patients with these aberrations will suffer a relapse; usually off-treatment. Despite their good outcome their high prevalence means that they account for roughly 40% childhood ALL relapse. Therefore predicting those that will suffer a relapse remains a significant clinical issue. Numerous studies have postulated that certain secondary genetic abnormalities or cytogenetic characteristics correlate with outcome. However, the results have been inconsistent and few abnormalities or characteristics have been studied or confirmed in independent cohorts.
In this study, we have investigated the prognostic impact of the major secondary abnormalities and characteristics among ETV6-RUNX1 and HeH patients treated on MRC ALL97/99 between 1997 and 2002. The cohort had a median follow-up time of 8.5 years and survival rates are quoted at 7 years. Additional genetic abnormalities were detected either by fluorescence in situ hybridization (FISH) using probes for ETV6 and RUNX1 or Multiplex Ligation-Dependent Probe Amplification (MLPA) using the SALSA P335 ALL IKZF1 kit. Patients were also analysed by National Cancer Institute (NCI) risk status: standard risk (SR) patient were less than 10 years old with a white cell count (WCC) lower than 50×109/L; high risk (HR) included all other patients.
Among 368 ETV6-RUNX1 patients, 47 (13%) relapsed and 20 died (5%) resulting in event free (EFS) and overall survival (OS) rates of 88% and 96%, respectively. The majority of patients were SR (n=283, 77%) and although they did not have a significantly lower relapse rate (32/283 (11%) v 15/85 (18%), p=0.14) they did have a lower death rate (8/283 (3%) v 12/85 (14%), p<0.001). Accordingly, HR patients had significantly inferior EFS and OS rates compared to SR patients: 76% v 90% (p=0.001) and 87% v 99% (p<0.001). A total of 247 (67%) patients were screened using FISH probes designed to detect deletions of the non-rearranged ETV6 allele (n=165, 67%), gain of chromosome 21 (n=57, 23%) and gain of der(21)t(12;21) (n=38, 16%). Analysis of these secondary abnormalities within NCI risk groups did not reveal any association with outcome. The incidence of micro-deletions detected by MLPA among 114 patients was: ETV6 (65%), PAX5 (27%), CDKN2A/B (23%), BTG1 (21%), RB1 (8%), IKZF1 (5%), EBF1 (4%). There was no difference in the distribution of micro-deletions between SR and HR patients and none of the deletions were associated with outcome in the two risk groups.
Among 553 HeH patients, 81 (15%) relapsed and 48 (9%) died resulting in EFS and OS rates of 83% and 91%, respectively. The majority of patients were SR (79%) with a significantly lower relapse and death rate: 57/439 (13%) v 24/114 (21%), p=0.033 and 30/439 (7%) v 18/114 (16%), p=0.002). HR patients had significantly inferior EFS and OS rates compared to SR patients: 76% v 85% (p=0.03) and 85% v 94% (p=0.002). HeH karyotypes were classified according to the presence of triple trisomy (+4,+10,+17) (47%), double trisomy (+4,+10) (60%), trisomy 18 (78%) and modal chromosome number (51–53, 21%; 54–57, 56%; 58–65, 23%). Only the incidence of trisomy 18 varied by NCI risk status: SR 80% v HR 69%, p=0.016. The incidence of micro-deletions detected among 144 patients was similar for SR and HR patients: CDKN2A/B (16%), IKZF1 (9%), ETV6 (8%), PAX5 (3%), RB1 (3%), BTG1 (1%) and EBF1 (0%). Among SR patients only trisomy 18 was significantly associated with a good outcome: EFS 88% v 73% (p=0.0013); OS 96% v 90% (p=0.016). There were no significant risk factors among the HR group; although all 4 patients with an IKZF1 deletion relapsed.
In contrast to previous studies most secondary genetic abnormalities or cytogenetic characteristics were not associated with outcome in this study. Although NCI HR patients did have a significantly inferior outcome compared to their SR counterparts with the same chromosomal abnormality, the EFS and OS rates at 7 years were in excess of 75%, highlighting the excellent prognosis for patients with these abnormalities. These findings support the risk stratification of ETV6-RUNX1 and HeH patients by NCI risk status on current protocols.
No relevant conflicts of interest to declare.
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