Treatment Intensification Improves Outcome in Children with iAMP21 positive ALL

Abstract ⁶⁵⁶

Chromosomal abnormalities present in the bone marrow cells of children with acute lymphoblastic leukaemia (ALL) are used to assist diagnosis and define risk groups that guide therapy. One such primary genetic aberration is intrachromosomal amplification of chromosome 21 (iAMP21) which is defined as the presence of 3 or more extra copies of the RUNX1 gene on a single abnormal chromosome 21. FISH with probes targeting the RUNX1 gene is the commonly used detection method. Approximately 2–3% children with ALL harbour iAMP21 and it is associated with older age (median 10 years) and a low white cell count (WCC, <20×10⁹/L).

Among 28 patients treated on the MRC ALL97 trial between 1997 and 2002, 27 (96%) achieved a complete remission (CR), 22 (81%) relapsed and 13 (46%) died. The event free survival (EFS), relapse rate (RR) and overall survival (OS) rates at 5 years were 29% (14–46%), 70% (53–86%) and 67% (47–82%), respectively. There was no evidence that National Cancer Institute (NCI) high risk (HR) and standard risk (SR) patients had differential outcomes and the RR appeared constant with time (figure). On the basis of this increased risk of relapse, we chose to stratify these patients to the most intensive arm of the ALL2003 protocol (regimen C) which included augmented Berlin-Frankfurt-Munster (BFM) consolidation, two blocks of escalating Capizzi maintenance and a double delayed intensification. First remission transplants were recommended for patients who were slow early responders (SER) or minimal residual disease (MRD) positive (>0.01%) at day 29. Due to a relatively high transplant related mortality, transplants were restricted to patients not in CR by day 29 after June 2008.

Prospective FISH screening of 2575 patients treated on ALL2003 between January 2003 and July 2011 identified 53 (2%) with iAMP21. The cohort showed a female predominance (30:23), had a median age of 10 years and 47 (89%) patients had a WCC <20×10⁹/L. Follow-up information was available for 52 (98%) patients with a median follow-up time of 4.9 years. The majority of patients (48/52, 92%) were transferred to regimen C as directed by the protocol. At least 2 of the remaining 4 patients did not transfer to regimen C because of induction toxicity problems. Treatment response was measured at day 15 or day 8 according to whether patients received a 3 (NCI SR) or 4 (NCI HR) drug induction, respectively. Whilst none of the SR patients were SER, 13/28 (46%) HR patients had >25% blasts at day 8. MRD was assessed in 45 patients: 23 (51%) were positive (>0.01%) and 22 (49%) were negative (<0.01%) at day 28. All patients achieved a CR, 6 (12%) have subsequently relapsed whilst 4 (8%) died in first remission following a transplant from infection (n=3) or transplant-related complications (n=1). One patient relapsed and died after receiving a transplant; so in total, 5 (10%) patients have died. Among 20 (38%) patients who received a transplant in first CR, 18 (90%) were either MRD positive at day 28 or a SER. The EFS, RR, OS rates at 5 years were 78% (61–88%), 16% (7–34%) and 89% (76–95%), respectively (figure). There were no significant differences in outcome according to sex, age, WCC, NCI risk status or MRD levels at day 28. Interestingly, among the 5 relapses who had MRD measured at day 28 only 1 was positive (>0.01%); although 2 more had borderline levels (>0.005%).

A comparison between the outcome of iAMP21 patients treated on ALL97 and ALL2003 showed a statistically significant decrease in RR (p<0.0001) with significant increases in EFS (p<0.0001) and OS (p<0.01). The key endpoint was the proportion of patients suffering a relapse which decreased nearly seven-fold (81% to 12%) between the two trials. Importantly none of the ALL2003 relapses occurred on treatment and all bar one were classified as late events (>6 months after the end of treatment). The findings presented herein clearly illustrate the benefit of this treatment intervention in improving survival in these patients who otherwise had an extremely poor outcome when given standard therapy. In light of these results, iAMP21 patients treated on our new trial, ALL2011, will continue to be classified in the high risk cytogenetic subgroup and will receive regimen C. They are recommended for transplant only if they fail to achieve a CR by day 29. This study illustrates how the discovery and characterisation of a disease-specific genetic aberration can be used to tailor therapy more precisely.

View largeDownload slide

View largeDownload slide

Close modal