P315: tp53 alterations and mrd refine prognosis of adult kmt2a-rearranged b-all

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: B-cell acute lymphoblastic leukaemia (B-ALL) with a rearrangement involving KMT2A/MLL (KMT2A-r) accounts for 80% of infant B-ALL and 10% of adult cases. This entity has been widely associated with a high risk of relapse and poor outcome in both children and adults. Aims: We set out to refine the prognosis of KMT2A-r B-ALL in adults treated with current intensive regimens, by analysing the impact of co-mutations and minimal residual disease (MRD) on outcome. Methods: Of 1091 Ph-negative B-ALL patients aged 15-59 years treated within the GRAALL-2003/05/14 trials, with available KMT2A-r screening, 141 (12.9%) harboured a KMT2A-r. Targeted sequencing was performed for 97 KMT2A-r B-ALL cases with available diagnostic material to identify additional mutations and copy-number alterations. MRD quantification was done by qPCR of clono-specific immunoglobulin and/or T-cell receptor genes rearrangements (IG/TR). The genomic KMT2A fusion breakpoint (gKMT2A-r) was used as an additional marker for a subset of patients. Cut-off for MRD positivity was set at 10-4. Results: Patients with KMT2A-r B-ALL had a median age of 42.0 years, a male/female ratio of 0.78, high white blood cell counts at diagnosis (median 94.4 G/L) and frequent immature pro-B phenotype (74.8 %). The complete remission (CR) rate was 92.9% and 48.9% of patients received allogeneic stem cell transplantation (allo-SCT) in first CR. At 5 years, the disease-free survival (DFS) and overall survival (OS) rates were 50.3% and 53.3%, respectively. The KMT2A-r partner gene was AFF1 in 121/141 cases (86%). The most frequent co-mutations involved signalling pathway genes (38%), mostly NRAS, KRAS and FLT3. CDKN2A, TP53 and IKZF1 were altered in respectively 14%, 14% and 8% of cases. TP53 alteration was the only genetic feature significantly associated with poorer outcome (DFS, HR=2.2, 95% CI [1.1-4.6], P=0.034; OS, HR=2.7, 95% CI [1.3-5.4], P=0.007) (fig. 1A-B). IG/TR MRD data was available for 77 patients. Of these, 44.2% had positive MRD at end of induction and this was strongly predictive of poorer outcome (DFS, HR=2.7, 95% CI [1.4-5.2], P=0.003; OS, HR=2.9, 95% CI [1.5-6.0], P=0.003) (fig. 1C-D). Studies in infant B-ALL have shown that IG/TR rearrangements could be absent or subclonal in KMT2A-r B-ALL, justifying the use of gKMT2A-r as an MRD marker. Thus, we conducted a retrospective comparative analysis for the 56 patients treated within the GRAALL-2014. 7/56 (13%) patients lacked clonal IG/TR rearrangement for MRD follow-up. Of 39 cases (70%) that could be evaluated for both MRD targets, 9 (16%) presented discrepant results, i.e IG/TR negative and gKMT2A-r positive. The latter had similarly poor survival rates as those positive on both markers (fig. 1D-E). The superiority of gKMT2A-r marker over IG/TR was subsequently validated by Harrell’s C concordance tests demonstrating that gKMT2A-r post-induction MRD predicts outcome with better accuracy than IG/TR MRD (0.68 vs 0.63 for DFS and 0.66 vs 0.62 for OS). Strikingly, patients with negative gKMT2A-r MRD (n=13) after induction course had an excellent outcome, although they did not receive allo-SCT in accordance with the protocol. Summary/Conclusion: Our study establishes the association between TP53 alterations and poor outcome in adult KMT2A-r B-ALL. It also demonstrates the relevance of using gKMT2A-r as MRD marker in adults, allowing the identification of good responders who had excellent survival rates. Altogether, the combination of genetic co-alterations and MRD refines the prognosis of adult KMT2A-r patients by identifying subsets of patients with contrasting outcomes.Keywords: TP53, ALL, Minimal residual disease (MRD), KMT2A