Type: Oral
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Genetic Markers and Outcomes in AML
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies, Measurable Residual Disease
Methods
NCRI AML17 (2009-2014) and AML19 (2015-2020) enrolled younger adults with newly diagnosed AML. Results from karyotype, FISH, RT-qPCR and RNA sequencing were reviewed to identify all patients with KMT2Ar. MRD was generally assessed by flow cytometry in AML17, while RT-qPCR was used in AML19.
Results
218 patients (AML17 n=135, AML19 n=83) were identified with a median age of 41y (range 16 – 68). 8 (4%) had a prior myeloid disorder and 22 (10%) were therapy related. 75 (34%) patients had ELN 2022 intermediate risk disease with t(9;11)/MLLT3::KMT2A and the remaining 66% were adverse risk. 131 patients (60%) had no other cytogenetic abnormalities. Complex cytogenetics (defined here as 3 structural abnormalities in addition to KMT2Ar) were seen in 12 patients (6%) and 7 (3%) had other adverse abnormalities (del5q or –7). FLT3 ITD mutations were present in 9 (4%) and TKD in 15 (7%). Treatment was with DA in 127 (58%), FLAG-Ida in 48 (22%), ADE in 35 (16%) and CPX-351 in 8 (3.7%). 82 (38%) received GO.
196 patients (90%) achieved CR or CRi by the end of the second induction, with 81% in CR/CRi after course 1. Higher rates of refractory disease were seen in patients with a complex karyotype (17%) or other adverse abnormalities (29%).
Median follow-up was 4.8y. Day 30 and 60 mortality were 4% and 5% respectively. Median overall survival (OS) was 2.1y (95CI 1.7 – 3.1) and was not significantly different between ELN intermediate (2.7y) and adverse risk (1.9y) disease. On multivariable analyses, higher WCC (HR 1.23, 95CI 1.08-1.41) and complex karyotype (HR 3.46, 95CI 1.72-6.98) were associated with worse survival while FLAG-Ida produced better survival (HR 0.42, 95CI 0.24-0.75). 2-yr OS was 68% (median not reached) for FLAG-Ida compared to 48% (median 1.8y) for other regimens.
Of 196 patients achieving remission, 99 (51%) were transplanted in CR1 (60% of ELN adverse and 31% of ELN intermediate patients). CR1 transplant was associated with improved RFS (0.66, 95CI 0.45 – 0.97) and a trend to better OS (HR 0.75, 95CI 0.50 - 1.11), with no heterogeneity based on ELN risk group.
69 patients were included in a direct randomisation of FLAG-Ida (n=42) vs DA (n=27) in AML19. FLAG-Ida was associated with a numerically higher remission after C1 (93% vs 81%, p=0.2) but not after second induction (95% vs 96%). Despite a lower rate of CR1 transplant after FLAG-Ida (40% vs 59%), relapse was significantly reduced (2y CIR 23% vs 61%, p<0.001). Median OS was not reached with FLAG-Ida vs 2.2y for DA, with 2y OS 67% vs 57% (HR 0.54, 95CI 0.26-1.13).
No survival difference was seen in the AML17 randomisations of DA vs ADE or DA with 60mg/m2 vs 90mg/m2 of daunorubicin, nor in the AML19 randomisations of GO1 vs GO2 or CPX-351 vs FLAG-Ida.
MRD was performed by flow cytometry in 76 and RT-qPCR in 61 patients. 50 patients had a post C2 qPCR result in either PB or BM, with results concordant in all patients with both samples (n=38). 18 patients (36%) remained MRD positive (52% for adverse risk, 14% for intermediate risk). Detectable MRD was strongly associated with relapse (CIR 74% vs 23%; HR 5.58, 95CI 2.4-13.2, p<0.001) and poor OS (2y OS 31% vs 77%, HR 4.42, 95CI 1.9-10.2, p<0.001). Only 3 MRD positive patients remain alive and relapse-free at last follow-up.
Flow MRD results were analysed at both post C1 and C2, examining thresholds of either 0.1% or any positivity. The only threshold predictive of outcomes was detection of any positivity post C1, with 60% of patients MRD positive and OS HR 1.88 (95CI 1.00-3.52).
Conclusion
Here we demonstrate a survival advantage for intensified induction treatment with FLAG-Ida in younger adults with KMT2Ar AML. We also show that molecular MRD after course 2 is a strong predictor of long-term survival. These data are important to inform the design of future trials incorporating menin inhibitors in front-line therapy, and suggest that intensified induction and RT-qPCR MRD should be incorporated into these studies.
Disclosures: Othman: Pfizer: Honoraria; Astellas: Honoraria; Jazz: Honoraria. Freeman: Jazz Pharma: Research Funding, Speakers Bureau; BMS: Research Funding; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; MPACT: Consultancy; BMS: Research Funding. Culligan: Gilead: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Celgene/BMS: Honoraria; Abbvie: Honoraria. Dillon: Jazz: Other: Consultancy and educational events (paid to institution); Abbvie, Amgen: Other: Research support (paid to institution); Abbvie, Astellas, Pfizer: Consultancy, Other: Educational events. Russell: Astellas: Honoraria; Servier: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding.