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588 Intensive Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction for Younger NPM1-Mutated AML Patient: Overcoming the Negative Prognosis of FLT3-ITD Mutation

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Commercially Available Therapy, excluding Transplantation I
Hematology Disease Topics & Pathways:
Clinically relevant
Monday, December 7, 2020: 9:00 AM

Paola Minetto, MD, PhD1, Anna Candoni2*, Fabio Guolo, MD1*, Marino Clavio, MD1*, Maria Elena Zannier, MD3*, Maurizio Miglino, PhD1*, Maria Vittoria Dubbini, MD4*, Anna Sicuranza, PhD5*, Sara Ciofini5*, Elisabetta Tedone6*, Nicoletta Colombo, PhD6*, Girolamo Pugliese1*, Filippo Ballerini, MD1*, Michele Cea1*, Monica Bocchia7*, Renato Fanin, MD4* and Roberto Massimo Lemoli, MD1*

1Clinic of Hematology, Department of Internal Medicine (DiMI), IRCCS Ospedale Policlinico San Martino, Genova, Italy
2Hematology, Azienda Sanitaria Integrata di Udine, Udine, ITA
3Division of Hematology and Bone Marrow Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
4Division of Hematology and BMT, Department of Medical Area, University of Udine, Udine, Italy
5Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy
6Clinical Flow Cytometry Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
7Hematology, University of Siena, Siena, Italy

NPM1 and FLT3 mutational status assessment is recommended in acute myeloid leukemia (AML) at diagnosis by European Leukemia Net (ELN) risk stratification. The presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. Targeted drugs are available for FLT3-mutated AML but no data are available so far on the efficacy of intensified front-line regimens in overcoming the negative prognostic role of FLT3-ITD mutation.

We investigated the efficacy of an intensive fludarabine, high dose cytarabine (ARA-C) and Idarubicin (IDA) induction regimen (FLAI) as frontline treatment for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status.

One-hundred and forty-nine consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty nine patients had isolated FLT3-ITD, 59 concomitant FLT3-ITD and NPM1-mut and 61 isolated NPM1-mut. Median age was 51 yrs (range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days 1 to 5 plus IDA 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction and IDA dose was increased to 12 mg/sqm. Before ELN 2017 risk stratification was adopted, patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (allo-BMT) in first CR regardless of allelic burden. For patients with AML with NPM1 mutation and concomitant FLT3-ITD indication to allo-BMT in 1st complete remission was mainly based on minimal residual disease (MRD) status. MRD was evaluated on marrow samples using multicolor flow-cytometry (MFC) or NPM1 expression levels. Negative MFC-MRD was defined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025%, Minetto et. al, BJH 2019). NPM1-mut (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients.

Overall, 60-days mortality was 4.7%. After first induction cycles, 129 patients achieved CR (86.6%). Thirty-five/129 (25.5%) CR patients underwent BMT in first CR. After a median follow up of 68 months, 3-year overall survival (OS) was 58.6% (median not reached). In univariate analysis OS duration was affected by NPM1, FLT3 mutational status and ELN risk score. However, NPM1-mutated patient was not negatively affected by the presence of FLT3-ITD, regardless of allelic burden. This observation was even more evident in patients younger than 55 yrs (3 yy OS 64% and 68% for NPM1-mutated with or w/o FLT3-ITD, respectively (p=n.s, Figure 1), regardless of FLT3-ITD allelic burden. ELN 2017 high risk patients displayed the worst prognosis (3-year OS 35.2%). Multivariate analysis showed that NPM1 mutation was the strongest predictor of survival.

In order to assess the impact of allo-BMT in 1st CR we performed a Landmark Analysis including patients alive and in CR at day 90. Interestingly, performing allo-BMT in 1st CR did not impact OS in the whole cohort of patients and irrespectively of NPM1 and FLT3 mutational status. The only subgroup who benefit from allo-BMT in first CR was high risk ELN2017 (p<0.05).

Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status. Our data potentially question the role of BMT in first CR in this setting.

Disclosures: Bocchia: CELGENE: Honoraria; Incyte: Honoraria.

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