MEASURABLE RESIDUAL DISEASE MONITORING IN ACUTE MYELOID LEUKEMIA (AML) WITH T(8;21)(Q22;Q22.1); RUNX1-RUNX1T1: RESULTS OF THE AML STUDY GROUP (AMLSG)
Author(s): ,
Frank G. Rücker
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Mridul Agrawal
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Andrea Corbacioglu
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Daniela Weber
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Silke Kapp-Schwoerer
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Verena I. Gaidzik
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Nikolaus Jahn
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Thomas Schroeder
Affiliations:
University Hospital of Düsseldorf,Düsseldorf,Germany
,
Mohammad Wattad
Affiliations:
Evangelisches Krankenhaus,Essen-Werden,Germany
,
Michael Lübbert
Affiliations:
University Hospital of Freiburg,Freiburg,Germany
,
Elisabeth Koller
Affiliations:
Hanusch-Krankenhaus,Wien,Austria
,
Thomas Kindler
Affiliations:
University Hospital of Mainz,Mainz,Germany
,
Katharina Götze
Affiliations:
Klinikum rechts der Isar der Technischen Universität München,München,Germany
,
Mark Ringhoffer
Affiliations:
Städtisches Klinikum Karlsruhe,Karlsruhe,Germany
,
Jörg Westermann
Affiliations:
Campus Virchow-Klinikum, Charité University Hospital of Berlin,Berlin,Germany
,
Walter Fiedler
Affiliations:
University Hospital Of Hamburg-Eppendorf,Hamburg,Germany
,
Heinz A. Horst
Affiliations:
University Hospital of Kiel,Kiel,Germany
,
Richard Greil
Affiliations:
University Hospital of Salzburg,Salzburg,Germany
,
Roland Schroers
Affiliations:
University Hospital of Bochum,Bochum,Germany
,
Karin Mayer
Affiliations:
University Hospital of Bonn,Bonn,Germany
,
Thomas Heinicke
Affiliations:
University Hospital of Magdeburg,Magdeburg,Germany
,
Jürgen Krauter
Affiliations:
Klinikum Braunschweig,Braunschweig,Germany
,
Richard F. Schlenk
Affiliations:
University Hospital of Ulm,Ulm,Germany;National Centrum für Tumorerkrankungen (NCT), University of Heidelberg,Heidelberg,Germany
,
Felicitas Thol
Affiliations:
University Hospital of Hannover,Hannover,Germany
,
Michael Heuser
Affiliations:
University Hospital of Hannover,Hannover,Germany
,
Arnold Ganser
Affiliations:
University Hospital of Hannover,Hannover,Germany
,
Lars Bullinger
Affiliations:
Campus Virchow-Klinikum, Charité University Hospital of Berlin,Berlin,Germany
,
Peter Paschka
Affiliations:
University Hospital of Ulm,Ulm,Germany
,
Hartmut Döhner
Affiliations:
University Hospital of Ulm,Ulm,Germany
Konstanze Döhner
Affiliations:
University Hospital of Ulm,Ulm,Germany
EHA Library. G. Rücker F. Jun 16, 2019; 267370; S1616
Frank G. Rücker
Frank G. Rücker
Contributions
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Abstract

Abstract: S1616

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 09:00 - 09:15

Location: Forum Hall

Background
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1) resulting into the RUNX1-RUNX1T1 gene fusion defines a distinct entity within the category ‘AML with recurrent genetic abnormalities’ of the World Health Organization classification and is considered as a favorable AML subset in the 2017 risk stratification by the European LeukemiaNet (ELN). Although most patients (pts) achieve complete remission (CR) following intensive chemotherapy, relapse occurs in about 50% of the cases and is associated with poor prognosis. In this AML subset monitoring of measurable residual disease (MRD) has been shown to identify pts at higher risk of relapse.

Aims
To assess the prognostic impact of MRD monitoring in bone marrow (BM) and peripheral blood (PB) in a large cohort of 155 homogeneously treated and clinically well-annotated patients with t(8;21)-AML.

Methods
Quantification of RUNX1-RUNX1T1 transcript levels (TL) was performed by RT-qPCR. TL were reported as normalized values of RUNX1-RUNX1T1 per 106 transcripts of the housekeeping gene B2M. Samples were analyzed in triplicate, the sensitivity of our assay was up to 10-6.

Results
While pretreatment RUNX1-RUNX1T1 TL did not impact prognosis, both reduction of RUNX1-RUNX1T1 TL and achievement of MRD negativity (MRDneg) at defined time points were of significant prognostic importance. First, achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after cycle 2 were significantly associated with a reduced risk of relapse (P=0.034 and P=0.028, respectively). Second, after completion of therapy, achievement of MRDneg in both, BM and PB, was an independent favorable prognostic factor for cumulative incidence of relapse (4-year CIR BM: 17% vs 36%, P=0.021; PB: 23% vs 55%; P=0.001) and overall survival (4-year OS rate BM: 93% vs 70%, P=0.007; PB: 87% vs 47%; P<0.0001). Finally, during follow-up serial RT-qPCR analyses allowed prediction of relapse in 77% of pts exceeding a cut-off of 150 RUNX1-RUNX1T1 TL in BM, and in 84% of pts with > 50 RUNX1-RUNX1T1 TL in PB, respectively. KIT mutation observed in 28% of pts predicted for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TL during treatment. Virtually all relapses occurred within one year after end of treatment (EOT) with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this period. Based on our data we suggest a refined practical guideline for MRD assessment in RUNX1-RUNX1T1-positive AML: Along with the current ELN MRD recommendations, BM and PB should be analyzed after each treatment cycle. According to MRD at EOT and during follow-up we suggest MRD monitoring as follows: (i) MRDneg: PB monthly can be used, (ii) MRDpos (TL <150 in BM and <50 in PB): BM 3-monthly and PB monthly, and (iii) MRDpos (TL >150 in BM and/or >50 in PB) or increase of MRD >1-log or conversion from MRDneg to MRDpos: BM and PB, both monthly, should be analyzed.

Conclusion
RUNX1-RUNX1T1 MRD monitoring allows for the discrimination of pts at high and low risk of relapse. MRDneg in both, BM and PB, after completion of therapy was the most valuable independent favorable prognostic factor for relapse risk and OS. During follow-up, serial MRD analyses allowed the definition of cut-offs predicting relapse. Moreover, considering that virtually all relapses occurred within one year after EOT with a very short latency from molecular to morphologic relapse, MRD assessment at shorter intervals during this period is indispensable.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, Minimal residual disease (MRD)

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