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3817 Retrospective Analysis of Minimal Residual Disease-Guided Preemptive Treatment in Patients with AML and MDS - the SAL Study Group Experience

Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Ekaterina Bulycheva, MD1*, Jiri Mayer2, William Hermann Krüger, MD, PhD3*, Peter Dreger, MD4, Anna Mies1,5*, Zuzana Sustkova, MD6*, Zdenek Racil, MD6*, Jirina Prochazkova, MD6*, Eva Walter, MD7*, Carsten Hirt3*, Mark Ringhoffer, MD8*, Wolfgang E Berdel, MD9, Hubert Serve, MD10*, Christoph Rollig11*, Katja Sockel, MD12*, Martin Bornhäuser, MD13*, Gerhard Ehninger, MD14, Christian Thiede, MD, PhD1,5 and Uwe Platzbecker, MD5,15

1Medical Department I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
2Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
3Department of Internal Medicine C, Hematology and Oncology, Marrow Transplantation, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany
4Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
5German Cancer Consortium, German Cancer Research Center Heidelberg, Heidelberg, Germany
6Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic
7Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany
8Department of Internal Medicine III, Municipal Hospital of Karlsruhe, Karlsruhe, Germany
9Department of Medicine A, University Hospital Münster, Muenster, Germany
10Dept. of Internal Medicine, University Hospital of Frankfurt, Frankfurt, Germany
11University Hospital Carl Gustav Carus Dresden, Dresden, Germany
12Medizinische Klinik I, Universitaetsklinikum C.G.Carus, Dresden, Germany
13Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
14Medical Dept. 1, University Hospital TU Dresden, Dresden, Germany
15Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany

Introduction

Detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in complete hematological remission (CR) offers a potential therapeutic window allowing early interventions in order to prevent overt hematological relapse. Due to the absence of generic markers in AML/MDS, MRD assessment seems to be a complex procedure. As prospective clinical studies are sparse, we initiated a retrospective survey within the SAL (Study Alliance Leukemia) study group and members of the German Cancer Consortium to evaluate the current clinical use of the approach and related clinical outcome of treated patients.

Patients

Based on questionnaires we analyzed 84 patients from five clinical centers (pts, m/f=46/38; median age 52 yrs (19-74)) with either AML (n=77) or MDS (n=7) in CR after conventional intensive chemotherapy (CTx; n=23) or allogeneic hematopoietic stem cell transplantation (allo-HSCT; n=61), undergoing preemptive therapy. Mutations, cytogenetic aberrations or donor chimerism analysis for transplanted pts were monitored as MRD markers. Thirty-three pts had a normal and 14 pts – a complex karyotype; 6 pts carried -7 and/or inv(3); other aberrations were detected in 29 pts; in 2 pts no data were available. Among molecular aberrations, NPM1 (n=23) and FLT3-ITD (n=13) were the most frequent, followed by CBFβ/MYH11 (n=8), RUNX1/RUNX1T1 (n=8) and MLL/AF6 (n=3). In 20 pts no mutations were found. For 5 pts data on molecular diagnostics were not available and MRD was assessed by chimerism.

Results

The median time to MRD positivity after completion of intensive therapy was 12 months (range, 1-97). Subsequent MRD-guided therapy in pts treated only with CTx included hypomethylating agents (HMA, 34%), clofarabine (17%), additional intensive CTx (9%), targeted therapy (gemtuzumab ozogamycin, 9%), low-dose cytarabine (9%), and allo-HSCT (22%). Other treatment strategies included interferon alfa and sorafenib. In transplanted patients the most preferred treatment for the molecular relapse was donor lymphocyte infusion (26 pts, 43%; median number of DLI=3, range, 1-6), alone or in combination (54% with HMA). 32 MRD-based treated pts (43%) did not experience a hematological relapse and were either alive (23 pts, median observation time 953 days, range, 30–3660), or died due to another cause (9 pts) with median survival of 359 days (range, 125-954). In 9 pts without hematological relapse more than one MRD recurrence was observed. In the remaining 57% relapsing patients, median time to hematological relapse was 252 days (range, 24–1161) after MRD positivity. Interestingly, in some pts the hematological relapse was observed in the absence of the known mutation, indicating that the disease probably progressed due to another subclone. Thus, an accurate initial diagnostic is essential, ideally a multiple gene approach and comprehensive follow-up.

Conclusions

The retrospective analysis demonstrates that MRD-guided therapies have already entered routine practice in patients with AML and MDS. The heterogeneous nature of both cancer entities is reflected by the variety of MRD surveillance protocols among clinical centers. Therefore, clinical trials are needed to better define molecular markers and subsets of patients who might benefit from this approach.

Disclosures: Mayer: Cell Therapeutics: Other: Grants, personal fees . Thiede: AgenDix GmbH: Equity Ownership . Platzbecker: Novartis: Honoraria ; GlaxoSmithKline: Honoraria , Research Funding ; Celgene: Honoraria ; Amgen, Inc.: Honoraria .

*signifies non-member of ASH