TRAMETINIB THERAPY AND DISEASE MONITORING BY MUTATION SPECIFIC DROPLET
DIGITAL PCR IN RELAPSED PEDIATRIC ACUTE MYELOID LEUKEMIA: A CASE REPORT
POSTER 23
Szilvia Krizsán1, Ambrus Gángó1, Lajos Hegyi1, Endre Sebestyén2, Tibor Nagy3, Dániel János Erdélyi4,
Gergely Kriván5, Krisztián Kállay5, Gábor Kovács4, Csaba Bödör1 and Donát Alpár1
(1)MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology
and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
(2)Computational Biology Group, 1st Department of Pathology and Experimental Cancer Research,
Semmelweis University, Budapest, Hungary
(3)Bioinformatics and Functional Genome Analysis Research Group, Department of Biochemistry and
Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
(4)2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
(5)Pediatric Hematology and Stem Cell Transplantation Unit, Central Hospital of Southern Pest -
National Institute of Hematology and Infectious Diseases, Budapest, Hungary
Introduction:
Pediatric acute myeloid leukemia (AML) has a relatively poor prognosis, as relapse remains the major
cause of treatment failure in 30% of patients. Another major issue in pediatric AML is the lack of
sensitive molecular markers for the detection of measurable residual disease (MRD), that is known as
strong prognostic marker of increased risk of relapse. Here, we present the case of a relapsed
pediatric AML patient with NRAS mutation, where droplet digital PCR (ddPCR) was used for MRD
monitoring following HSCT and trametinib maintenance treatment.
Clinical history:
A 1.5-year-old boy presented with fever, tonsillitis, jaundice and pronounced hepatosplenomegaly in
August 2016. The peripheral blood count revealed severe anemia and thrombocytopenia. Flow
cytometry detected 10% blasts, while histology examination of the bone marrow showed 20% blasts.
Monosomy 7 was detected by fluorescent in situ hybridization (FISH). The patient was treated
according to the AML-BFM 98 protocol. The treatment resulted in complete remission with MRD
positivity as determined by flow cytometry. In February 2017, he received allogeneic hematopoietic
stem cell transplantation (HSCT) with Bu-Flu + ATG conditioning regimen.
Eighteen months following the HSCT, the patient relapsed with 25% blasts detected in the bone
marrow. FISH analysis revealed, in addition to the previously identified monosomy 7, a subclonal
trisomy 8. FLA-HAM salvage therapy was administered to the patient. At this time, targeted next-generation
sequencing of 54 genes was performed revealing an NRAS p.Q61R mutation with a
variant allele frequency (VAF) of 8%. For disease monitoring purposes, droplet digital PCR assay was
designed specifically for this mutation. We were able to detect the mutation retrospectively both at
diagnosis and at relapse with VAFs of 14% and 8%, respectively. In January 2019, the patient
underwent a second HSCT. One-month post-HSCT, MEK inhibitor trametinib maintenance therapy
was initiated with an aim of targeting the residual cells with NRAS mutation leading to elimination of
the NRAS mutant subclone. Patient is currently monitored every 3 months using ddPCR, and he
remained in complete clinical and molecular remission for more than a year following his second
HSCT.
Conclusion:
Treatment of pediatric AML remains an unsolved challenge, as risk of relapse is high in these
patients. Due to the lack of molecular markers early recognition of relapses are difficult. The
presented case demonstrates how NGS can identify potent targets of novel therapies and how novel
technologies can be utilized for the sensitive residual disease monitoring in pediatric AML.
SCIENTIFIC
PROGRAMME
RARE SUBSETS OF
ACUTE LEUKAEMIA
TRACKING LEUKAEMIC
STEM CELLS (LSCs)
ROUTINE DIAGNOSIS
GENE EXPRESSION
AND MUTATIONAL
PROFILING
DEBATE 1 – ALL
PATIENTS WITH
INTERMEDIATE-RISK
AML MUST BE
TRANSPLANTED
INTERACTIVE
CASES 1 – MUTATION-BASED
THERAPY
OFF-LABEL
ROUNDTABLE –
SHOULD WE REALLY
USE NEW TARGETED
INHIBITORS AS SINGLE
AGENTS ?
ADDITION OF A 3RD
AGENT TO FRONTLINE
7+3
ROUNDTABLE –
CURATIVE OPTIONS
FOR OLDER AML
INTERACTIVE CASES 2
DEBATE 2 - BEST
TREATMENT FOR
NPM1-MUTATED AML IN
THE NEXT FUTURE ?
ALLOGENEIC
HAEMATOPOIETIC
STEM CELL
TRANSPLANTATION
(HSCT)
IMMUNOTHERAPY FOR
ACUTE LEUKAEMIA
DEBATE 3 - T-ALL:
WHERE ARE WE GOING
NOW?
SELECTED ABSTRACTS
AND CLINICAL
CASES FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
DISCLOSURES