ASSESSMENT OF INDIVIDUAL MOLECULAR RESPONSE IN CHRONIC MYELOID
LEUKEMIA PATIENTS WITH ATYPICAL BCR-ABL1 FUSION TRANSCRIPTS.
RECOMMENDATIONS BY THE EUTOS COOPERATIVE NETWORK
Thomas Ernst1, Vivien Günther1, Helen E White2, Susanne Möbius1, Susanne Saussele3, Georg-Nikolaus
Franke4, Gareth Gerrard5, François-Xavier Mahon6, Rodica Talmaci7, Dolors Colomer8, Katerina
Machova Polakova9, Simona Soverini10, Nicholas C. P. Cross11 and Andreas Hochhaus1
(1)Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
(2)Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust and School of Medicine,
University of Southampton, Salisbury, United Kingdom
(3)Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University,
Heidelberg, Germany
(4)Department of Hematology and Oncology, Leipzig, Germany
(5)Sarah Cannon Molecular Diagnostics, HCA Healthcare, London, United Kingdom
(6)Institut Bergonie, Bordeaux, France
(7)Center of Hematology and Bone Marrow Transplant, "Fundeni" Clinical Institute, Bucharest,
Romania
(8)Hospital Clínic, BARCELONA, Spain
(9)Institute of Pathophysiology, 1st Medicine Faculty, Charles University, Prague, Czech Republic,
(10)Department of Experimental, Diagnostic and Specialty Medicine - DIMES, Institute of Hematology
"L. and A. Seràgnoli", Bologna, Italy
(11)Wessex Regional Genetics Laboratory, Salisbury, United Kingdom
Purpose: Approximately 1-2% of patients with chronic myeloid leukemia (CML) harbor BCR-ABL1
transcript variants that cannot be monitored by reverse transcription real-time
quantitative polymerase chain reaction (RT-qPCR) using standard methodologies. Most rare
variants are accounted for by seven variant fusions (e1a2/3, e6a2, e8a2, e13/14a3, e19a2).
Within the European Treatment and Outcome Study (EUTOS) for CML we sought to establish
and validate robust RT-qPCR methods for these abnormalities.
Methods: Multiplex endpoint RT-PCR experiments were performed to identify atypical BCR–
ABL1 transcript types which were then sequenced to characterize the underlying BCR–
ABL1 fusion. Monitoring of residual disease during treatment with tyrosine kinase inhibitors
(TKI) was carried out by RT-qPCR with specific forward and/or reverse primers and probes
using serial dilutions of bespoke BCR-ABL1 and GUSB plasmid DNA calibrators. Results were
expressed as log reduction of the BCR–ABL1/GUSB ratio relative to the patient specific
baseline value and evaluated as individual molecular response (IMR).
Results: A total of 330 blood samples (2-34 per patient, median 8) from 33 CML patients (19
male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1
transcripts (e1a2, n=6; e6a2, n=1; e8a2, n=2; e13a3, n=4; e14a3, n=6; e13a3/e14a3, n=2;
e19a2, n=12). Most of the patients (61%) responded well to therapy with TKIs and achieved
an IMR of at least one log reduction three months after diagnosis. Eighteen patients (55%)
reached a deep molecular response with BCR-ABL1 below the detection limit. Four patients
relapsed with a significant increase of BCR-ABL1/GUSB ratios during the observation period.
SCIENTIFIC PROGRAMME
SESSION I
OPTIMIZING
CYTOREDUCTION
SESSION II
MANAGEMENT OF CML
WITH TKI
SESSION III
MPN RISK
STRATIFICATION
INCLUDING VASCULAR
EVENTS
DEBATE 1
INTERFERON ALPHA
SHOULD BE FRONT LINE
THERAPY IN ALL ET/PV
PATIENTS
ROUNDTABLE 1
INFECTIONS IN
MYELOPROLIFERATIVE
DISORDERS, INCLUDING
CML
ROUNDTABLE 2
PREGNANCY AND
PARENTING
DEBATE 2
ALLOGENEIC STEM CELL
TRANSPLANTATION
SHOULD BE CONSIDERED
THIRD LINE OPTION IN
CHRONIC PHASE CML
SESSION IV
EVOLVING THERAPIES
IN MYELOFIBROSIS
SESSION V
MANAGEMENT OF
ADVANCED AND UNUSUAL
DISEASE (MPN AND CML)
SESSION VI
TREATMENT FREE
REMISSION IN CML
KEYNOTE LECTURE
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FO R A POSTER
PRESENTATION
DISCLOSURES