IN SEARCH OF THE RESIDUAL LEUKAEMIC CLONE IN CHRONIC MYELOID LEUKAEMIA PATIENTS IN TREATMENT-FREE REMISSION
Author(s): ,
Ilaria Stefania Pagani
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia
,
Phuong Dang
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia
,
Verity A Saunders
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia
,
Randall Grose
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia
,
Naranie Shanmuganathan
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia;Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia;Genetic and Molecular Pathology,SA
,
Lisa Carne
Affiliations:
Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia
,
Zandi Rwodzi
Affiliations:
Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia
,
Sophie M Watts
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia
,
Jennifer McLean
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia
,
Jodi Braley
Affiliations:
Genetic and Molecular Pathology,SA Pathology,Adelaide,Australia
,
David T Yeung
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia;Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia
,
Susan Branford
Affiliations:
Genetic and Molecular Pathology,SA Pathology,Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Centre for Cancer Biology,University of South Australia and SA Pathology,Adelaide,Australia;School of Biological Sciences,Faculty of Sciences, University of Adelaide,Adelaide,Australia
,
Agnes Yong
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia
,
Deborah L White
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia;School of Biological Sciences,Faculty of Sciences, University of Adelaide,Adelaide,Australia;School of Paediatrics,Faculty of Health Sc
,
Timothy P Hughes
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia;Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia
David M Ross
Affiliations:
Precision Medicine Theme,South Australian Health & Medical Research Institute (SAHMRI),Adelaide,Australia;School of Medicine,Faculty of Health Sciences, University of Adelaide,Adelaide,Australia;Australasian Leukaemia and Lymphoma Group,Melbourne,Australia;Department of Haematology and Bone Marrow Transplantation,Royal Adelaide Hospital,Adelaide,Australia;Centre for Cancer Biology,Universi
EHA Library. Pagani I. Jun 15, 2019; 267468; S885
Dr. Ilaria Stefania Pagani
Dr. Ilaria Stefania Pagani
Contributions
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Abstract

Abstract: S885

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:00 - 17:15

Location: Forum Hall

Background

Approximately half of the patients with chronic myeloid leukaemia (CML) who stop tyrosine kinase inhibitors (TKIs) after a stable deep molecular response (DMR) remain in treatment free remission (TFR), while the remaining patients need to re-start TKI therapy. In an updated report of the TWISTER study we demonstrated the persistence of BCR-ABL1-positive cells with falling levels of residual disease, detected by highly-sensitive patient-specific genomic DNA PCR. The characteristics of the leukemic cells that remain after successful TKI treatment are not known. Understanding which cells persist despite TKI therapy could inform strategies aimed at recruiting more patients to TFR.

Aims

To determine the lineage of residual BCR-ABL1-positive cells from patients in TFR.

 

 

Methods

Twenty CML patients in TFR with undetectable BCR-ABL1 transcript (uMR4.5) for 1-11 years (median 3.0 years) provided peripheral blood for fluorescence-activated cell sorting into granulocytes (CD16+CD66+), monocytes (CD14+), B cells (CD3-CD19+), T cells (CD19-CD3+), and NK cells (CD3-CD19-CD56+). B-cells were then separated into mature-naïve (CD27-IgD+) and memory cells (CD27+IgD- switched memory; CD27+IgD+ non-switched memory; CD27-IgD- double-negative). DNA nested Q-PCR was performed on sorted cells using 20 replicates of 500 ng of DNA (total 10 ug) reaching a sensitivity of MR6.2 (one in ~2 million cells) in the various cell fractions.

Results

BCR-ABL1 DNA was detected in total leukocytes from 14/20 TFR patients with a median value of MR5.6 (range MR5.1-MR6.2). Even when BCR-ABL1 DNA was not detected in total leukocytes it was sometimes detected in sorted fractions (4/6), likely reflecting concentration of measurable residual disease (MRD) in the relevant population. BCR-ABL1 DNA was detected in B cells (n=18 patients), T cells (n=11), NK cells (n=5) and monocytes (n=4). Notably, BCR-ABL1 was not detected in T cells if the B cell fraction was negative and BCR-ABL1 values were consistently higher in B cells than in T cells (median MR4.9 vs MR5.7; P=0.01). Only one patient in TFR for 8 years had undetectable BCR-ABL1 DNA in all of the fractions analysed. BCR-ABL1 DNA was not detected in granulocytes in any of the 20 patients. To verify whether BCR-ABL1 positive lymphocytes identified during TFR are arising pre-TKI treatment, we analysed 11 patients at the time of diagnosis. A variable fraction of B (median 1.9%, range 0.1-12%) and T lymphocytes (1.7%, range 0.009-36%) were leukaemic (BCR-ABL1 DNA). BCR-ABL1 mRNA was expressed in the sorted cell fractions at levels similar to the DNA values. Subsequent sorting of B lymphocytes from TFR patients into naïve and memory subsets showed that both fractions contained BCR-ABL1 DNA. The absolute number of naïve B-cells did not change during years in TFR, but the absolute number of BCR-ABL1-positive naïve B-cells significantly decreased with longer duration of TFR.

Conclusion

Lymphocytes are part of the BCR-ABL1 clone at diagnosis. Their relative contribution to MRD measured in the blood increases over time in TKI-responsive patients as BCR-ABL1+ granulocytes rapidly decline. Diminishing numbers of leukemic naïve B cells in TFR support the hypothesis that leukemic lymphocytes are long-lived. In contrast, no patient in stable TFR had BCR-ABL1-positive granulocytes. The lineage-specific assessment of MRD needs to be further explored as a means to improve the prediction of TFR.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): B cell, Chronic myeloid leukemia, Clonality, Treatment-free remission

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