TELOMERE LENGTH AT DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA PREDICTS THE ACHIEVEMENT OF DEEP MOLECULAR RESPONSE TO IMATINIB
Author(s): ,
Natalia Estrada
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain;Departament de Bioquímica i Biologia Molecular,Universitat Autònoma de Barcelona,Bellaterra (Barcelona),Spain
,
Blanca Xicoy
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Olga García
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Cristian Morales-Indiano
Affiliations:
Core-Hematology Department,Clinical Laboratory ICS-Metropolitana Nord, Hospital Germans Trias i Pujol,Badalona,Spain
,
Miguel Sagüés
Affiliations:
Hematology,Hospital Universitario de Girona, Doctor Josep Trueta,Girona,Spain
,
Concha Boqué
Affiliations:
Hematology, Institut Català d'Oncologia, Hospital Duran i Reynals,Hospitalet de Llobregat,Spain
,
Fabian Beier
Affiliations:
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation,RWTH Aachen University,Aachen,Germany
,
Tim H. Brümmendorf
Affiliations:
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation,RWTH Aachen University,Aachen,Germany
,
Rolando Vallansot
Affiliations:
Hematology,ICO-Hospital Universitario Joan XXIII,Tarragona,Spain
,
Silvia Marcé
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Diana Dominguez
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Javier Grau
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Marc Sorigué
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
,
Elisa Orna
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
Lurdes Zamora
Affiliations:
Hematology,ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute,Badalona,Spain
EHA Library. ESTRADA N. Jun 15, 2019; 266788; PS1171
Natalia ESTRADA
Natalia ESTRADA
Contributions
Abstract

Abstract: PS1171

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Telomere length (TL) is shortened with every cell division. Critically short telomeres are associated with genetic instability. In chronic myeloid leukemia (CML), increased cellular turnover of clonal BCR-ABL1-positive hematopoietic stem and progenitor cells leads to significantly shortened telomeres in myeloid cells from peripheral blood (PB). Retrospective studies have related accelerated telomere shortening in CML to disease stage, clinical risk score at diagnosis as well as cytogenetic remission.

So far, no study has considered the possible association between TL at diagnosis of CML and the achievement of deep molecular response (DMR) with imatinib (IM) treatment.

Aims

To explore if TL at diagnosis of CML is predictive of DMR achievement with IM as first-line treatment.

Methods

Samples from 100 patients with de novo CML at diagnosis of three different Catalan hospitals between 2004 and 2016 were included. Three patients were considered as missing due to no valid PCR results. All patients provided informed consent. Patients’ median age was 49 yrs (range 24-80 yrs) and 59% were males. Thirty-one (38%) patients had the e13a2 p210 BCR-ABL1 isoform whereas 51 (62%) had the e14a2 isoform. According to Sokal and ELTS scores, 48(50%) and 52(60%) patients were low risk, 30(32%) and 24(28%) were intermediate risk while 17(18%) and 10(12%) were high risk, respectively.

Patients were treated with first line IM 400 mg QD orally. For the molecular response (MR) analysis, only response to IM was considered. Response during the first year was assessed according to European Leukemia Net 2013 guidelines. DMR was defined as MR4.0 or MR4.5 The median time from IM start to MR4.0 achievement was 16.1 months (5.5, 100.7). Follow-up was at least 24 months for all patients.

For TL determination, DNA was extracted from PB or bone marrow cells. TL was analysed by monochrome multiplex quantitative polymerase chain reaction and the results were expressed as the standardized T/S ratio. Age adaptation of TL, indicated as ΔTL (delta-TL), was performed using data from 107 healthy controls (age range 16-84 years). The ΔTL for every patient was calculated subtracting the subject’s linear predicted TL (linear regression analysis of healthy controls) from the observed TL. 

Results

Healthy controls showed the expected decline in TL with increasing age (R2=0.1693), which was not detectable in CML (R2=0.0002), suggesting that telomeres are not age-dependent in CML at diagnosis. 

Analysing the clinical data, no significant correlation between ΔTL and clinical prognostic scores (Sokal and ELTS, with p=0.816 and p=0.314, respectively) was observed, nor between ΔTL and p210 BCR-ABL1 onco-protein isoforms (e13a2 and e14a2, p=0.981).

Finally, focusing on the ΔTL representing the difference between TL expected by age and TL determined in the CML cells, patients with lower ΔTL at diagnosis were significant associated with achievement of MR4.0 and MR4.5 (HR [95%CI]: 0.24 [0.1, 0.74], p=0.013 and 0.23 (0.1, 0.76), p=0.016, respectively). In addition, when patients were stratified according to median value of ΔTL (0.40), those with ΔTL<0.40 significantly achieved MR4.0 earlier than patients with ΔTL>0.40 (median in months [95%CI]: 21 [8.2, 33.7] vs 46.2 [23.6, 68.8], p=0.034) (Fig1).

Conclusion

TL at diagnosis of CML is a predictive biomarker of DMR achievement with IM as first-line treatment. Acknowledgements: FIS (AES 2016) PI16/01200 and FEHH.

Session topic: 7. Chronic myeloid leukemia - Biology & Translational Research

Keyword(s): Chronic myeloid leukemia, Imatinib, Molecular response, Telomere length

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