PS1171 TELOMERE LENGTH AT DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA PREDICTS THE ACHIEVEMENT OF DEEP MOLECULAR RESPONSE TO IMATINIB
Authors: Estrada N. , Xicoy B. , García O. , Morales‐Indiano C. , Sagüés M. , Boqué C. , Beier F. , Brümmendorf T.H. , Vallansot R. , Marcé S. , Dominguez D. , Grau J. , Sorigué M. , Orna E. , Zamora L. 
Published: June 2019

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).

Summary/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.

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