Telomere Length In MDS Patients Bone Marrow Is Highly Correlated with Complex Cytogenetics, IPSS Risk Groups and Transfusion Dependency,

Abstract 3826

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by ineffective haematopoiesis. Age, gender, mutagen exposure and telomere length have been linked to MDS. Previous studies have demonstrated that patients with MDS have shortened telomeres compared to healthy controls, based on measurements obtained from either peripheral blood mononuclear cells, peripheral blood granulocytes, bone marrow, and/or CD34+ stem cells, indicating that individuals with shorter telomeres may be at increased risk of developing MDS.

To investigate the association between telomere length and pathogenesis of MDS, we measured the telomere length (T/S ratio) by a multiplex quantitative real-time PCR in bone marrow mononuclear cells of 307 MDS patients and PBMCs of 182 healthy controls. In the assay, the relative telomere length is measured by the fluorescence signal of telomere amplification normalized to the signal obtained from a single copy gene, albumin.

The median age of patients was 64 years (range 17–89 years). The median haemoglobin levels was 9.9 g/dl(IQR 8.6–11.6), neutrophil 1.4 × 10⁹ /l (IQR 0.6–2.99) and platelet 98x 10⁹ /l (IQR 39–187).The WHO subtypes were RA/RARS/Isolated de5q; 50 (16%), RCMD/RCMD-RS; 116 (38%), RAEB 1/2; 70 (23%), AML secondary to MDS; 29(9%),therapy related MDS; 18 (6%) and MDS/MPD; 24 (8%). IPSS cytogenetic risk groups were; good risk-199(65%), intermediate -34 (11%) and poor risk-55(18%) and cytogenetics failed in 19 patients (6%). The IPSS categories were, low risk: 80(26%), intermediate-1:97(32%), intermediate-2:50 (16%), high risk: 26 (9%) and 54(18%) patients were not evaluable (proliferative CMML and MPD/MDS).Transfusion dependency was present in 141(46%) patients. Progression to AML occurred in 68 patients (20%).

In healthy controls (n=182; age range: 2–90 years), the T/S ratios measured in PBMCs demonstrated a progressive decline with ageing (Y=2.3–0.014X; R²=0.2417; P < 0.0001).

The median telomere length was 0.97(range 0.3–2.8).In patients with MDS, T/S values did not show a correlation with age (P=0.327). Neither statistically difference in T/S values was observed between male and female patients (P=0.976). However, compared to PBMCs of the age-matched healthy controls, the mean T/S value obtained from BMNC of the MDS patients was significantly lower (P<0.0001; n=112; age range: 31–90; mean age: 61.9 ± 14.8). Among cases of MDS, telomere lengths were compared with variables, such as IPSS score, cytogenetics, WHO subtype, and platelet count. Using the nonparametric correlation, the T/S values measured from MDS patients had significantly negative correlations with □&IPSS score (n=253; P<0.0008), WPSS score (n=196; P<0.0002), IPSS cytogenetic groups(n=288; P<0.0468), bone marrow blasts (n=307; P=0.03),WHO subtypes (n=307; P<0.0157), transfusion dependency (n=275; P<0.0306), but positively correlated with platelet counts (n=307; P<0.0012); However, no statistically significant difference in telomere length were observed by hemoglobin levels (n=307; P=0.057), numbers of and PNH clones (n=151; P=0.507).

MDS patients with complex cytogenetics(n=35, med T/S value 0.919) had a shorter telomere length compared to patients with normal cytogenetics (n=204, med T/S value 1.02).We did not observe any statistically significant difference in T/S values in patients with isolated 5q, trisomy 8, monosomy 7. We could not find any association between short telomere and MDS patients with TP53 mutation.

In multivariate logistic regression, telomere length was associated with transfusion dependency (P<0.007) and also with IPSS score (p<0.04).There was no correlation between telomere length and proabability of progression to AML. Worse survival was seen in patients with telomere length <1.2 when compared with patients with T/S values >1.2, though this was not statistically significant.

This study shows that MDS patients have short telomeres compared to age matched controls and the relative telomere length is strongly associated with IPSS risk group and transfusion dependency.

Telomere attrition seen in patients with MDS could lead to destabilization of genome and subsequent chromosomal instability. This study shows shortening of telomeres associated with complex cytogenetics, transfusion dependency and also in patients with intermediate-2/high risk MDS.