From the Journals

Short telomeres predict poorer response to chemo in CLL



A telomere-length analysis tool appears to identify reliably which chronic lymphocytic leukemia (CLL) patients will benefit from frontline chemotherapy, according to an analysis of 260 patients across two separate trials.

High-power magnification (1000 X) of a Wright's stained peripheral blood smear showing chronic lymphocytic leukemia (CLL). The lymphocytes with the darkly staining nuclei and scant cytoplasm are the CLL cells. VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

The analysis compared the use of high-throughput, single telomere–length analysis (HTSTELA) with other commonly used markers including beta-2 microglobulin, fluorescence-in-situ hybridization (FISH) cytogenetics, CD38 expression, ZAP70 expression, and IGHV mutation status. The researchers looked specifically at whether telomere length could predict response to frontline treatment with fludarabine, cyclophosphamide, rituximab (FCR)–based regimens.

“[T]elomere length is a powerful predictor of both [progression-free survival] and [overall survival] in patients treated with FCR-based therapies. In contrast, CD38 expression and beta-2 microglobulin expression were not predictive, and IGHV mutation status was only predictive of PFS (progression-free survival),” Kevin Norris, PhD, of Cardiff (Wales) University and his colleagues wrote in Leukemia.

Previous studies have shown that telomere-length analysis offers independent prognostic information in all stages of CLL. In the present study, the researchers used HTSTELA to analyze patient samples taken from two concurrent, phase 2 clinical trials of frontline FCR-based treatment – ARCTIC and ADMIRE.

The researchers divided the cohort based on a threshold of telomere dysfunction – the point at which the chromosome end-capping function is lost and there is genomic instability. Shorter telomeres are inside the fusogenic range (TL-IFR) and longer telomeres are outside fusogenic range (TL-OFR).

Patients with TL-IFR had significantly shorter PFS on FCR-based treatment (P less than .0001). They also had reduced overall survival (OS; P = .0002). In the same cohort of patients, IGHV mutation status was predictive of PFS (P = .0016), but it was not predictive for OS (P = .38), while CD38 and beta-2 microglobulin were not predictive of PFS or OS.

The researchers also looked at the value of telomere length in predicting outcomes among IGHV-mutated and -unmutated patients.

Patients with IGHV-mutated disease and TL-IFR had worse PFS and OS than did patients with TL-OFR. TL-IFR patients in this cohort were more likely to progress (hazard ratio, 4.35; P less than .0001) and more likely to die from their disease (HR, 3.81; P = .006).

“Although the number of IGHV-mutated patients with TL-IFR was relatively small (n = 16), our data suggests that telomere length can identify a subset of “bad risk” IGHV-mutated patients who do not respond well to FCR,” the researchers wrote.

Among IGHV unmutated patients, those with short telomeres had worse PFS (HR, 1.48; P = .08) and OS (HR, 2.18; P = .025) than did those with longer telomeres.

In multivariate modeling of all the potential markers, telomere length was the statistically significant dominant covariable for both PFS and OS.

The study was funded by a Bloodwise grant and the Wales Cancer Research Center. Dr. Norris and three coauthors reported that they are coinventors of patents relevant to the study and hold shares in a company set to provide telomere length testing.

SOURCE: Norris K et al. Leukemia. 2019 Jan 30. doi: 10.1038/s41375-019-0389-9.

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