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Study Authors: Carmen D. Herling, Kevin R. Coombes, et al.; Lukáš Smolej

Target Audience and Goal Statement: Oncologists, hematologists, pathologists, hospitalists, family physicians, internists

The goal of this study was to develop and validate a gene expression signature to identify which treatment-naive patients with IGHV-unmutated chronic lymphocytic leukemia (CLL) would benefit from treatment with chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).

Question Addressed:

• Was it possible to identify a gene expression signature that could predict a favorable outcome in IGHV-unmutated CLL patients treated with first-line FCR?

Study Synopsis and Perspective:

CLL -- the adult leukemia in the U.S., accounting for about of new leukemia cases -- is a malignancy of CD5+ . The clinical course of CLL can be , ranging from slow to rapidly progressive, and defying prediction in some patients.

Generally speaking, patients with CLL cells with unmutated IGHV have more aggressive disease than patients with CLL cells with mutated IGHV. Upfront FCR treatment can lead to long-lasting remissions in younger fit CLL patients with a mutated IGHV status. Why chemoimmunotherapy-treated CLL patients with unmutated IGHV than their counterparts with mutated IGHV is currently not known.

What is known is that a carefully selected CLL patient subset can achieve long-term durable remissions with the gold-standard FCR regimen for physically fit patients. CLL cells from these patients typically have somatic IGHV mutations and do not have high-risk cytogenetic abnormalities.

Lynne Abruzzo, MD, PhD, of the Ohio State University in Columbus, and colleagues have now published a article describing the identification of a largely CLL-specific 17-gene signature (genes associated with the metabolic activity of CLL cells, e.g., oxidative phosphorylation and purine analog metabolism) that could possibly be used to identify patients with IGHV-unmutated CLL who are likely to achieve long-term remissions with FCR.

For the first time, the researchers were able to identify a patient subgroup who were likely to achieve a relatively long remission after first-line FCR, despite having an unmutated IGHV gene. Specifically, the 17-gene signature was associated with a significantly increased risk of disease progression in a training set of patients (hazard ratio [HR] 3.83, 95% CI 1.94-7.59, P<0.001) and in a validation set (HR 1.90, 95% CI 1.18-3.06, P=0.008).

To develop an accurate, easily assessable prognostic tool, researchers performed gene expression analyses using multiple microarray kits on samples from the University of Texas MD Anderson Cancer Center (MDACC) training cohort of 101 patients and an independent validation cohort from the German Chronic Lymphocytic Leukemia Study Group CLL8 trial of 109 patients. Both trials previously confirmed that chemoimmunotherapy with FCR was effective as upfront treatment for CLL.

Established markers of CLL prognosis in the MDACC training cohort included IGHV somatic mutation status, ZAP70 expression, and serum β-2 microglobulin. Median time to progression was 92.4 months and median progression-free survival (PFS) was 66.6 months. Median overall survival (OS) from the start of FCR therapy was not reached at the end of follow-up (median follow-up of survivors after treatment was 146.5 months).

Compared with the IGHV-unmutated subset of the MDACC training cohort, there were fewer patients in the CLL8 validation cohort that were ZAP70 positive, but more patients had high CD38 expression and unfavorable cytogenetics. Assessments after 73.4 months, on average, showed a median time to progression of 46.5 months, a median PFS of 42.4 months, and a median OS of 80.8 months for the validation cohort.

Analysis of the gene sets was partly informed by previous reports that -- unlike many other highly proliferative lymphoid neoplasms and other cancers -- CLL cells do not rely upon aerobic glycolysis to generate energy. Rather, they chiefly rely on oxidative phosphorylation.

IGHV-unmutated samples were clustered into low-risk (intermediate) and high-risk (unfavorable) prognostic groups using univariate Cox proportional hazards analyses and significant genes. Following cross-validation, the researchers applied the method to standardize the gene expression values to identify a minimum gene signature.

Because of the well-known difficulties in reproducing lists of prognostic genes from different datasets, the researchers took great care to validate multiple steps in model construction in the training cohort and validated the model in a separate cohort treated in a different trial. Thus, the final model used only 17 of 1,136 genes that were related to time to progression in univariate analyses. The 17 genes that were ultimately included in the signature were OSBPL5, MSI2, KSR2, NME1, SLC35A4, TXN, LAG3, ZNHIT1, PDE8A, RGS10, TSPO, CRLF3, DCAF12, ADSL, AQP1, GRN, and TTC38.

Focusing on the CLL8 cohort, researchers found that the 17-gene signature could be used to successfully stratify patients with an unmutated IGHV status into high- and low-risk groups, with median times to progression of 39 months and 59 months, respectively.

Limitations of the study included possible selection bias in the MDACC cohort (only 114 of 162 had high-quality RNA available for assessment), small patient samples, and differences in disease characteristics between the MDACC and CLL8 groups.

Source References: 2019; DOI: 10.1016/S1470-2045(19)30503-0

Editorial: 2019; DOI: 10.1016/S1470-2045(19)30622-9

Study Highlights and Explanation of Findings:

Development of a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated CLL who might substantially benefit from treatment with FCR chemoimmunotherapy has set the stage for testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomized clinical trial.

Based on the transcriptional profiling data, differences in therapeutic responses in patients with IGHV-unmutated CLL could be partially attributed to variations in the expression of genes involved in oxidative phosphorylation and purine metabolism. Thirteen of the 17 genes had positive coefficients, suggesting a correlation between increased expression and increased risk of progression. By contrast, three of the 17 genes had negative coefficients, suggesting that increased expression corresponded to decreased risk.

Consistent with current knowledge, most of the patients with a favorable prognosis were those with mutated IGHV. But nearly a third of intermediate or poor prognosis cases also had mutated IGHV, and one-third of these also showed del(13)(q). Thus, the presence of these two abnormalities did not ensure a good prognosis.

"Other than the clinical outcome and the results of the 17-gene signature, we could not identify any clinical or laboratory features that would allow us to distinguish these cases from those with a good prognosis," the researchers wrote.

FCR's role as front-line therapy for those with IGHV-unmutated CLL has been put into question following data from the phase III ECOG-ACRIN E1912 trial, which showed that the Bruton tyrosine kinase (BTK) inhibitor ibrutinib improved PFS compared with FCR in fit patients with CLL (and also improved PFS in older patients treated with bendamustine plus rituximab).

However, FCR has advantages over ibrutinib, including its brief treatment course (6 months) and lower costs. Downsides include that a small proportion of FCR-treated patients go on to develop therapy-related myelodysplastic syndromes or acute myeloid leukemia, and older unfit patients often cannot tolerate the regimen and have an increased infection risk.

"Ibrutinib treatment is associated with some disadvantages: it requires long-term administration until progression; it might be complicated by clinically significant adverse events such as bleeding or atrial fibrillation; and, it might be associated with other important factors such as the development of treatment resistance, poor patient compliance to therapy, and substantial financial toxicity," explained Lukáš Smolej, MD, of University Hospital in Hradec Králové, Czech Republic, in an .

Smolej said that FCR might still be a "suitable first-line option" for carefully selected CLL patients, such as those with IGHV-mutated status and, based on the current findings, possibly those with unmutated IGHV status and a favorable genetic profile.

"A clear and growing trend towards a patient-specific treatment approach in chronic lymphocytic leukemia is emerging -- both from the viewpoint of patient characteristics (e.g., avoiding fludarabine-based treatment in patients with advanced age or substantial comorbidities, or both) as well as on the basis of features related to chronic lymphocytic leukemia (e.g., avoiding chemoimmunotherapy in patients with a mutation or deletion of the TP53 gene)," Smolej concluded. "Therefore, the present study deals with a very up-to-date topic."