FCR Still an Option in IGHV-Unmutated CLL?

A chronic lymphocytic leukemia (CLL)-specific gene expression signature accurately identified patients with IGHV-unmutated disease who achieved durable remissions with chemoimmunotherapy, a retrospective study found.

Using blood samples from CLL patients undergoing chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the signature revealed a high-risk group of IGHV-unmutated patients with the shortest time to progression (HR 3.83, 95% CI 1.94-7.59, P<0.0001), reported Lynne Abruzzo, MD, PhD, of the Ohio State University in Columbus, and colleagues.

“We have developed and independently validated a robust and reproducible 17-gene signature that distinguishes treatment-naive patients with IGHV-unmutated chronic lymphocytic leukemia who are likely to achieve durable remissions following front-line FCR chemoimmunotherapy from those who might benefit from alternative regimens,” they wrote in the Lancet Oncology.

For the validation set, the authors examined samples from IGHV-unmutated patients who took part in a German CLL trial. Here, high-risk patients had a median time to progression of 39 months compared with 59 months for the intermediate-risk group (HR 1.90, 95% CI 1.18-3.06, P=0.008).

“It is well known that it is difficult to reproduce lists of prognostic genes selected from different datasets,” Abruzzo and colleagues wrote. “To address this limitation, we validated multiple steps in the model construction and, more importantly, validated the model in an independent patient cohort treated in a separate clinical trial.”

The group’s final prognostic model was culled from 1,136 genes that in univariate analyses were found to be related to time to disease progression. The 17 genes that were ultimately included in the signature were mostly related to metabolic activity of CLL cells, and include (in order of importance): OSBPL5, MSI2, KSR2, NME1, SLC35A4, TXN, LAG3, ZNHIT1, PDE8A, RGS10, TSPO, CRLF3, DCAF12, ADSL, AQP1, GRN, and TTC38.

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

But FCR has advantages over ibrutinib, including its brief treatment course (6 months) and lower costs. Downsides meanwhile 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 accompanying editorial.

He 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.”

For their study, Abruzzo’s group first examined 101 CLL patients with IGHV-unmutated (n=66) or IGHV-mutated disease (n=35) treated from 2000 to 2006 at MD Anderson Cancer Center in Houston. Compared with the IGHV-mutated patients, patients in the intermediate-risk (HR 4.64, 95% CI 1.06-20.18) and high-risk unmutated groups (HR 18.36, 95% CI 4.37-77.18) both naturally had shorter times to progression. When they applied their gene signature to the group with IGHV-mutated disease, they found that just 11% would be assigned to the unfavourable group.

For the validation set, they examined 109 IGHV-unmutated CLL patients from the German Chronic Lymphocytic Leukaemia Study Group CLL8 trial treated with FCR from 2003 to 2006.

Limitations included possible selection bias in the MD Anderson set (only 114 of 162 had high-quality RNA available for assessment), small patient samples, and differences in disease characteristics between the MD Anderson and CLL8 groups — the validation set had greater numbers of advanced patients and unfavorable cytogenetics, most notably.