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IGHV mutation without 11q, 17p deletions defines very low-risk CLL subgroup
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Patients with chronic lymphocytic leukemia who harbor IGHV mutations and lack 11q or 17p chromosome deletions may experience a durable remission following first-line treatment with fludarabine, cyclophosphamide and rituximab, according to results of a retrospective observational analysis.
Researchers have sought to identify a subgroup of patients most likely to benefit from fludarabine, cyclophosphamide and rituximab (Rituxan; Genentech, Biogen Idec), or FCR, the standard regimen for untreated patients with CLL who are young and in good physical condition.
“In the era of personalized medicine, challenges of CLL treatment will involve correctly matching therapy to the unique risk profile of each individual patient,” Davide Rossi, MD, PhD, assistant professor of hematology and consultant in the division of hematology in the department of clinical and experimental medicine at Amedeo Avogadro University of Eastern Piedmont in Novara, Italy, and colleagues wrote. “Our data support front-line FCR as a highly active option in physically fit patients with progressive CLL whose disease has a low-risk molecular profile.”
The researchers evaluated data from 404 patients with CLL who received FCR as first-line therapy between 2001 and 2010.
PFS — measured from the date of treatment initiation to the date of progression — served as the primary endpoint of the study. OS served as the secondary endpoint.
Data on three biomarkers — IGHV mutations status and 11q and 17p chromosome deletions — were available from 80% of the cohort. Twenty-eight percent of patients harbored IGHV mutations but lacked 11q and 17p deletions and were considered very low risk.
Seventy-one percent of very low-risk patients remained progression free following treatment. Researchers noted risk for relapse in this subgroup continued to decrease 4 years following FCR.
The 5-year life expectancy for this subgroup was 91%, which researchers noted was similar to the matched general population, an indication that neither the disease nor treatment-related complications affected survival in this group.
“To responsibly and effectively advance the development of these new therapies, novel drugs should be targeted specifically to patient subgroups in which they can provide the greatest benefit compared to established chemoimmunotherapy,” Rossi and colleagues wrote. “Given the highly favorable outcome of IGHV-mutated CLL lacking 17p and 11q deletion hereby reported following frontline FCR treatment, assessment of whether novel agents provides additional benefit in this biologic subgroup will require highly-powered studies with long follow-up and should include quality of life and long-term toxicities among endpoints.” – by Anthony SanFilippo
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Kanti R. Rai, MD
Fludarabine plus cyclophosphamide plus rituximab [Rituxan; Genentech, Biogen Idec (FCR)] and bendamustine (Treanda, Teva) plus rituximab (BR) regimens have been the most frequently used for front-line treatment of chronic lymphocytic leukemia. More recently, obinutuzumab (Gazyva, Genentech) plus chlorambucil (Leukeran, GlaxoSmithKline) has been added to these choices. However, clinicians did not have much help in knowing for whom each regimen would offer the greatest benefit and, therefore, much guesswork and anecdotal experience was used.
Rossi and colleagues performed a meticulous and thorough retrospective analysis of results on a large number of patients with previously untreated CLL and were able to clearly identify a rather large subgroup (28% of all patients) who benefited the most from the FCR regimen.
The criteria to define this special subgroup need just three tests, all of which are readily available and are currently being done on virtually all CLL patients — mutated IGHV, no chromosome 11q deletion, and no deletion 17p. Patients who fulfill all the above criteria have excellent course, and prolonged duration of remission.
There are two obvious and very positive consequences of this laudable study. First, if these results are confirmed by prospectively performed studies, there will no longer be any guesswork, and a very low-risk group of CLL patients will be readily identified and offered the right — and effective — therapy. Second, investigators can now start to test newer therapies for all those (72%) patients for whom better therapies than FCR are urgently necessary. Perhaps clinical trials using the newly developed inhibitors of B-cell receptor (BCR) signaling, such as ibrutinib (Imbruvica; Pharmacyclics, Janssen) and idelalisib (Zydelig, Gilead) can now be undertaken in front-line patients who do not fulfill the criteria for “very low-risk” CLL.
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