Biomarkers Shift Treatment Paradigm in CLL

Published: Wednesday, Jun 14, 2017
Based on improved insight into chronic lymphocytic leukemia (CLL) biology and pathophysiology, approaches to identify patients who are at higher risk for disease progression have been refined, as have strategies to select therapies that maximize treatment outcomes due to their selectivity for distinctive phenotypic or physiological features of the respective CLL cells.1

With changing treatment paradigms, particularly the use of oral targeted agents, predictive value and use of prognostic factors to determine treatment choice are shifting. Traditional risk factors, including disease stage and lymphocyte doubling time, are becoming less relevant for treatment selection, and the predictive value of cytogenetic and molecular markers on response to treatment with novel agents is being redefined based on the outcomes of recent trials.2-5

Disease Characteristics Affecting Prognosis and Therapy

The presence of a deletion of chromosome 17p [del(17p)] and mutated TP53 represent the most relevant disease characteristics that guide the choice of therapy in patients with CLL.6 Del(17p) causes the loss of 1 TP53 allele and is associated with mutations in the remaining TP53 allele in more than 80% of patients, resulting in loss or dysfunction of TP53. Both del(17p) and mutated TP53 are associated with poor response to chemotherapy-based regimens, short progression-free survival (PFS), and poor overall survival (OS), independently of IGHV mutation status (Table).1,7,8

Table. Disease Characteristics and Prognostic Outcomes


OS indicates overall survival; PFS, progression-free survival.

Recent trials have demonstrated activity of novel targeted agents in patients with del(17p)/TP53-mutant CLL, who are considered a distinct subgroup who require a specific therapeutic approach.1,9 This has significantly changed outcomes for this subgroup for whom previous options to increase the duration of response were largely limited to stem cell transplant in eligible patients.1

Ibrutinib (Imbruvica), a first-in-class oral covalent inhibitor of Bruton tyrosine kinase (BTK), blocks an essential component of the B-cell receptor cascade, inhibiting survival signaling between CLL cells and the tumor microenvironment. The agent was first approved by the FDA in 2014 for the treatment of patients with relapsed/refractory CLL, supported by outcomes of phase II and III studies demonstrating high response rates (71%),10 higher objective response rates (ORR; 43% vs 4%), and significantly improved PFS compared with treatment with ofatumumab (Arzerra; not reached vs 8.1 months at median follow-up of 9.4 months), and OS benefit [1-year OS, 90% vs 81%; HR for death, 0.43; P = .005].3 Importantly, the phase III RESONATE study showed that efficacy differences were retained in patients carrying del(17p) and in those resistant to purine analogues.2

The CLL indication of ibrutinib has recently been expanded to include frontline therapy, in part based on outcomes from the phase III RESONATE-2 study comparing ibrutinib with chlorambucil in 260 elderly treatment-naïve patients with CLL.11 Ibrutinib induced a significantly higher ORR (86% vs 35%), longer median PFS (not reached vs 18.9 months), and a longer OS (98% vs 85% at 2 years).11 This study specifically excluded patients with known del(17p) CLL; however, a recently published single-arm phase II study also demonstrated activity in previously untreated patients and in those with relapsed/refractory CLL with del(17p) or TP53-mutant disease, with an objective response rate of 97% among untreated patients and 80% among relapsed/refractory patients after a median follow-up of 2 years.12

Ibrutinib is considered the preferred first-line therapy for patients with del(17p)/TP53-mutant CLL, and is a category 1 recommendation for patients with CLL without del(17p)/TP53 mutation who are frail, or are ≥65 years of age, or younger with significant comorbidities, according to the National Comprehensive Cancer Network (NCCN) guidelines on CLL.1

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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 14th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 30, 20192.0
Oncology Consultations®: The Advancing Role of CAR T-Cell Therapies in Hematologic MalignanciesApr 30, 20191.5
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