Biomarkers Shift Treatment Paradigm in CLL

OncologyLive, Vol. 18/No. 12, Volume 18, Issue 12

With changing treatment paradigms, particularly the use of oral targeted agents, predictive value and use of prognostic factors to determine treatment choice are shifting in CLL.

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

Disease Characteristics Affecting Prognosis and Therapy

Table. Disease Characteristics and Prognostic Outcomes

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.2-5The 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

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

Del(11q) and Response to Ibrutinib

With the availability of targeted therapies, which also include idelalisib (Zydelig) and venetoclax (Venclexta) for the treatment of patients with relapsed/refractory CLL, the question how to optimally sequence agents has become highly pertinent. Findings of a retrospective study evaluating outcomes with targeted therapies suggest better outcomes with ibrutinib as the first kinase inhibitor compared with idelalisib, superior outcomes with an alternate kinase inhibitor or venetoclax than with chemoimmunotherapy combinations after kinase inhibitor failure, and possibly better outcomes with venetoclax after ibrutinib failure.13 Consequently, the authors emphasized the need for clinical trials testing sequencing strategies to optimize treatment algorithms.The del(11q22.3) cytogenetic abnormality, which is detected in up to 20% of patients with CLL at diagnosis and at a higher frequency in relapsed/ refractory CLL, has traditionally been considered an unfavorable cytogenetic alteration associated with extensive lymphadenopathy, disease progression, and shorter median survival (79 months).7 The presence of del(11q) predicts poor response to chlorambucil-, fludarabine-, or FCR (fludarabine, chlorambucil, rituximab [Rituxan])-based regimens, with shorter duration of remission and OS compared with other cytogenetic groups.7,14 Previous findings have shown that adding an alkylating agent such as cyclophosphamide to fludarabine-based chemoimmunotherapy can improve outcomes.1

A recent study has now investigated whether the presence or absence of del(11q) was associated with clinical outcomes following treatment with the BTK inhibitor ibrutinib in phase III studies. Lead investigator Thomas J. Kipps, MD, PhD, from the University of California Moores Cancer Center, and colleagues presented these findings at the 2016 American Society of Hematology Annual Meeting.3

The study was based on patient data from 3 phase III studies that had demonstrated superiority of single-agent ibrutinib to treatment with ofatumumab in relapsed/refractory CLL (RESONATE),3 to chlorambucil in treatment-naïve CLL (RESONATE-2),11 and of ibrutinib in combination with bendamustine and rituximab (BR) to treatment with BR in relapsed CLL (HELIOS).15

Analyses of pooled data of 1210 patients with available data on del(11q) revealed that the presence of del(11q) was not an adverse prognostic factor for PFS in patients who received ibrutinib-based treatment (n = 609 patients; 179 with del(11q), 430 without) but was in those who received the respective comparator treatment (n = 601; 149 with del(11q), 452 without).3

IGHV Mutational Status

The presence versus absence of del(11q) was associated with prolonged PFS (24-month, 82% vs 75%) and OS (30-month, 93% vs 86%) in ibrutinib-treated patients, but shorter PFS (9% vs 19%) in comparator-treated patients. Furthermore, treatment with ibrutinib was associated with superior clinical outcomes versus comparators regardless of del(11q) status.3Mutational status of the immunoglobulin heavy chain variable region gene (IGHV) in the CLL clone has been increasingly considered as a parameter when determining treatment choice, whereas del(11q) is no longer considered a marker with relevance for treatment selection in current guidelines by NCCN.1 CLL cells expressing unmutated IGHV originate from B cells that have not undergone somatic hypermutation, which has been associated with a more aggressive disease course and poor outcomes with standard chemotherapy-based regimens.16

Long-term follow-up from the CALGB 9712 study of first-line therapy with concurrent versus sequential fludarabine and rituximab found unmutated IGHV a significant independent predictor for shorter PFS and OS, and del(17p) or del(11q) independent predictors for shorter survival.5

Recently updated results from the phase III CLL8 study found TP53 mutation, del(17p) and unmutated IGHV the strongest predictors of shorter PFS and OS.5 Study findings further confirmed survival benefits of FCR versus FC in physically fit previously untreated patients with CLL <65 years (5-year OS, 80.9% vs 69.2%; P = .002).1 In patients with mutated IGHV, FCR was associated with improved survival in all cytogenetic groups except del(17p) compared with FC (median PFS not reached vs 41.9 months, P <.001; 5-year OS, 86.3% vs 79.8%).

In contrast, IGHV mutational status does not predict response to ibrutinib, according to an integrated analysis of data from the phase III RESONATE, RESONATE-2, and HELIOS studies presented at the 2017 American Association for Cancer Research Annual Meeting.17 According to Kipps et al, “IGHV-unmutated CLL was an adverse predictor of outcome for comparator-treated, but not for ibrutinib-treated patients.”17

The pooled analysis was comprised of data from 985 CLL/SLL participants in the 3 studies, including 494 patients who received ibrutinib (351 with IGHV-unmutated disease and 143 with mutated IGHV) and 491 patients who received the respective control treatment ofatumumab, chlorambucil, and/or BR (366 with IGHV-unmutated CLL and 125 with IGHV mutations). At a median follow-up of 21.4 months for patients receiving ibrutinib and 20.6 months for those on control treatment, PFS and OS were similar among ibrutinib-treated patients (P = .93 for ibrutinib vs control), regardless of IGHV mutation status (2-year OS, 88% vs 89% for IGHV-unmutated and mutated disease, respectively; P = .86).

Evolving Basis For Treatment Decisions In CLL

In patients receiving control treatments, IGHV-unmutated disease was associated with shorter survival than IGHV-mutation—harboring disease, also in multivariate analyses that adjusted for age, sex, baseline ECOG performance status, del(11q) and del(17p) status, prior lines of therapy, and other prognostic variables (2-year OS, 78% vs 87%; adjusted P = .01).17Treatment decisions in CLL are generally based on the distinct molecular profile of their disease and age as well as the fitness of the patient.1,6

However, current NCCN guideline recommendations for the group of patients with CLL who have del(17p)/TP53 mutations are universal and not stratified by patient age or condition.1 Recommended frontline therapy options in order of preference are ibrutinib, dose-dense high-dose methylprednisolone (HDMP) plus rituximab, obinutuzumab (Gazyva) plus chlorambucil (category 3), and the anti-CD52 antibody alemtuzumab (Lemtrada) alone or in combination with rituximab.

Ibrutinib also leads the list of preferred regimens for relapsed/refractory disease, followed by venetoclax with or without rituximab, idelalisib plus rituximab, single-agent idelalisib, and other rituximab and ofatumumab-based therapies. Suggested post—first- and second-line maintenance therapies include lenalidomide (Revlimid) in high-risk patients, and lenalidomide or ofatumumab, respectively.1

In patients with CLL without del(17p)/TP53 mutations, the most important features directing treatment choices are advanced age of >65 years, the presence of medical comorbidities, and the objectives of treatment.6

Preferred first-line therapies for frail patients are obinutuzumab plus chlorambucil, followed by ibrutinib (both category 1 recommendations), ofatumumab plus chlorambucil, rituximab plus chlorambucil, single-agent obinutuzumab, rituximab, and chlorambucil. The same treatment options are available for patients ≥65 years of age and younger patients with significant comorbidities, with the inclusion of bendamustine with rituximab following rituximab and chlorambucil in preference.1

For patients younger than 65 years without comorbidities, chemoimmunotherapy remains the standard frontline treatment, with FCR as category 1, FR, and PCR, and bendamustine plus rituximab, as well as ibrutinib (category 2A).1

For the treatment of relapsed/refractory CLL without del(17p)/TP53 mutations, ibrutinib is the preferred regimen in patients of all performance groups, followed by idelalisib plus rituximab, venetoclax with or without rituximab, chemoimmunotherapy regimens that are again guided by patient performance, and various CD20 monoclonal antibody-based regimens. Lenalidomide or ofatumumab can be considered for post—secondline maintenance therapy.1 With accumulation of data from clinical trials, these recommendations are likely going to evolve in the near future.


  1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2017. National Comprehensive Cancer Network website. Published February 21, 2017. Accessed May 15, 2017
  2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi: 10.1056/NEJMoa1400376.
  3. Kipps TJ, Hillmen P, Demirkan F, et al. 11q Deletion (del11q) is not a prognostic factor for adverse outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with ibrutinib: pooled data from 3 randomized phase 3 studies. Presented at: 58th ASH Annual Meeting and Exposition; December 2-6, 2016; San Diego, CA. Abstract 2042.
  4. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2):208-215. doi: 10.1182/blood-2015-06-651125.
  5. Woyach JA, Ruppert AS, Heerema NA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011; 29(10):1349-1355. doi: 10.1200/JCO.2010.31.1811.
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  11. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi: 10.1056/NEJMoa1509388.
  12. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176. doi: 10.1016/S1470-2045(14)71182-9. mm
  13. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056. doi: 10.1093/annonc/mdx031.
  14. Woyach JA, Byrd JC. Established prognostic markers in chronic lymphocytic leukemia and use in clinical practice. Am Soc Clin Oncol Educ Book. 2011;242-245.
  15. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
  16. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002;100(4):1177-1184.
  17. Kipps TJ, Fraser G, Coutre S, et al. Unmutated IGHV is not an adverse predictor of outcome to therapy with ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 2017 AACR Annual Meeting, March 1-5, 2017; Washington DC. Abstract CT158/24.!/4292/presentation/12565.