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Factors Affecting Prognosis and Treatment in CLL

Published Online: Jun 09,2017
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 rede ned based on the outcomes of recent trials.2–5
In 2008, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) published revised guidelines for the diagnosis and treatment of CLL.6 These revised guidelines acted as an update to the National Cancer Institute sponsored Working Group's (NCI-WG) 1996 guidelines,7 which sought to create recommendations for the design and conduct of clinical trials for patients with CLL. The iwCLL updates these guidelines following significant progress in determining prognostic markers, diagnostic parameters, treatment options, and more for the diagnosis and response to treatment for patients with CLL.
When assessing the level of response to treatment in patients with CLL, a physical exam is required, along with evaluation of the blood and marrow. Unlike response assessment in solid tumors, imaging studies, particularly CT scans, are not usually necessary.
The characterization of a complete remission (CR) as defined by the iwCLL requires the absence of clonal lymphocytes in the peripheral blood, no hepatomegaly or splenomegaly, and the absence of constitutional symptoms, all within 3 months of the completion of therapy.6 Additionally, polymorphonuclear leukocyte levels should be above 1500/μL, platelets above 100,000/μL, and hemoglobin above 11 g/dL untransfused (TABLE 12). Previously, a CR according to the NCI-WG still had detectable minimal residual disease (MRD). A partial remission (PR) depends upon at least 1 parameter relating to the tumor load and another relating to the function of the hematopoietic system or marrow improving, with 1 of these factors lasting for at least 2 months. Progressive disease (PD) is also determined by a change in the tumor load and/or a decrease in platelet or hemoglobin levels. Additionally, the guidelines define a CR in the absence of MRD as the complete eradication of the leukemia, where blood or marrow expresses less than 1 CLL cell per every 10,000 leukocytes.

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.8 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 2).1,9,10 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.1,11 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’s 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 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%),12 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) (TABLE 33). 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.13 Ibrutinib induced a signi cantly higher ORR (86% vs 35%), longer median PFS (not reached vs 18.9 months), and a longer OS (98% vs 85% at 2 years) (TABLE 413).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.14
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, or younger with significant comorbidities, according to the National Comprehensive Cancer Network (NCCN) guidelines on CLL.1
As Steven E. Coutre, MD, a hematologist with Stanford University and co-investigator of the RESONATE-2 trial, explained in an interview with the American Journal of Managed Care®, “We had patients between the ages of 65 and 70, and then we had those 70 years and older. Again, those patients 70 years and older would be an average CLL patient who’s starting therapy. And we saw benefit in both groups. There really was no distinction. It also speaks to the fact that it’s well tolerated. So, often patients who are older, of course, have more comorbidities—diabetes, hypertension, the usual things that we see. And that didn’t impact either the ef cacy or the tolerability of the treatment.”15
The long-term outcomes with first-line ibrutinib remain to be determined. Coutre added, “The real value is going to be to see how those patients do as they continue on ibrutinib.... In the RESONATE-2 trial, there are only 3 patients who came off ibrutinib because of progressive disease. And, although follow-up of them is still short—measured in months, not years—none of those patients have gone on to subsequent treatment yet.



We have a limited experience from our very first trial. I have a few patients on that trial who have been receiving ibrutinib for more than 6 years now.”16
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.17 Consequently, the authors emphasized the need for trials testing sequencing strategies to optimize treatment algorithms.

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Factors Affecting Prognosis and Treatment in CLL
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