ONCAlert | 2018 Gastrointestinal Cancers Symposium

Current Treatment Strategies in CLL

Published Online: Jun 08,2017
The clinical course of chronic lymphocytic leukemia (CLL) is highly variable, and a subset of patients may never need clinical intervention. However, most patients will eventually require treatment during their disease. Indications for treatment are advanced clinical stage, significant disease-related symptoms (severe fatigue, night sweats, and fever without infection), progressive bulky disease, threatened end-organ function, progressive anemia, progressive thrombocytopenia, and transformation to diffuse large B-cell/Hodgkin lymphoma (Richter transformation). The goals of treatment for the patient are the induction of remission and pro- longing life while minimizing treatment-related adverse effects.1 Except for allogeneic hematopoietic stem cell transplantation (HSCT), none of the current therapies are considered curative, but a subset of patients experience long-term remissions.2
Treatment options for the management of patients with CLL have evolved significantly in the past decades. The historical stan- dard of initial chemotherapy with chlorambucil has been largely replaced with more effective chemoimmunotherapy regimens incorporating monoclonal antibodies (mAbs) targeting CD20 (rituximab [Rituxan], obinutuzumab [Gazyva], and ofatumumab [Arzerra]), and targeted therapy with the small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), ibrutinib (Imbruvica).1 Current standards of care for patients with relapsed or refractory CLL are ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib (Zydelig) alone or with rituximab, and the B cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta) alone or with rituximab.1 The availability of these agents has substantially changed outcomes for patients with relapsed CLL and adverse risk features, who had survival expectancies of less than 1 year in the past, but can now achieve progression-free survival (PFS) in the range of 24 months or longer.3–5 Recent trial outcomes have shown the superiority of ibrutinib over chlorambucil as a front-line treatment in older patients.6 Yet, novel kinase inhibitors are also becoming increasingly available in the frontline setting.

Findings from a phase II study in 300 patients,7 followed by outcomes of the randomized German CLL study group CLL8,8 have established chemoimmunotherapy with udarabine, cyclophosphamide (FC), and rituximab (FCR) as the standard-of-care front- line therapy for patients under 65 years of age with CLL without a 17p deletion (del[17p]) or a TP53 mutation.2
The landmark phase III CLL8 trial involving 817 physically fit previously untreated CLL patients demonstrated that the addition of rituximab to FC (6 courses of treatment) improved the overall response rate (ORR; 90% vs 80%, respectively) (TABLE 18), complete response (CR) rate (44% vs 22%; P <.0001), 3-year PFS (65% vs 45%; HR, 0.56; 95% CI, 0.46-0.69; P <.0001), and overall survival (OS; 87% vs 83%; P = .01).8
Recently updated results show long-term remissions in patients treated with FCR, with a 5-year OS of 80.9% in patients less than 65 years of age versus 69.2% in patients treated with FC (HR, 0.63; 95% CI, 0.47-0.84; P = .002). The overall median PFS was 56.8 months with FCR versus 32.9 months for FC (HR, 0.59; 95% CI, 0.50-0.69; P <.001); the median OS was not reached for FCR and was 86.0 months for FC (HR, 0.68; 95% CI, 0.54-0.89; P = .001).9 Long-term remissions were also shown in the phase II study, which reported an ORR of 95% (72% CR) at a median follow-up of 12.8 years, a median PFS of 6.4 years, and an overall 12.8-year PFS rate of 30.9% (53.9% and 8.7% for patients with mutated and unmutated IGHV, respectively).2
Furthermore, 50.7% of patients with mutated IGHV had minimal residual disease (MRD) negativity after treatment, and a subset of 42 patients with mutated IGHV had no relapse after 10 years.2 In an accompanying editorial, Farrukh Awan, MBBS, the assistant professor of internal medicine, The Ohio State University Wexner Medical Center, commented: “This represents the first time in the history of CLL that a nontransplant therapeutic option has resulted in sustained disease-free intervals and raises the possibility of a cure for a subset of patients with generally good-risk disease and excellent response to therapy.”10
Benefits of FCR come at the cost of higher toxicity, with 76% of patients treated with FCR experiencing a grade 3/4 adverse event (AE) compared with 63% among those treated with FC, particularly notable is grade 3/4 neutropenia in 34% of patients and a significant increase in infectious complications with FCR.8 Prophylactic measures include supplementation with myeloid growth factors and antimicrobial therapy.11 Treatment with FCR has also been associated with a 6% to 10% incidence of secondary hematologic malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).10
A combination regimen of the alkylating agent bendamustine (Treanda) and rituximab (BR) is an alternative, less myelotoxic frontline treatment option in fit patients with CLL without del(17p) or a TP53 mutation. The CLL10 trial compared FCR with BR in this patient population, and found similar ORR and OS rates (TABLE 212). In patients treated with FCR compared with those treated with BR, the ORR was 95% versus 96%, respectively and the 3-year OS rate was 91% versus 92%. However, FCR produced a higher CR rate (40% vs 31%; P = .034), more MRD negativity (59% vs 26% at 12 months; P <.0001; 55% vs 27% at 18 months; P = .002), and longer median PFS (55.2 months vs 41.7 months; P = .0003). The 3-year PFS favored FCR over BR in patients 65 years or younger (53.6 vs 38.5 months); however, for patients over the age of 65, the outcome was similar for both regimens with less toxicity for BR. More patients experienced a grade 4/5 AE with FCR, most of which were hematologic, including neutropenia, leukocytopenia, and thrombocytopenia; grade 3/4 neutropenia was also common in the BR arm.12 An update analysis with a median follow-up of 58.2 months reported a decreased risk of secondary AML or MDS following BR treatment (0.7%) versus FCR (4.3%).13
FCR is also considered suitable for the treatment of patients with relapsed/refractory CLL without high-risk features based on phase II and III study outcomes showing high response rates.1

Ibrutinib, an oral small-molecule irreversible inhibitor of BTK, which is central to the B-cell antigen receptor (BCR) survival pathway, was first approved for the treatment of patients with CLL who had received at least 1 previous therapy, and became available as a frontline therapy in 2016 for patients both with and without del(17p).
The approval of single-agent ibrutinib for the treatment of patients with relapsed and refractory CLL was based on data from the phase III randomized RESONATE study demonstrating ORR, PFS, and OS benefits with ibrutinib, including a 57% reduction in risk of death, compared with the anti-CD20 mAb ofatumumab in patients with advanced and high-risk disease, including del(17p) CLL.14 Updated results at 16 months’ follow-up reported significantly better ORR with ibrutinib compared with ofatumumab (90% vs 25%, respectively; P <.0001), as well as median PFS (not reached vs 8.1 months; HR, 0.106; 95% CI, 0.073-0.153; P <.0001) and OS rates (18-month, 85% vs 78%).15
The frontline indication of ibrutinib is supported by outcomes of the randomized phase III RESONATE-2 study in 269 patients aged 65 years or higher with untreated CLL without del(17p) demonstrating a significantly higher ORR (86% vs 35%; P <.001) and PFS (90% vs 52% by independent review committee; P <.0001) with ibrutinib compared with those treated with chlorambucil at 18 months’ median follow-up.6 By investigator review, patients treated with ibrutinib showed an 89% PFS rate at 18 months in both the subgroup with mutated IGHV and in those without an IGHV mutation. A recent update at a median follow-up of 28.6 months reported that PFS benefits were sustained across high-risk groups, including those with del(11q) and in those with unmutated IGHV, with an overall 88% reduction in risk for progression or death with ibrutinib versus chlorambucil.16 At 24 months, the overall PFS rate was 89% with ibrutinib compared with 34% with chlorambucil (HR, 0.121; 95% CI, 0.074-0.198; P <.0001), and estimated OS rates in the intent-to-treat population were 95% and 84%, respectively, despite high crossover rates to ibrutinib (41%).
According to Steven E. Coutre, MD, professor of medicine (hematology) at Stanford University Medical Center, and co-investigator of the RESONATE-2 study, “We’re fortunate that we have a body of experience now from our trials, where we’ve used ibrutinib in a variety of clinical settings for CLL; heavily pretreated, refractory patients. We have trials in the upfront setting...and what we’ve learned is that you see efficacy across a broad range of patients. In fact, I can’t think of a subgroup who doesn’t benefit from treatment.”17
Ibrutinib was generally well tolerated in clinical trials; AEs included cytopenias, pneumonia, rash, diarrhea, fatigue, and nausea, and notable AEs were bleeding (4%), hypertension (all-grade, 14%; grade 3, 4%), and atrial brillation (6%).6 In the RESONATE-2 trial, 9% of patients discontinued treatment due to AEs compared with 23% in the chlorambucil arm.
Treatment with ibrutinib results in rapid reduction of lymphadenopathy associated with a concomitant transient increase in absolute lymphocyte count; this lymphocytosis does not signify disease progression and subsides with continued therapy.1,11 In addition, an incomplete resolution of lymphocytosis does not seem to affect PFS rates.18 According to Coutre, “It’s well tolerable across many different types of patients; patients who are fit, patients who are unfit. We have a fair amount of long-term follow-up now to understand the safety profile.”17

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Current Treatment Strategies in CLL
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