Current and Emerging Treatment Options in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a malignant disease characterized by progressive accumulation of immature, immunophenotypically distinct (CD5- and CD23-positive) lymphocytes in the blood, bone marrow, and lymphatic tissues.¹Although the clinical course of CLL can be unpredictable, this disease is typically slow-progressing and occurs most often in patients ≥65 years of age.¹As such, treatment, if indicated, is typically conservative.¹Current CLL treatments are not considered to be curative; however, long-term remission can be achieved in some patients using allogenic stem cell transplantation.¹This article focuses on the shifting treatment options observed in recent years, both in first-line and subsequent settings, and the emerging treatment strategies that are likely to continue to shape the therapeutic landscape for patients with CLL.

TREATMENT VARIABLES

Given the highly variable clinical presentation and progression of CLL, not all patients require treatment at the time of diagnosis. In fact, most patients undergo active surveillance for many years before treatment.²However, treatment is indicated for CLL that is classified as being at an advanced clinical stage; as progressive bulky disease; or has transformed to B-cell/Hodgkin lymphoma (ie, Richter syndrome).³In addition, patients with CLL are indicated for treatment if they have significant disease-related symptoms (ie, severe fatigue, night sweats, weight loss, fever without infection [B-type symptoms]), threatened end-organ function, progressive anemia, and progressive thrombocytopenia.³

Treatment selection for CLL is based on distinct molecular profiles of the disease and takes into consideration the patient’s age and fitness level (TABLE 1).⁴Genetic aberrations that currently guide treatment decisions include p17 deletion (del[17p]) andTP53mutations, as well as immunoglobulin heavy-chain variable region gene (IGHV) mutational status.^3,4In CLL, del(17p) andTP53mutations are associated with poor responses to chemotherapy-based regimens and are predictors of poor patient outcomes including shorter median progression-free survival (PFS) and median overall survival (OS).^5,6Accordingly, this subgroup of patients with CLL requires specific therapeutic approaches.³IGHVmutational status has been demonstrated as a prognostic factor in CLL, as unmutatedIGHVis associated with poorer responses to chemotherapy and shorter median PFS compared with mutatedIGHV.^3,6For example, recent data demonstrate long-term disease-free-survival in patients withIGHV-mutated CLL who received fludarabine, cyclophosphamide, and rituximab (FCR),⁷suggestingIGHVmutational status can be used as a biomarker of response, and these patients can potentially be cured when using FCR in the frontline setting. Although not incorporated into the guidelines to direct treatment decisions, the National Comprehensive Cancer Network recommends IGHV mutation testing based on reproducibility and availability.³However, leading oncology treatment centers, including The University of Texas MD Anderson Cancer Center and Mayo Clinic, currently stratify patients according toIGHVmutational status to guide treatment decisions.^2,4

Recent years have seen significant changes to the therapeutic landscape for CLL treatment. The historical standard first-line therapy of chlorambucil was replaced with more effective treatment regimens including chemoimmunotherapy, combining standard chemotherapy and immunotherapy with monoclonal antibodies targeting CD20 (eg, rituximab, obinutuzumab, and ofataumumab) and targeted therapy for Bruton tyrosine kinase (BTK) with the oral small-molecule inhibitor ibrutinib.³Similarly, in patients with relapsed or refractory (R/R) CLL, small-molecule inhibitors including ibrutinib, idelalisib (a PI3K inhibitor), and venetoclax (a B-cell lymphoma 2 inhibitor) have become standards of care.³These treatments are not likely to be the last in the shifting paradigm of CLL treatment; current ongoing and planned studies in both treatment-naïve and treatment-experienced patients with CLL will no doubt bring further changes to the first-line, second-line, and subsequent treatment settings for this disease.

FIRST-LINE TREATMENT OPTIONS IN CLL

Combined Chemotherapy and Immunotherapy With Anti-CD20 Monoclonal Antibodies

The chemoimmunotherapy regimen FCR is the standard of care for patients with CLL without del(17p) orTP53mutation who are under the age of 65, according to a guideline based on the groundbreaking phase III trial CLL8 (the German CLL Study Group) that evaluated 817 physically fit, previously untreated patients with CLL.^3,6The addition of rituximab to fludarabine and cyclophosphamide over 6 courses of treatment significantly improved the objective response rate ([ORR], 90% vs 80%;P<.0001) and complete response rate (44% vs 22%;P<.0001) in these patients.⁶Additionally, at 3 years, median PFS (65% vs 45%; HR, 0.56; 95% CI, 0.46-0.69;P<.001) and OS (87% vs 83%; HR, 0.76; 95% CI, 0.49-0.92;P= .012) were also significantly improved.⁶The survival benefits of FCR versus fludarabine and cyclophosphamide in this patient population was further confirmed in updated study results demonstrating a 5-year OS of 80.9% versus 69.2%, respectively (HR, 0.63; 95% CI, 0.47-0.84;P= .02).⁸In this study, the strongest predictors of shorter median PFS and shorter median OS wereTP53mutation, del(17p), and unmutatedIGHV.^8,9Additionally, patients with mutated IGHV achieved a significantly longer median PFS with FCR compared with fludarabine and cyclophosphamide (PFS, median not reached [NR] vs 41.9 months; HR, 0.47; 95% CI, 0.33-0.68;P<.001).⁸As such, this study clearly validated the benefit of anti-CD20 monoclonal antibody use in combination with chemotherapy for the treatment of patients with CLL and specific mutations (without del[17p]/TP53).¹⁰

Bendamustine plus rituximab (BR) is another preferred first-line regimen for the treatment of patients under the age of 65 with CLL lacking del(17p) orTP53mutations.³This patient population was examined in CLL10, a phase III, international, open-label randomized trial that compared BR treatment with FCR.¹¹In this study, similar ORR (95% vs 96%) and OS rates (3 years, 91% vs 92%; HR, 1.034; 95% CI, 0.620-1.724) were observed between treatment groups.¹¹The primary endpoint was PFS to demonstrate noninferiority of BR to FCR.¹¹The median PFS was significantly shorter for BR versus FCR (41.7 vs 55.2 months; HR, 1.634; 90.4% CI, 1.308-2.064;P= .0003) (Table 1).¹¹BR treatment resulted in fewer complete responses (CRs), although the difference was not statistically significant (31% vs 40%), and more patients treated with BR had minimal residual disease. In elderly patients (>65 years), median PFS was similar between treatment groups (BR, 48.5 months; FCR, median NR); however, FCR produced more incidences of neutropenia, leukocytopenia, infections, and secondary neoplasms than did BR in this patient population (&ge;65 years).¹¹

Other anti-CD20 monoclonal antibodies indicated for the treatment of CLL in the frontline setting are obinutuzumab and ofatumumab; both are recommended as first-line therapy in combination with chlorambucil in elderly patients and those with significant comorbidities who do not have del(17p) orTP53mutations.3In the CLL11 study, obinutuzumab plus chlorambucil showed significant improvement in ORR and PFS over chlorambucil alone and over rituximab plus chlorambucil. Median PFS was 26.7, 11.1, and 16.3 months for the obinutuzumab plus chlorambucil, chlorambucil alone, and the rituximab plus chlorambucil groups, respectively (P <.001),12 while ORRs were 77.3%, 31.4%, and 65.7%, respectively (P<.001).12On the basis of this study, obinutuzumab plus chlorambucil is considered the standard of care for elderly patients and for those with significant comorbidities.³

Ofatumumab, originally approved for fludarabine- and alemtuzumab-refractory CLL, recently received frontline indication in CLL based on the findings of the COMPLEMENT study, an open-label, phase III study in treatment-na&iuml;ve patients (n = 447) who were not eligible for fludarabine-based therapy due to age or comorbidities.¹³The results of this study demonstrated that ofatumumab plus chlorambucil compared with chlorambucil alone significantly improved ORR (82% vs 69%; odds ratio [OR], 2.16; 95% CI, 1.36-3.42;P= .001) and median PFS (22.4 vs 13.1 months; HR, 0.57; 95% CI, 0.45-0.72;P<.0001).¹³

Inhibition of BTK With Small Molecules

Interest in targeting BTK, a key player in the B-cell antigen receptor survival pathway, resulted in the approval of ibrutinib for the treatment of R/R patients with CLL. In 2014, ibrutinib also became available as first-line therapy for both del(17p) and non-del(17p) CLL.¹⁴Currently, ibrutinib is the only small-molecule targeted therapy that is approved by the FDA for first-line treatment of CLL.³

The phase III RESONATE study demonstrated significant ORR, PFS, and OS benefits with ibrutinib compared with ofatumumab in previously treated patients with advanced or high-risk CLL, both with and without del(17p); a 57% reduction in risk of death was observed.¹⁵Significant improvements in hematologic function (improved platelet and neutrophil counts, improved hemoglobin levels) were observed in patients with cytopenia treated with ibrutinib compared with ofatumumab (79% vs 43%;P<.0001).¹⁶Additionally, ibrutinib treatment resulted in clinically meaningful improvements in patient-reported outcomes measured by the Functional Assessment of Chronic Illness Therapy-Fatigue measurement system.¹⁶

The RESONATE-2 study supported the use of ibrutinib in the frontline setting for CLL, demonstrating improved ORR and median PFS compared with chlorambucil in treatment-na&iuml;ve, elderly (&ge;65 years) patients without del(17p).¹⁷Although this open-label, phase III trial excluded patients with known del(17p) CLL,¹⁷1 study demonstrated ibrutinib efficacy in patients with del(17p) and TP53 mutations including both previously untreated patients and those with R/R CLL; ORRs of 97% and 80% were observed with ibrutinib treatment for treatment-na&iuml;ve patients and those with R/R CLL, respectively, after a median 2-year follow-up for all patients.18 Of note, an integrated analysis of the results from multiple phase III studies in CLL (RESONATE, RESONATE-2, and HELIOS) showed that IGHV mutational status does not predict response to ibrutinib.¹⁹TABLE 2 lists clinical trial outcomes for first-line agents for the treatment of CLL.^{6,11-13,15,17}

More recently, follow-up data from studies assessing ibrutinib in treatment-na&iuml;ve and those with R/R CLL (PCYC-1102 and -1103 studies) demonstrated sustained efficacy of single-agent ibrutinib at 5 years; the ORR in treatment-na&iuml;ve and treatment-experienced patients was 87% and 89%, respectively, with CR rates improving over time.20 Increased tolerability was also observed with long-term use, as treatment-limiting adverse events (AEs) decreased from years 1 to 5.²⁰

Based on these data, ibrutinib is recommended as first-line therapy for patients with CLL without del(17p) or TP53 mutations who are either frail, elderly (&ge;65 years), or who are younger (<65 years) but with significant comorbidities, and for patients with CLL with del(17p) or TP53 mutations.³

Both chemoimmunotherapy and ibrutinib treatment are preferred regimens used in the frontline setting for CLL without del(17p) or TP53 mutations.³A recent cross-trial comparison of multiple phase III CLL studies (ie, CLL8, CLL10, CLL11, COMPLEMENT, RESONATE-2) directly compared the outcomes of ibrutinib and several chemoimmunotherapy regimens.²¹Results demonstrated that ibrutinib resulted in longer PFS than chemoimmunotherapy regimens among the entire sample population and in high-risk patients (ie, those with advanced and bulky disease, unmutated IGHV, del[11q]).²¹The OS achieved by ibrutinib was longer than chemoimmunotherapy in older, less-fit subgroups (eg, patients with presence of comorbidities, poor Eastern Cooperative Oncology Group [ECOG] performance status, or high Cumulative Illness Rating Scale [CIRS] scores), but similar to the OS achieved by chemoimmunotherapies FCR and BR in younger, more fit patient populations (eg, those with less comorbidities, good ECOG performance status, and low CIRS scores).²¹In addition, the overall safety profile of ibrutinib was more favorable than that of chemoimmunotherapy regimens, with reduced frequency of grade 3 AEs including infections and neutropenia.²¹The results of this study suggest that the benefits of ibrutinib use outweigh its risks, and ibrutinib use in the frontline setting may spare some patients toxic chemotherapy while providing improved responses.²¹Further, a recent pilot study in CLL demonstrated that BTK inhibition was effectively maintained over 3 cycles of ibrutinib therapy even when dosage reductions were employed after the first 28-day cycle of therapy (from 420 mg/day to 140 mg/day), potentially decreasing patient costs and unwanted AEs.²²

TREATMENTS FOR R/R CLL

In addition to inhibition of BTK with ibrutinib, other preferred regimens for the treatment of patients with R/R CLL are idelasib or venetoclax in combinations with rituximab.3 The availability of these agents has significantly improved the outcome of patients with R/R CLL, including those with high-risk features (del[17]p), TP53 mutations, unmutated IHGV), extending the PFS and OS of these patients and improving their response rates.

Idelalisib Plus Rituximab

Idelalisib is an oral PI3K-delta inhibitor. PI3K plays a key role in the B-cell antigen receptor survival pathway. As such, its inhibition leads to increased apoptosis.²³Approval was based on results from a phase III trial demonstrating that idelalisib plus rituximab compared with rituximab alone resulted in significantly longer median PFS (NR vs 5.5 months; HR, 0.15; 95% CI, 0.08-0.28;P<.001) and median OS (92% vs 80% at 12 months; HR, 0.28; 95% CI, 0.09-0.86;P= .02) and improved ORR (77% vs 15%; OR, 19.6; 95% CI, 9.6-39.9) in patients with R/R CLL.^24,25

Venetoclax Plus Rituximab

Venetoclax is a B-cell lymphoma 2 inhibitor that was shown to promote apoptosis in CLL cells.²⁶An ORR of 79.4% was observed in a phase II study of single-agent venetoclax in patients with R/R CLL with del(17p).²⁷Additionally, the median PFS and OS were estimated to be 72% and 86.7%, respectively, at 12 months with single-agent venetoclax treatment.²⁷

Recent study results from the phase III MURANO study in patients with R/R CLL demonstrated significantly better outcomes with venetoclax plus rituximab than with BR. After nearly 2 years, estimated PFS rate for the venetoclax plus rituximab group was 84.9%, compared with 36.3% of the BR group (HR, 0.17; 95% CI, 0.11-0.25;P<.0001).²⁸On the basis of these data, venetoclax received FDA approval in June 2018 for the treatment of patients with CLL with or without del(17p) who had undergone at least 1 previous therapy.²⁹

MAINTENANCE THERAPY

Treatment with lenalidomide can be considered for maintenance therapy for patients with high-risk CLL after first-line therapy or for patients who responded (CR or partial response [PR]) after therapy for R/R disease.3 The latter is supported by data from the CONTINUUM trial, which demonstrated a longer median PFS with lenalidomide than placebo (33.9 vs 9.2 months; HR, 0.40; 95% CI, 0.29-0.55;P<.001), although no differences in median OS were observed (HR, 0.96; 95% CI, 0.63-1.48; P = .86).³⁰

Similarly, ofatumumab is a recommended maintenance therapy for patients with CLL who responded (CR or PR) after treatment for R/R disease.³PROLONG, a phase III, open-label, randomized trial, investigated ofatumumab versus observation and demonstrated an improved median PFS (29.4 vs 15.2 months; HR, 0.50; 95% CI, 0.38-0.66;P<.0001) in patients with CLL who were in remission after second-line therapy.³¹

EMERGING TREATMENT STRATEGIES: ONGOING COMBINATION TRIALS

Despite recent progress to improve outcomes for patients with CLL, including the recent changes in the therapeutic landscape to first-line and subsequent use of new chemoimmunotherapy and targeted therapies, other treatment strategies are still needed for some patients who do not respond.²In addition, the advent of new biologic therapies brings with it new challenges, such as agent-specific toxicities, that need to be managed. As such, new treatment strategies are emerging and include novel treatment schedules and fresh combinations of small-molecule inhibitors, chemotherapy, and immunomodulatory agents (TABLE 3).^32-34

CAPTIVATE: Ibrutinib Lead-In Followed by Ibrutinib Plus Venetoclax

The combination of ibrutinib plus venetoclax is supported by early studies that demonstrated increased antitumor activity when used sequentially; to this end, BTK inhibition with ibrutinib has been shown to enhance CLL cell killing with venetoclax.³⁵This concept is currently being tested in the ongoing phase II CAPTIVATE study in treatment-na&iuml;ve patients with CLL; in this trial, patients receive ibrutinib monotherapy for 3 cycles followed by ibrutinib plus venetoclax for at least 12 cycles. Early data suggest this treatment regimen is safe and effective, with no dose-limiting toxicities or occurrence of clinical tumor lysis syndrome and an ORR of 100% (CR and PR; 14 patients).^32,33

GA-101: Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab

An ongoing phase II study (GA-101) is investigating the combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab as first-line treatment for CLL with mutated IGHV without del(17p).³⁴The estimated completion date for this study is March 2022.

CONCLUSIONS

As published findings continue to demonstrate the benefit, safety, and tolerability of BTK inhibitors, both as monotherapies and in combination with other agents, the therapeutic outlook for CLL is potentially promising.

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