Will combination therapy with targeted drugs be better for achieving remission in chronic lymphocytic leukemia?

KEYWORDS:

• Chronic lymphocytic leukemia
• B-cell receptor
• ibrutinib
• idelalisib
• PI3Kδ inhibitor
• venetoclax
• combined treatment

1. Introduction

Chronic lymphocytic leukemia (CLL) is one of the most common types of adult leukemia with an annual incidence of five cases per 100,000 people in the United States and approximately 20,000 new cases diagnosed each year [1]. Currently, immunochemotherapy is the standard of care for treatment-naive patients, as it prolongs progression-free survival (PFS) and overall survival (OS) [2]. The achievement of deep remission with minimal residual disease (MRD)-negativity after immunochemotherapy correlates with better PFS and OS [3]. In recent years, B-cell receptor (BCR) signaling inhibitors, such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib, and the BCL-2 antagonist venetoclax, have emerged for CLL patients [4]. In addition, the novel nti-CD20 monoclonal antibodies (mAbs) ofatumumab and obinutuzumab have been approved for the treatment of CLL. New targeted drugs have significantly improved the prognosis of CLL patients, particularly those with high-risk disease including (del(17p)/TP53 mutated), elderly/unfit patients, and those refractory for previous therapies.

2. BCR signaling inhibitors

Ibrutinib and idelalisib have demonstrated impressive clinical activity in CLL but do not induce deep response and are not able to cure patients themselves [5,6]. In the clinical trials, both drugs have been combined with mAbs and chemotherapeutic agents with the primary aim of increasing activity and decreasing lymphocytosis [6–7]. However, it is not clear whether these combinations are more effective than ibrutinib or idelalisib used as a single drug. The clinical results suggest that in high-risk CLL patients, the combination of ibrutinib with rituximab or ofatumumab has an additive effect over the use of ibrutinib alone. However, there is a need for clinical trials directly comparing novel agents and their combinations in CLL. A randomized trial comparing the combination of rituximab and ibrutinib with rituximab monotherapy in patients with relapsed CLL is ongoing (NCT02007044).

In studies of patients treated with ibrutinib monotherapy, the complete response (CR) rate was found to be low and assessments of MRD status were not routinely performed. However, the addition of an anti-CD20 mAb or immunochemotherapy to ibrutinib may increase the CR rate and MRD-negativity. Recently, ibrutinib was combined with fludarabine, cyclophosphamide, and rituximab (FCR) in front-line therapy for 26 patients with available bone marrow MRD data, 23 (89%) of whom had bone marrow MRD-negativity [8]. The combination of ibrutinib with bendamustine and rituximab (BR) was investigated in a large randomized, placebo-controlled study in previously treated CLL patients with no 17p(del) (HELIOS study) [9]. The combination of ibrutinib with bendamustin and rituximab (BR) was found to be a more effective treatment for relapsed CLL patients with high-risk disease than BR alone. The overall response (OR) rate was higher for the ibrutinib + BR arm (82.7%) than the BR-alone arm (67.8%) (p < 0.0001), with respective CR rates of 10.4% and 2.8%. Importantly, MRD-negativity was also higher in the ibrutinib + BR group than in the BR group. In the BR plus ibrutinib arm, 13% of patients achieved MRD-negative status, compared with 5% in the BR arm. In addition, two-year PFS was higher in patients achieving <0.01% MRD (91.5%) than in those with >0.01% MRD (75%) [10]. These results suggest that the addition of ibrutinib to BR immunochemotherapy is associated with significant improvements in outcome in comparison with standard immunochemotherapy. In addition, the combination of ibrutinib with mAbs and/or cytotoxic drugs can reduce the lymphocytosis commonly seen in the early phase of treatment with ibrutinib alone. However, recent observations indicate that no clinical adverse events were attributed to lymphocytosis, and prolonged lymphocytosis during ibrutinib therapy is not related to poor outcome or relapse [11,12]. The efficacy of BR versus ibrutinib + rituximab, versus ibrutinib alone in previously untreated CLL is the subject of another clinical trial (NCT01886872).

Idelalisib is an orally bioavailable, elective competitive inhibitor of PI3K-δ. Combined idelalisib and rituximab treatment was approved by the FDA and EMA for relapsed/refractory CLL based on a placebo-controlled study including a control group treated with rituximab [6]. Patients treated with idelalisib plus rituximab showed significantly longer PFS (10.7 months) than those who received placebo plus rituximab (5.5 months) (p < 0.001). The OR rate for the combination of idelalisib and rituximab was 81% while that of rituximab alone was 13% (p < 0.001). OS was also longer for the idalalisib and rituximab arm than for the rituximab arm. Again, similar to ibrutinib, there are no reports of any direct comparison between idelalisib administered alone and in combination with rituximab. The combination of idelalisib with ofatumumab was also more effective in patients with high-risk, previously treated CLL [13]. In another large randomized trial, the PFS and OS of a group treated with idelalisib combined with BR were found to be superior to a placebo group treated with BR [14]. In this study, patients received 150 mg idelalisib orally, twice daily or matching placebo. Treatment was continued until disease progression, death, intolerable toxicity, substantial noncompliance with study procedures, study discontinuation, or withdrawal of consent. During the period after completion of BR treatment, a higher proportion of patients in the placebo group demonstrated disease progression than those in the idelalisib group. Median PFS was 23 months in the idelalisib arm and 11 months in the placebo arm (p < 0.001) at a median follow up of 12 months. Median OS was 41 months in the BR-only arm, and not reached in the idelalisib arm (p = 0.036). However, in patients who discontinued the study because of an adverse event, the median OS was 16 months in the idelalisib group compared with 7 months in the placebo group. Moreover, median OS was not reached among the patients who discontinued idelalisib because of progressive disease, and was 32 months in the placebo group. In addition, the survival benefit with idelalisib increased over time, indicating that ongoing maintenance treatment with idelalisib is a better approach than the following treatment at the time of progression.

Recently, three Phase 3 studies of idelalisib in combination with BR or other drugs were initiated in first-line treatment of CLL patients. However, these trials were prematurely closed due to concerns raised in relation to the development of serious adverse events, mainly severe infections and deaths. According to recent recommendations, patients treated with idelalisib-containing regimens should receive treatment with adequate Pneumocystis jirovecii pneumonia prophylaxis and cytomegalovirus monitoring measures.

3. Venetoclax

Venetoclax is a selective inhibitor of the BCL-2 antiapoptotic protein, which is strongly expressed in CLL cells. As a single agent, venetoclax induces OR in approximately 80% of patients with relapsed/refractory CLL, including 16–20% of CR [15]. The drug is active to a similar degree in both patients with and without del 17p. In contrast to BCR pathway inhibitors, venetoclax can induce MRD-negativity in a significant proportion of patients. In an initial dose-escalation study, MRD status was evaluated on bone marrow samples from 17 of the 23 CR patients; 6 of these (35%) patients were MRD negative. Subsequently, a Phase 2 study was performed in patients with del17p relapsed or refractory disease, the results of which demonstrated an OR of 79.4%. Peripheral blood MRD was evaluated in 45 patients, and 18 of them demonstrated MRD-negativity. However, it is unclear today whether this MRD-negativity translates into longer PFS or OS duration in patients treated with venetoclax and the current protocol prescribes continued treatment. It is therefore important to investigate whether treatment with venetoclax can be discontinued after achieving MRD-negativity. Currently, venetoclax seems to be the treatment of choice for patients who have discontinued BCR signaling inhibitor therapy. In the Phase 2, open label study, venetoclax monotherapy was evaluated in patients who were refractory to ibrutinib or idelalisib or relapsed after treatment; the objective response rate was 70% in patients previously treated with ibrutinib and 48% in those treated with idelalisib [16]. In addition, 42 (33%) of the patients achieved MRD-negativity in peripheral blood. In the refractory setting, 14 of 22 patients treated with ibrutinib and 3 of 5 patients treated with idelalisib achieved a response. Venetoclax use was associated with longer PFS than immunochemotherapy combinations in patients who discontinued BCR inhibitors [17]. Preclinical data indicated synergistic cytototoxic activity in combined venetoclax and rituximab treatment [18]. A recent clinical trial including 49 patients found that the combination of venetoclax with rituximab was an effective and safe course of therapy in relapsed and refractory CLL patients, with an OR rate of 86%, and CR observed in 51% [19]. The 2-year estimate for PFS was 82% and ongoing response was 89%. MRD-negativity in bone marrow was noted in 20 of 25 (80%) patients with CR and 28 (57%) of all patients. However, the relationship between MRD-negativity and PFS was not reported. These reports indicate that venetoclax can induce MRD-negative status when used in monotherapy or in combination with rituximab. However, a recent meta-analysis indicates that MRD-negative rates are higher in patients treated with venetoclax plus rituximab. Trials are currently ongoing to evaluate whether continuous therapy or time-limited approaches with venetoclax in MRD-negative patients are required to obtain durable responses [20]. The depth and durability of responses observed with the combination of venetoclax with rituximab suggests an attractive potential treatment option for patients with relapsed or refractory CLL and this combination should be further investigated in randomized studies. Preclinical studies also suggest that venetoclax is able to increase the antileukemic activity of ibrutinib and support the simultaneous use of these two drugs in the clinic. Phase 2 clinical trials examined the use of combined venetoclax and ibrutinib therapy in CLL patients refractory to and/or relapsed after at least one prior therapy and in untreated patients harboring del(17p)/TP53 mutation, unmutated IGHV, or are aged over 65 are ongoing (NCT03226301, NCT03128879, NCT03045328, NCT02910583).

4. Expert opinion

Despite the impressive therapeutic progress represented by the advent of immunochemotherapy, CLL remains incurable by conventional modalities. Immunochemotherapy, especially FCR, has significantly improved PFS and OS in fit younger patients without a TP53 deletion/mutation. The achievement of deep remission with MRD-negativity after immunochemotherapy correlates with better PFS and OS [3]. Patients with mutated IGHV showed a PFS of 53.9% at 12.8 years with a plateau on the PFS curve following treatment with FCR [21]. It is therefore very difficult to consider replacing frontline FCR with combinations of novel agents in patients without del 17p/TP53 mutation and with mutated status of IGHV. In this group of patients, the per-patient cost of lifetime therapy is expected to fall compared to that of novel drugs, which consequently should be employed as second-line treatment. In older or unfit patients, the standard treatment regimen is based on a combination of anti-CD20 mAbs with bendamustine or chlorambucil. The recent developments in the treatment of CLL during the last decade have opened up an exciting era in the treatment of this disease.

Over the last few years, targeted drugs, particularly the kinase inhibitors ibrutinib and idelalisib, and the BCL-2 antagonist venetoclax, have been developed and investigated in CLL. These new drugs have improved the prognosis of the majority of CLL patients, particularly those with high-risk disease del17p/TP53 mutated, elderly/unfit patients, and those refractory for previous therapies. In addition to ibrutinib and idelalisib, second-generation kinase inhibitors of BTK and PI3K have demonstrated promising clinical activity and greater selectivity in CLL. These compounds are well tolerated and seem to be more potent when used in combination with other drugs than in monotherapy. New targeted agents have provided a personalized approach to caring for CLL patients and optimizing their long-term outcomes. However, until now, only idelalisib has been approved for use in combination with rituximab. Ibrutinib and venetoclax are only approved as single agents. Today, all these drugs are under intensive investigation in combination with chemotherapy regimens, mAbs, and other targeted synthetic molecules. Such novel agents can be used in combination to increase efficacy, decrease the risk of resistance, and reduce toxicity. Moreover, there is a hope that novel agents, combined with immune chemotherapy, may increase deeper responses and allow novel therapies such as ibrutinib and idelalisib to be stopped in patients achieving MRD-negativity. Studies examining the effect of discontinuing novel therapies such as ibrutinib and idelalisib would clarify whether these treatments can be safely stopped without reducing their efficacy.

These combinations of novel synthetic drugs can change the current treatment standards of CLL and may eventually replace a chemotherapy-free approach. However, the likelihood of novel targeted agents displacing immunochemotherapy as the first-line treatment of patients with CLL is at present only speculative due to lack of clear evidence. Patients with an elevated co-morbidity score constitute a special subgroup treated less intensively with chlorambucil plus CD20 mAbs or ibrutinib monotherapy. A number of studies have evaluated combining ibrutinib with anti-CD20 to further improve the quality and duration of response. The ongoing iLLUMINATE study compares the chemotherapy-free combination of ibrutinib plus obinutuzumab to that of chlorambucil/obinutuzumab in treatment-naive patients who are not candidates for fludarabine-based imunochemotherapy due to comorbidity, age, or presence of del 17p [22].

Another combination therapy being explored concerns the addition of BCR inhibitors to immunochemotherapy. Results from several trials have shown that the addition of mAbs and cytotoxic drugs obviated early lymphocytosis and increases the OR and CR rates; these combinations appeared to be relatively safe in previously treated patients. However, trials of kinase inhibitor–chemotherapy combinations in previously untreated CLL patients have returned some unpredictable side effects: Recently, three trials of idelalisib combined with BR or other drugs have been prematurely closed because of the development of serious adverse events, including deaths mostly attributed to infection and severe morbidity due to immune-related effects. It is too early to determine whether these safety concerns will impact the future first-line potential of novel targeted drugs. According to the current guidelines, novel synthetic drugs, should be administered indefinitely, until disease progression or uncontrolled toxicity. However, some of them, especially venetoclax used as a single agent or in combination, can induce MRD-negativity in a significant proportion of patients. In addition, newer combination trials are ongoing and should confirm whether the novel treatments can be discontinued safely in patients who achieve MRD-negative responses. The results of these and other ongoing trials should also clarify the best sequence for using these novel therapies. Researchers, clinicians, and patients share the hope that small synthetic targeted drugs, used alone or more likely in combination, perhaps with immunotherapy, may eventually lead to a chemotherapy-free approach and improve outcomes in all CLL patients.

Declaration of interest

T Robak received research grants and personal fees from Hoffmann-La Roche, GlaxoSmithKline, Gilead, Pharmacyclix, Abbvie, and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgements

We thank Edward Lowczowski from the Medical University of Lodz for editorial assistance.

Additional information

Funding

The study was supported in part by grant funding from the Medical University of Lodz, Poland: No. 503/1-093-01/503-11-004 and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland.