Emerging Treatment Strategies in CLL

¹The potential synergy of ibrutinib with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials with the hope of identifying novel combinations that increase responses and improve duration of response.

New targeted agents in development in CLL include second- generation inhibitors of Bruton’s tyrosine kinase (BTK) designed to improve safety and efficacy, and novel inhibitors of phosphoinositide 3-kinase (PI3K).^2,3Emerging therapies in CLL also include novel immunotherapeutic regimens using immune checkpoint inhibitors and adoptive immunotherapy using modified T lymphocytes.⁴

IMPROVING MODULATION OF APOPTOSIS WITH BCL-2 INHIBITION

Venetoclax (Venclexta), a selective inhibitor of the B-cell lymphoma- 2 (BCL-2) family of proteins, which regulate cellular apoptosis and oncogenic functions, is a standard-of-care treatment of relapsed or refractory 17p deletion (del[17p]) CLL, alone or in combination with rituximab (Rituxan), and has activity in patients relapsing or refractory to ibrutinib or idelalisib (Zydelig).⁵

The combination of venetoclax and rituximab is reported to significantly improve progression-free survival (PFS) versus rituximab plus bendamustine (Treanda) in patients with relapsed/ refractory CLL, based on findings from the phase III MURANO study. In the MURANO study, the venetoclax/rituximab combination reduced the risk of disease progression or death by 83% versus bendamustine/rituximab (BR).⁶The median PFS had not yet been reached with venetoclax/rituximab compared with 17.0 months with the BR arm (HR, 0.17; 95% CI, 0.11-0.25; P <.0001). At 2 years, the PFS rate was 84.9% with venetoclax/rituximab and 36.3% with BR.

Pretreating CLL cells with a BTK inhibitor, such as ibrutinib, has been shown to increase the dependence of CLL cells on BCL-2, enhancing CLL killing in response to venetoclax in cell culture studies.⁷

Supported by this rationale, the clinical utility and safety of a sequenced regimen of ibrutinib monotherapy for 3 cycles followed by combination therapy with ibrutinib and dose-escalated venetoclax is being explored in an ongoing phase II study in patients with relapsed/refractory CLL and in previously untreated patients with high-risk CLL, defined as the presence of either del(17p), mutated TP53, 11q deletion (del[11q]), unmutated IGHV, or &ge;65 years.⁸In cohort 1 with patients with relapsed/refractory CLL, all patients who completed at least 3 months of combination therapy experienced a response, including 9 CRs or CRs with incomplete hematologic recovery (CR/CRi) and 5 partial remissions (PRs).⁹In the high-risk untreated patient cohort, among 16 patients who completed at least 3 months of treatment with the combination, 9 had a CR/CRi and 7 had a PR. Eight patients (11%) developed atrial fibrillation and 1 patient had laboratory tumor lysis syndrome (TLS).

The TAP CLARITY study looked at the combination of ibrutinib and venetoclax in patients with previously treated relapsed/refractory CLL and elicited a CR/CRi in 47% of 38 efficacyevaluable patients and an objective response rate of 100% in initial results from the study.¹⁰

The phase III FLAIR study is also enrolling patients to evaluate ibrutinib/venetoclax as a frontline therapy compared with ibrutinib alone; ibrutinib/rituximab; or fludarabine, cyclophosphamide, and rituximab (FCR) in patients with CLL.¹¹

Potential synergy of BTK and BCL-2 inhibition is also being explored in a phase Ib/II study in patients with relapsed/ refractory CLL, using a combination of obinutuzumab (Gazyva), ibrutinib, and venetoclax started sequentially, with gradual escalation of the venetoclax dose.¹²The regimen was tolerated with toxicities consistent with those of the single agents. Response has been evaluated in 6 of 12 patients treated in the phase Ib portion of the study, with an objective response rate (ORR) of 100% (5 PRs and 1 CR).10 In initial results from the phase II portion of the study in the treatment-na&iuml;ve patient cohort, the triplet combination induced an objective response in all 23 evaluable patients without incidence of TLS.¹³The safety profile was similar to that seen in the phase Ib portion of the study.

EXPLORING SYNERGY OF IBRUTINIB WITH IMMUNOTHERAPEUTIC REGIMENS

The upregulation of inhibitory immune checkpoint pathways that control T-cell responses represents a major mechanism by which cancer cells escape elimination by the immune system. CLL cells express elevated levels of checkpoint inhibitory molecules, including programmed death 1 (PD-1), and its main ligands, PD-L1 and PD-L2.¹⁴This provides a strong rationale to investigate immunotherapy with PD-1 checkpoint inhibitors in CLL, which is expected to enhance the activity of anti-CLL T-effector cells, resulting in immune-mediated elimination of CLL cells. The small molecule inhibitor ibrutinib has immunomodulatory properties because it also blocks interleukin-2—inducible T-cell kinase (ITK), in addition to BTK, shifting the balance of T-helper cell populations.

Adding ibrutinib with PD-1 checkpoint blockade has enhanced antitumor activity in preclinical models, including ibrutinibresistant lymphomas.¹⁵An ongoing phase II trial is investigating combined checkpoint inhibitor therapy with the PD-1 inhibitor nivolumab (Opdivo) and ibrutinib in patients with relapsed/refractory CLL or Richter&rsquo;s transformation (RT), or untreated patients with high-risk del(17p) CLL.¹⁶An initial report of the first 12 patients was presented at the 2016 ASH Annual Meeting, reporting activity in ibrutinib-na&iuml;ve patients with relapsed/refractory CLL (PRs in 3 of 5 patients) or RT (2 of 4 patients), including 1 patient with del(17p), unmutated IGHV, complex karyotype CLL.¹⁷

A single-arm phase II study has previously demonstrated activity of ibrutinib in combination with rituximab in patients with highrisk CLL.¹⁸The therapy was well tolerated and produced an ORR of 95%, including a CR of 8% and a PR of 87%, and an 18-month PFS rate of 78% in all patients and 72.4% in patients with del(17p) or a TP53 mutation.

An open-label, single-center trial randomized patients with either relapsed CLL or high-risk treatment-na&iuml;ve disease to either ibrutinib plus rituximab or ibrutinib alone.¹⁹The ORR was 100% with the combination regimen, and CRs were achieved in 28% in the combination arm compared with 21% of those treated with ibrutinib alone (P = .309). Lower levels of residual CLL cells were found upon bone marrow flow cytometry assessments for minimal residual disease (MRD) at last follow-up in the combination arm versus the ibrutinib monotherapy arm (4.9% vs 17.1%; P = .002). However, PFS was not improved with the combination (91.2%) compared with ibrutinib alone (90.4%; P = .788).

In a randomized phase II CALGB 9712 study comparing concurrent or sequential rituximab with fludarabine, a higher ORR was shown with the concurrent regimen (90% vs 77%; CR, 47% vs 28%), and similar median PFS (42 months) and overall survival (OS; 85 months) rates between the 2 arms.²⁰

Promising clinical activity of ibrutinib in combination with the CD20-targeted monoclonal antibody ofatumumab (Arzerra) has been reported from a phase I/II trial in 71 patients with relapsed/refractory CLL; the combination produced a high ORR (71% to 100% in different dose schedules) and an estimated 12-month PFS rate of 75% to 89%.²¹Frontline treatment with ibrutinib plus obinutuzumab is currently being compared with chlorambucil plus obinutuzmab in the phase III iLLUMINATE study in 212 treatment- na&iuml;ve patients with CLL, with results expected in late 2017.²²

Ibrutinib has also been combined with the investigational glycoengineered CD20 antibody ublituximab (TG-1101). In a phase II study, 88% of patients (n = 41) with relapsed/refractory CLL responded to the combination, and the ORR was 95% among patients with high-risk (del(17p), del(11q), or TP53 mutation) CLL, including a subset (n = 3, 15%) who achieved negative MRD.²³

The phase III GENUINE study was designed to validate this combination in patients with previously treated high-risk CLL.²⁴Approximately 50% of patients in the study had del(17p). The study met its primary endpoint of an improved ORR with 80% for the ublituximab/ibrutinib combination compared with 47% for ibrutinib alone after a median follow-up of 12 months (P <.001). Improvements were also seen in PFS and CR rates with the combination without clinically significant increased toxicity.

Ublituximab and ibrutinib were also combined with umbralisib (TGR-1202), a PI3K&delta; inhibitor, in an investigation of the triplet regimen in patients with advanced CLL and other subsets of non- Hodgkin lymphomas. The ORR in patients with CLL was 100%, including 6 CRs and 13 PRs.²⁵

The combination of ibrutinib with obinutuzumab is the focus of a phase I/II study in 32 previously untreated patients with CLL, with safety, tolerability, dose-limiting toxicity, and ORR as primary outcomes.²⁶Preliminary results from the induction phase of the French phase II Icll-07 Filo study exploring obinutuzumab and ibrutinib in symptomatic, medically fit, previously untreated patients with CLL were presented at the 2017 ASH Annual Meeting.²⁷At month 9, 73 of 135 enrolled patients were evaluable for response. Each of these 73 patients experienced a response, including CRs in 37% and PRs in 63% without excess toxicity. However, subsequent immunochemotherapy treatment was required in the majority of patients due to detectable MRD in the bone marrow. Serious adverse events (AEs) were observed in 37 patients and were deemed to be treatment-related in 24 patients.

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COMBINING AND COMPARING TARGETED THERAPY WITH CHEMOIMMUNOTHERAPY

Recent outcomes from the randomized, placebo-controlled, phase III HELIOS study in patients with relapsed/refractory CLL have confirmed that the addition of ibrutinib to bendamustine and rituximab (BR) was beneficial and tolerable.²⁸After a median follow-up of 17 months, median PFS was not reached in the ibrutinib group versus 13.3 months in the placebo group (HR, 0.203; P <.0001), demonstrating a reduction of the risk of progression and death by 80%. PFS at 18 months was 79% versus 24% (P <.0001), and PFS benefits of ibrutinib were maintained in subgroups including refractoriness to purine analog therapy, del(11q), and unmutated IGHV. The ORR was 82.7% versus 67.8% (P <.0001), and the median OS was not reached in either group.²⁸

An ongoing trial is evaluating ibrutinib in combination with chemotherapy as frontline therapy with the addition of shortcourse fludarabine to ibrutinib.²⁹A phase II study is investigating ibrutinib plus FCR as a frontline regimen in younger patients (<65 years) with CLL.³⁰The combination regimen induced negative MRD status in the bone marrow in 83% of patients, which was consistent across all risk categories. Additionally, 13 patients (37%) achieved a CR in association with their negative MRD status, which increased to 57% at best response assessment.

On the basis of promising initial findings, investigators initiated an expansion trial. Based on results from the 35-patient study, investigators made several protocol modifications.³⁰Patients who are MRD negative in the bone marrow will be taken off treatment after 2 years of ibrutinib maintenance, patients who convert to MRD positive after discontinuation will resume ibrutinib treatment and patients with del(17p) will be excluded. Enrollment in the expansion study began in April, and 30 patients have been accrued since then.⁴

An ongoing phase III study of the German CLL Study Group has been designed to compare frontline standard chemoimmunotherapy (FCR, BR) therapy in physically fit patients with CLL who do not have del(17p) or TP53 mutations with combination regimens of targeted drugs, specifically rituximab plus venetoclax, obinutuzumab plus venetoclax, and obinutuzumab plus ibrutinib plus venetoclax.³¹

IMMUNOMODULATORY AGENTS FOR MAINTENANCE

The immunomodulatory agent lenalidomide (Revlimid) is approved for various hematologic malignancies, and is evolving as a maintenance therapy option for patients with high-risk CLL after first-line therapy. Although, currently the label suggests not using lenalidomide outside of clinical trials for patients with CLL.

Recent reports from the CLL M1 and CONTINUUM trials have shown prolonged PFS with maintenance lenalidomide following first- and second-line treatment, respectively.³²In the CLL M1 study of the German CLL Study Group, patients with a high risk for disease progression after first-line treatment with BR or FCR were randomized to lenalidomide (n = 56) or placebo (n = 29) based on MRD levels and the presence of unmutated IGHV, del(17p), or mutated TP53 at baseline.³²Interim results at a medium follow-up of 17.7 months, demonstrated significantly longer median PFS with lenalidomide (not reached vs 14.6 months for placebo; P <.00001).

The CONTINUUM trial investigated lenalidomide versus placebo in patients with CLL who achieved at least a partial response to second-line therapy. Patients reported a significant increase in median PFS with lenalidomide at a median follow-up of 31.5 months (33.9 vs 9.2 months for placebo; HR, 0.40; 95% CI, 0.29-0.55; P <.0001), however there was no significant difference in OS (HR, 0.96; 95% CI, 0.63-1.48; P = .86).³³In both studies, neutropenia, gastrointestinal, nervous system, respiratory, and skin disorders were more common in the lenalidomide arms,32,33 but the CONTINUUM study noted that a clinically meaningful difference in quality of life was not found between the 2 arms.³³

As a frontline therapy, single-agent lenalidomide showed an ORR of 72% in a phase II study with a 20% CR rate.34 At 3 years, the PFS rate was 65% and the OS rate was 85%. AEs of note included grade 3/4 neutropenia (76%) and thrombocytopenia (28%) and grade 1/2 tumor flare reaction occurred at a rate of 88%. However, tumor flare reaction is correlated with a response in patients receiving lenalidomide.5

SECOND-GENERATION BTK INHIBITORS

The second-generation small molecule BTK inhibitors acalabrutinib (Calquence) and BGB-3111 exhibit greater selectivity for BTK than ibrutinib, which may reduce toxicity related to off-target activity of ibrutinib on other kinases including EGFR, ITK, and Tec family kinases, and may also overcome drug resistance related to incomplete BTK inhibition with ibrutinib.²Both agents also exhibit rapid oral bioavailability and a short half-life, allowing for twice-daily dosing, which has been associated with high plasma exposure— producing continuous and greater-than-95% blockade of BTK.^35,36

In updated findings from the uncontrolled, multicenter phase I/II ACE-CL-001 trial of acalabrutinib in patients with relapsed/ refractory CLL or small lymphocytic leukemia, treatment was associated with a high rate of responses and durable remissions.³⁷Among the 134 patients enrolled, 73% had unmutated IGHV, 23% had del(17p), and 18% had del(11q). After a median follow-up of 19.8 months, the ORR was 85%. The ORR including PR with lymphocytosis was 93%. The median duration of response (DOR) was not reached, but at 18 months the DOR rate was 85%. The median PFS was also not reached, but at 18 months, the PFS rate was 88%. The ORR in patients with del(17p) was 85%, 86% in patients with del(11q), and 88% in patients with unmutated IGHV. Patients with del(11q) had an 18-month PFS and DOR rate of 100%.

A phase III trial of acalabrutinib versus ibrutinib in previously treated patients with high-risk CLL with either del(17) and/or del(11q) is underway.³⁸A second ongoing phase III trial is evaluating acalabrutinib versus rituximab plus idelalisib or bendamustine in patients with relapsed/refractory CLL.³⁹

Acalabrutinib is also being investigated for the frontline treatment of CLL, based on positive outcomes of a phase I/II study in treatment-na&iuml;ve patients with CLL, which reported good tolerability and an ORR of 96%.⁴⁰The ongoing phase III Elevate CLL TN study is comparing acalabrutinib plus obinutuzumab versus obinutuzumab plus chlorambucil as a frontline treatment.⁴¹

The phase Ib/II ACE-CL-003 trial is also looking at acalabrutinib with obinutuzumab in both the frontline and in patients with relapsed/ refractory disease.⁴²In the patients with relapsed/refractory disease, the ORR was 92%, including 2 CRs. In the treatment-na&iuml;ve patients, the ORR was 95%, including 3 CRs. The median DOR and median PFS had not been reached in either cohort. There were no serious AEs, central nervous system hemorrhage, or grade &ge;3 contusion or petechiae observed in the study.

Phase I study outcomes with BGB-3111 in patients with relapsed/ refractory CLL were recently reported and included an ORR of 96% (67% PR; 28% PR with lymphocytosis) and a 100% ORR in patients with del(17p).³⁶Two ongoing phase I trials are evaluating BGB-3111 in patients with B-cell lymphoid malignancies as a single agent and in combination with obinutuzumab and BGB-A317, an early-stage PD-1 inhibitor.^43,44

NEW PI3K INHIBITORS

Duvelisib (IPI-145) is an oral inhibitor of PI3K3&gamma; and PI3K&delta; isoforms that suppresses B-cell proliferation and promotes apoptosis in CLL cells.⁴⁵Clinical activity of single-agent duvelisib was reported from a phase I trial in patients with relapsed/refractory CLL, including those with del(17p) or TP53 mutations.⁴⁶Data from the phase III DUO trial of patients with relapsed/refractory CLL/SLL showed a median PFS of 13.3 and 9.9 months for duvelisib and ofatumumab, respectively (HR, 0.52; P <.001).⁴⁷In patients with del(17p), the median PFS was 12.7 and 9.0 months for duvelisib and ofatumumab, respectively (HR, 0.41; P = .0011). Additionally, initial data from an ongoing phase Ib study of duvelisib plus FCR as frontline therapy suggested tolerability and high response rate (100% in 12 patients).⁴⁸A new drug application was recently submitted to the FDA for full approval of duvelisib for the treatment of patients with CLL/small lymphocytic lymphoma.

CELL-BASED IMMUNOTHERAPY

A unique immunotherapy currently in development in CLL is adoptive immunotherapy using chimeric antigen receptor (CAR) T-cell therapy. This technology involves the genetic modification of autologous T cells ex vivo to express a fusion construct CAR consisting of a B cell-specific antigen, such as the pan B-cell antigen CD19, and the signaling component of T-cell receptor.⁴This approach results in target specificity of the effector T cell, and later-generation designs incorporate additional co-stimulatory domains to enhance antitumor activity of the modified T cells. Clinical outcomes of CAR T-cell therapy in patients with CLL have been reported in small numbers at single institutions.⁴

A phase I study demonstrated a 57% ORR (8 of 14 patients; including 4 CRs and 4 PRs) among patients with heavily pretreated relapsed/refractory CLL.49 CD19 CAR T-cell responses persisted for 4 years in the first 2 patients who achieved CR, and none of the patients with CR relapsed or had detectable MRD, suggesting this treatment may be a possible cure for CLL. All patients with response developed B-cell aplasia and had cytokine release syndrome, which coincided with T-cell proliferation.⁴⁹

Single-arm results of a small phase I/II study of JCAR014 CAR T-cell therapy in adults with relapsed/refractory B-cell malignancies, which were presented at the 2017 SOHO Annual Meeting, showed that the subgroup of patients who met International Working Group on CLL criteria for response and had no malignant IgH sequences in marrow had a PFS and OS of 100% after a median follow-up of 6.6 months.⁵⁰

A large number of early-stage clinical trials is ongoing to investigate CAR T-cell treatment in advanced B-cell malignancies, including relapsed/refractory CLL.

Multiple clinical trials are underway that address efficacy and tolerability of novel agents and agent combinations in CLL. Pertinent outcomes include the durability of remissions in patients who achieve MRD-negative CR on regimens and the effects of treatment discontinuation.

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