Emerging immunological drugs for chronic lymphocytic leukemia.

Review

Emerging immunological drugs for chronic lymphocytic leukemia

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 07/15/15 For personal use only.

Pawel Robak, Piotr Smolewski & Tadeusz Robak† Medical University of Lodz, Departments of Experimental Hematology and Hematology, Lodz, Poland

1.

Background

2.

Medical need

3.

Existing treatments

4.

Current research goals

5.

Scientific rationale

6.

Competitive environment

7.

Potential development issues

8.

Conclusion

9.

Expert opinion

Introduction: Over the last few years, several new immunological drugs, particularly monoclonal antibodies (mAbs), immunomodulatory drugs and B-cell receptor (BCR) pathway inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). This article summarizes recent discoveries regarding their mechanism of action, pharmacological properties, clinical activity and toxicity, as well as the emerging role of these agents in CLL. Areas covered: A literature review of mAbs, BCR pathway inhibitors and immunomodulating drugs was conducted of the MEDLINE database via PubMed for articles in English. Publications from 2000 through February 2015 were scrutinized. The search terms used were alemtuzumab, BI 836826, duvelisib ibrutinib, idelalisib, lenalidomide, monoclonal antibodies, MEDI-551, MOR208, obinutuzumab, ocaratuzumab, ofatumumab, ONO-4059, otlertuzumab, spebrutinib, veltuzumab and XmAb5574 in conjunction with CLL. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: The use of mAbs, BCR inhibitors and immunomodulating drugs is a promising new strategy for chemotherapy-free treatment of CLL. However, definitive data from ongoing and future clinical trials will aid in better defining the status of immunological drugs in the treatment of this disease. Keywords: alemtuzumab, BI 836826, chronic lymphocytic leukemia, duvelisib, ibrutinib, idelalisib, lenalidomide, MEDI-551, monoclonal antibodies, MOR208, obinutuzumab ocaratuzumab, ofatumumab, ONO-4059, otlertuzumab, spebrutinib, veltuzumab, XmAb5574 Expert Opin. Emerging Drugs [Early Online]

1.

Background

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in the Western Hemisphere. It is a clonal lymphoid disease characterized by the proliferation and accumulation of small CD5/CD19/CD23-positive lymphocytes in the blood, lymph nodes, spleen, liver and bone marrow. The diagnosis of CLL requires the presence of at least 5000 leukemic B lymphocytes per microliter in the peripheral blood [1]. The natural clinical course of CLL is highly variable, and its management is determined by the stage and activity of the disease, patient age and comorbidities [2,3]. Patients with symptomatic and/or progressive disease are treated at diagnosis, whereas others, regardless of their prognostic indicators, are offered treatment only at disease progression. Randomized studies and a metaanalysis indicate that early initiation of chemotherapy based on alkylating agents does not show benefit in CLL and may increase mortality [3].

10.1517/14728214.2015.1046432 © 2015 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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P. Robak et al.

Over the past few years, the introduction of chemoimmunotherapy led to a marked improvement in treatment efficacy with an overall response (OR) rate of up to 95% and a significant proportion of the patients achieving not only a complete, but also a molecular remission [4]. A large Phase III randomized trial demonstrated that rituximab combined with fludarabine and cyclophosphamide (FCR) increased the OR and complete response (CR) rates, prolonged progression free survival (PFS) and overall survival (OS) compared with fludarabine and cyclophosphamide (FC) in previously untreated and relapsed/refractory patients [5,6]. Currently, regimens based on the purine analog, cyclophosphamide, and rituximab are considered the standard first-line therapy for patients who are able to tolerate intensive treatment. The results of the CLL10 study indicate that FCR is more effective than bendamustine combined with rituximab (BR) in the first-line treatment of physically fit patients, who were found to demonstrate higher CR rate and longer PFS. However, these advantages are balanced by a higher rate of severe adverse events in FCR-treated patients [7]. More recently, findings from the CLL11 and COMPLEMENT1 studies suggest that the combination of anti-CD20 monoclonal antibodies with chlorambucil should become a new standard of care in frail, elderly and unfit patients, because of the apparent increase in toxicity of purine nucleoside analogs in this patient population [8,9]. In the recent years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the biology and prognosis of CLL. These achievements provided new opportunities for the development of innovative, more effective therapies in this disease. There has been an important increase in the range of available therapeutic options in the recent years, and many drugs are now in the process of making the transition to the clinic. 2.

Medical need

An annual incidence rate of CLL is three to five cases per 100,000. The estimated incidence for 2014 in the United States is 15,720 [10]. It is the most common form of adult leukemia accounting for ~ 11% of all hematologic neoplasms and ~ 30% of all leukemias in Europe and North America [11]. The median age at diagnosis is 72 years with 80% of patients diagnosed > 60 years of age. Despite advances in research and the development of effective treatment regimens, CLL is still largely an incurable disease. Within 2 years of first- and second-line therapy, around 25% and 50% of patients relapse, respectively [12]. In addition, relapsed/refractory patients exhibit poor responses to subsequent therapies and decreasing response duration with subsequent lines of treatment is observed. Recent advances in CLL pathobiology research, the use of high-throughput technologies, and most importantly, the introduction of novel targeted therapies with high efficacy and low toxicity are currently transforming the treatment of CLL. 2

3.

Existing treatments

New immunological agents and their combinations with cytotoxic drugs have achieved very promising results in Phase I/II studies and some of them in randomized Phase III trials. In addition, the results of recent preclinical and clinical studies indicate that immunological drugs, especially new mAbs, BCR pathway inhibitors and immunomodulating drugs are useful in the treatment of patients with CLL. 3.1

Monoclonal antibodies Anti-CD20 monoclonal antibodies

3.1.1

In recent years, anti-CD20 mAbs based on selective B-cell depletion -- rituximab, ofatumumab and obinutuzumab -have been approved for use in CLL therapy (Table 1). Rituximab (IDEC-C2B8; Mabthera, Roche, Rituxan, Biogen Idec, and Genentech, Inc.) was the first mAb approved for the treatment of lymphoid malignancies. It is a chimeric, human/mouse, anti-CD20 mAb containing murine lightand heavy-chain variable-region sequences and human constant-region sequences [13]. The drug can induce complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and apoptosis, although which of these are important in the treatment of CLL is unclear [14]. Numerous studies have confirmed the efficacy of rituximab as a single agent and in combination therapy in CLL. Unfortunately, only a subset of patients with CLL respond to monotherapy with this agent and the majority of those eventually relapse following rituximab treatment. However, rituximab combined with purine analogs and/or alkylating drugs can improve the response rate, response duration and survival of patients relative to those treated with rituximab alone or chemotherapy alone [4,5]. Rituximab maintenance after chemoimmunotherapy induction in CLL is also feasible and shows signs of efficacy in CLL patients [15]. However, no randomized data concerning the efficacy of such an approach is available. According to recent guidelines, maintenance or consolidation therapy with rituximab should not be used outside clinical trials. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) granted approval to rituximab, in combination with fludarabine and cyclophosphamide, for the treatment of both previously untreated and previously treated patients with CLL. The cost-effectiveness of FCR from a US third-party payer perspective over a lifetime horizon in the base case was compared with that of FC [16]. The results indicate that FCR is cost effective for previously untreated CLL. The authors report that adding rituximab to FC in newly diagnosed CLL patients resulted in an incremental cost-effectiveness ratio from a US third-party perspective of ~ $23 500 per QALY gained over a 30-year time horizon. Ofatumumab (HuMax-CD20; Arzerra, GlaxoSmithKline plc/Genmab A/S) is a fully human, IgG1 mAb recognizing targeting a unique CD20 epitope to rituximab, resulting in

Expert Opin. Emerging Drugs (2015) 20(3)

Immunological drugs for CLL


Table 1. Monoclonal antibodies approved in CLL. Compound

Company

Structure

Indication

Rituximab (IDEC-C2B8; Mabthera, Rituxan)

Roche, Biogen Idec and Genentech

Ofatumumab (HuMax-CD20; Arzerra)

GlaxoSmithKline plc/Genmab A/S

Chimeric, human/ mouse, anti-CD20 mAb containing murine light- and heavy-chain variable-region sequences and human constantregion sequences Fully human, IgG1 anti-CD20 mAb mAb

Obinutuzumab (Gazyva), Gazyvaro, GA-101, RO5072759)

Roche/ Genentech

Humanized and glyco-engineered anti-CD20 mAb

Alemtuzumab (Campath))

Sanofi/Genzyme

Recombinant IgG1 mAb with human Ig G1 heavy chain constant region

Stage of development

Mechanism of action

Potential clinical activity

PreviouslyApproved by FDA untreated and and EMA previously-treated patients with CLL in combination with chemotherapy

Induction CDC, ADCC and apoptosis

Chronic lymphocytic leukemia, non-Hodgkin lymphoma, rheumatoid arthritis [24]

Fludarabine- and alemtuzumabrefractory CLL, patients, first-line treatment in combination with chlorambucil for patients with CLL for whom fludarabine-based therapy is inappropriate. Older patients with previously untreated CLL in combination with chlorambucil

Greater CDC activity and similar ADCC activity compared to rituximab

Rheumatoid arthritis and lymphoid malignancies [29,30]

CLL patients with (del)17p/TP53 defective and/or refractory to fludarabine

Approved by FDA and EMA

Approved by FDA and EMA

Increase ADCC and direct cell death compared to rituximab and/or ofatumumab Approved by FDA mAb targeting in 2007, in CD52 antigen 2012 withdrawn with ADCC by Sanofi and and CDC currently provided activity through the Campath Distribution Program

Leukemias, myeloma [36]

Chronic lymphocytic leukemia [28,30,31]

ADCC: Antibody-dependent cell-mediated cytotoxicity; CDC: Complement-dependent cytotoxicity.

increased binding affinity to CD20, prolonged dissociation rate, and increased cell kill due to greater CDC activity and similar ADCC activity compared to rituximab [17]. The results of a Phase III study demonstrate that ofatumumab monotherapy shows promising efficacy in heavily pretreated patients with fludarabine- and alemtuzumab-refractory CLL [18]. In this study, patients received eight once-weekly infusions of ofatumumab followed by four once-monthly infusions during a 24-week period. The overall response rates were 58% in the fludarabine- and alemtuzumab-refractory groups, and 47% in patients with fludarabine-refractory CLL with bulky lymphadenopathy. Median progression free survival (PFS) values were 5.7 months in the fludarabine- and alemtuzumabrefractory groups, and 5.9 in the fludarabine-refractory patients with bulky lymphadenopathy. The overall survival times were 13.7 months and 15.4 months, respectively. In a

recent randomized trial (Complement1), combined ofatumumab and chlorambucil therapy was compared with chlorambucil alone in patients with CLL who required therapy and were considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities [9]. The results of this study indicate that ofatumumab + chlorambucil is superior to chlorambucil alone in this patient population. The ofatumumab + chlorambucil arm demonstrated a higher OR rate than the chlorambucil arm (8 vs 69%) (p = 0.001), as well as a superior CR rate (1 vs 1%, respectively). PFS was also significantly prolonged in the ofatumumab + chlorambucil arm (22.4 months) compared to chlorambucil alone (13.1 months, p < 0.001). Currently, the role of ofatumumab in maintenance therapy is under investigation in CLL patients. In an open-label, two-arm randomized study (PROLONG), ofatumumab was used at doses of 300 mg followed


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1 week later by 1000 mg, every 8 weeks for up to 2 years. According to an interim analysis of the PROLONG study, ofatumumab improved PFS but not OS [19]. The median PFS was 28.6 months in patients who received ofatumumab and ~ 15.2 months for patients who did not receive maintenance (p < 0.0001). The time to the start of the following therapy was also significantly longer in the ofatumumab arm compared to the placebo arm (median 38.0 vs 27.4 months, p = 0.0076). Ofatumumab was well-tolerated with no unexpected side effects. Currently, ofatumumab is approved in the USA and EU for fludarabine- and alemtuzumab-refractory CLL patients. Moreover, FDA and EMA approved ofatumumab for firstline treatment in combination with chlorambucil for patients with CLL for whom fludarabine-based therapy is considered inappropriate. Obinutuzumab (Gazyva(), Gazyvaro(), GA-101, RO5072759, Roche/Genentech) is the type II humanized and glycoengineered mAb [20,21]. The antibody is based on proprietary GlycoMAb() technology, which incorporates glycoengineered mAbs that specifically increase ADCC and thereby increase immune-mediated target cell death. In contrast to type I antibodies, obinutuzumab does not provoke the localization of CD20 to lipid rafts and demonstrates low CDC. Obinutuzumab treatment leads to 5 -- 100 times greater induction of ADCC, as it binds with high affinity to the CD20 epitope, and induces direct cell death to a significantly greater extent than rituximab and/or ofatumumab [22,23]. In a Phase I/IIa study, obinutuzumab was administered as a single agent to 24 patients, at doses from 50 mg to 2000 mg [24]. The antibody has shown a similar safety profile to rituximab and promising efficacy in patients with CLL and other CD20+ malignant diseases, for whom no therapy of higher priority was available [25]. The results of a large randomized Phase III trial testing three first-line chemo-immunotherapy regimes, i.e. obinutuzumab combined with chlorambucil, rituximab combined with chlorambucil and chlorambucil monotherapy, in patients with comorbidities have been recently reported (CLL11) [11]. In this study, 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) or an estimated creatinine clearance of 30 -- 69 ml per minute were included. Treatment with obinutuzumab + chlorambucil resulted in higher rates of CR (20.7%) in comparison with rituximab + chlorambucil (7.0%). Moreover, treatment with obinutuzumab + chlorambucil or rituximab + chlorambucil increased OR rates and prolonged PFS as compared with chlorambucil monotherapy. Median PFS was 26.7 months with obinutuzumab + chlorambucil, 15.2 months for rituximab + chlorambucil, and 11.1 months for chlorambucil alone (p < 0.001). In addition, patients treated with obinutuzumab + chlorambucil had longer OS than chlorambucil alone (p = 0.002). However, infusion-related reactions and neutropenia were more common in patients treated with obinutuzumab + 4

chlorambucil than with rituximab + chlorambucil. Obinutuzumab combined with BCL-2 inhibitor venetoclax (GDC-0199, ABT-199, Genentech/AbbVie) shows synergistic activity in CLL [26]. In Phase Ib study evaluating the safety and tolerability of this combination, the drugs were safely administered at the doses given and no clinical tumor lysis syndrome (TLS) was observed. Recently, obinutuzumab has been approved by the FDA and EMA for use in combination with chlorambucil to treat older patients with previously untreated CLL [27]. The results of a cost-effectiveness analysis based on indirect treatment comparison data suggest that treatment with obinutuzumab + chlorambucil is cost-effective compared to ofatumumab + chlorambucil in previously untreated CLL patients [28]. Treatment with obinutuzumab + chlorambucil increased of 0.83 life years and 0.79 qualityadjusted life years (QALYs) relative to ofatumumab + chlorambucil. However, the average total cost of ofatumumab + chlorambucil was lower by $3,581 per patient relative to obinutuzumab + chlorambucil. The analysis of cost-effectiveness of obinutuzumab + chlorambucil versus rituximabmab + chlorambucil has not been reported so far. Anti-CD52 monoclonal antibody Alemtuzumab (Campath. Sanofi/Genzyme) is a recombinant humanized IgG1 mAb targeting the CD52 antigen. The drug was approved by the FDA as second-line therapy for CLL patients who have failed alkylating agents or fludarabine-based therapy. In the pivotal CAM 211 trial, 93 patients with relapsed or refractory CLL who had failed prior therapy with fludarabine and an alkylating agent were treated with alemtuzumab 30 mg three times weekly for a total of 12 weeks [29]. The OR rate was 33% and CR in 2% of the patients. Overall median PFS was 4.7 months and 9.5 months for responders. Importantly, alemtuzumab is an active drug in patients with del 17p and/or TP53 mutations. However, it is not effective in patients with bulky lymphadenopathy. The currently approved schedule of alemtuzumab administration involves a dose of 3 mg delivered i.v. on day 1, escalating to 10 mg on day 2 and then to 30 mg three times weekly as tolerated, for a total of 8 -- 12 weeks [30]. In addition, subcutaneous alemtuzumab has similar activity and safety to intravenous formulation. In a Phase II CLL2H trial performed in 103 CLL patients refractory to fludarabine, alemtuzumab was given subcutaneously at a dose of 30 mg three times weekly for up to 12 weeks [31]. The OR rate was 34% and CR in 4% of the patients with median PFS 7.7 months and the median OS 19.1 months. Low-dose alemtuzumab is another therapeutic option for the treatment of relapsed/ refractory CLL. Cortelezzi et al. used low-dose alemtuzumab defined as a total weekly dose of £ 45 mg and a cumulative dose of £ 600 mg given for up to 18 weeks in the treatment of 108 relapsed/refractory CLL patients [32]. The OR rate was 56% including 22% CR and the median PFS was 19.4 months. A cumulative dose of alemtuzumab was not 3.1.2




associated to response. In one study, low-dose alemtuzumab was combined with fludarabine and cyclophosphamide (FCA) for previously untreated high-risk CLL patients [33]. Three-year PFS was 53% for FCA and 37% for the fludarabine and cyclophosphamide (FC) group. However, OS was similar in both arms. In addition, subsequent analysis showed longer OS for FCA in patients younger than 65 years with 3-year OS 85 vs. 76%, (p = 0.035). FCA also increased the bone marrow minimal residual disease (MRD)-negative CR rate (64 vs 43%, p = 0. 016). In chemotherapy free protocol alemtuzumab was combined with rituximab (AR) in 30 previously untreated patients with CLL [34]. This regimen resulted in robust responses and long asymptomatic therapy-free intervals. OR was 100%, including 60% CR with no evidence of MRD in the bone marrow by 6-color flow cytometry in 67% of the patients. Median PFS was 24.4 months and 5-year OS 80%. However, similar to other reports, none of the patients with bulky lymphadenopathy achieved a CR. The AR combination was well tolerated with hematological toxicities representing a major portion of all complications. Grade 3/4 neutropenia was reported in 30% and thrombocytopenia in 7% of patients. Eight patients suffered from cytomegalovirus (CMV) reactivation at a median time of 6 weeks from the beginning of therapy. More recently, alemtuzumab has been used in combination with ofatumumab as first-line treatment of symptomatic, previously untreated CLL [35]. This regimen was found to induce a high OR rate and demonstrated acceptable toxicity. The overall response rate was 97% with 42% CR and 55% partial response (PR) in 31 patients with completed treatment. MRD by bone marrow flow-cytometry was negative in 12/13 CR patients and 4/17 PR patients. Consolidation treatment with alemtuzumab has been also evaluated in CLL patients [36]. In this study, patients with CLL responding to standard initial therapy with fludarabinebased regimens were randomized for treatment with alemtuzumab 30 mg three times per week for a maximum 12 weeks of observation. The study was prematurely closed because of severe infections in 7 of 11 patients treated with alemtuzumab. However, after alemtuzumab treatment, five patients achieved molecular remission, whereas all patients in the control group showed MRD. In addition, updated analysis after a median follow-up of 48 months confirmed significantly prolonged PFS for patients receiving alemtuzumab consolidation compared with those who received no further treatment. The study shows that, despite toxicity, consolidation treatment with alemtuzumab induces molecular remission and significantly improves long-term clinical outcome. The most common alemtuzumab administration-related side effect is a flu-like syndrome, observed mainly during the first alemtuzumab infusion. However, subcutaneous administration significantly reduces the intensity of the first administration reaction. Treatment with alemtuzumab is also associated with high risk of bacterial and viral infections.

CMV reactivation is observed in 15 -- 25% of alemtuzumab treated refractory or relapsed CLL [37]. At present, aggressive anti-infective prophylaxis is a mandatory procedure. In 2001, alemtuzumab was approved by the FDA to treat patients with CLL refractory to fludarabine and in 2007, regular approval for alemtuzumab for the treatment of CLL was granted. However, in 2012, alemtuzumab was withdrawn by Sanofi from the markets and alemtuzumab is not commercially available for CLL patients at the present time. Currently, it is provided through the Campath Distribution Program free of charge. BCR signaling inhibitors In recent years, the B-cell receptor (BCR) signaling pathway inhibitors are being actively explored as a therapeutic target in CLL [38]. Promising clinical results have been observed with ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, and idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase (PI3K)-d (Table 2). These drugs are available in oral preparations and are given as continuous treatment. They seem to be active in traditionally poor risk disease groups, including fludarabine-refractory patients, patients with bulky lymphadenopathy and patients with del 17p/ TP53 abnormalities. These agents induce rapid resolution of lymphadenoapathy and a transient increase of lymphocytosis due to mobilization of CLL cells into the peripheral blood. In consequence, after several months of continuous therapy, response can be achieved in a substantial number of patients [39,40]. Early clinical studies have demonstrated that BCR signaling inhibitors are well tolerated and have an excellent safety profile in patients with refractory CLL. 3.2

Bruton’s tyrosine kinase inhibitors Bruton’s tyrosine kinase is a member of the src-related BTK/ Tec family of cytoplasmic tyrosine kinases and plays a crucial role in the development and activation of B-cells through association with the BCR signalosome. In B-cells, BTK acts as an anti-apoptotic protein upstream of Bcl-xl within the B-cell antigen receptor activation pathway [39]. Ibrutinib (PCI-32765; Imbruvica, Janssen -- Cilag International NV/ Pharmacyclics) is an irreversible covalent inhibitor of the BTK, a critical enzyme in the BCR signaling pathway [41]. This agent prevents B-cell activation and B-cellmediated signaling, and inhibits the growth of malignant B-cells that over-express BTK. It also promotes apoptosis and inhibits proliferation and migration of CLL cells [42]. Ibrutinib is well-tolerated and active in CLL patients. Initial reports on the use of ibrutinib as a single agent found that it was particularly active in patients with refractory/relapsed CLL patients, including patients with high-risk genetic characteristics [43]. Byrd et al. first reported the results of the study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) [43]. Ibrutinib was given 3.2.1


5

6


O

F

N

Structure

N

N

N

O

N

N

N

N

HN

NH2

NH

N

O

N


Relapsed CLL in combination with rituximab

FDA approval

CLL patients who FDA and EMA received at least one approval prior therapy

Indication

BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; PI3Kd: Phosphatidylinositol 3-kinase P110d.

Calistoga Pharmaceuticals/ Gilead Sciences

Pharmacyclics/ Janssen

Ibrutinib (PCI-32765, Imbruvica)

Idelalisib (GS-1101, CAL-101 ZYDELIG)

Company

Compound

Table 2. BCR signaling inhibitors approved in CLL.

Inhibitor of PI3Kd, reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B-cells cells in lymphoid tissues

Inhibition of BTK phosphorylation on Tyr223, Inhibition of BCR signaling, promotion of apoptosis of B-cells.

Mechanism of action


Rheumatoid arthritis and lymphoid malignancies [29,30]

Rheumatoid arthritis, chronic lymphocytic leukemia, nonHodgkin lymphoma [24]

Potential clinical activity

P. Robak et al.



orally once daily at a dose of 420 mg in 51 patients, and at a dose of 840 mg in 34 patients. The OR rate was 71% in both groups. An additional 2 and 15% of patients in the respective groups had a PR with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the presence of 17p13.1 deletion. At 26 months, the estimated PFS rate was 75% and the rate of OS was 83%. Recently, Byrd et al. reported a median 3-year follow-up of 132 patients with symptomatic treatment-naive and relapsed/refractory CLL patients [44]. They demonstrated that even multiply relapsed patients, without del(17p) or del (11q) experienced long response times, with 87% of them being estimated with PFS at 30 months. However, a subset of heavily pretreated patients, in particular those with del (17p), were predisposed to relapse. Importantly, treatmentrelated lymphocytosis was usually asymptomatic, even after 1 year of therapy, without any influence on the duration of PFS and OS, compared to patients without persistent lymphocytosis. In addition, ibrutinib was well tolerated for an extended period of time. Ibrutinib is also an active and safe drug in older CLL patients. O’Brien et al. investigated ibrutinib in treatmentnaive patients with symptomatic CLL, aged 65 years and older [45]. After a median follow-up of 22.1 months, 22 (71%) of 31 patients achieved a response, with four (13%) achieving a CR, one (3%) a nodular PR, and 17 (55%) a PR. Ibrutinib was well tolerated, but mild diarrhea was a common, adverse event, particularly early in the course of treatment. Farooqui et al. investigated the activity of ibrutinib in 51 previously untreated and relapsed or refractory CLL patients with deletion 17p13.1 or TP53 mutation in the absence of deletion 17p13.1 in a single-arm Phase II study [46]. Patients were treated with ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. An objective response was achieved in 32 (97%) of 33 previously untreated patients. Among the 15 patients with relapsed or refractory CLL, 12 (80%) achieved an objective response, including a PR in 6 (40%) and a PR with lymphocytosis in 3 (20%) patients. The most frequent grade 3 or higher treatment-related adverse events were neutropenia (24%), anemia (14%) and thrombocytopenia (10%). In a randomized, Phase III trial (RESONATE) ibrutinib was compared with ofatumumab in patients with relapsed or refractory CLL [47]. After interim analysis, the trial was stopped early because of an improvement in PFS and OS in the ibrutinib arm. Overall, 43% of the patients in the ibrutinib arm had a PR, as compared with 4% in the ofatumumab group (p < 0.001). Additional 20% of the patients had a PR with lymphocytosis in the patients treated with ibrutinib. At a median follow-up of 9.4 months, ibrutinib significantly prolonged the duration of PFS (median not reached) in comparison with ofatumumab arm (8.1 months, p < 0.001). At 6 months, the OS rate with no disease progression was

88% in the ibrutinib group as compared with 65% in the ofatumumab group. Moreover, the OS rate at 12 months, was 90% in the ibrutinib arm and 81% in the ofatumumab arm (p = 0.001). Ibrutinib can also be a valuable drug in CLL patients who had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT) [48]. The safety profile and efficacy of ibrutinib in this patient population was similar to that observed in other patients with relapsed/refractory CLL. The study evaluating efficacy of ibrutinib in the treatment of chronic graft-versus-host disease (GVHD) is ongoing (NCT 02195869). Anti-CD20 mAbs were recently combined with ibrutinib in two studies, and encouraging safety and activity results in patients with high-risk CLL have been reported. Burger et al. treated 40 high-risk CLL patients with an ibrutinib and rituximab combination [49]. Twenty patients had deletion 17p or TP53 mutations, 13 had relapsed CLL with deletion 11q (del[11q]), and seven had a PFS shorter than 36 months after first-line chemoimmunotherapy. The treatment induced a high rate of responses with an OR rate of 95%, including 87% of PR and 8% of CR with 18-month PFS in 78.0% of the patients. Treatment was well tolerated and associated with significant improvements in quality of life (QOL). Diarrhea occurred in 25% patients, mainly grade 1 and 2, and grade 1 and 2 bleeding events were noted in 33% of the patients. Ofatumumab combined with ibrutinib was also investigated in CLL patients [50]. In a Phase Ib/II study, a total of 27 patients, including 24 with CLL/SLL and prolymphocytic leukemia and three patients with Richter transformation, were treated with ibrutinib until disease progression, followed by concomitant ofatumumab. The OR rate was 100%, with a median follow-up of 9.8 months. The most frequent grade 3 -- 4 side effects included anemia (11%), pneumonia (11%), and urinary tract infection (7%). Even better results were observed in previously untreated CLL patients. O’Brien et al. assessed the safety and activity of ibrutinib in 29 treatment-naive patients, aged 65 years and older, in open-label Phase Ib/II trial [51]. After a median follow-up of 22 months, 22 of 31 patients (71%) achieved an objective response, including 4 CR (13%), 1 (3%) nodular PR, and 17 (55%) PR. In 21 (68%) patients, diarrhea was observed including grade 2 in three patients, and grade 3 in four patients. However, some patients treated with ibrutinib demonstrated disease progression, and various mechanisms have been identified as being responsible for ibrutinib resistance, including a BTK mutation (BTKC481S) [52,53]. A way of overcoming the ibrutinib resistance demonstrated by these patients is urgently needed. Recent studies suggest that therapeutic intervention with other kinase inhibitors, such as idelalisib, spleen tyrosine kinase (SYK) inhibitors, or OSU-T315, which directly abrogates AKT activation can be particularly useful [54]. In addition, ibrutinib is an expensive drug. Some analysts estimate that it will cost $98,000 a year [42]. In February 2014, FDA granted accelerated approval


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to ibrutinib for the treatment of patients with CLL who have received at least one prior therapy. In July 2012 FDA expanded the approved use of ibrutinib for first-line treatment of patients with del(17p). The recommended dose and schedule of ibrutinib for patients with CLL is 420 mg taken orally once daily. In the UK, the cost of ibrutinib for a 4-week cycle at the list price (including VAT) is £5151 (Ibrutinib - NHS England). Inhibitors of phosphatidylinositol 3-kinase Phosphatidylinositol 3-kinases (PI3K) are a family of lipid kinases that mediate signals from cell surface receptors. The class IA PI3K isoforms (PIK3C-a, PIK3C-b, and PIK3C-d) are heterodimeric proteins that contain a p110 catalytic subunit and a p85 regulatory subunit. Expression of the PI3K p110 d isoform (PI3K-d) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. Identification of the hematopoietic-selective isoform PI3K-d unlocks a new therapeutic potential for B-cell malignancies. The PI3K-d is hyperactive in many B-cell malignancies and is critical for the activation, proliferation, survival and trafficking of B lymphocytes. Signaling via PI3K-d and PI3K-g has distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity, and on the tumor microenvironment involved in the support and maintenance of B-cell neoplasms, including CLL. Herman et al. demonstrated that PI3K has increased enzymatic activity and that its isoform, PI3K-d, is expressed in CLL-cells [55]. In addition, PI3K-d activity was found to be higher in these cells than in B-cells from healthy volunteers. Identification of the hematopoieticselective isoform PI3K-d unlocks a new therapeutic potential for CLL. Idelalisib (GS-1101, CAL-101, ZYDELIG, Calistoga Pharmaceuticals/Gilead Sciences) is a highly selective inhibitor of PI3K-d. This drug reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B-cells in lymphoid tissues [56]. Idelalisib used in monotherapy has shown substantial clinical activity and a favorable safety profile in heavily pretreated, refractory and high-risk patients with CLL [57]. The clinical observations with idelalisib include rapid lymph node shrinkage and high lymph node response rate in refractory CLL. In a Phase I study, 54 patients with relapsed/refractory CLL were treated with idelalisib at a dose of 50 -- 350 mg once or twice daily and remained on continuous therapy while deriving clinical benefit [58]. The OR rate was 72%, including 39% of PR and 33% of PR with treatment-induced lymphocytosis. The median PFS for all patients was 15.8 months. The most commonly noted grade ‡ 3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib was found to demonstrate substantial activity in older, treatment-naive patients with CLL when used as a single agent [59]. Similarly to ibrutinib monotherapy, patients treated with idelalisib combined with weekly rituximab displayed early lymphocytosis.


3.2.2

8

Idelalisib combined with rituximab was recently compared with rituximab alone in relapsed/refractory CLL patients with comorbidities [60]. In this study, combination therapy achieved a response and survival benefit compared with rituximab alone. The patients receiving idelalisib and rituximab had improved rates of OR (81%) in comparison with rituximab monotherapy (13%, p < 0.001). Median PFS was 5.5 months in the rituximab group, but was not reached in the idelalisib combined with rituximab arm (p < 0.001). Moreover, OS at 12 months was 92% for idelalisib + rituximab, compared to 80% for rituximab alone (p = 0.02). Serious AEs were similar in both arms and occurred in 40% of the patients receiving idelalisib + rituximab and in 35% of those receiving rituximab. Idelalisib and rituximab therapy is also highly active in patients with high-risk genomic markers such as del(17p), TP53 mutations, and del(11q) [61]. Another Phase III, randomized study evaluating the efficacy and safety of idelalisib in combination with ofatumumab for previously treated CLL has been initiated (NCT01659021). Idelalisib in combination with rituximab has received approval by the FDA for the treatment of relapsed CLL and is under regulatory review in the EU [57]. The annual cost of idelalisib in the UK, 150 mg orally twice daily, is £37,792 (www.scotishmedicines.org.UK) Immunomodulating agents Except for monoclonal antibodies and BCR signaling inhibitors, immunomodulating agents have been explored and have shown promise in treating CLL. Immunomodulating agents are a new class of drugs that influence the expression of various cytokines and costimulate immune effector cells. Lenalidomide (Revlimid; Celgene, Summit, NJ) is a secondgeneration thalidomide analog with possible immunomodulating and antiangiogenic properties, which may also modulate cytokine activity in the tumor microenvironment [62]. Lenalidomide induces immunomodulation in CLL and enhances antitumor immune responses mediated by NK and CD4 T-cells. Lenalidomide is orally available and has significant activity in multiple myeloma and myelodysplastic syndrome. More recently it has been shown to be effective in the treatment of CLL [63-65]. Lenalidomide has demonstrated antileukemic activity in relapsed/refractory CLL and in the front-line setting when administered as monotherapy [63-69]. As a single agent, lenalidomide induced overall response rates of 32 -- 58% of relapsed/refractory CLL [64,65]. The most common AEs include neutropenia, thrombocytopenia, fatigue and TFR. Recently, the combination of lenalidomide and rituximab has been investigated as the initial treatment of patients with CLL [66-69]. The OR rate for younger patients with a median age of 56 years was 95%, with 20% CRs. Older patients, with a median age of 75 years, less frequently completed the maximum planned therapy. In this group, the OR rate was 78% and CR rate 11%, with the median PFS values being 19 and 20 months respectively. Thompson et al. report the 3.3




initial results of lenalidomide and rituximab combination therapy used as initial treatment of CLL [67]. Fifty-eight patients were treated with 375 mg/m2 i.v. rituximab given weekly for 4 weeks then monthly during months 3 -- 12, and 10 mg p.o./day lenalidomide from day 9 for 24 months. Among 48 patients evaluated for response and toxicity, 40 responded with an OR rate of 83% including a 14.6% CR and 68.8% PR. Myelosuppression was frequently observed, but serious infections were uncommon. Grade 3 neutropenia was noted in 11 (23%) and grade 4 in 13 (27%) patients. Grade 3 thrombocytopenia occurred in 6 (13%) and grade 4 in four patients (8%). These results compare favorably with a historical lenalidomide monotherapy cohort observed in the same center. Similar efficacy was seen in older patients and in patients with unfavorable baseline characteristics, with the potential exception of patients with complex cytogenetics. Treatment was equally well tolerated in younger and older patients. Fludarabine, cyclophosphamide, rituximab (FCR-lite) in combination with lenalidomide also demonstrates encouraging clinical activity and an acceptable toxicity profile in a high-risk CLL [70]. Recently Costa et al. performed a multi-center, Phase II trial of sequential treatment with ofatumumab and lenalidomide in patients with relapsed and refractory CLL [71]. The OR rate was 47.6% and median OS was 21.5 months. Neutropenia and thrombocytopenia were the most frequent adverse events. In addition, the tumor flare reaction (TFR) occurred in 43% of patients. The study on combination of lenalidomide and obinutuzumab in patients with recurrent CLL or SLL (NCT02225275) and a Phase I study of lenalidomide, rituximab and ibrutinib in relapsed/refractory CLL (NCT02200848) has been also initiated. Preliminary results indicate that maintenance with lenalidomide is a promising and safe form of management [72]. However, lenalidomide is currently not approved for CLL patients. 4.

Current research goals

Despite progress in CLL treatment, new therapies are needed especially for relapsed/refractory patients. Among promising approaches, combining anti-CD20 antibodies with mAbs directed against other surface antigens such as CD19 or CD37, immunomodulatory drugs or inhibitors of the BCR pathway is of paramount interest. Preclinical data suggest that mAbs combined with BCR or BCL-2 inhibitors may show synergistic activity in CLL. Venetoclax was designed to block the function of the anti-apoptotic protein BCL-2. It is an orally bioavailable drug that rapidly induces responses in the vast majority of patients with relapsed or refractory CLL. The combination of this drug with mAbs has the potential to improve efficacy. It has been documented recently that venetoclax and rituximab act synergistically in preclinical models of CD20-positive lymphoid neoplasms, and the results of Phase II clinical trial with combination of both drugs have been reported recently [73]. The combination was

well tolerated. The most common overall treatment-related AEs were neutropenia (47%), nausea (41%) and diarrhea (37%). The overall response rate was 86%, and 31% of the patients achieved a CR. A Phase III trial comparing venetoclax and rituximab versus bendamustine and rituximab in patients with previously treated CLL is ongoing (NCT01671904). It is also rational to explore safe and effective maintenance treatment in CLL. Consolidation and maintenance therapy is a promising concept that can further improve response quality and duration in CLL patients. Several agents can be useful in the post-induction therapy of CLL patients, including antiCD20 mAbs, alemtuzumab, lenalidomide, and recently, the BCR signal transduction inhibitors, ibrutinib and idelalisib. However, recent findings suggest that rituximab maintenance therapy significantly increases the risk of both infection and neutropenia, and possibly other complications in patients with lymphoma or other hematological malignancies [74]. Moreover, long-term outcomes following novel therapies for CLL have rarely been reported. Today it is not clear whether prolonged administration of any drug in CLL patients can increase the development of clonal evolution and drug resistance [75]. However, better strategies are awaited for maintaining remissions in patients with CLL. In particular, further studies are needed to characterize the benefits of maintenance therapy. Moreover, effective drugs with low toxicity, optimal dosing and a schedule should be selected for future studies. 5.

Scientific rationale

Immunochemotherapy with FCR and chlorambucil combined with anti-CD20 mAbs is the standard of care for firstline CLL patients. However, few drugs are currently available after relapse and in patients with deletion of chromosome 17p. In particular, one major challenge remains to choose the best salvage strategy in high-risk and ultra-high-risk patients. Multiple new targeted agents have been used in the treatment of CLL, resulting in improved clinical outcomes. In this article we focus on the novel treatments that are being studied or already approved in the treatment of this disease. The anti-CD20 mAbs rituximab, ofatumumab and obinutuzumab are approved for the treatment of CLL. In addition, two newer anti-CD20 mAbs, veltuzumab and ocaratuzumab, have been developed and are under investigation in early clinical trials. The unique antigens present on the CLL cell surface have enabled development of several other monoclonal antibodies, including anti- CD37, CD25, CD40, Apol/TRAIL and CD19 antibodies. Application of mAbs in combination with traditional chemotherapies and newer targeted drugs result in significant improvement in clinical effects. In addition, recently several new mAbs have been developed using novel bioengineering techniques. These antibodies have the potential to improve long-term outcomes for CLL. In the treatment of CLL, there are several small molecules in various stages of clinical development that target novel aspects of CLL biology. The BCR signaling pathway has


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long been considered a potential target for therapy in CLL. The compounds that have been currently investigated in patients with CLL include ibrutinib -- inhibitor of BTK, and idelalisib (GS-1101) -- a specific isoform of the PI3K inhibitor. The activity of BCR inhibitors is observed in patients with abnormalities of the p53 pathway including those with deletion of chromosome 17p, which is the most common mechanism of resistance to chemotherapy in CLL. Further clinical development of BCR signaling inhibitors with low toxicity, optimal dosing and a schedule should be continued in future studies. The strategy of targeting BCL-2 through ABT-199 (venetoclax) and other agents is also an important step in changing the therapeutic approach in CLL treatment. The BCL-2 family of proteins is key regulators of the apoptotic process, comprising proapoptotic and prosurvival proteins. In addition, immunomodulators will likewise play a role in the treatment of CLL. CLL is characterized by a defect in microenvironment that promotes the selective survival of leukemic cells. Immunomodulatory drugs are effective drugs for CLL by altering the cytokine and cellular characteristics of the neoplastic cell microenvironment. Lenalidomide is well-studied immunomodulatory drug produced with the goal of enhancing the immunomodulatory potential and improving the drug’s safety profile in comparison with thalidomide. Monoclonal antibodies appear as an appropriate drug for combination with BCR and BCL-2 inhibitors, for example ibrutinib, idelalisib or venetoclax. The combination of new non-chemotherapeutic agents can alter the treatment of CLL and may lead to create therapy that is both more effective and less toxic. Well-designed, carefully controlled, randomized clinical trials should confirm any advantages attributable to develop new strategies over current standard therapies. 6.

Competitive environment

Novel monoclonal antibodies In addition to anti-CD20 mAbs, antibodies targeting CD37, CD19 and other targets may have clinical applications in CLL (Table 3). Development of these antibodies for the treatment of CLL, particularly for patients resistant or refractory to anti-CD20 mAb therapy or relapsing after such treatment is particularly important. 6.1

New anti-CD20 antibodies Several new anti-CD20 mAbs directed against malignant and nonmalignant B-cells have been developed and some of them introduced to the clinical practice [76]. The new anti-CD20 antibodies have even higher clinical efficacy and/or fewer side effects than rituximab. Ocaratuzumab (AME-133v, LY2469298, Mentrik Biotech/Eli Lilly and Company) is a type I, third-generation, humanized, Fab- and Fc-engineered IgG1 anti-CD20 mAb. It was optimized through protein engineering for increased CD20 affinity and greater ability to mediate ADCC [77]. In 6.1.1

10

preclinical studies, ocaratuzumab is ~ 20 times more effective at mediating ADCC at very low concentrations that may facilitate sub-cutaneous dosing [78]. This antibody induces higher NK cell-mediated ADCC over rituximab and ofatumumab and in a similar way to obinutuzumab. Further studies are needed to establish the role of ocaratuzumab in the treatment of patients with CLL. Veltuzumab (IMMU-106, hA20, Immunomedics, Inc., Morris Plains, NJ, USA) is a second-generation humanized anti-CD20 mAb, which is structurally and functionally different from rituximab [79]. This antibody differs from rituximab by one amino acid in the complementarity-determining region 3 of the variable heavy chain. In addition, it has completely different framework regions. Its anti-proliferative, apoptotic, and ADCC activity effects in vitro are very similar to those of rituximab, as is its antigen-binding specificity, binding avidity and dissociation constant. However, it has enhanced binding avidities and a stronger effect on CDC compared with rituximab [80]. Recently, a multicenter, Phase I/II study was undertaken to evaluate the safety and efficacy of subcutaneous formulation of veltuzumab patients with untreated or relapsed CLL [81]. In this study, 20 CLL patients received four doses of veltuzumab given every other week at 80, 160, or 320 mg or 16 doses of the drug administered twice weekly at doses of either 160 or 320 mg. After treatment, 15 of 18 evaluable patients achieved either PR or stable disease (SD) and the number of leukemic cells in peripheral blood decreased in all patients by 7.7 -- 90.8%. These results indicate that veltuzumab administered subcutaneously is convenient, well-tolerated, and active in CLL patients. Anti-CD37 antibodies CD37 is a tetraspanin protein, which consists of four potential membrane-spanning regions, highly expressed on CLL cells [82,83]. The relative lineage restriction of CD37 to B-cells makes it an ideal target for immunotherapy of B-cell malignancies. It may be advantageous to target CD37 over CD20 in CLL because the level of CD37 expression is higher in this disease than that of CD20. The predominant expression of CD37 on CLL cells makes it an ideal candidate as a target for therapeutic antibodies [84,85]. Anti-CD37 antibodies may be useful for patients with CLL, particularly resistant or refractory to anti-CD20 mAb therapy or relapsing after such a treatment. The development of these is followed with great interest by laboratory investigators and clinicians. Potentially useful anti-CD37 antibodies in the treatment of CLL include otlertuzumab, BI 836826 and IMGN529. Otlertuzumab (TRU-016, Emergent BioSolutions, Inc.) is a humanized anti-CD37-engineered protein, produced using ADAPTIR Modular Protein Technology [86]. ADAPTIR proteins may mediate CDC and Fc-dependent cytotoxicity in a similar way to mAbs and can generate a unique signaling response. Otlertuzumab includes anti-CD37 variable regions linked to an immunoglobulin constant domain, produced by humanizing the precursor agent SMIP-016. SMIP-016 is 6.1.2



Fully human recombinant anti-CD40 IgG1 mAb Humanized IgG1 antibody mAb against CD38

MedImmune/Astra Zeneca

Immunomedics

Novartis Pharmaceuticals

Genmab/Janssen Biotech, Inc.

MEDI-551

Milatuzumab (hLL1, IMMU-115)

Lucatumumab (HCD122, CHIR-0.12.12) Daratumumab (HuMax-CD38)

B-cell lymphoid malignancies, autoimmune disorders, graftversus- host disease Tested CLL, MM, and non-Hodgkin’s lymphoma (NHL) Clinical activity in relapsed/refractory MM

B-cell lymphoma and acute lymphoblastic leukemia B-cell lymphoid malignancies and autoimmune disorders

B-cell lymphoid malignancies


B-cell lymphoid malignancies -- CLL and NHL



Indication

No clinical trials in CLL yet

Clinical activity in relapsed and refractory CLL in a Phase I study

Phase II study in patients with CLL and other B-cell malignancies ongoing (NCT02005289) Phase I/II study in R/R advanced B-cell malignancies completed, Phase II study in relapsed or refractory CLL ongoing (NCT01466153) The drug is currently being tested for CLL, NHL and multiple myeloma (NCT00603668, NCT00868478)

Phase I study in B-cell NHL (NCT01534715)

Phase I clinical trial in refactory/ relapsed CLL (NCT01296932)

Completed studies in pretreated NHL, Phase I study of subcutaneous formulation in pretreated CD20+BCell malignancies (NCT01858181) Phase I/II study of subcutaneous formulation in untreated or relapsed CLL and NHL completed (NCT00546793) Efficacy against CLL in Phase I study, preliminary response in combination with rituximab and bendamustine


NK cell-mediated ADCC and CDC, ADCP, cell death by directly inducing cytotoxicity

Blocks interaction of CD40L with CD40 and mediates ADCC

Alteration B-cell migration, and adhesion molecule expression, reducion B-cell proliferation

ADCC and ADCP

Directly cytotoxicity to human CLL; promotes killing by macrophages and NK cells. Enhanced binding of FcgammaRIIIa

ADCC and direct pro-apoptotic activity

NK cell mediated killing and induction of apoptosis

Increased CD20 affinity and greater ADCC than rituximab, ofatumumab and similar to obinutuzumab Apoptotic, and ADCC activity similar to rituximab stronger CDC

Mechanism of action

ADCP: Antibody-dependent cellular phagocytosis ; ADCC: Antibody-dependent cell mediated cytotoxicity; CDC: Complement-dependent cytotoxicity; MM: Multiple myeloma; NHL: Non-Hodgkin’s lymphoma; R/R: Relapsed and refractory.

Fully humanized IgG1 mAb against CD74

MorphoSys AG

MOR208 (XmAb5574)

Humanized engineered protein, includes anti-CD37 variable regions linked to an immunoglobulin constant domain. Chimeric, Fc-engineered IgG1-type of anti-CD37 antibody Anti-CD37 K7153A antibody conjugated to the maytansinoid, DM1 Humanized IgG1 anti-CD19 mAb with engineered Fcdomain Affinity-optimized and afucosylated humanized IgG anti-CD19 mAb

ImmunoGen, Inc.

Emergent BioSolutions, Inc.

Otlertuzumab (TRU-016)

Humanized anti-CD20 mAb

IMGN529

Immunomedics, Inc., Morris Plains

Veltuzumab (IMMU-106, hA20)

Humanized, Fab- and Fcengineered IgG1 anti-CD20 mAb

Boehringer Ingelheim Pharmaceuticals

Mentrik Biotech/Eli Lilly and Co.

Ocaratuzumab (AME-133v, LY2469298)

Structure

BI 836826 (mAb 37.1)

Company

Compound

Table 3. Novel monoclonal antibodies potentially useful in CLL.



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a single-chain monospecific protein that retains Fc-mediated effector functions [86-88]. In preclinical studies this agent was found to use a distinct mechanism of apoptosis from those of agents other used for CLL treatment. Otlertuzumab mediated greater NK cell-mediated killing of CLL cells as compared to either alemtuzumab or rituximab and mediates superior direct apoptosis of CLL and other B-cell malignancies. Moreover, otlertuzumab acts synergistically with ofatumumab and bendamustine [85]. A Phase I study investigated the safety and preliminary efficacy of otlertuzumab administered intravenously to patients with relapsed/refractory CLL [89]. Otlertuzumab was given weekly for up to 8 weeks followed by one dose per month for 4 months. The doses ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 -- 30 mg/kg in the dose-expansion phase. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab was well tolerated with minimal infusional toxicity. Only PR was noted in 19 (23%) of 83 treated patients, more commonly in patients with symptomatic untreated CLL. The preliminary response rate with otlertuzumab in combination with rituximab in patients with CLL is promising [90], and a Phase Ib trial was conducted to evaluate the safety and efficacy of this combination. The IWCLL response rate was 54% including 8% CR and median progression-free survival is 16 months. Recently, a randomized trial of otlertuzumab combined with bendamustine versus bendamustine alone was performed in patients with relapsed CLL who had undergone 1 -- 3 prior therapies [91]. The patients received otlertuzumab at a dose of 20 mg/kg weekly by i.v. infusion for two 28-day cycles then every 14 days and bendamustine at a dose of 70 mg/m2 i.v. on days 1 and 2 of each cycle. In the control arm, bendamustine (70 mg/m2) was given i.v. on days 1 and 2 of each cycle. Sixty-five patients were included in the study and 32 received otlertuzumab plus bendamustine. A higher response rate was observed in patients treated with otlertuzumab + bendamustine (75%) than in patients treated with bendamustine alone (52%), with the CR rates observed in the two arms being 48 and 9%, respectively. A higher rate of neutropenia was observed, but no greater rate of infection was seen in the otlertuzumab + bendamustine arm. These results indicate that otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. BI 836826 (mAb 37.1, Boehringer Ingelheim Pharmaceuticals) is a chimeric IgG1-type of anti-CD37 antibody with superior in vitro effects on CLL cells than the mAbs in current clinical use for CLL. It has been Fc-engineered to improve ADCC activity and enhance affinity for Fc-gRIIIa. BI 836826 displays also direct pro-apoptotic activity. Both BI 836826 and its humanized version, MAb 37.2, deplete CLL cells in vitro more effectively than rituximab and alemtuzumab [92]. Preliminary in vitro data indicates that BI 836826 can be used in combination with idelalisib for treatment of high-risk CLL. These agents offer the added benefit of directly 12

killing inhibitor-resistant P53-null primary CLL cells, while lacking complete inhibitor-induced ADCC ablation [93]. BI 836826 is investigated in a Phase I clinical trial in refactory/ relapsed CLL patients (NCT01296932). IMGN529 (ImmunoGen, Inc.) is a novel anti-CD37 antibody-drug conjugate consisted of K7153A antibody conjugated to the maytansinoid, DM1, an anti-microtubule agent, via the thioether linker, SMCC [94]. Preclinical studies have documented that IMGN529 is directly cytotoxic to human CLL cells, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells [94]. In addition, this agent rapidly eliminated peripheral blood leukemia and improved overall survival in a CD37 transgenic murine leukemia model [95]. These results support evaluation of the CD37-targeted antibodies in clinical trials in patients with CLL. Anti-CD19 antibodies CD19 is a transmembrane protein that forms a signaling complex together with CD21, CD81 and CD225 [96]. This molecule is expressed early during pre-B cell ontogeny and until terminal differentiation into early plasma cells. It is an excellent tumor target for antibody therapy of CLL patients as it is not expressed on hematopoietic stem cells or other normal tissue. Many studies have shown that the antibodies recognizing this antigen hold clinical therapeutic potential in B-cell lymphoid malignancies. Several anti-CD19 mAbs are being explored for clinical applications in B-cell lymphoid malignancies, including MOR208, MEDI-551 and blinatumomab. However, only MOR208 is under investigation in patients with CLL. MOR208 (XmAb5574, MorphoSys AG) is a novel humanized IgG1 anti-CD19 mAb with an engineered Fc-domain incorporating two substituted amino acids within the Fc portion designed to enhance the binding of Fcgamma RIIIa [97]. The ADCC of MOR208 is 100 -- 1000 times greater than that of the anti-CD19 IgG1 analog against a broad range of B-lymphoma cell lines, acute lymphoblastic leukemia and mantle cell lymphoma cells. The MOR208dependent ADCC is mediated by natural killer (NK) cells through a granzyme B-dependent mechanism [97]. In vivo, MOR208 significantly inhibited lymphoma growth in mouse xenograft models and showed more potent antitumor activity than its IgG1 analog. In nonhuman primates, MOR208 infusion caused immediate and dose-related B-cell depletion in the blood [98]. In the first clinical study, MOR208 was found to have a tolerable toxicity profile and preliminary evidence of antitumor activity was observed in high-risk patients with relapsed/refractory CLL [99]. Grade 1 or 2 infusion reactions were observed in 18 of 27 patients (67%). Responses occurred at the 6, 9, and 12 mg/kg dose levels. A Phase II study of this agent in patients with CLL and other B-cell malignancies is ongoing (NCT02005289). MEDI-551 (MedImmune/Astra Zeneca) is an affinityoptimized and afucosylated humanized IgG anti-CD19 mAb 6.1.3




[100]. It is an a-fucosylated antibody with increased affinity for human FcgRIIIA, mediating both ADCC and antibodydependent cellular phagocytosis (ADCP). MEDI-551 inhibits tumor growth in preclinical models of B-cell malignancies [101]. In a Phase I/II study, 91 patients with relapsed or refractory advanced B-cell malignancies, including 26 patients with CLL, received monotherapy with MEDI-551 [102]. The OR responses to single-agent MEDI-551 was 24% in CLL, 24% in DLBCL and 31% in FL. Median PFS was 9 months. A Phase II study of MEDI-551 in combination with bendamustine in relapsed CLL patients is currently ongoing (NCT01466153). GBR 401 (Glenmark) is a defucosylated humanized mAb targeting the domain II of CD19 and derived from the parental mouse anti human CD19 antibody clone FMC63 [103]. This antibody exerts potent in vitro and in vivo cytotoxic activity against human malignant B-cells mainly in the mechanism of ADCC. In addition, GBR 401 prolongs mouse survival in SCID mouse models [104]. SAR-3419 (Sanofi-Adventis) is an antibody-drug conjugate combining the maytansinoid DM4 tubulin inhibition with the B-cell selectivity of a humanized anti-CD19 antibody [105]. It is an effective novel therapeutic agent for ALL and refractory/relapsed patients with NHL [106]. However, whereas SAR3419 offers promise in the treatment of CLL, it has not yet been fully investigated in that regard. Blinatumomab (MEDI-538, MT103, BLINCYTO, Amgen) is a bispecific T-cell antibody targeting CD19 antigen that can effectively redirect T-cells for highly selective lysis of CD19+ target cells [107]. It belongs to the class of bispecific T-cell engagers (BiTE) with potential immunostimulating and antineoplastic activities. BiTE antibodies are genetically engineered single-chain antibodies that use a linker combining two variable regions of a normal antibody with different specificities. Single-agent blinatumomab showed antileukemic activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia characterized by negative prognostic factors [108]. In 2014, the FDA granted approval of blinatumomab for the treatment of patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. Blinatumomab also offers potential for CLL therapy, but the recent study has been withdrawn prior to enrollment (NCT00676871).

Other antibodies potentially useful in CLL Monoclonal antibodies directed against CD22, CD23, CD74 and CD40 also have shown some activity and are potentially useful in the treatment of CLL. CD22 is a 135 kDa B-cell-specific transmembrane sialoglycoprotein expressed in the cytoplasm of virtually all B-lineage cells but expressed on the B-cell surface only at mature stages of differentiation on B-cells [109]. It is expressed in ~ 70% of B-cell leukemias but not expressed on plasma cells, memory B-cells, stem cells, monocytes and T-cells. CD22 is a negative regulatory molecule of the BCR signal leading to inhibition of 6.1.4

B-cell activation and an adhesion receptor for the homing of re-circulating IgD-positive B-cells [110]. Several anti-CD22 immunotoxins, including inotuzumab, ozogamicin, moxetumomab pasudotox, anti-CD22-MCC-DM1, DCDT2980S and combotox, are currently under clinical investigation in B-cell malignancies [111]. Whereas some have shown promising anti-CLL activity in preclinical studies, clinical data remains insufficient [112]. The CD23 antigen is a low-affinity Ig E receptor expressed on the majority of CLL cells [113]. Lumiliximab (Biogen Idec) is a genetically engineered chimeric monoclonal antibody against CD23 that induces ADCC and CMC in CD23-bearing lymphoid cell lines. In a Phase I trial, lumiliximab demonstrated clinical activity and acceptable toxicity in patients with relapsed or refractory CLL [114]. Subsequently, lumiliximab has been combined with fludarabine, cyclophosphamide and rituximab (FCR) in a Phase I/II study in previously treated CLL patients, giving an OR rate of 65% and CR rate of 52% [115]. However, a randomized trial (LUCID trial) in relapsed CLL failed to confirm any advantage of the lumiliximab + FCR combination over FCR alone [116]. CD74 is a type II transmembrane protein associated with the a- and b-chains of HLA-DR expressed on B-cells. This molecule regulates chemo-attractant migration of macrophages and dendritic cells and is directly involved in the maturation of B-cells through the nuclear factor NF-kappa B [117]. Milatuzumab (IMMU-115, hLL1, Immunomedics) is a humanized mAb-directed against CD74 that rapidly internalizes [118]. Milatuzumab induces direct cytotoxicity with low ADCC and CDC. Milatuzumab demonstrated antiproliferative activity in transformed B-cell lines and improved survival in preclinical models. The drug is currently being tested for the treatment of multiple myeloma, non-Hodgkin’s lymphoma and CLL (NCT00603668, NCT00868478). CD40 is a transmembrane glycoprotein costimulatory molecule expressed on various antigen-presenting cells (APCs) as well as some tumor cells, including CLL cells [119]. It is a member of the tumor necrosis factor (TNF) receptor superfamily. Dacetuzumab and lucatumumab are the antiCD40 mAbs in the most advanced stage of development as treatment for CLL. Dacetuzumab (SGN-40, Seattle Genetics, Inc., Bothell, WA) is a humanized version of a murine antihuman CD40 mAb S2C6, which mediates ADCC and ADCP, and induces apoptosis in CD40-positive lymphoid cells [120]. In preclinical studies dacetuzumab has shown synergy with rituximab, lenalidomide or combination chemotherapy [121]. In a Phase I study, stable disease was observed after one cycle of therapy in 5 of 12 patients with refractory CLL [122]. Lucatumumab (HCD122, CHIR-0.12.12; Novartis Pharmaceuticals) is a fully human recombinant anti-CD40 IgG1 antibody that blocks the interaction of CD40L with CD40. It also mediates ADCC and inhibits the growth and survival of malignant B-cells [123]. In preclinical studies the lysis of the B-cells was higher with lucatumumab than with


13


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rituximab [124]. Byrd et al. have reported the results of with lucatumumab in 24 relapsed and refractory CLL [125]. In a Phase I study, the drug was found to have some clinical activity in relapsed and refractory CLL with one PR and stable disease in 17 of 24 treated patients. Daratumumab (HuMax-CD38, Genmab/Janssen Biotech, Inc.) is a humanized antibody against CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. In Phase I and II clinical trials, this antibody has demonstrated significant reduction in serum M-protein and bone marrow plasma cell percentage in refractory patients, with an acceptable toxicity profile in patients with multiple myeloma [126]. However, daratumumab also offers potential in other hematological neoplasms with CD38 expression, including CLL, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, follicular lymphoma and mantle cell lymphoma. In preclinical studies, daratumumab expressed Fc-mediated cell killing activity via CDC, ADCC and ADCP in primary CLL cells and leukemic cells from CLL patients [127]. In addition, daratumumab significantly prolonged overall survival of animals in a CLL mouse model [128]. These results warrant further investigation of daratumumab in clinical trials for CLL. New BTK inhibitors In recent years, several other BTK inhibitors have been developed to target and disrupt the survival of normal B-cells and their malignant counterparts. The most promising are spebrutinib, ONO-4059, GDC-0834, CGI-560, CGI-1746, HM-71224, CNX-774 and FM-A13 (Table 4) [38]. Spebrutinib and ONO-4059 are currently in clinical trials. ONO-4059 (Ono Pharmaceuticals Ltd/Gilead Sciences, Inc.) covalently binds to BTK and reversibly blocks BCR signaling and B-cell proliferation and activation. ONO-4059 is a more specific BTK inhibitor than ibrutinib. This compound demonstrated anti-tumor activity in pre-clinical models and in the clinic in both CLL and NHL patients. ONO-4059 has a favorable safety profile along with promising efficacy over a long duration in heavily pre-treated CLL, including refractory and currently poor prognostic 17p-deleted patients [129]. In an ongoing Phase I study, ONO-4059 was administered at doses ranging from 20 to 600 mg in 25 heavily pretreated CLL patients. The drug was well tolerated with few adverse reactions over a long duration. Rapid reductions in lymphadenopathy were observed in all patients in cycle 1 and cycle 3, accompanied by an increase in absolute lymphocyte count in 72% of patients. The overall response rate was 84%, with 17 PR and 4 PR with lymphocytosis for 21 responding patients. Spebrutinib (AVL-292, CC-292, Avila Therapeutics, Inc./Celgene) is another orally available drug that forms a covalent bond on its BTK target and silences its activity. Spebrutinib was well-tolerated across the first two dose levels of 125 mg -- 400 mg [130]. At each dose level, spebrutinib was administered orally once per day on a continuous basis. 6.2

14

Similarly to ibrutinib, in patients with CLL, absolute lymphocyte counts increased within four weeks of treatment initiation. An ongoing Phase Ib clinical trial of spebrutinib is being conducted in patients with B-cell malignancies including B-cell NHL, CLL, and Waldenstrom’s macroglobulinemia (NCT01351935). New inhibitors of phosphatidylinositol 3-kinase Duvelisib (IPI-145, Infinity Pharmaceuticals, Inc.) is a novel dual inhibitor of PI3K-d and -g that was initially developed as an anti-inflammatory drug [131]. However, this agent has also shown clinical activity in patients with relapsed/refractory CLL, including those with poor prognostic risk factors. Duvelisib antagonizes BCR crosslinking activated pro-survival signals and causes directly kills I primary CLL cells [132]. Importantly, duvelisib overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Duvelisib causes direct killing in primary CLL cells in a dose- and time-dependent fashion. However, it does not directly interact with normal B-cells. In addition, pharmacodynamic data demonstrates that duvelisib inhibits pAKT in CLL patients, including those with an IBR-resistance mutation in BTK [133]. Among 54 patients treated with duvelisib by O’Brien et al., the best observed OR rate was 55% in a heavily pretreated CLL population [134]. Treatment emergent adverse events were predominantly grade 1 -- 2. The most common grade 3 or higher AEs were transient cytopenias including neutropenia (31%), thrombocytopenia (11%) and febrile neutropenia (15%). Duvelisib is currently being evaluated in the Phase III setting as monotherapy for CLL (NCT02004522). Acalisib (GS-9820, CAL-120, Calistoga Pharmaceuticals/ Gilead Sciences) is a second-generation, class I PI3K - b/dspecific inhibitor. Interim analysis of a dose-escalation Phase Ib study in patients with recurrent lymphoid malignancies demonstrates that it has clinical activity and acceptable toxicity [135]. A Phase Ib, open-label, dose-escalation study to evaluating the safety and antitumor activity of GS-9820, administered alone and in combination with rituximab in CLL and other lymphoid malignancies, is ongoing (NCT01705847). Buparlisib (NVP-BKM120, BKM120; Novartis) is an orally bioavailable 2,6-dimorpholino pyrimidine derivative selective pan class I PI3K inhibitor, which has entered clinical trials for solid tumors, and T-cell lymphoid malignancies. This drug exerts its effects in a p53-dependent manner with p53 wild-type cells undergoing apoptosis. In p53-mutant/ deleted cells mitotic catastrophe through the regulation of Aurora B kinase protein was observed [136]. In vivo administration of buparlisib to a subcutaneous xenotransplant model of human T-ALL delayed tumor growth and prolonged survival time. A Phase II study in patients with primary central nervous system lymphoma and recurrent/refractory secondary central nervous system lymphoma is ongoing (NCT02301364). 6.3



Novartis

Piramed Ltd/F. Hoffmann-La Roche/ Genentech

Buparlisib (NVPBKM120, BKM120)

Pictilisib (GDC-094, RG7321)

O

N

Cl

N

NH

O S

O

F

F

N

N

N

N

O

N

O

N H

S

O

N

N

F

F

N

N

N H

N

N

O

F

N H

N

H N

O

HN

O

Structure unavailable

Structure

N

N

N

NH

NH

NH2

N

N

N

N

N

O

Investigated in R/R CLL (NCT02340780) and NHL (NCT01719250) and central nervous system lymphoma (NCT02301364)

Phase Ib study evaluating GS-9820 in patients with lymphoid malignancies (NCT01705847)

Phase Ib/II study of IPI-145 + FCR in untreated CLL (NCT02158091); Phase III study of IPI-145 versus ofatumumab in R/ R CLL/SLL (NCT02004522: IPI-145 with obinutuzumab in CLL/SLL previously treated with BTK inhibitor (NCT02292225)

Clinical activity in Study on the bioavailability of in healthy solid tumors, CLL volunteers completed (NCT02092831), and NHL several ongoing or completed studies in solid tumors, Phase I study for NHL completed

Solid tumors and lymphoid malignancies

Lymphoid malignancies

Solid tumors and lymphoid malignancies

Biological and early clinical activity in CLL

Mechanism of action

Potent PI3K inhibitor; IC50 3, 3, 33 and 75 nM for p110a, p110d, p110b and p110g, respectively, more active compared with idelalisib against MCL

Selective PI3K inhibitor of p110a/b/d/g with IC50 52 nM/166 nM/116 nM/ 262 nM,respectively

Class I PI3K highly selective and potent p110d inhibitor with 114- to 400-fold selectivity over the other class I PI3K enzymes with IC50 of 14 nM

PI3K-d,g inhibitor, antagonizes BCR crosslinking activated pro-survival signals in primary CLL cells with IC50 of 23 pM/243 pM and 1 nM/50 nM

Selectively inhibits BCR signaling and B-cell proliferation and activation with IC50 of 22 nM Early clinical development for CLL and Highly selective BTK inhibitor with IC50 related B-cell lymphoproliferative disorders of < 0.5 nM (NCT01351935)


Clinical activity in Phase I study as monotherapy in R/R NHL CLL and NHL and CLL (NCT01659255)

Indication

BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; CLL: Chronic lymphocytic leukemia; IC50: 50% inhibitory concentration; MCL: Mantle cell lymphoma; NHL: Non-Hodgkin lymphoma; PI3K: Phosphatidylinositol3-kinase; R/R: Relapsed and refractory.

Calistoga Pharmaceuticals/Gilead Sciences

Acalisib (GS-9820, CAL-120)

Duvelisib (IPI-145)

Infinity Pharmaceuticals, Inc.

Ono Pharmaceuticals LTD/Gilead Sciences, Inc. Avila Therapeutics, Inc./Celgene

ONO-4059

Spebrutinib (AVL-292, CC-292)

Company

Compound

Table 4. Novel BTK and PI3K inhibitors potentially useful in CLL.



15

P. Robak et al.


Pictilisib (GDC-094, RG7321, Piramed Ltd/Genentech, Inc.) is a highly specific PI3K inhibitor of class I PI3Ks with some activity against mTOR [137]. The drug is currently being investigated for use in solid tumors as well as NHL. A Phase I, open-label, dose-escalation study has recently been completed for NHL, and Phase II trials have been initiated (NCT00876122). Pictilisib also displays anti-proliferative and pro-apoptotic effects and is active against primary T-cell acute lymphoblastic leukemia (T-ALL), from wild-type and Kras (G12D) mice [138]. Buparlisib and pictilisib have not been investigated in CLL yet. However, they have a potential for antileukemic activity in this disease. Bcl-2 inhibitors Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. The dysregulation of Bcl-2 family proteins results in the inhibition of apoptosis and uncontrolled proliferation of B-cells, leading to the development of many hematological malignancies and contributing to the development of resistance to chemotherapy. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. Therapeutic modulation of the Bcl-2 pathway represents a promising new therapeutic strategy in this disease [139]. Currently, a number of small molecules binding to anti-apoptotic inhibitors of Bcl-2 family are undergoing preclinical and clinical study [140]. Among the various small molecules that have entered preclinical studies, only navitoclax (ABT-263), venetoclax (ABT-199) and obatoclax (GX15-070) are under clinical trials for CLL; the others display limited therapeutic activity as single agents [141,142]. Navitoclax (ABT-263, Abbott Laboratories) is a first generation, NOXA-like BH3 mimetic developed for apoptosis-based therapy for CLL. Navitoclax inhibits Bcl-2 and other members of the same protein family. This agent binds with high affinity to Bcl-XL, Bcl-2 and Bcl-w, but not Mcl-1 or A1 [143,144]. In a CLL Phase I study including 26 patients with relapsed or refractory disease, PR was achieved in 35% of patients, an additional seven patients had stable disease for > 6 months and the median PFS was 25 months [145]. Activity was observed in patients with fludarabine-refractory disease, bulky lymphadenopathy, and del(17p) CLL. However, thrombocytopenia due to BCL-x(l) inhibition was a frequent toxic event. Venetoclax (GDC-0199, ABT-199, RG7601; Genentech/ AbbVie) is a small-molecule, orally bioavailable, Bcl-2 specific inhibitor [146]. The molecular mechanism of venetoclax was established by studies demonstrating that the drug is efficient at disrupting Bcl-2 [147]. The agent is highly selective for Bcl2, binding to it more avidly than to BCL-XL by > 3 orders of magnitude [25]. It binds to BCL- XL and BCLW but not to MCL1. The affinity of this agent for Bcl-2 (Ki < 0.10 nM) is > 500-times higher than for BCL-XL (Ki = 48 nM). Venetoclax is likely to play an important role in the future therapy of CLL. It induces apoptosis in CLL cells at concentrations 10-fold lower than those required by navitoclax. In addition, 6.4

16

a 200-fold higher concentration of venetoclax was required for induction of platelet apoptosis compared with navitoclax [148]. Unfortunately, venetoclax also induces the tumor lysis syndrome (TLS), in which the debris of dying cancer cells overwhelms the kidney and other organs. Venetoclax was evaluated in a Phase I study in 56 patients with relapsed/refractory CLL [149,150]. A single oral dose was administered followed by 6 days off drug, before continuous once-daily dosing. The OR rate was 85%, including 7 (13%) patients achieving a CR. Efficacy was independent of del (17p) and fludarabine-refractory disease. The most common non-hematological adverse events (AEs) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). In addition, the tumor lysis syndrome (TLS) was a frequent event. Venetoclax and rituximab demonstrate synergy in preclinical models of CD20positive lymphoid malignancies. The combination of these two agents has the potential to improve efficacy and was recently evaluated in a Phase II study [151]. The treatment was well-tolerated and induced an OR rate of 86% including 31% CRs in patients with relapsed or refractory CLL. An ongoing Phase Ib study evaluated the safety and tolerability of venetoclax given in combination with bendamustin and rituximab in relapsed/refractory or previously untreated CLL patients. Although five patients were identified as medium or high risk for TLS, none developed TLS [142]. In a Phase Ib study evaluating the safety and tolerability of this combination, the drugs were safely administered at the doses given and no clinical TLS was observed. A Phase III study comparing the combination of venetoclax and rituximab with a combination of bendamustine and rituximab in patients with previously treated CLL is ongoing (NCT02005471). PD-1/PD-L1 inhibitors In CLL both cellular and humoral immunity are impaired with qualitative and quantitative defects in B-cells, T-cells, NK cells, neutrophils and the monocyte/macrophage lineage [152-154]. Therapeutic agents that target immune checkpoints should enhance and improve endogenous antitumor response and clinical outcome in patients with preexisting antitumor immunity. In recent years, special attention has been awarded to the role of programmed death-1 (PD-1), an inhibitory receptor, and its ligands PD-L1 or PD-L2 in the negative control of cancer progression. These proteins have been described as key regulators of T-cell responses. PD-1 inhibits T-cell activation when engaged by its ligands expressed on tumor cells and/or stromal cells [155,156]. Blocking the interaction between the PD-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. PD-1 is expressed by activated T-cells, activated B-cells, NK cells, and myeloid cells. PD-L1 and to a lesser extent, PD-L2 are also expressed on many human hematological malignancies [157]. These proteins are also expressed on CLL cells and are strongly upregulated in patients with this form of leukemia [156,158]. Blocking the PD-1/PD-L1 axis using 6.5




monoclonal antibodies has resulted in promising results in different malignancies. The anti-PD-1 and anti-PD-L1 agents, particularly the monoclonal antibodies pidilizumab (formerly CT-011) and nivolumab, have been reported to have impressive antitumor effects in lymphoid malignancies, follicular lymphoma and Hodgkin’s lymphoma [159,160]. Targeting PD-1 or PD-L1 may also be a valid strategy in CLL. In a Phase I dose-escalation study of pidilizumab, evidence of response was noted in 6 of 18 patients with advanced hematologic malignancies [161]. Of the three CLL patients who were included in this study, two stable diseases were observed. Chimeric antigen receptor (CAR) T-cell therapy Recently, a novel therapeutic approach in CLL has been taken, which involves chimeric antigen receptor (CAR) T-cell therapy. CD19 is a promising anticancer target because it is broadly expressed on normal and malignant B-cells through several stages of maturation but is absent on pluripotent stem cells. CART-19 (CTL019) therapy involves adoptive transfer of autologous T-cells genetically modified via lentiviral transduction to express chimeric antigen receptors (CAR) designed to target CD19+ cells (CART-19, CTL019) [162,163]. In patients with refractory or relapsed CLL, CART-19 therapy has shown to have potent antileukemic activity, with longterm persistence of transduced cells at doses from 1.4 107 to 1.1 109 CART-19 cells. The results of a clinical trial that included 14 patients with heavily pretreated, relapsed and refractory CLL have been recently presented [164]. The overall response rate was 57% including a CR in four patients (29%) and a PR in four (29%) patients. In some patients, CAR-modified T-cells have been detected by flow cytometry later than 3 years after infusion correlating with a similar remission duration of > 3 years. CART-19 therapy may overcome many limitations of conventional therapies and induce remission in patients with refractory/relapsed CLL, including patients with p53-deficient CLL [162-164]. A limitation of the current autologous approach is that CAR T-cells must be manufactured on a “per patient basis”. 6.6

7.

Potential development issues

The introduction of anti-CD20 mAbs and BCR inhibitors has revolutionized the treatment of CLL. Approved mAbs are well-tolerated and effective drugs in CLL. In addition, they can be administered in combination with a wide variety of products. Recently, chemotherapy-free immunotherapeutic approaches have been developed for patients with CLL. A combination of mAbs with ibrutinib and other BCRtargeted therapies can accelerate and improve the response rate and duration. However, despite high efficacy of approved mAbs and BCR inhibitors in CLL patients, resistance to this drug exists. Resistance to rituximab and ofatumumab can occur due to loss of CD20 as a consequence of trogocytosis [165,166]. In addition, resistance can be due to internalization of the mAb--CD20 complexes by B-cells [167].

Resistance can also develop due to the effector mechanism exhaustion [168,169]. Rituximab-mediated internalization may contribute to treatment failure of mAb therapy in CLL patients. Acquired resistance to ibrutinib is mainly due to recurrent mutations in BTK and PLCg2. A way of overcoming the resistence to mAbs and ibrutinib is urgently needed. Recent studies suggest that therapeutic intervention with other kinase inhibitors, such as idelalisib, spleen tyrosine kinase (SYK) inhibitors, or OSU-T315, which directly abrogates AKT activation can be particularly useful [54]. The clinical application of anti-CD37 and anti CD-19 mAbs is very limited compared with the approved antiCD20 mAbs. In addition, with the introduction of the BCR-targeted therapies the therapeutic scenario for CLL has changed significantly. Further studies should clarify whether the new mAbs and BCR inhibitors are better tolerated and more effective than chemotherapeutic agents combined with currently approved anti-CD20 mAbs. Novel mAbs, kinase inhibitors and BCL-2 inhibitors will form the basis for innovative therapeutic strategies. In addition, several recent studies have demonstrated the activity of CAR T-cell in heavily pretreated patients with CLL. Further studies should clarify whether these new agents have the potential to improve the treatment results in patients with CLL. 8.

Conclusion

In recent years, therapies for patients with CLL have progressed from providing palliative relief to inducing CR and eradicating MRD. In particular, chemoimmunotherapy combining anti-CD20 mAb, rituximab, ofatumumab and obinutuzumab with purine nucleoside analogs and/or alkylating agents has been a substantial advance for patients with CLL, which has resulted in increased OR, PFS and OS rates. More recently, several new mAbs, including anti-CD20, anti-CD37 and anti-CD19 mAbs, have been developed and investigated in preclinical studies and early clinical trials. Among the inhibitors of the BCR pathway, the BTK inhibitor ibrutinib and the PI3K inhibitor idelalisib might soon become key treatment of CLL due to their high potency and favorable toxicity profile. The most mature data is currently available for these drugs in patients with CLL. Recent reports indicate that BTK inhibitors combined with rituximab offer major and rapid reductions in lymphadenopathy and longer tumor control. Data about the safety of ibrutinib and idelalisib, especially in long-term applications, are at this time unknown and likely will become an area of research within the next few years, once these agents have been longer available are more widely used. Moreover, other BTK and PI3K inhibitors are also promising and have entered into early clinical trials. In addition, immunomodulating drugs, such as lenalidomide, have provided encouraging results as monotherapy and in combination with other agents in previously treated and untreated patients. Combinations of these drugs with monoclonal antibodies and/or cytotoxic agents are likely


17

P. Robak et al.


to shorten the time to remission and increase the depth of remissions. However, combined treatment is usually more toxic than monotherapy. Given the heterogeneity of the clinical manifestations and prognosis, CLL patients are likely to benefit from a personalized therapeutic approach with these immunological drugs. The clinical development of mAbs and other immunological agents for the treatment of CLL is challenging, and future preclinical studies and clinical trials of these drugs in CLL patients should be continued. The progress will be followed with great interest by laboratory investigators and clinicians. 9.

Expert opinion

CLL is the most prevalent adult leukemia in the western world and remains incurable with current therapies in the vast majority of patients. In a matter of only a few years, immunological drugs have changed the landscape for CLL treatment. The development of anti-CD20 mAbs has improved the outcome of CLL. Their use in immunochemotherapy regimens is the current gold standard, both in physically fit younger patients and, more recently, in older patients with comorbidities. In addition to rituximab, several novel anti-CD20 mAbs have been investigated. They were engineered or possess characteristics that allow them to avoid the resistance seen with rituximab therapy. Two newer antiCD20 mAbs, ofatumumab and obinutuzumab, have been recently approved by the FDA and EMA for the treatment of CLL. In addition, patients with CLL could benefit from anti-CD19 and anti-CD37 treatment as an alternative or complementary strategy to circumvent the resistance to, or the failure of, anti-CD20 mAb therapies associated with low levels of CD20 expression. The introduction of novel targeted therapies with high efficacy is currently transforming the treatment of CLL. Among them, BTK and PI3K inhibitors such as ibrutinib and idelalisib are emerging as a novel class of highly active targeted agents for patients with CLL. However, BCR inhibitors are not toxicity-free and the longer-term follow-up of these agents is needed to have a complete knowledge about the frequency of such long-term risks. The BCR inhibitors will need to be closely monitored for durability of responses, drug resistance, risk of disease transformation and long-term side effects. Ongoing clinical trials will help to determine if ibrutinib and idelalisib need to be combined with other drugs to achieve maximum effect and to establish optimal drug

18

combinations. Theoretically, a combination with mAbs and/ or cytotoxic drugs should shorten the time to remission and increase the depth of responses, but the toxicity of such combinations will be probably higher. Combining mAbs with BCL-2 inhibitors could also be synergistic and further improve treatment efficacy in CLL. Monoclonal antibodies and BCR inhibitors present the foundation for innovative non-chemotherapeutic strategies in the treatment of CLL. As effective immunotherapies become more widely available and introduced into routine clinical practice outside of clinical trials, it will also be important to identify those CLL patients who are most likely to benefit from such therapies. A personalized approach that includes early intervention in selected patients with CLL is likely to bring physicians closer to the goal of attaining cures in most patients with CLL. Over the next 5 -- 10 years, the focus of clinical research in CLL will be to identify and assess new non-chemotherapy drug combinations with synergistic antitumor activity and reduced toxicity. Another challenge is increasing the number of patients who achieve durable remissions from immunological drugs and finally, cure the majority of the patients. The hope is that mAbs, BCR inhibitors and immunomodulatory agents may move us closer to achieving that goal. However, immunochemotherapy-based treatments are still the standard of care for first-line treatment, and chemo-free regimens cannot be recommended outside of clinical trials. Ongoing research promises to further explore the role of these new strategies in CLL.

Declaration of interest This work was supported in part by the grants from the Medical University of Lodz (No 503-1093-1 and No 503-1019-1) and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland. T Robak received research grants from Hoffmann-La Roche, GlaxoSmithKline, Trubion Pharmaceuticals, Inc., Janssen, Pharmacyclics and Gilead, and travel grants from Hoffmann-La Roche. P Smolewski received research grants from Hoffmann-La Roche and Gilead, and travel grants from Hoffmann-La Roche. 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.



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Affiliation Pawel Robak MD, PhD, Piotr Smolewski MD, PhD & Tadeusz Robak† MD, PhD † Author for correspondence Medical University of Lodz, Departments of Experimental Hematology and Hematology, Copernicus Memorial Hospital, 93-510 Lodz, Ul. Ciolkowskiego 2, Poland Tel: +48 42 689 51 91; Fax: +48 42 689 51 92; E-mail: [email protected]

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Emerging drugs for acute lymphocytic leukemia.

Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond.

Chemoimmunotherapy for chronic lymphocytic leukemia.

Obinutuzumab for chronic lymphocytic leukemia.

Chronic myeloid leukemia and chronic lymphocytic leukemia.

SnapShot: chronic lymphocytic leukemia.

Chronic lymphocytic leukemia.

Chemoimmunotherapy for chronic lymphocytic leukemia. Author reply.

Current and emerging monoclonal antibody treatments for chronic lymphocytic leukemia: state of the art.

Developing Molecular Signatures for Chronic Lymphocytic Leukemia.

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small lymphocytic lymphoma, version 1.2015.

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Chronic lymphocytic leukemia of the genital tract.

Ibrutinib resistance in chronic lymphocytic leukemia.

PARP1-driven apoptosis in chronic lymphocytic leukemia.

Bronchogenic carcinoma in chronic lymphocytic leukemia.