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

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Review

Current and emerging monoclonal antibody treatments for chronic lymphocytic leukemia: state of the art Expert Rev. Hematol. 7(6), 841–857 (2014)

Tadeusz Robak Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, 93-510 Lodz, Ul. Ciolkowskiego 2, Poland Tel.: +48 426 895 191 Fax: +48 426 895 192 [email protected]

Anti-CD20 monoclonal antibodies (mAbs), rituximab, ofatumumab and obinutuzumab, have a significant impact in the treatment of chronic lymphocytic leukemia (CLL), particularly in combination with chemotherapy. Over the last few years, several new mAbs have been developed and investigated in CLL. The most promising newer mAbs are directed against CD20, CD19, CD37 and CD40. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib or lenalidomide will probably replace chemotherapy-based combinations in the near future. This review gives a critical overview of established mAbs as well as new antibodies potentially useful in CLL. KEYWORDS: CD19 • CD20 • CD23 • CD37 • CD40 • CD52 • CLL • dacetuzumab • GA-101 • lucatumumab • lumiliximab • MOR208 • ocrelizumab • ofatumumab • otlertuzumab • TRU-016 • veltuzumab

Over the last few years, several monoclonal antibodies (mAbs) have been investigated in clinical trials in patients with chronic lymphocytic leukemia (CLL). Among them, anti-CD20 mAbs and the anti-CD52 antibody alemtuzumab play the most important roles (TABLE 1) [1]. While rituximab, ofatumumab, obinutuzumab and alemtuzumab have already been approved for the treatment of CLL, several other mAbs directed against lymphoid B-cells have been developed and investigated in preclinical studies and clinical trials. These antibodies include anti-CD37, anti-CD19 and antiCD40 mAbs (TABLE 2). This review presents a number of mAbs with established value, as well as antibodies which are potentially useful in the treatment of CLL. Anti-CD20 mAbs

The anti-CD20 mAbs rituximab, ofatumumab and obinutuzumab have been 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 [2]. informahealthcare.com

10.1586/17474086.2014.963048

Rituximab

Rituximab (Rituxan, Mabthera, F. HoffmannLa Roche, Basel, Switzerland) is a chimeric, human/mouse, IgG1 anti-CD20 mAb containing murine light- and heavy-chain variableregion sequences and human constant-region sequences [3]. The variable murine region of rituximab binds specifically to the CD20 antigen. The Fc domain recruits the immune effect or functions to mediate B-cell lysis [4]. Rituximab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellmediated cytotoxicity (ADCC) and direct growth arrest [5]. NK cells, macrophages and Kupffer cells are the most important effectors in the ADCC mechanism of cell killing [6]. Fc-receptor-dependent mechanisms contribute substantially to the action of rituximab against tumors, and indicate that an optimal antibody for treating tumors would bind preferentially to activating Fc receptors and minimally to the inhibitory partner FcgRIIB [7]. Recent studies suggest that reactive oxygen species may play a central role in the mediation of antibody-induced non-apoptotic cell death,

2014 Informa UK Ltd

ISSN 1747-4086

841

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Table 1. Monoclonal antibodies approved for chronic lymphocytic leukemia. mAb

Target

Antibody characteristics

Clinical application

Rituximab (Rituxan, Mabthera, F. HoffmannLa Roche)

CD20

Chimeric, human/mouse, IgG1 mAb with murine light- and heavy-chain variable-region sequences and human constant-region sequences

Approved by US FDA for the treatment of patients with previously treated and untreated CLL

Ofatumumab (HuMaxCD20; ArzerraTM , GlaxoSmithKline plc/ Genmab A/S)

CD20

Type I, second generation, human IgG1, binding to different CD20 epitope than rituximab, more effective at CDC and less at ADCC than rituximab

In 2009, the FDA granted accelerated approval for the treatment of patients with fludarabine- and alemtuzumab-refractory CLL. In 2010, similar approval by the EMA

Obinutuzumab (GA-101, RO5072759, F. Hoffmann-La Roche)

CD20

Type II, third generation, glycoengineered, humanized IgG1, antibody with superior ADCC than rituximab and superior direct cell-killing properties

In 2013, FDA approved obinutuzumab for use with chlorambucil in patients with previously untreated CLL

Alemtuzumab (Campath-1H, Sanofi/Genzyme)

CD52

Recombinant, humanized IgG1k mAb, active in previously treated and untreated CLL, including patients with del(17p13) and/or TP53 abnormality

Regular approval for single-agent alemtuzumab for CLL granted by the FDA in 2007. In 2012, withdrawn by Sanofi from the markets and is provided free of charge through the Campath Distribution Program

ADCC: Antibody-dependent cell-mediated cytotoxicity; CLL: Chronic lymphocytic leukemia; mAb: Monoclonal antibody.

either through the activation of pro-death signal transduction programs or direct damage to the cellular structure [8]. Despite the high efficacy of rituximab in CLL patients, innate as well as acquired rituximab resistance is an important issue. Resistance to Rituxan or to ofatumumab can occur due to loss of CD20 as a consequence of trogocytosis [9,10]. Other types of resistance can occur in response to internalization of the mAb-CD20 complexes by B cells [11,12]. It can also develop due to effector mechanism exhaustion [9]. Rituximab-mediated internalization may also contribute to treatment failure of mAb therapy in CLL patients. Rituximab is usually well tolerated. However, intravenous administration of rituximab can be associated with infusionrelated reactions in the majority of patients. The symptoms are usually brief and occur during the first infusion [13]. Infusionrelated adverse events (AEs) occur within the first 30 min to 2 h of starting the first infusion and are usually reversible with interruption or discontinuation of rituximab along with supportive care. Subcutaneous administration of rituximab may reduce these symptoms and facilitate administration with equivalent efficacy while avoiding infusion-related reactions [14]. Rituximab increases the risk of viral and bacterial infections including hepatitis B virus reactivation in patients with resolved infection [15]. All patients should be screened for hepatitis B virus reactivation infections and, if found positive, prophylaxis or treatment should be implemented before initiating rituximab. Although rituximab was initially approved by the US FDA in 1997 for the treatment of non-Hodgkin lymphoma (NHL), the drug also has a significant impact in the treatment of CLL. 842

Numerous studies have confirmed the efficacy of rituximab for treating CLL, both as a single agent and in combination therapy [16–18]. Unfortunately, only a subset of patients respond to monotherapy, and the majority of those eventually relapse following rituximab treatment. Rituximab demonstrated limited activity in previously treated CLL when used as a single agent at doses 375 mg/m2 [19–24]. O’Brien et al. reported a correlation between the dose of rituximab and the clinical response, an odds ratio (OR) rate of 36%, ranging between 22% for lower doses and 75% for the highest doses, for pretreated CLL patients who received an initial dose of rituximab of 375 mg/m2, increasing to a fixed dose of between 500 and 2250 mg/m2 once weekly for 4 weeks [21]. In another study, Byrd et al. administered rituximab at doses ranging from 250 to 375 mg/m2, three-times weekly for 4 weeks, to give an overall response rate (ORR) of 45%, including 3% complete response (CR) [22]. Single-agent rituximab has also been evaluated in patients with previously untreated CLL. In one study, 44 previously untreated, symptomatic patients were treated with 4 weekly doses of rituximab at 375 mg/m2 [23]. The ORR was 51% and CR 4%. More recently, standard doses of rituximab (375 mg/m2) were given weekly for 8 consecutive weeks in early-stage, untreated CLL patients [24]. The ORR in 34 patients was 82% including 9% CR, and the 8-year overall survival (OS) rate was 74%. The approval of rituximab-based immunochemotherapy can be viewed as a substantial therapeutic advance in CLL. Rituximab combined with fludarabine, or fludarabine and cyclophosphamide (FCR), as frontline therapy induce higher OR and CR rates than rituximab alone or FCR chemotherapy. A study Expert Rev. Hematol. 7(6), (2014)

mAbs for CLL

Review

Table 2. Monoclonal antibodies for chronic lymphocytic leukemia in clinical trials. mAb

Target

Antibody characteristics

Clinical trials

Ocaratuzumab (AME-133v, LY2469298, Mentrik Biotech)

CD20

Type I, third-generation, humanized, Fab- and Fc-engineered IgG1 anti-CD20 mAb

Phase I and II study of subcutaneous ocaratuzumab in patients with previously treated CD20+ B-cell malignancies [79,82,134]

Type I, second generation, humanized IgG1; binding to different CD20 epitope than rituximab; enhanced ADCC and reduced CDC, enhanced affinity for FcgRIIIa RIIIa

Phase I/II study in previously untreated or relapsed CD20+ indolent NHL or CLL patients [77,78,135]


Veltuzumab (IMMU-106, hA20, Immunomedics, Inc.)

CD20

BI 836826 (MAb 37.1; Boehringer Ingelheim)

CD37

Chimeric IgG1-type of anti-CD37 molecule which has been Fc-engineered to improve ADCC activity and enhance affinity for FcgRIIIa

Phase I clinical trial in pretreated CLL ongoing [106]

Otlertuzumab (TRU-016; Emergent BioSolutions Inc.)

CD37

Antibody-based single-chain homodimeric therapeutic protein produced on the platform of ADAPTIRTM consisting of antibody-derived, single-chain variable fragments linked to immunoglobulin constant domains

Phase I study in relapsed/refractory CLL or SLL completed [109]; Phase II study of otlertuzumab/bendamustine versus bendamustine alone ongoing [95,136]

MOR208 (XmAb5574) MorphoSys AG)

CD19

Humanized IgG1 mAb with a engineered constant fragment (Fc)-domain designed to enhance binding of FcgRIIIa

Phase I study in relapsed/refractory CLL [116]; Phase II study in patients with CLL and NHL ongoing [117]

Lumiliximab (Biogen Idec)

CD23

Macaque/human chimeric anti-human high-affinity anti-mAb

Phase I dose-finding trial in refractory/ relapsed CLL [125]; Phase I/II study of lumiliximab + FCR [126]; Phase II/III study evaluated lumiliximab + FCR versus FCR (LUCID Trial) [127]

Lucatumumab (HCD122, CHIR-0.12.12; Novartis Pharmaceuticals)

CD40

A fully human anti-CD40 mAb that blocks CD40/CD40L interactions

Phase I study in relapsed CLL completed [129]

Dacetuzumab (SGN-40, Seattle Genetics)

CD40

A non-blocking, partial agonist, humanized IgG1, mAb

Phase I study in pre-treated CLL [131,132,137]

ADCC: Antibody-dependent cell-mediated cytotoxicity; CDC: Complement-dependent cytotoxicity; CLL: Chronic lymphocytic leukemia; FCR: rituximab + fludarabine + cyclophosphamide; mAb: Monoclonal antibody; SLL: Small lymphocytic lymphoma.

performed by Byrd et al. was based on a group of patients receiving 6 monthly courses of rituximab concurrently with fludarabine, followed 2 months later by 4 weekly doses of rituximab for consolidation therapy, and another receiving sequential fludarabine alone, followed 2 months later by rituximab alone for consolidation [25]. An OR of 77% and CR of 28% were observed in the sequential regimen compared with 90% OR and 47% CR in the concurrent regimen. The FCR regimen has even higher activity in patients with treatment-naı¨ve disease [26,27]. Investigators at the MD Anderson Cancer Center (Houston TX, USA) conducted a singlearm study of FCR as an initial therapy in 224 patients with progressive or advanced CLL [27]. The median age was 58 years (range, 24–86 years). Efficiency results and safety were compared with previous regimens using FC alone. The CR rate was 70% and the OR was 95%. Moreover, preliminary analysis suggested that chemotherapy with FCR improved remission duration and OS. At a median follow-up of 6 years, 6-year OS and failure-free survival were 77 and 51%, respectively and median time to progression was 80 months [28]. These results were subsequently confirmed in a randomized, multicenter, informahealthcare.com

multinational Phase III trial. The German CLL Study Group (GCLLSG) initiated a randomized Phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of fit patients with advanced CLL [16]. In this study, patients received 375 mg/m2 rituximab on day 1 of the first cycle followed by 500 mg/m2 on day 1 of up to 6 subsequent 28-day cycles. At 3 years after randomization, 65% of patients in the FCR group were free of progression, compared with 45% in the FC group (p < 0.0001), and 87% of FCR were alive versus 83% of FC (p = 0.01). However, FCR treatment was more frequently associated with grade 3 and 4 neutropenia (34 vs 21%; p < 0.0001). FCR may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with CLL [29]. After a median observation time of 5.9 years, the CLL8 trial confirmed that FCR immunochemotherapy leads to a prolongation of progression-free survival (PFS) and OS in up-front treatment of physically fit patients [30]. By this time, 38.0% of the patients in the FCR group were free of disease progression compared with 27.4% in the FC group (p < 0.0001). Median OS was not reached for patients in the FCR arm, while median OS was 86.0 months 843


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for the FC arm (p = 0.001). A recent GCLLSG CLL7 study has demonstrated that in high-risk asymptomatic patients, event-free survival substantially improves in early stage highrisk CLL [31]. However, this study did not clearly demonstrate that even high-risk asymptomatic patients have a survival advantage after early treatment. Currently, FCR is the standard frontline treatment for younger, fit patients with symptomatic, progressive CLL. The FCR regimen has also higher therapeutic activity than the FC regimen in patients with refractory/relapsed disease [32]. A randomized, multicenter, Phase III study evaluated the efficacy and tolerability of FCR versus FC regimens in relapsed or refractory patients with CLL (REACH study) [17]. In this study, PFS was significantly prolonged in the FCR arm (30.6 months) compared with FC (20.6 months; p = 0.0002). The ORR was also higher for FCR than for FC (70 vs 58%; p = 0.0034) due to superior CR rates (24 vs 13%; p = 0.0007). The direct and long-term side effects need to be taken into consideration after FCR immunochemotherapy [33]. In particular, cytopenia and infections are common FCR complications, both in refractory/relapsed disease and in previously untreated patients. Importantly, chemoimmunotherapy is more frequently associated with grade 3 and 4 neutropenia than FC alone [16,17]. FCR induced an increase in prolonged neutropenias during the first year after the end of treatment but not thereafter [16,17,30]. The application of more aggressive therapy in CLL can have implications for development of secondary neoplasms and Richter syndrome. In a long-term follow-up study of first-line FCR therapy, with a median follow-up period of 44 months, a total of 28 therapy-related myeloid neoplasm patients were identified, giving an estimated frequency of 4.5% (1.9– 8.3%) [34]. Eight occurrences of myelodysplastic syndrome (2.8%) occurred during first remission [28]. However, initial chemoimmunotherapy without the use of alkylating agents may reduce the risk of secondary neoplasia [35]. In addition, no increase of secondary malignancies in the FCR arm (9.9%) was noted in an extended follow-up of the GCLLSG CLL8 study in comparison with FC arm (12.1%) [30]. Similarly, no greater occurrence of myelodysplastic syndrome/acute myeloid leukemia has been observed with FCR treatment in comparison with the FC arm so far. Four drug combination therapies with FCR and other agents, including mitoxantrone, alemtuzumab and lumiliximab, have also been investigated in pretreated CLL patients. However, the advantage of such combinations over FCR has not been confirmed so far [36]. Recent clinical observations reveal that a combination of rituximab with pentostatin or cladribine and cyclophosphamide (PCR or RCC regimens) is also a highly active regimen in CLL [37,38]. A combination of chlorambucil with rituximab is currently accepted as the first-line treatment of progressive CLL in unfit, usually elderly, patients, because of the apparent increase in toxicity of purine nucleoside analogs in this patient population. This combination regimen was evaluated with and without rituximab maintenance as first-line treatment in two Phase II 844

studies (Italian ML21445 study and the UK National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup study) [39,40]. In both studies, the median age of patients was 70 years and the rate of comorbidities increased consistently with age. In the Italian ML21445 study, treatment consisted of eight 28-day cycles of chlorambucil (8 mg/m2/day, days 1–7) and rituximab (day 1 of cycle 3, 375 mg/m2; cycles 4–8, 500 mg/m2) [39]. The responding patients were randomized to maintenance treatment with 375 mg/m2 rituximab for 12 doses or observation. The ORR was 82.4% and CR rate 16.5%. The median PFS was 34.7 months with a better PFS for rituximab maintenance group compared with the control arm. Importantly, the frequency of neutropenia and infections were similar in both the rituximab maintenance arm and the control group. In the UK National Cancer Research Institute study, a total of 100 previously untreated patients with median age of 70 years were treated with rituximab and chlorambucil [40]. In this study, rituximab was given at a dose of 375 mg/m2 on day 1, cycle 1, and 500 mg/m2 thereafter. Chlorambucil was given at a dose 10 mg/m2 for 7 days for six 28-day cycles. For patients not achieving CR, six additional cycles of chlorambucil alone could be administered. ORRs were 84%, with CR noted in 10% of patients and median PFS 23.5 months. Neutropenia occurred in 41% of patients. The results of these two studies compare favorably with previously published results for chlorambucil monotherapy and suggest that rituximab added to chlorambucil may improve efficacy in patients who are ineligible for more intensive treatment. Chemoimmunotherapy with bendamustine and rituximab (BR) is also effective and safe in patients with previously untreated CLL. Fisher et al. investigated the safety and efficacy of this regimen in 117 previously untreated patients [41]. Bendamustine was administered at a dose of 90 mg/m2 on days 1 and 2, combined with 375 mg/m2 rituximab on day 0 of the first course, and 500 mg/m2 on day 1 during subsequent courses, for up to six courses. The ORR was 88% with a CR rate of 23% and a median event-free survival of 33.9 months. Subsequently, the GCCLSG initiated an international Phase III CLL-10 study in order to evaluate the efficacy and tolerability of BR compared with FCR in the first-line therapy of physically fit patients without del(17p) [42]. The ORR was similar in both arms. However, the CR rate with FCR was higher (47.4%) as compared with BR (38.1%; p = 0.031). There was a significantly longer PFS in patients 65 years, median PFS was not reached in the FCR arm and was 45.6 months in the BR arm (p = 0.757). Recent results from the CLL-10 trial not only confirm the efficacy of FCR, but also highlight its higher toxicity when compared with BR: grade 3–5 AEs were significantly more common in the FCR arm (90.8%) than in the BR arm (78.5%; p < 0.001). In particular, the higher rate of severe neutropenia caused a significantly higher rate of severe infections in the patients treated with FCR (39.0%) than in those treated with BR Expert Rev. Hematol. 7(6), (2014)


mAbs for CLL

(25.4%; p = 0.001). The OS rate at 2 years for the FCR group was 94.2% compared with 95.8% for the BR arm (p = 0.593). In pretreated patients, bendamustine was administered at a dose of 70 mg/m2 on days 1 and 2 in combination with rituximab given at a dose of 375 mg/m2 on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses, for up to six courses. In pretreated patients treated with BR, an OS of 45.5% was observed in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients with a median event-free survival of 14.7 months [43]. Therefore, a combination of bendamustine with rituximab can be considered as a therapeutic option for previously untreated and relapsed/refractory CLL patients. Combinations of high doses of methyl prednisolone with rituximab can also be useful in advanced CLL resistant to fludarabine and in patients with p53 abnormalities [44,45]. Castro et al. achieved an ORR of 93%, a CR rate of 36%, with a median PFS of 15 months using combination high doses of methyl prednisolone and rituximab therapy [46]. This regimen is well tolerated and has relatively low toxicity and can be particularly useful for patients with a limited myeloid reserve who might not tolerate other therapies. Recently, B-cell antigen receptor (BCR) signal transduction inhibitors ibrutinib (PCI-32765) and idelalisib (GS-1101, CAL-101) are a promising new strategy for targeted CLL treatment [47]. Ibrutinib used alone is associated with a high frequency of durable remissions in patients with relapsed/refractory CLL, including patients with high-risk genetic lesions [48]. Ibrutinib was also combined with rituximab in Phase II trial in 40 relapsed/refractory patients [49]. Patients with high-risk CLL received ibrutinib 420 mg orally daily, continuously throughout the study. Rituximab was administered weekly at a dose of 375 mg/m2 for the first 4 weeks in cycle 1 and then monthly until cycle 6. At a median follow-up of 14 months, the ORR was 95%, including an 87% partial response (PR) and 8% CR. Importantly, the ORR in the 20 patients with del17p or TP53 mutation was 90%. This combination of ibrutinib and rituximab was safe and well tolerated in the CLL patients and induced high rates of durable responses. Combined ibrutinib-BR therapy was evaluated in 30 patients with relapsed/refractory CLL [50]. The treatment was well tolerated and highly active, with an OR of 93%, including five CRs and three nodular PRs, with an estimated 90% 12-month PFS. In July 2014, the FDA approved a license extension for use of ibrutinib in patients with CLL and a 17p deletion. At the same time, EMA approved ibrutinib to treat relapsed/refractory CLL. Idelalisib has also shown substantial clinical activity and a favorable safety profile in heavily pretreated, refractory and high-risk patients with CLL when used in monotherapy [51]. Moreover, rituximab plus idelalisib achieved a response and survival benefit compared with rituximab alone in relapsed/ refractory CLL patients with comorbidities [52]. The patients receiving idelalisib and rituximab had improved rates of overall response (81%) in comparison with rituximab monotherapy (13%) (p < 0.001). Median PFS was 5.5 months in the rituximab group, and was not reached in the idelalisib + rituximab informahealthcare.com

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group (p < 0.001); overall survival rates at 12 months were 92 versus 80%, respectively (p = 0.02). In July 2014, the FDA approved idelalisib for the treatment of CLL. Moreover, the scientific committee of the EMA recommended the granting of marketing authorization for the use of idelalisib in combination therapy for the treatment of patients with CLL. Lenalidomide is an immunomodulatory active drug in CLL [53]. James et al. reported the results of a Phase II study evaluating the combination of lenalidomide and rituximab as initial treatment in 69 CLL patients [54]. The response rate for younger patients with a median age of 56 years was 95%, with 20% CRs and 20% nodular PRs. Older patients with median age 75 years less frequently completed the maximum planned therapy. In this group, the ORR was 78% and CR rate 11%. Median PFS was 19 months for the younger patients and 20 months for the older patients. Neutropenia was the most common AE. Ofatumumab

Ofatumumab (HuMax-CD20; ArzerraTM , GlaxoSmithKline, Brentford, London, UK) is a second-generation, fully human, anti-CD20, IgG1 mAb recognizing a different CD20 epitope to rituximab, and demonstrating a higher cytotoxic potential [55]. Ofatumumab has been found to demonstrate superiority over rituximab for the CDC of B cells [56,57]. The results of a Phase II study demonstrate that ofatumumab monotherapy shows some efficacy in heavily pretreated patients with fludarabine- and alemtuzumab-refractory CLL [58]. In this study, patients received eight once-weekly infusions of ofatumumab followed by four once-monthly infusions during a 24-week period. The ORRs were 58% in the fludarabine- and alemtuzumab-refractory group and 47% in patients with fludarabine-refractory CLL and bulky lymphadenopathy. The ORRs among patients refractory to FCR were 50 and 44% in the fludarabine- and alemtuzumabrefractory groups, respectively. Median PFS and OS times were 5.7 and 13.7 months in the fludarabine- and alemtuzumabrefractory groups, and 5.9 and 15.4 months in the fludarabinerefractory patients with bulky lymphadenopathy. Preliminary data suggest that a combination of ofatumumab with 1250 mg/m2, prednisone administered daily for 5 days or 187.5 mg/m2 dexamethasone daily for 4 days can increase response rate in fludarabine-refractory patients in comparison with single-agent ofatumumab [59]. Ofatumumab was given at a test dose of 300 mg on week 1, followed by 7 weekly injections of 2000 mg and then 2000 mg every 4 weeks for 4 further injections. PRs were observed in 10 of 13 (78%) patients, including 5 of 8 (62%) patients with 17p deletions. The newly targeted drug, ibrutinib, seems to be superior to ofatumumab in patients with relapsed/refractory CLL. Recently, the results of a multicenter, open-label, randomized, Phase III trial comparing ibrutinib with ofatumumab in patients with relapsed/refractory CLL (RESONATE) were published [60]. Overall, 43% of the patients in the ibrutinib arm demonstrated a PR, as compared with 4% in the ofatumumab group (p < 0.001), while an additional 20% of the ibrutinib 845


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patients had a PR with lymphocytosis. At a median follow-up of 9.4 months, ibrutinib was found to have significantly prolonged duration of PFS (median not reached), as compared with the median duration of PFS with ofatumumab (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 overall survival rate at 12 months was 90% in the ibrutinib arm and 81% in the ofatumumab arm (p = 0.001). According to Jaglowski et al., the interim data from a Phase Ib/II trial indicate combined ibrutinib and ofatumumab therapy was well tolerated in patients with relapsed/refractory CLL/small lymphocytic lymphoma who had received two or more prior therapies, and was highly active in patients with heavily pretreated relapsed/refractory CLL with an 100% ORR [61]. A Phase III, randomized controlled study evaluating the efficacy and safety of ofatumumab in combination with idelalisib for previously treated CLL has been also initiated [62]. Combined ofatumumab and chlorambucil therapy was investigated in treatment-naı¨ve patients with CLL. A recent randomized trial (Complement 1) compared the application of chlorambucil, as monotherapy and in combination with ofatumumab, in patients with CLL who required therapy and were not able to receive fludarabine-based therapy due to advanced age and/or co-morbidities [63]. The results of this study indicate that ofatumumab + chlorambucil is superior than chlorambucil alone in this patient population. ORR was higher for ofatumumab + chlorambucil (82%) than chlorambucil alone (69%) (p = 0.001). In addition, a superior CR rate was noted in the patients receiving immunochemotherapy: 12% compared with 1% in those who were treated with chlorambucil. Moreover, ofatumumab + chlorambucil achieved eradication of minimal residual disease in a proportion of patients. PFS was also significantly prolonged in the ofatumumab + chlorambucil arm (22.4 months) compared with chlorambucil alone (13.1 months; p < 0.001). With a median follow-up of 29 months, median OS was not reached for both groups. In 2009, based on a clinically meaningful and durable ORR observed in the above trial (Hx-CD20-406), the FDA granted accelerated approval to ofatumumab for the treatment of patients with fludarabine- and alemtuzumab-refractory CLL. In 2010, the EMA conditionally authorized ofatumumab to be marketed for the treatment of fludarabine- and alemtuzumabrefractory CLL patients. In 2014, the FDA approved ofatumumab in combination with chlorambucil for the treatment of previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate. Obinutuzumab

Obinutuzumab (GazyvaTM , GA-101, RO5072759, Roche, Basel, Switzerland) is a novel, third-generation humanized and glycoengineered, type II anti-CD20 mAb for the treatment of B-cell malignancies [64]. The antibody production is based on GlycArt Biotechnology’s (later Roche Glycart AG) proprietary GlycoMAb technology, which uses glycoengineered antibodies 846

that specifically increase ADCC and thereby increase immunemediated target cell death. Compared with rituximab, obinutuzumab binds with high affinity to the CD20 epitope and, as a result, induction of ADCC is 5- to 100-times greater than rituximab [65,66]. Obinutuzumab induces two- to threefold more efficient NK cell degranulation than rituximab in isolated CLL cells [67]. However, reduction in CDC upon binding to CD20 was observed. Obinutuzumab is a promising therapeutic agent for CLL. In a Phase I/IIa study, obinutuzumab was administered as a single agent to 24 CLL patients, at doses from 50 to 2000 mg [68]. 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 [69]. The results of a large randomized Phase III trial (CLL11) comparing chemo-immunotherapy with first-line obinutuzumab + chlorambucil, chlorambucil + rituximab and chlorambucil alone in patients with comorbidities have been recently reported [70,71]. The trial comprised 781 patients with previously untreated CLL and a score higher than 6 on the cumulative illness rating scale or an estimated creatinine clearance of 30–69 ml/min. Treatment with obinutuzumab + chlorambucil was found to result in higher rates of CR (20.7 vs 7.0%) and higher molecular response compared with rituximab + chlorambucil. Treatment with obinutuzumab + chlorambucil or rituximab + chlorambucil also prolonged PFS to a greater degree than 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 demonstrated a longer OS than chlorambucil alone (p = 0.002). However, infusion-related reactions and neutropenia were more common in patients treated with obinutuzumab + chlorambucil than with rituximab + chlorambucil. Obinutuzumab + chlorambucil treatment was associated with more grade 3–4 AEs, which were mainly infusion-related reactions that occurred during the first infusion. Infusion-related reactions were noted in 20% of patients treated with obinutuzumab + chlorambucil and 4% of patients treated with rituximab + chlorambucil. In contrast, the risk of infection was similar in both arms. Obinutuzumab has been approved for use with chlorambucil in patients with previously untreated CLL with comorbidities by the FDA [72]. In addition, this combination has been approved in the EU in this indication [73]. Veltuzumab

Veltuzumab (IMMU-106, hA20, Immunomedics, Inc, Morris Plains, NJ, USA) is one of the first second-generation humanized anti-CD20 mAbs. It was constructed by recombination on the framework regions of the humanized anti-CD22 mAb epratuzumab. Veltuzumab differs from rituximab by one amino acid in the complementarity-determining region 3 of the heavy chain [74]. The mechanism of cytotoxicity of veltuzumab is similar to that of rituximab, and includes ADCC and CDC [75,76]. Veltuzumab has enhanced binding avidities and a stronger effect on CDC than rituximab in selected cell lines [65]. Expert Rev. Hematol. 7(6), (2014)


mAbs for CLL

Veltuzumab is at least as effective as rituximab in treating NHL and CLL. Subcutaneous administration of veltuzumab was investigated in a multicenter, Phase I/II study on previously untreated or relapsed CD20+ indolent NHL or CLL patients [77]. All patients received 4 subcutaneous injections of veltuzumab 2 weeks apart at doses of 80, 160 or 320 mg. Twenty-six patients, including 15 NHL patients and 11 CLL patients, received subcutaneous veltuzumab at doses of 80, 160 or 320 mg. Five of the seven (71%) CLL patients showed stable disease (SD) with >70% decreases in B-cell levels for up to 12 weeks. Recently, a multicenter Phase I/II study was undertaken to evaluate the safety and efficacy of veltuzumab given subcutaneously in patients with previously untreated or relapsed CLL with high levels of circulating leukemic cells [78]. In this study, 11 CLL patients in cohort 1 received 4 doses of veltuzumab given every other week at 80, 160 or 320 mg. In the second cohort, 9 patients were treated with 16 doses of the drug administered twice weekly at doses of either 160 or 320 mg. The number of leukemic cells in peripheral blood decreased after treatment in all patients by 7.7–90.8% and 15 of 18 evaluable patients achieved either PR or SD. These results indicate that veltuzumab administered subcutaneously is convenient, well tolerated and active in CLL patients. Ocaratuzumab

Ocaratuzumab (AME-133v, LY2469298, Mentrik Biotech, Dallas, Texas, USA) is a type I, third-generation, humanized, Fab- and Fc-engineered IgG1 anti-CD20 mAb. It is characterized by two amino-acid changes introduced into its Fc portion that lead to increased affinity to CD20. Cell-binding assays showed ocaratuzumab and rituximab compete for an overlapping epitope on the CD20 antigen [79–81]. In preclinical studies, ocaratuzumab induces CDC and antibody-dependent cellular phagocytosis against CLL in vitro [80]. However, its ADCC properties are approximately 20-times as effective at very low concentrations, which may facilitate subcutaneous dosing. The safety, pharmacokinetics and efficacy of ocaratuzumab were assessed in a Phase I trial in patients with previously treated follicular lymphoma (FL) [81]. In this study, ocaratuzumab was safe and well tolerated in FL patients. In the Phase II study, 50 patients were treated with ocaratuzumab at a dose of 375 mg/m2 weekly for 4 doses, and it was found to be safe and well tolerated at this dose [82]. The ORR was 30% with a CR in 4 patients. However, further studies are needed to establish the role of ocaratuzumab in the treatment of patients with CLL. Alemtuzumab

Alemtuzumab (Campath-1H, Sanofi SA, Paris, France) is an unconjugated, recombinant, humanized IgG1k mAb directed against the CD52 antigen. The drug is highly active in previously treated and untreated patients with CLL, including patients with del(17p13) and/or TP53 abnormality [83]. The effectiveness of alemtuzumab in CLL patients with relapsed/ refractory CLL resistant to conventional treatment was first reported in 29 patients by Osterborg et al. [84]: the ORR was informahealthcare.com

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43%, CR 4% and the median duration of response 12 months. However, resolution of lymphadenopathy was only observed in 7% and bulky lymphadenopathy did not respond to therapy. Further reports have confirmed that alemtuzumab possesses significant activity in relapsed/refractory CLL. Keating et al. investigated its efficacy and safety in 93 patients with relapsed/ refractory CLL exposed to alkylating agents and having failed previous fludarabine therapy [85]. The ORR was 33% including CR of 2% and PR of 31%. The median response duration was 8.7 months and overall median survival 16 months. In other studies, the ORR ranged from 31 to 60% and the CR rate from 0 to 31% [86,87]. In the majority of studies, the antitumor effects of alemtuzumab were more significant in blood and bone marrow than in lymph nodes. Alemtuzumab has also been investigated as first-line therapy in CLL. A pilot study published in 1996 by Osterborg et al. based on nine patients with progressive, previously untreated CLL reported an ORR of 89%, including CR in three and PR in five patients [88]. Subsequently, a prospective randomized Phase III trial (CAM 307) comparing high-dose chlorambucil with alemtuzumab in the frontline treatment of progressive CLL was initiated [89]. In this trial, 149 patients received alemtuzumab 30 mg three-times per week for up to 12 weeks, and 148 patients received chlorambucil 40 mg/m2 every 28 days for a maximum of 12 months. PFS was found to be superior for alemtuzumab, with a 42% reduction in risk of progression or death (p = 0.0001) and median time to alternative treatment of 23.3 months compared with 14.7 months for chlorambucil (p = 0.0001). The ORR was 83% with alemtuzumab, including 24% CR and 55% with chlorambucil including 2% CR (p < 0.0001). Moreover, elimination of minimal residual disease occurred in 31% of cases: 11 of 36 complete responders to alemtuzumab and none to chlorambucil. AEs were found to be similar in both arms, with the exception of increased infusion-related and CMV events for alemtuzumab. At present, aggressive anti-infective prophylaxis is a mandatory procedure. Prophylaxis directed co-trimoxazole and acyclovir has been found to decrease the occurrence of Pneumocystis carinii pneumonia and herpes virus infections. Monitoring with antigenemia or PCR and antiviral treatment is recommended for patients receiving alemtuzumab who test positive for CMV and display symptoms compatible with a CMV infection. Regular monitoring is recommended during the treatment and until 2 months after the end of therapy. Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Stilgenbauer et al. reported the results of Phase II CLL2H trial evaluating the safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory CLL [90]. In this trial, 103 patients were treated with subcutaneous alemtuzumab at 30 mg three-times weekly for up to 12 weeks to give a total ORR of 34%, including 4% CR and 30% PR, with a median PFS of 7.7 months and median OS of 19.1 months. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of IGHV gene 847


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mutation status, TP53 mutation and genomic aberrations. In addition, NOTCH1(mut) patients demonstrated significantly longer PFS than wild-type cases (15.47 vs 6.74 months; p = 0.025), but no difference in OS was noted [91]. NOTCH1 (mut) was identified as an independent favorable marker for PFS. Injection-site skin reactions were generally mild. Grade 3–4 neutropenia occurred in 56%, thrombocytopenia in 57% and anemia in 49% of the patients. Cytomegalovirus infections were noted in 8% of patients. The currently approved schedule of alemtuzumab administration involves a dose of 3 mg delivered intravenously 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 [92]. However, low-dose alemtuzumab (total weekly dose £45 mg and the cumulative dose £600 mg) is also a valid therapeutic option for the treatment of relapsed/refractory CLL [93]. In a retrospective analysis of 108 patients, Cortelezzi et al. reported a 56% ORR and 22% CR with mild and manageable toxicity and a low rate of infections. This treatment strategy seems to be particularly suitable for frail and elderly patients. In previously treated patients, alemtuzumab was used in combination with fludarabine (FA). In a Phase II study, the ORR was found to be 83%, including a CR in 30%, with a time to progression of 35.6 months in heavily pretreated, relapsed or refractory patients [94]. Similar results have been obtained in a large randomized Phase III trial (FluCam) [95]. In this study, 335 patients with relapsed or refractory disease were randomized to FA or fludarabine alone. FA demonstrated an advantage both in PFS (23.7 vs 16.5 months) and OS. Subsequently, alemtuzumab was combined with FC chemotherapy (FCCam) by the German CLL Study Group in a prospective, multicenter, open-label, non-randomized Phase II trial in 57 patients with primary high-risk (deletion 17p), relapsed/ refractory CLL [96]. The ORR was 56% with 6 (11%) patients achieving a CR. Leukocytopenia and neutropenia were the most frequent hematological side effects and were noted in 40.7% of the patients. During therapy, or within 6 months after the last cycle, a total of 12 patients developed fatal serious AEs, 5 of which were most likely associated with FCCam treatment. These results do not justify the use of FCCam in pretreated patients with CLL. Recently, Montillo et al. reported the efficacy and tolerability of subcutaneous alemtuzumab given on days 1–3 with intravenous bendamustine given on days 1 and 2 in 50 patients with relapsed and refractory CLL [97]. The ORR was 68%, with 24% of patients achieving CR with median PFS 17.3 months and median OS 37 months. Alemtuzumab has been proven to be effective when combined with rituximab [98]. Faderl et al. studied safety and efficacy of combination alemtuzumab and rituximab in 48 patients with relapsed and refractory lymphoproliferative disorders including 32 patients with CLL [99]. Patients received rituximab at a dose of 375 mg/m2/week for 4 weeks. Alemtuzumab doses were escalated during the first week from 3 to 10 mg and 30 mg during week 1 followed by a dose of 30 mg on days 3 and 5 of weeks 2–4, respectively. 848

Twenty-four patients responded, including 20 (63%) among CLL patients and 4 (44%) in the CLL/prolymphocytic leukemia group. CR was achieved by four (8%) patients. Infections were noted in 52% of the patients, and although positive CMV antigenemia occurred in 27% of the patients, it was symptomatic in only 15% and required therapy. Recently, Frankfurt et al. reported long-term outcomes of alemtuzumab and rituximab combination therapy in 30 previously untreated CLL patients: 90% with Rai clinical stages II–IV and 67% without favorable cytogenetics [100]. All patients responded and a 60% CR was noted. In addition, 6-color flow cytometry indicated that 67% of patients were found to be minimal residual disease negative in the bone marrow. Median PFS was 24.4 months and 5-year OS was 80%. CMV reactivation was observed in eight patients but was asymptomatic in all but one patient. Recently, Zent et al. reported a Phase II trial evaluating the combination of pentostatin, alemtuzumab and low-dose high-frequency rituximab in 39 patients with progressive CLL that was either relapsed/refractory or previously untreated with 17p13 deletion [101]. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatmentlimiting toxicity and no treatment-related deaths. Twenty-two (56%) of the 26 patients who completed therapy responded to treatment, with 11 achieving (28%) CR. However, median PFS was only 7.2 months and OS was 34.1 months. These results indicate that immunotherapy with alemtuzumab and rituximab is an effective and well-tolerated treatment in previously untreated patients. In 2001, alemtuzumab was initially approved by the FDA to treat patients with CLL refractory to fludarabine. In 2007, the FDA expanded the labeling and granted regular approval for single-agent alemtuzumab for the treatment of CLL. However, alemtuzumab was withdrawn by Sanofi from the markets in the USA and Europe in 2012 to prepare for the approval of this drug under a different brand name (Lemtrada) for multiple sclerosis. Since 4 September 2012, Campath (alemtuzumab) has no longer been available commercially, but is provided through the foundation Campath Distribution Program free of charge for appropriate CLL patients. Anti-CD37 mAbs

CD37 is a heavily glycosylated 40- to 52-kDa tetraspanin transmembrane family protein consisting of four potential membrane spanning regions, two extracellular loops and two short intracytoplasmic tails [102]. CD37 is selectively expressed on mature B cells, with its highest expression levels on peripheral blood B cells and with significant expression levels on the neoplastic cells of patients with CLL, hairy cell leukemia and NHL [103]. The relative lineage restriction of CD37 to B cells makes it a suitable target for immunotherapy. Until recently, only minimal effort has been directed toward CD37 immunotherapy. However, the predominant expression of CD37 on CLL cells makes it an ideal candidate as a therapeutic target for treatment of CLL and has led to the investigation of anti-CD37 antibodies [104]. The results of Expert Rev. Hematol. 7(6), (2014)

mAbs for CLL

recent preclinical and early clinical studies suggest that antiCD37 antibodies can be useful in the treatment of CLL. BI 836826


BI 836826 (MAb 37.1 Boehringer Ingelheim am Rhein, Germany) is a chimeric IgG1-type of anti-CD37 molecule, which has been Fc-engineered to improve ADCC activity and enhance affinity for FcgRIIIa. MAb 37.2 is a humanized version of BI 836826 [105]. Both antibodies deplete CLL cells in vitro more effectively than rituximab and alemtuzumab. BI 836826 is currently under investigation in CLL in as Phase I clinical trial [106]. Otlertuzumab

Otlertuzumab (TRU-016; Emergent BioSolutions Inc. Rockville, Maryland, USA) is a CD37-specific, single-chain, homodimeric therapeutic protein produced on the ADAPTIRTM (Modular Protein Technology) platform, consisting of antibody-derived, single-chain variable fragments linked to immunoglobulin constant domains [107]. ADAPTIR proteins have a differentiated structure from classical mAbs and can generate a unique signaling response. In addition, ADAPTIR proteins may mediate CDC and Fc-dependent cytotoxicity in a similar way to mAbs. Otlertuzumab is an engineered protein that includes anti-CD37 variable regions linked to an immunoglobulin constant domain, produced by humanizing of the precursor agent, SMIP-016. This is single chain monospecific protein that retains Fc-mediated effector functions [108]. In preclinical studies, this agent revealed distinct mechanism of apoptosis than other agents used for CLL treatment. In addition, otlertuzumab has demonstrated a significantly greater ability to directly kill CLL cells than rituximab and greater Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab. Otlertuzumab also mediates greater NK cellmediated killing of CLL cells compared with either alemtuzumab or rituximab, and mediates superior direct apoptosis of CLL and other B-cell malignancies. Moreover, otlertuzumab acts synergistically with bendamustine. In a Phase I study, otlertuzumab was investigated in patients with relapsed/ refractory CLL or SLL [109]. Otlertuzumab was well tolerated with minimal infusional toxicity. Response occurred in 19 of 83 treated patients (23%) by NCI-96 criteria. All responses were partial, and occurred more commonly in patients with symptomatic, untreated CLL. Recently, the results of a randomized trial of otlertuzumab/ bendamustine versus bendamustine alone were reported [110]. Patients with relapsed CLL who had received 1–3 prior therapies were administered otlertuzumab (20 mg/kg) weekly by intravenous infusion for two 28-day cycles then every 14 days for four 28-day cycles, during which bendamustine (70 mg/ m2) was administered intravenously on days 1 and 2 of each cycle for up to six 28-day cycles. In the control arm, bendamustine (70 mg/m2) was given intravenously on days 1 and 2 of each cycle. Among 65 patients included in the study, 32 received otlertuzumab plus bendamustine and 33 were treated with bendamustine alone. According to the NCI informahealthcare.com

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assessment, the ORR for the combination therapy was 75% with a CR rate of 48%. In the bendamustine-alone arm, the ORR was 52% with a CR rate of 9%. No increase in serious AEs was noted in the otlertuzumab plus bendamustine arm. A higher rate of neutropenia was observed but no increased rate of infections was seen in the combination arm. Grade 3/ 4 thrombocytopenia was observed in 19% of the patients receiving monotherapy and 12% of the patients receiving combination therapy. These results suggest that otlertuzumab can be a valuable drug in CLL. Otlertuzumab in combination with rituximab and bendamustine was also investigated in patients with relapsed, indolent B-cell NHL [111]. The drug was well tolerated and induced responses in the majority of patients. To summarize, the clinical development of anti-CD37 mAbs and related agents for the treatment of CLL is challenging, and future Phase II and III clinical trials of otlertuzumab and BI 836826 in CLL patients should be undertaken. Anti-CD19 antibodies

CD19 is a transmembrane protein that forms a signaling complex together with CD21, CD81 and CD225 [112]. 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. Two CD19 mAbs are being explored for clinical applications in B-cell lymphoid malignancies, including MOR208 and blinatumomab. However, only MOR208 is under investigation in patients with CLL. MOR208

MOR208 (XmAb5574, MorphoSys AG; Munich, Germany) 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 FcgRIIIa [113]. The ADCC of MOR208 is 100- to 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 MOR208-dependent ADCC is mediated by NK cells through a granzyme Bdependent mechanism. Studies based on CLL cells reveal that NK cell-mediated ADCC with MOR208 was enhanced further by lenalidomide [114]. 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 an immediate and dose-related B-cell depletion in the blood [115]. This antibody warrants further clinical evaluation in CD19+ lymphoid malignancies. In preclinical studies, MOR208 has shown antitumor activity including direct cytotoxicity, ADCC and antibodydependent cellular phagocytosis against leukemic CLL cells [115]. Unlike other anti-CLL mAbs, XmAb5574 demonstrated no CDC activity. In the first clinical study, MOR208 was found to have a tolerable toxicity profile and preliminary evidence of 849

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antitumor activity was observed in high-risk patients with relapsed/refractory CLL [116]. 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 [117].


GBR 401

GBR 401 (Glenmark Pharmaceuticals S.A, La Chaux de-Fonds, Switzerland) is a partially defucosylated humanized mAb GBR 401 derived from the parental mouse anti-human CD19 antibody clone FMC63 [118]. Both in vitro and in vivo data show that GBR 401 is highly effective at depleting human malignant B cells mainly via ADCC [119]. Preclinical data suggest that GBR 401 can be an efficacious therapeutic agent for CLL and warrants further clinical studies. MEDI-551

MEDI-551 (Medimmune, LLC, Gaithersburg, Maryland, USA) is an affinity-optimized and afucosylated humanized IgG anti-CD19 mAb [120]. It is an afucosylated antibody with increased affinity for human FcgRIIIA, mediating both ADCC and antibody-dependent cellular phagocytosis. MEDI-551 inhibits tumor growth in preclinical models of B-cell malignancies [121]. 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 [122]. OR response to single-agent MEDI-551 was 24% in CLL, 24% in diffuse large B-cell lymphoma and 31% in FL. Median PFS achieved in this single-agent study in heavily pretreated patients was 9 months, including 11.6% CR, 14.0% PR, objective response of 25.6% and SD of 48.8%. A Phase II study of MEDI-551 in combination with bendamustine in relapsed CLL patients [123] is currently ongoing. Anti-CD23 antibody: lumiliximab

The CD23 antigen is a low-affinity IgE receptor expressed on mature resting cells and some activated B cells. High expression of CD23 is characteristic of CLL cells. Lumiliximab (Biogen Idec, Cambridge, MA, USA) is a genetically engineered macaque human dimeric anti-CD-23 IgA1 mAb [124]. This mAb induces ADCC, CMC and apoptosis. In a Phase I dose-finding trial, lumiliximab was given to 46 CLL patients with refractory/ relapsed CLL from a lowest dose of 125 mg/m2/week for 4 weeks, to a highest dose of 500 mg/m2 three-times a week for 4 weeks [125]. No remissions were achieved but reductions in absolute lymphocyte counts and lymphadenopathy were observed in 42 of 46 (91%) patients. Moreover, decreases in absolute lymphocyte counts ‡50% were observed in 11 of 40 (28%) patients enrolled at 375 mg/m2/week or higher. Reduction of lymphadenopathy was observed in 22 of 37 (59%) patients. This Phase I study has shown that lumiliximab is clinically active and safe in pretreated patients with CLL. Subsequently, Byrd et al. initiated a combination study of lumiliximab with FCR in previously treated patients with 850

progressive symptomatic CLL [126]. Thirty-one patients received either 375 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR. An ORR of 71% was observed, including 48% CR, 10% PR and 13% unconfirmed PR. However, CR was more frequent in FCR + lumiliximab (48%) than in FCR alone (25%). Subsequently, a large randomized, openlabel, multicenter study of lumiliximab in combination with FCR versus FCR alone (LUCID trial) has been initiated [127]. However, an interim analysis failed to show any clear advantage of combined lumiliximab and FCR therapy over the administration of FCR alone: for FCR + lumiliximab and FCR regimes, the ORRs were 71 versus 72%, CR 16 versus 15%, respectively. The study was, therefore, stopped prematurely and development of lumiliximab in CLL was discontinued. Anti-CD40 antibodies

CD40 is a type-1 transmembrane glycoprotein belonging to the TNF receptor family, which is broadly expressed on hematological cells, including the vast majority of those associated with CLL [128]. Preclinical and early clinical data with CD40 antibodies have validated CD40 as a target for B-lineage malignancies. Dacetuzumab and lucatumumab are anti-CD40 antibodies for clinical use in the most advanced stage and are being tested as treatment for malignancies such as CLL, multiple myeloma and NHL. Lucatumumab

Lucatumumab (HCD122, CHIR-0.12.12, Novartis Pharmaceuticals, Basel, Switzerland) is a fully human anti-CD40 mAb that blocks CD40/CD40L interactions in vitro and inhibits CD40L-induced proliferation of human peripheral blood lymphocytes without disturbing baseline lymphocyte proliferation. Lucatumumab triggers cell lysis via ADCC in cells overexpressing CD40 [128]. A Phase I study of lucatumumab in pretreated CLL patients has shown some activity with a favorable safety profile at a dose up to 3 mg/kg [129]. Of the 26 patients included into the study, 17 patients had SD with mean duration of 76 days, and 1 patient had a nodular PR for 230 days. Dacetuzumab

Dacetuzumab (SGN-40, Seattle Genetics, Inc, Bothell, WA, USA) is a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody. This antibody induces ADCC and apoptosis of NHL cells, contributing to in vivo antitumor activity observed in NHL cell lines and human lymphoma xenograft models [130]. Dacetuzumab was found to have antitumor activity in patients with refractory or recurrent B-cell NHL [131]. In a Phase I study in pre-treated patients with CLL, it exhibited minimal clinical activity. Five patients experienced a SD and no objective responses were observed [132]. Dacetuzumab was well tolerated and no dosedependent trends in AEs were noted. No further single-agent study of dacetuzumab was conducted due to low antileukemic activity in this patient population. Expert Rev. Hematol. 7(6), (2014)

mAbs for CLL

XmAbCD40

XmAbCD40 (Xencor Inc., Monrovia, CA, USA) is a humanized anti-CD40 antibody with Fc-engineered for increased FcgR binding [133]. XmAbCD40 has significantly enhanced ADCC relative to anti-CD40 IgG1 against B-lymphoma, leukemia and multiple myeloma cell lines, and against primary tumors. In addition, it significantly inhibited lymphoma growth in disseminated and established mouse xenografts and was more effective than rituximab. However, no results of clinical studies have yet been reported.


Conclusion

Monoclonal antibody therapy is one of the most significant advances in the treatment of lymphoid malignancies in the last two decades. The introduction of the anti-CD20 mAbs, rituximab, ofatumumab and obinutuzumab, has revolutionized the treatment of CLL. These antibodies were first studied as single agents in relapsed CLL, but recently they have been increasingly used in combination chemotherapy regimens in previously untreated and pretreated patients. Further studies should clarify whether new mAbs have the potential to improve the treatment results in patients with CLL. Expert commentary

Over the last few years, several mAbs directed against lymphoid cells have been developed and investigated in CLL. Among them, anti-CD20 mAbs play the most important role. Rituximab, ofatumumab and obinutuzumab have been approved for the treatment of CLL, either as single agents or in combination therapy. FCR is the treatment of choice for younger, fit patients with CLL, whether they are previously untreated or not. More recently, chlorambucil in combination with rituximab, ofatumumab or obinutuzumab is currently used as firstline treatment for unfit elderly patients. However, for those patients who experience relapse or develop a resistance to available treatments, a need exists for additional therapeutic options, including new mAbs. Over the last few years, the number of clinical trials with new mAbs with potent cytotoxicity to CLL cells has significantly increased. In particular, new generations of anti-CD20 mAbs have been developed with potential benefits over the classical, first-generation mAb rituximab. A number of additional mAbs are in development and recently, several of them have advanced into clinical testing as a treatment for CLL, and some clinical data have been reported. The high expression of CD37, CD19, CD23, CD40 and other antigens in CLL cells has revealed the potential for targeted immune therapy with other mAbs. Recently, chemotherapy-free immunotherapeutic approaches have been developed for patients with CLL, including the BCR inhibitors ibrutinib and idelalisib, which cause a transient increase in blood lymphocyte levels and are associated with a low complete remission rate. mAbs are well-tolerated and non-toxic drugs when administered in combination with a wide variety of products. It has been hypothesized that in CLL, a combination of ibrutinib and other BCR-targeted therapies with mAbs can accelerate and improve responses. Ibrutinib has been studied in informahealthcare.com

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combination with rituximab or ofatumumab with exciting results. This therapy offers improved dosing regimens and sustained response in newly diagnosed and relapsed/refractory CLL patients. Further studies should clarify whether mAbs combined with other targeted drugs have the potential to improve the treatment results in patients with CLL. Five-year view

mAbs have significant value in the treatment of CLL. Unfortunately, the clinical application of newer mAbs so far has been very limited compared with the approved anti-CD20 mAbs, rituximab and ofatumumab, and the anti-CD52 mAb alemtuzumab. Preclinical studies suggest CD37 is expressed to a greater degree than CD20 on CLL lymphocytes. Antibodies targeting CD37 may have clinical applications similar to those using CD20-directed antibodies. Further studies should elucidate whether these new antibodies can be more effective than currently used anti-CD20 antibodies in patients with CLL, both as single agents and in combination. Until today, most clinical trials in CLL with newer mAbs have been designed as single-arm studies, and a limited number of patients were included. Arguably, a direct comparison of newer antibodies, particularly the anti-CD37 drugs, together with the anti-CD20 antibodies used in current therapeutic standards, would more precisely describe their true role in the clinical management of CLL patients. The success of these drugs will be based on demonstrating their superiority over available mAbs and other emerging therapies in achieving and sustaining CRs and in improving survival. Although the development of new mAbs into a clinically useful form of therapy is probably many years away, its progress will be followed with great interest by laboratory investigators and clinicians. With the introduction of the BCRtargeted therapies and other agents, and the exciting results which will doubtlessly occur in these studies, the therapeutic scenario for CLL will dramatically change in the years to come. Without a doubt, combination therapy with mAbs and BCR inhibitors will prove to be a useful combination in routine clinical practice. The excellent toxicity profile of mAbs and BCR inhibitors would be an appropriate choice for CLL patients, particularly for those in whom chemotherapy is contraindicated. Nevertheless, well-designed Phase II and III clinical trials are intended in the near future, which should deliver further evidence of the safety and clinical activity of newer mAbs. Financial & competing interests disclosure

This work was supported in part by Medical University of Lodz grant No 503/1-093-01/503-0. The author received research grants and travel grants from F. Hoffmann-La Roche, and research grants from GlaxoSmithKline, Trubion Pharmaceuticals Inc, Janssen and Gilead. The author has 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. No writing assistance was utilized in the production of this manuscript. 851

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Key issues • The anti-CD20 monoclonal antibodies rituximab, ofatumumab and alemtuzumab play an important role in the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) and relapsed/refractory patients. • Rituximab when used as a single agent demonstrated lower activity than in combination with cytotoxic or targeted drugs. • Ofatumumab monotherapy shows promising efficacy in heavily pretreated patients with fludarabine- and alemtuzumab-refractory CLL. • Chlorambucil in combination with rituximab or ofatumumab is currently accepted as the first-line treatment of progressive CLL in unfit, usually elderly, patients. • Obinutuzumab combined with chlorambucil was approved by the US FDA for older patients with previously untreated CLL who are not as fit.


• New anti-CD20 monoclonal antibodies, veltuzumab (IMMU-106) and ocaratuzumab, are under evaluation for safety and efficacy in patients with CLL. • Alemtuzumab, directed against the CD52 antigen, is highly active in previously treated and untreated CLL patients, including those with del(17p13) and/or TP53 abnormality or who are refractory to fludarabine. • The results of preclinical and early clinical studies suggest that the anti-CD37 antibodies otlertuzumab (TRU-016) and BI 836826 (MAb 37.1) are active and show promising activity in CLL. • MOR208 (XmAb5574), a novel humanized IgG1 anti-CD19 mAb, showed a tolerable toxicity profile and preliminary evidence of antitumor activity in high-risk patients with relapsed/refractory CLL. • Lumiliximab, an anti-CD23mAb, has antitumor activity against CLL cells in preclinical studies, but its development in CLL was discontinued due to low clinical activity in Phase III study. • Dacetuzumab and lucatumumab are anti-CD40 antibodies undergoing tests for treating CLL.

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Emerging immunological drugs for chronic lymphocytic leukemia.

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

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Obinutuzumab: A FDA approved monoclonal antibody in the treatment of untreated chronic lymphocytic leukemia.

Update on emerging treatments for chronic myeloid leukemia.

The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia-Microenvironment Interactions in Chronic Lymphocytic Leukemia.

3D Biomaterial Microarrays for Regenerative Medicine: Current State-of-the-Art, Emerging Directions and Future Trends.

Current concepts in diagnosis and treatment of chronic lymphocytic leukemia.

Current and emerging treatments for severe asthma.

Emerging drugs for acute lymphocytic leukemia.

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Chronic myeloid leukemia and chronic lymphocytic leukemia.

Chemoimmunotherapy for chronic lymphocytic leukemia.

Obinutuzumab for chronic lymphocytic leukemia.

Background and current state-of-the-art.

Chronic lymphocytic leukemia monitoring with a Lamprey idiotope-specific antibody.

Psychological interventions for chronic pediatric pain: state of the art, current developments and open questions.

Cancer chemoprevention: current state of the art.

Pharmacogenomics: Current State-of-the-Art.

Myocardial revascularization: Current state of the art.

Dupuytren's disease: current state of the art.

Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines.

SnapShot: chronic lymphocytic leukemia.