Ofatumumab for the Treatment of Chronic Lymphocytic Leukemia

Drug Evaluation

Ofatumumab for the treatment of chronic lymphocytic leukemia

Over the last few years, several new monoclonal antibodies (mAbs) directed against lymphoid cells have been developed and investigated in chronic lymphocytic leukemia (CLL). Two mAbs have been demonstrated to have the most important clinical value in patients with CLL – rituximab, which targets the CD20 antigen, and alemtuzumab, which is active against the CD52 antigen. Recently, several new mAbs have been explored and evaluated in preclinical studies and in early clinical trials. One of these is ofatumumab (HuMax-CD20™),

a fully human monoclonal immunoglobulin (Ig)G1-k antibody targeting a CD20 molecule on B cells. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20, distinct from the epitope recognized by rituximab. Ofatumumab, in comparison with rituximab, shows superiority in complement-dependent cytotoxicity of B cells, and does not induce cell death of tumor B cells by apoptosis. In a Phase I/II study, ofatumumab demonstrated significant depletion of CD19+/CD5+ CLL cells, and showed a favorable safety profile in previously treated CLL patients. A recent study demonstrates the effectiveness of ofatumumab in patients with fludarabine-refractory CLL. Ofatumumab potentially represents an active treatment option with clinical benefit for patients with very poor prognosis who have exhausted standard treatment options. In December 2004, the US FDA granted Fast Track status for the use of ofatumumab in therapy of CLL in patients who failed treatment with fludarabine.

Keywords: chronic lymphocytic leukemia n CLL n leukemia n monoclonal antibody Tadeusz Robak n ofatumumab n therapy Medical University of Lodz, Department of Hematology, Chronic lymphocytic leukemia (CLL) is a clonal Current treatment options in chronic Pabianicka 62 , Lodz, 93-513, disease characterized by proliferation and accu- lymphocytic leukemia Poland mulation of small CD5-positive B cells. It is the The management of CLL patients is deter- Tel.: +48 426 895 191 most common adult leukemia in Europe and mined by the stage and activity of the disease. Fax: +48 426 895 192 North America, with an annual incidence rate of There is no evidence that cytotoxic therapy has [email protected] 3–5 cases per 100,000 [1,2]. The disease is gener- beneficial effects in patients with the indolent ally perceived as indolent but incurable, affecting form of the disease [7]. However, patients with predominantly elderly people. The median age at symptomatic and/or progressive disease should diagnosis is 65–70 years, with only approximately be immediately treated [8]. Widely accepted 20% of patients aged below 55 years. Clinical guidelines for the initiation of chemotherapy in staging systems proposed in the early 1980s by CLL patients have been proposed by the National Binet et al. [3] and Rai et al. [4] are still the most Cancer Institute Sponsored Working Group common and validated prognostic factors in (NCI-WG) [8,9]. According to these guidelines, patients with CLL. However, these systems do the criteria for the initiation of therapy may not not allow identification of patients in early stages be identical for routine clinical practice and for who are likely to progress, and those in whom the patients included in clinical trials. disease will remain stable for many years. In the past 20 years, the purine nucleoside Within the past few years, several biological analogs (PNAs) fludarabine (FA), cladrib- markers, including serum markers, immuno- ine (2-CdA, 2-chlorodeoxyadenosine) and globulin heavy chain variable region (IgVH) pentostatin (DCF, 2’-deoxycoformycin) have mutation status, some cytogenetic abnormali- been introduced for treatment of CLL [10]. ties, P53 mutations, cell membrane expression Significantly higher overall response (OR), com- of CD38 and z-associated protein-70 (ZAP-70) plete response (CR) and longer progression-free have become important prognostic factors [5,6]. survival (PFS) in patients with CLL treated with Several serologic parameters such as thymidine FA or 2-CdA have been confirmed in random- kinase (TK), b2-microglobulin (b2M) and soluble ized, multicenter trials, and more recently in CD23 (sCD23) also provide valuable information meta-analysis [11–15]. However, the median sur- regarding disease progression and survival. vival time did not differ between patients treated

with PNA and alkylating agents. Combination relapsed or refractory CLL exposed to alkylating therapies with PNA and cyclophosphamide (CY) agents, and having failed previous FA therapy. are more active than monotherapy in terms of The OR rate was 33%, including a CR of 2% OR, CR and PFS [16–19]. However, higher overall and PR of 31%. The median response duration response OR, CR and PFS do not translate to was 8.7 months. Overall median survival was longer overall survival. 16 months and median survival for respond- Over the last few years, several monoclonal ers was 32 months. The results of other stud- antibodies (mAbs) and immunotoxins have been ies in smaller groups of previously treated CLL investigated in clinical trials in patients with patients have also been published. In different CLL [20–24]. There are two antibodies that have studies, the OR rate ranged from 31 to 60%, the most important clinical value in patients with and the CR rate from 0 to 31% [29–32]. In the CLL at present. The first is the human–mouse majority of studies, anti-tumor effects of alemtu- antibody rituximab (Rituxan®, Mabthera®) zumab were more significant in blood and bone that targets the CD20 antigen [23]. The second marrow than in lymph nodes. Alemtuzumab is alemtuzumab (Campath-1H), a humanized has also been investigated as first-line therapy form of a rat antibody active against CD52 [24]. in CLL. In a pilot study reported in 1996 by O’Brien et al. treated CLL patients with an ini- Osterborg et al. [33], nine patients with progres- tial dose of rituximab 375 mg/m2, which was sive, previously untreated CLL were included. then increased to a fixed dose of between 500 Alemtuzumab was administered subcutaneously 2 and 2250 mg/m once-weekly for 4 weeks [25]. or intravenously. The OR rate was 89%, which The OR rate was 36% and ranged between 22 included CR in three and PR in five patients. and 75%. All responses were partial responses In 2002, a prospective randomized Phase III (PR). Median time to progression in responded trial (CAM 307) comparing high-dose chloram- patients was 8 months, with the longest remis- bucil with alemtuzumab in front-line treatment sion duration being 15+ months. In the study of progressive CLL was commenced [34]. In this performed by Byrd et al., 83 previously treated trial, 279 patients were randomized, 149 patients CLL patients were treated with different doses received alemtuzumab 30 mg three-times per of rituximab (250–375 mg/m2) three-times week for up to 12 weeks, and 148 patients 2 weekly for 4 weeks [26]. The OR rate was 45% received chlorambucil 40 mg/m every 28 days (3% CR and 42% PR). Responses were noted in for a maximum of 12 months. PFS was superior all groups of patients, including those with bulky for alemtuzumab, with a 42% reduction in risk lymphadenopathy and those for which alkylator of progression or death (p = 0.0001), and median and/or FA-based therapy had failed. time to alternative treatment of 23.3 months Alemtuzumab is a humanized therapeu- compared with 14.7 months for chlorambucil tic mAb that recognizes the CD52 antigen, (p = 0.0001). The overall response rate was expressed on normal and neoplastic lympho- 83% with alemtuzumab, including 24% CR, cytes, monocytes and natural killer cells. In and 55% with chlorambucil, including 2% CR 2001, alemtuzumab was approved in the USA (p < 0.0001). Moreover, elimination of minimal and Europe to treat patients with CLL refractory residual disease occurred in 31% (11 of 36 of to FA. Alemtuzumab is highly active in previ- complete responders to alemtuzumab and none ously treated patients with CLL [27,28]. The effec- to chlorambucil). Adverse events were similar in tiveness of this mAb in patients with CLL resis- both arms, with the exception of infusion-related tant to conventional treatment was first reported and CMV events for alemtuzumab. Recent ana in 1997 by Osterborg et al. [27]. They found an lysis indicates that CMV reactivation occurred OR rate of 43% in 29 patients, with a CR in 4% in 15–25% of alemtuzumab-treated refractory of patients with relapsed or refractory CLL. The or relapsed CLL. At present, aggressive anti- median duration of response was 12 months. In infective prophylaxis is a mandatory procedure. 36% of patients, a CR was obtained in the bone In patients with CLL deletion, 17p13 is an marrow, and in 32% splenomegaly completely independent prognostic factor identifying resolved. However, resolution of lymphadeno patients with rapid disease progression and short pathy was observed only in 7%, and bulky survival time in multivariate analysis [35,36]. The lymphadenopathy did not respond to therapy. deletion 17p affecting the TP53 gene has been Several reports have confirmed significant associated with failure after treatment with activity of alemtuzumab in relapsed or refractory alkylating agents, purine analogs and rituximab CLL. Keating et al. [28] investigated the efficacy [37–39]. Lozanski et al. who treated 36 patients and safety of alemtuzumab in 93 patients with with FA refractory B-cell CLL (B-CLL) with

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alemtuzumab, including 15 patients with p53 combination treatment or prior rituximab were mutations or deletion, reported clinical responses not eligible. The median observation time was in six patients (40%) with p53 mutations, dele- 25 months. The primary end point of PFS was tion or both [29]. Subsequently, interim analysis significantly prolonged by a median of 10 months of the CLL2H trial [40] and the study of Osuji in the R‑FC arm (30.6 months), compared with et al. [41], confirmed the efficacy of alemtuzumab FC (20.6 months; p = 0.0002). Secondary end in patients with p53 abnormalities. Stilgenbauer points showed similar results. Overall response et al. reported the responses (CR or PR) in seven rate was higher for R-FC versus FC (70 vs 58%; of 13 (53.8%) cases with 17p abnormalities [40]. p = 0.0034), due to superior CR rates (24 vs Similarly, Ossuji et al. observed OR in four out 13%; p = 0.0007). Grade 3/4 adverse events of eight (50%) patients with p53 deletion [41]. were higher in the R-FC arm (80%) versus FC Thus, alemtuzumab might be a more rational (74%), but serious adverse events were similar initial treatment choice for patients with these (50 vs 48%, respectively). Grade 3/4 neutro abnormalities. penia and febrile neutropenia were only mar- Monoclonal antibodies and chemotherapy have ginally increased for R-FC (42 and 15%) versus synergistic activity in patients with CLL [42,43]. FC (40 and 12%, respectively), and the same Several recent reports suggest that in patients was seen for thrombocytopenia (R-FC 11% vs with CLL, rituximab combined with PNA can FC 9%). Grade 3/4 infections (R-FC 18%, FC increase the OR and CR rates and prolong PFS 19%) were similar, and there was no difference as compared with PNA or rituximab alone, with in bacterial, viral or fungal infections between acceptable toxicity [44–50]. The addition of ritux- the two arms. Grade 3/4 anemia was slightly imab to a variety of chemotherapy regimens for increased in the FC arm (R-FC 2%, FC 5%). the treatment of patients with CLL has yielded FC ± rituximab is now the standard first-line promising results in Phase II and III trials. therapy in younger patients with symptom- The combination of rituximab with FC (R-FC atic and/or progressive CLL. Moreover, sev- regimen) demonstrated particularly high rates of eral studies have confirmed significant activity overall response, CR, PFS and overall survival of these agents in relapsed or refractory CLL. in previously untreated and relapsed/refractory Management decisions are more difficult in CLL [47,48]. In order to validate this concept, the frail, elderly patients because of the apparent German CLL study group (GCLLSG) initiated increase in toxicity of PNAs, especially in com- a multicenter, multinational Phase III trial, bination with CY and rituximab. In this patient CLL8, to evaluate the efficacy and tolerability population, chlorambucil is still accepted as the of R-FC versus FC for the first-line treatment of first-line treatment [51–53]. Chlorambucil, with patients with advanced CLL [44]. In this study, or without steroids, gives the initial response 817 patients were randomly assigned to receive rate of 60–90%, with a CR in up to 20% of all six courses of either FC or R-FC. At the time patients, depending on the dose and response cri- of analysis (June 2008) the median observation teria [52]. Other alkylating agents have been less time was 25.5 months. The OR rate was signifi- extensively investigated than chlorambucil, and cantly higher in the R-FC arm (95%) compared mainly in combination therapy. CY has a simi- with the FC arm (88%) (p = 0.001). The CR lar activity to chlorambucil, and is usually used rate of the R-FC arm was 52% as compared with when chlorambucil is poorly tolerated. CY was 27.0% in the FC arm (p < 0.0001). PFS was more frequently used in combination therapy 76.6% at 2 years in the R-FC arm and 62.3% with vincristine and prednisone (COP, CVP) in the FC arm (p < 0.0001). There was a trend or with doxorubicin, vincristine and prednisone for an increased overall survival rate in the R-FC (CHOP) [51]. arm (91 vs 88% at 2 years; p = 0.18). Bendamustine is an agent with alkylating and In the REACH trial, 552 relapsed or refrac- purine-like qualities [54]. This agent seems to have tory patients from 17 countries were randomized a low cross-resistance with alkylating agents and (1:1) to receive either R-FC or FC [48]. A median FA. Various doses and treatment schedules have of one prior treatment had been administered, shown significant efficacy and acceptable toxicity consisting of single-agent alkylator therapy in previously treated patients. The dose of 70 mg/ (66%), purine-analogs (16%) or combination m2 on days 1 and 2 every 4 weeks is suggested treatments (cyclophosphamide, doxorubicin, in heavily pretreated and treatment-refractory vincristine and prednisolone [CHOP], cyclo- patients [54,55]. Recently, the safety and efficacy phosphamide, vincristine, prednisone [COP], of bendamustine were also confirmed in an F-containing, 18%). Patients with prior FC open-label, randomized, comparative trial [56].

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In March 2008, bendamustine was approved Epratuzumab (Immunomedics, Inc.) is a by the US FDA for the treatment of previously humanized anti-CD22 mAb currently in clinical untreated patients with CLL. However, efficacy trials for the treatment of NHL and autoimmune of this agent, relative to first-line therapy with FA disorders [63–65]. Epratuzumab is selectively and other first-line therapies than chlorambucil, active against normal and neoplastic B cells. The has not been investigated. single-agent activity of epratuzumab was assessed in Phase I/II trials in patients with NHL [65]. Novel mAbs potentially useful in CLL Overall, 24% of patients showed an objective Over the last few years, several new mAbs response in the diffuse large B-cell lymphoma directed against lymphoid cells have been devel- (DLBCL) group. However, there was no objec- oped and investigated in preclinical studies and tive response among the group of 12 patients clinical trials [43]. Some of these are highly with small lymphocytic lymphoma (SLL). Other active in chronic lymphoid malignancies and studies demonstrated higher efficacy of epratu- are potentially useful in the treatment of CLL. zumab in combination with rituximab. However, New mAbs directed against CD20 include the further studies are needed to elucidate the role of human mAb ofatumumab (HuMax CD20™), epratuzumab in the treatment of CCL. GA-101 and IMMU-106 (hA20) [57–59]. These Lumiliximab (anti-CD23 mAb) is a geneti- agents are highly cytotoxic against B-cell lymphoid cally engineered macaque–human chimeric anti-

cells, and are evaluated in lymphoid malignancies. CD-23 IgG1-k mAb [66]. This mAb binds specifi- GA-101 (Hoffman La Roche, Basel, cally to CD23 and induces ADCC, CDC and Switzerland) is a novel third-generation, human- apoptosis. The CD23 antigen is a cell-surface ized anti-CD20 IgG1 mAb [57,60]. GA-101 has protein considered one of the most useful mark- a significantly increased antibody-dependent ers for identifying CLL [67]. In a Phase I study, cytotoxicity (ADCC), reduced complement- the safety, efficacy and pharmacokinetics of dependent cytotoxicity (CDC) and exhibits lumiliximab were evaluated in 46 patients with superior caspase-independent apoptosis induc- refractory/relapsed CLL [68]. Reductions in abso- tion in comparison with rituximab [60]. In this lute lymphocyte counts and lymphadenopathy Phase I/IIa study, GA-101 was administered were observed in 42 of 46 (91%) patients. This as a single agent to 24 patients with CD20+ study has shown that lumiliximab is clinically malignant disease for whom no therapy of active and safe in pretreated patients with CLL. higher priority was available [57]. Patients have Galiximab (B 7.1) (Biogen Idec Inc., CA, been treated with GA-101 at doses from 50 to USA) is a macaque–human chimeric anti- 2000 mg. Antibody has shown a similar safety CD80 monoclonal antibody with human IgG1 profile to rituximab, and promising efficacy in constant region and macaque variable region, this difficult-to-treat patient population. Based structurally indistinguishable from human anti- on this data, GA-101 mAb is a promising thera- bodies [69]. Promising results have been obtained peutic agent for CD20-positive B-cell lymphoid in the in vitro and in vivo studies evaluating the malignances, including CLL. anti-tumor activity of galiximab in lymphoma IMMU-106 (hA 20; Immunomedics, Inc., models, especially if this mAb was combined NJ, USA) is a new humanized anti-CD20 mAb with chemotherapeutic agents, such as FA and evaluated to elucidate its action as an anti doxorubicin [70,71]. lymphoma therapeutic [59,61,62]. The mecha- CD40, a member of the TNF receptor super nism of cytotoxicity of IMMU-106 is similar to family is highly expressed in a variety of B-cell rituximab and includes direct apoptosis, ADCC malignancies including CLL [72]. A fully human and CDC. A Phase I/II dose-escalation study of anti-CD40 mAb HCD122 (Abgenix, Inc., IMMU-106 was performed in 55 patients with CA, USA), formerly known as CHIR-1212, relapsed/refractory non-Hodgkin lymphoma has been recently selected based on its inhibi- (NHL), including 37 follicular lymphomas (FLs) tion of CD40L-induced biological sequelae and 18 other B-cell lymphomas [59]. A total of 39 [73]. HCD122 can mediate ADCC in vitro and patients with at least 12 weeks follow-up had one has antiproliferative and anti-tumor activities or more responses evaluated by the Cheson’s cri- as a single agent in CLL, multiple myeloma

teria, with all CR occurring in FL and one with and NHL [74]. Recently, Byrd et al. reported a marginal zone lymphoma (MZL). These results Phase I trial of HCD122 in 14 patients with may indicate that IMMU-106 is at least as effec- relapsed/refractory CLL after FA treatment tive as rituximab, and further studies in B-cell [75]. This study has shown that HCD122 is lymphoid malignancies should be undertaken. safe and well-tolerated up to the 3 mg/kg dose

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level. SGN-40 is another anti-CD40 IgG1 mAb cells [84–87]. Ofatumumab was more effective that induces cytotoxicity against CLL cells [76]. than rituximab in inducing CDC in nine of ten SGN-40 induces apoptosis and mediates ADCC DLBCL tumor samples obtained from chemo- + against CD40 NHL B-cell lines, contributing therapy-refractory DLBCL patients [80]. In this

to in vivo anti-tumor activity observed in human experiment, the lethal dose (LD50) for ofatu- lymphoma xenograft models. mumab was 0.1 ± 2.8 µg/ml and 6.4 ± 4.9 µg/ml for rituximab. Moreover, ofatumumab-induced Ofatumumab: mechanism of action CDC of DLBCL cells was less sensitive to expres- & pharmacokinetics sion of complement defense molecules CD55

Ofatumumab is an IgG1-k human anti-CD20 mAb and CD59 than CDC induced by rituximab. that binds human B cells [58,77–80]. Ofatumumab Importantly, the sensitivity to ofatumumab- is produced with a recombinant murine cell line induced CDC appeared to also be independent (NSO) using standard mammalian cell cultiva- of expression of Bcl-2 and XIAP. The real-time tion and purification technologies [81]. The NSO dynamics of complement activation promoted by cell line has been transfused with a GS vector car- ofatumumab and rituximab on CD20-positive rying the antibody genes derived from the human Daudi and ARH77 has also been investigated anti-CD20 hybridoma cell line (2F2) generated [85]. Both mAbs activated complement and via transgenic mouse technology [80,81]. HCo7 and induced significant changes of the cells morphol- KM mice were immunized with human CD20- ogy, including rapid blebbing, and long string- transfected NS/0 cells [82]. For priming, mice like structures (referred to as streamers) were received 1 × 107 CD20 transfected cells in com- cast off the cells. Interestingly, ofatumumab plete Freund adjuvant (CFA) intraperitoneally, readily promoted complement activation, C3b and were boosted with cells in phosphate-buffered deposition and killing of ARH77 cells, whereas saline. After development of positive CD20 anti- rituximab-mediated C3b deposition was lower, body titer, mice received a final intravenous boost and killing was close to background levels in 7 of 0.5 × 10 cells 3 days prior to fusion [82]. The comparison with ofatumumab [87,88]. Maximum molecular weight of the antibody is 149 kDa as deposition of C3b fragments on ARH77 cells determined by mass spectrometry [81]. was observed more rapidly for ofatumumab Ofatumumab specifically recognizes a dis- (30 sec) than for rituximab (5 min) [86]. In line tinct epitope encompassing both the small and with this observation, binding of ofatumumab large extracellular loops, and binds specifically to to ARH77 cells generated streamers five- to ten- the amino acid residues 159, 163 and 166 in the fold more than was observed for cells opsonized large extracellular loop of the CD20 molecule. with rituximab. In addition, ofatumumab is able The epitope is therefore distinct from the bind- to effectively induce ADCC [89]. ing site recognized by other CD20 mAbs, such Pharmacokinetic parameters were evaluated as rituximab [81,83]. Rituximab had an absolute in patients with relapsed or refractory FL and requirement for alanine and proline at position CLL in Phase I/II studies [58,90,91]. There were 170 and 172, respectively, within the large extra- four cohorts of patients with FL who received cellular loop of CD20. In contrast, ofatumumab four weekly intravenous infusions of 300, 500, recognizes a novel epitope located N-terminally 700 or 1000 mg of ofatumumab [90]. The median

of this motif in the small extracellular loop of Cmax values per dose group were 129, 185, 380

CD20 that is not bound by rituximab. The and 610 µg/ml, respectively. The t½ values were recognition of this epitope seems to be closely calculated as 447, 245, 322 and 621 h. Plasma linked with C1q capture and CDC potency [83]. clearance values were 9, 19, 10 and 7 ml/h/kg, In in vitro experiments, ofatumumab was able to with AUC values of 75,000, 51,000, 18,500 and lyse a range of rituximab-resistant targets, such 32,6000 h/µg/ml, respectively. A correlation

as primary CLL cells, in the presence of human between exposure (AUC and Cmax) and clinical plasma or unfractionated blood [81]. The close response to treatment at weeks 19 and 26 was binding proximity of ofatumumab to the cell not found. For other pharmacokinetic param-

membrane likely results in highly efficient com- eters (t½, volume of distribution [Vz], clearance plement deposition on B-cell membranes, with- [Cl]), correlation to responses was only found

out high levels of systemic release of activated for clinical response at week 26 and t½ and Cl complement components [83]. (p < 0.05) [90]. Recent laboratory studies confirmed previous The pharmacokinetics of ofatumumab has observations that ofatumumab is more effective also been investigated in CLL patients [58,91]. In than rituximab at CDC and killing of the target this study, a significant corelation between time

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to progression and time to the next anti-CLL Subsequently, an international pivotal trial therapy with AUC (p = 0.005 and p = 0.001, of ofatumumab in patients with CLL refractory respectively) and Cl (p = 0.003 for both correla- to both FA and alemtuzumab, or refractory to tions) was found. Comparing the clinical phar- FA with bulky lymphadenopathy (>5 cm) has macokinetic data of ofatumumab and rituximab, been undertaken (Hx-CD20-406 Phase III it can be seen that ofatumumab appears to have study) [92]. Patients with FA-refractory CLL a longer half-life. In a study of patients who and refractory to alemtuzumab or ineligible received rituximab 375 mg/m2 once-weekly for for alemtuzumab due to bulky lymphadenopa- four doses over 22 days, rituximab serum concen- thy remain difficult to treat, and outcomes tration increased over the treatment course, with with current salvage regimens remain poor. In the median concentration being 464.7 µg/ml addition, no standard treatments are available after the fourth infusion of antibody (the maxi- for this patient population [93]. Patients in the mum concentration measured as 996.6 µg/ml) ongoing pivotal trial receive ofatumumab in 8

[89]. The half-life increased from 76.3 h after the weekly infusions followed by 4 monthly infu- first infusion to 205.8 h after the fourth infusion, sions for a total of 12 planned doses (dose 1: alongside a decrease (fourfold) in the clearance 300 mg; doses 2–12: 2000 mg). The primary (from 38.2 to 9.2 ml/h). From this, it can be seen end point is OR rate assessed by an Independent that ofatumumab appears to have a longer half- Review Committee over a 24-week period. This life, although the doses of the antibodies vary and interim analysis included 59 patients refractory need due consideration for comparative purposes. to FA and alemtuzumab (FA and alemtuzumab refractory; FA-ref) and 79 patients refractory Efficacy of ofatumumab in to FA with bulky lymphadenopathy (bulky CLL patients FA-refractory; BF-ref). The preliminary results Ofatumumab has been investigated in a reported in the abstract form demonstrate Phase I/II study in 33 CLL patients with refrac- promising efficacy of ofatumumab monotherapy tory or relapsed diseases [59]. Median age was in a heavily-pretreated patient population with 61 years (range 27–82). Median time from FA-refractory CLL [92]. Full efficacy results from diagnosis to ofatumumab therapy was 6.3 years this trial are awaited. (range 1.2–14). Median number of prior treatments was three (range 1–9) and 67% of the Safety profile & side effects patients were Binet stage B. Three cohorts of The majority of side effects in CLL and NHL patients with relapsed or refractory CLL received patients were related to the first infusion of the 4 weekly intravenous infusions of ofatumumab. drug, and their number and severity decreased at The first infusion was 100, 300 and 500 mg in each subsequent infusion [58,90]. These included cohort A, B and C, and subsequent doses were grade 1–2 pruritus, dyspnea, rigors/chills, sweat- 500, 1000 and 2000 mg, respectively. Maximum ing, nausea, hypotension, urticaria, fatigue, tolerated dose was not reached. All patients had pyrexia, headache and rash, and were relative significant reduction in leukemia cells. Moreover, to infusion. These probably resulted from the several flow cytometry results showed that ofa- cytokine-release syndrome, which is a symptom tumumab caused rapid and prolonged depletion complex associated with the use of many mAbs of normal B lymphocytes in all patients. Their [94]. It results from the release of cytokines from recovery to normal levels was not observed until cells targeted by the antibody. When cytokines 5–6 months after completion of therapy. The are released into the circulation, systemic symp- objective response rate was 50% (13 out of 26) toms such as fever, nausea, chills, hypotension, in cohort C. All responses were a PR, except for tachycardia, asthenia, headache, rash, scratchy one nodular partial response in cohort C. There throat and dyspnea can result [94]. The severity was no CR of the 33 patients previously treated of these symptoms can be partially reduced by with rituximab (7), alemtuzumab (6) and/or FA the use of premedication with antihistamines (20). However, not all of these responses were and corticosteroids [94]. sustained. At week 19, only nine patients were in In 33 CLL patients receiving multiple doses sustained response. The median time to progres- of ofatumumab, the dose schedule was found sion was 133 days, and the median duration of to be well-tolerated in patients with CLL in response was 112 days. Time to the next antileu- doses up to 2000 mg [58]. There were a total of kemic therapy was 366 days [91]. This Phase I/II 246 adverse events reported in 27 patients, with study indicates that ofatumumab is an active and 150 of these being considered related to treat- well-tolerated agent in refractory/relapsed CLL. ment. There were 92% mild (grade 1–2) and

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19 grade 3–4. There were 10 serious adverse Conclusion & future perspective events in nine patients throughout the study Ofatumumab is a novel, second-generation, being treatment related: grade 3 herpes zoster fully human monoclonal antibody recognizing (n = 1), grade 4 neutropenia (n = 2), infectious different epitopes of CD20 antigen than broadly interstitial lung disease (n = 1; fatal at week 4) used rituximab. Currently available Phase I/II and grade 3 hepatic cytolysis (n = 1; after clinical trials data suggest that this antibody is the first infusion, this patient had increased effective and relatively well-tolerated in CLL, liver enzymes before therapy and completely and its efficacy appears to be comparable or bet- recovered after 3 days of therapy). The serious ter to that of rituximab used alone in patients adverse events that were considered to not be with this leukemia. In addition, the preliminary drug-induced included angina pectoris (n = 1), results from the Hx-CD20-406 Phase III study carotid artery stenosis (n = 1), grade 3 pneu- suggest promising activity of ofatumumab in monia (n = 1), grade 2 sinusitis (n = 1) and patients with FA-refractory disease. This mAb grade 2 hemolytic anemia (n = 1). There were potentially represents an active treatment option 17 (51%) patients who had infections, 88% of with clinical benefit for patients with very poor these grade 1–2. Of these, the most frequent prognosis who have exhausted standard treat- was nasopharyngitis (n = 8, with 1 being grade ment options. Ofatumumab is well-tolerated 3). Other nonrelated hematological toxicities with no unexpected toxicities. Similarly to included two additional neutropenias and two rituximab, the majority of related adverse events worsenings of thrombocytopenias to grade 3 occurred at the first infusion, and the number [58]. In addition, CLL patients receiving up to of adverse events decreased at each subsequent 2000 mg ofatumumab were negative for the infusion. However, its advantage over ritux- presence of human antihuman antibodies [48]. imab seems to be lack of the development of Furthermore, no dose-limiting toxicities were antibodies against ofatumumab in the treated reported, with up to 2000 mg ofatumumab. No patients, and higher cytotoxic potential against patient tested developed antibodies to ofatu- lymphoid cells due to superior CDC activity, at mumab. In the preliminary data from the 406 least in the in vitro studies. Hx-CD20-406 Phase III study, the safety pro- In contrast to rituximab, data concerning file of ofatumumab appeared to be consistent activity and toxicity of ofatumumab combined with the prior Phase I/II study, with no unex- with chemotherapy in CLL are not yet available. pected toxicities [92]. Infusion-related reactions It should be noted that immunochemotherapy were common. These events generally subsided with rituximab is currently often used in clini- with subsequent infusions. Further results from cal practice, and there are no data on the com- this study are awaited. Contraindications bination of ofatumumab and chemotherapy. to the use of ofatumumab have not yet been However, relatively low immunogenicity and established. significant activity of ofatumumab in lymphoid

Executive summary Mechanism of action of ofatumumab

Ofatumumab is an IgG1-k human mAb anti-CD20 reacting with human B cells. Ofatumumab specifically recognizes a CD20 epitope localized in the small extracellular loop distinct from the site of epitope recognized by rituximab. Ofatumumab is significantly more active than rituximab in complement-dependent cytotoxicity of target cells and has demonstrated equally effective antibody-dependent cytotoxicity in vitro as compared with rituximab. Clinical efficacy of ofatumumab In a Phase I/II study in 33 chronic lymphocytic leukemia (CLL) patients with refractory or relapsed diseases, all patients had significant reduction in leukemia cells, and the objective response rate was 44%. In the Hx-CD20-406 Phase III study in patients with CLL refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky lymphadenopathy (BF-ref), preliminary data suggests promising efficacy with high response rates. Safety & tolerability of ofatumumab Data on the toxicity and safety of ofatumumab were reported in a Phase I/II study in patients with relapsed or refractory CLL. The majority of all adverse events were observed on the day of the first infusion. The most common infusion-related symptoms were transient rigors, pyrexia, fatigue, rash and increased sweating. Hematologic toxicities were rarely observed. The maximum tolerated dose of ofatumumab has not been reached in the studies performed so far. Contraindications to the use of ofatumumab have not yet been established.

future science group www.futuremedicine.com 583 Drug Evaluation Robak Ofatumumab for the treatment of chronic lymphocytic leukemia Drug Evaluation

malignancies indicate that this agent should be Financial & competing interests disclosure further investigated in combination with alkyl- Dr Robak has carried out consulting work and received a ating agents and/or purine nucleoside analogs research grant from GlaxoSmithKline, Genmab and to elucidate its potential advantage over ritux- Hoffman LaRoche. The author has no other relevant affili- imab in immunochemotherapy of these disor- ations or financial involvement with any organization or ders. The encouraging single-agent activity in entity with financial interest in or financial conflict with patients with refractory CLL warrants further the subject matter or materials discussed in the manuscript investigation of ofatumumab in earlier disease apart from those disclosed. settings, in combination with other agents This work was supported in part by the grant from the and as maintenance therapy. Such data should Medical University of Lodz (No 503–1093–1) and by the come from direct comparison of ofatumumab Foundation for the Development of Diagnostics and and rituximab in well-designed, randomized, Therapy, Warsaw, Poland. No other writing assistance was multicenter Phase III studies. utilized in the production of this manuscript.

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