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Abstract

There are now many therapeutic CD20 monoclonal antibodies undergoing clinical trials for B-cell malignancy and autoimmune conditions; which is optimal for cancer therapy is not clear. The novel human IgG1 CD20 monoclonal antibody ofatumumab has shown significant activity in difficult to treat patients with chronic lymphocytic leukemia, namely those resistant or refractory to fludarabine and alemtuzumab and has now been licensed for this uncommon indication. This brief review summarizes the clinical data obtained with ofatumumab in CLL in terms of both efficacy and toxicity.

Keywords

CD20 therapeutic monoclonal antibodies chronic lymphocytic leukemia ofatumumab

Introduction

There is now a plethora of CD20 monoclonal antibodies (MAbs) available for clinical use (Table 1). Some of these MAbs differ widely in their biological properties at least in vitro; which is optimal for cancer immunotherapy, particularly when used in combination chemotherapy, remains uncertain.

Table 1.

Some CD20 therapeutic MAbs in clinical development (for more details please see Oflazoglu and Audoly [2010] and Alduaij et al. [2011]).

MAb	Company/Website	Properties	Indications/stage of clinical development	References
Rituximab	Roche/Genentech	Chimeric human IgG1	Approved for DLBCL, CLL, follicular lymphoma, etc.	See the text.
Ofatumumab	Genmab/GSK http://www.genmab.com/en/Science%20And%20Research/Products%20in%20Development/Ofatumumab.aspx	(a) Human IgG1 (b) Unique CD20 epitope (c) Enhanced CDC (d) High-affinity CD20 binding	B-cell malignancies. Approved for refractory CLL	See the text
Ocrelizumab	Roche/Genentech/Biogen IDEC	(a) Humanized IgG1 (b) Enhanced ADCC (c) Decreased CDC	Multiple sclerosis	[Kappos et al. 2011]
Veltuzumab	Immunomedics http://www.immunomedics.com/veltuzumab.shtml	(a) Humanized IgG1 (b) Slower off rate	Autoimmune thrombocytopenia CLL	[Goldenberg et al. 2009] [Morschhauser et al. 2009]
Ocaratuzumab	Mentrik http://www.mentrik.com/	(a) Human IgG1 (b) High affinity CD20 binding (c) Enhanced ADCC through Fc modification	Orphan drug designation for follicular lymphoma	[Forero-Torres et al. 2012]
Ublituximab	LFB http://www.lfb.fr/	(a) Chimeric human IgG1 (b) Enhanced ADCC via Fc glycosylation	CLL Orphan drug status	[Le Garff-Tavernier et al. 2011]
Obinutuzumab	Glycart/Roche http://www.biooncology.com/pipeline-molecules/ga101/index.html	(a) Type II CD20 MAb – mediates enhanced direct cell death (b) Humanized IgG1 (c) Increased ADCC via afucosylated Fc region.	B-cell malignancies Multiple Phase 3 studies in CLL and NHL ongoing	[Mossner et al. 2010] [Alduaij et al. 2011] [Niederfellner et al. 2011]

MAb, monoclonal antibody, DLBCL, diffuse large B-cell lymphoma; CLL, chronic lymphocytic leukaemia; CDC, complement-dependent cytotoxicity; ADCC, antibody-directed cellular cytotoxicity; NHL, non-Hodgkin’s lymphoma.

The purpose of this short review is to outline the efficacy of a unique CD20 monoclonal (MAb), ofatumumab (Arzerra; GSK/Genmab), which has been licensed for use in a relatively small, but very difficult subgroup of chronic lymphocytic leukaemia (CLL), namely those refractory or resistant to fludarabine and alemtuzumab.

CD20 as a therapeutic target for B-cell malignancies

CD20 is a tetraspanin cell surface molecule expressed at high levels on the cell surface of the majority of normal and malignant B cells (see http://www.ncbi.nlm.nih.gov/gene/931). Despite the huge clinical success of the first therapeutic CD20 monoclonal antibody, rituximab, CD20 is not such an obvious therapeutic target and might not be ‘validated’ today using modern, much stricter criteria for new drug/antibody development. First, CD20 is not involved in disease pathogenesis; CD20 mutations are not usually present in B-cell malignancies [Morin et al. 2011; Pasqualucci et al. 2011a, 2011b]. Second, the precise molecular functions of CD20 remain obscure. Study of kindred lacking CD20 expression due to a homozygous mutation in a splice junction of the CD20 (MS4A1) gene revealed a central role in the generation of T-cell-independent antibody responses [Kuijpers et al. 2010]; CD20 may act as a calcium ion channel and regulate early steps in B lymphocyte activation. Third, surface levels of CD20 are not increased in malignant as compared with normal B cells; on the contrary, CD20 levels on CLL are much lower than on normal peripheral blood B cells [Rossmann et al. 2007]. Also, in at least some B-cell malignancies, CD20 is either lost by ‘shaving’ or internalizes once crosslinked, effectively rendering the malignant cells CD20 negative [Beers et al. 2010; Beum et al. 2011; Lim et al. 2011]. Whilst internalization is necessary for the action of MAb–drug conjugates (such as SGN-35), such internalization significantly compromises the action of ‘naked’ unconjugated MAbs. Fourth, the broad expression of CD20 on normal B cells might be anticipated to result in severe depletion of normal B cells, resulting in prolonged immunosuppression. Finally, the results of single-agent rituximab in patients with all forms of B-cell malignancy are not particularly impressive, with only minor and short-lived responses in the majority of cases [Maloney et al. 1997; McLaughlin et al. 1998; Tobinai et al. 2004], as reviewed by Grillo-Lopez and colleagues [Grillo-Lopez et al. 1999].

Nevertheless, despite these potential problems or perhaps in part because of them, rituximab is now an integral part of first-line therapy regimens for most subtypes of mature B-cell malignancy. It has proved possible to incorporate rituximab into nearly all chemotherapy regimens without significant additional toxicities. Immunosuppression in most instances appears to be only short-lived and clinically inconsequential, even in the context of long-term rituximab administration as maintenance therapy in follicular lymphoma. Infusional toxicities are usually very manageable.

In terms of efficacy, however, rituximab has improved clinical outcomes significantly, even in diseases where single-agent activity has been minimal [Coiffier, 2007]. Perhaps the most impressive results have been obtained in diffuse large B-cell lymphoma (DLBCL) where the addition of rituximab to first-line chemotherapy consistently improves remission rates and overall survival [Coiffier et al. 2002]. More than that, the natural history of the disease appears to have been altered insofar as DLBCL patients who fail to remit or relapse early are now more difficult to salvage and most of such patients now die with chemotherapy-resistant disease [Friedberg, 2011].

The marked efficacy of rituximab in combination with CHOP chemotherapy is in marked contrast to the limited efficacy of single agent MAb in DLBCL [Coiffier et al. 1998]. Similarly, the addition of rituximab to fludarabine/cyclophosphamide (FC) chemotherapy for first-line treatment of CLL significantly improves outcomes and yet the efficacy of single-agent rituximab in CLL, even at high doses, is not marked [O’Brien et al. 2001; Hallek et al. 2010]. In CLL, the effects of rituximab are usually minor and short-lived. There is, for example, little or no clearance of bone marrow with single-agent rituximab in CLL. Even the use of high doses of rituximab (up to 2000 mg) and more frequent administration (three times per week) failed to overcome this problem. It is now clear that CD20 is not an optimal immunotherapeutic target in CLL, not only because of the uniformly low CD20 expression (some cases may express only 2000 molecules per cell), but also because CD20 internalizes rapidly following antibody-induced crosslinking in CLL as mentioned above. It has been suggested that lower, more frequent doses of CD20 MAbs may be more effective in CLL because of this problem [Williams et al. 2006]; more may not always be better in the context of antibody therapy. Nevertheless, adding rituximab to FC markedly improves clinical outcomes (it is interesting to note that adding rituximab to FC chemotherapy in CLL produces a similar magnitude of improvement in response as seen with the addition of rituximab to CHOP chemotherapy in DLBCL). Taken together, these data indicate a synergistic interaction between rituximab and several forms of chemotherapy, over and above that anticipated from rituximab-induced activation of immune effector mechanisms, such as antibody-directed cellular cytotoxicity (ADCC), phagocytosis and/or complement-dependent cytotoxicity (CDC) or complement activation. What might these mechanisms be? Given that the effects of rituximab are obvious almost immediately after completion of therapy (at least in DLBCL), induction of an active immune response (a ‘vaccinal’ effect) by rituximab, as has been suggested, may be unlikely clinically [Abes et al. 2010]. One alternative possibility is that rituximab-induced CD20 signalling may downregulate BCL2 expression, thus making tumour cells more sensitive to chemotherapy; the mechanisms behind this, however, remain unclear [Alas and Bonavida, 2001]. Another possibility is that the infusion of relatively high doses of human IgG1 antibody may induce nonspecific anti-inflammatory immune effects comparable to those seen following intravenous immunoglobulin (IVIg) infusion [Anthony et al. 2011].

Understanding the basis of the observed synergy of rituximab with chemotherapy is of more than academic interest. Much effort is now being expended to improve on the efficacy observed with rituximab, with many second-generation CD20 MAbs now available for clinical use, as well as generic forms of rituximab (Table 1) [Oflazoglu and Audoly, 2010, Alduaij and Illidge, 2011]. Many of these MAbs have at least theoretical reasons for being superior to rituximab for cancer therapy; however, none has yet proved superior in directly comparative clinical trials. Moreover, the reasons for failure of rituximab-based immunochemotherapy have not been clearly defined; if failure is due to loss of surface CD20 expression (as has been suggested for DLBCL failing R-CHOP), then alternative CD20 antibodies will be equally ineffective. Surface CD20 expression can be lost in the presence of maintained cytoplasmic CD20 detected by immunohistochemistry [Johnson et al. 2009]. However, in the context of combination immunochemotherapy, it is difficult to be certain that failure of response truly represents resistance to rituximab per se in the presence of maintained surface CD20 expression. Given this uncertainty, it is difficult to predict how best to improve on this MAb.

Current immunochemotherapeutic approaches for CLL

CLL for the most part is an indolent leukaemia of mature B cells that co-express CD5 and CD23. The pathogenesis of CLL remains poorly understood, although new generation sequencing and mapping approaches are revealing a plethora of pathogenic mutations, as well as genetic predispositions [Crowther-Swanepoel et al. 2010; Rossi et al. 2011; Quesada et al. 2011]. Over and above the genetic causes of disease, there are microenvironmental influences that may also ‘drive’ disease pathogenesis [Bertilaccio et al. 2010]. Unlike other B-cell malignancies, CLL is associated with profound immunosuppression that often plays a significant role in patient management.

Despite recent advances, the treatment of CLL remains unsatisfactory and essentially palliative in nature. Fludarabine-based chemotherapy remains the standard of care for most patients without significant comorbidities (particularly renal impairment). The UK CLL4 study established that fludarabine and cyclophoshphamide (FC) yielded better results in terms of remission induction as compared to single-agent fludarabine or chlorambucil, although in this study there was no significant overall survival benefit to FC [Catovsky et al. 2007]. The German CLL-08 study established that the addition of rituximab to FC (R-FC) significantly improved remission rates in comparison to FC and furthermore, for the first time in a clinical trial in CLL, lead to improvement in overall survival [Hallek et al. 2010]. R-FC is therefore now the standard of care for most patients with CLL requiring therapy. Although not curative, given the age of some CLL patients, the length of remission obtained may obviate the need for further chemotherapy, resulting in an ‘operational cure’.

However, significant problems remain with the use of R-FC. First, for many patients with CLL and with concurrent comorbidities, and particularly those with renal impairment, R-FC may simply not be an option. Second, the toxicities of R-FC in the general population may be much greater than those reported in the CLL-08 study. Myelotoxicity and immunosuppression appear to be significant problems and may be long lasting; one American report has cited an incidence of 8% of myelodysplasia and acute myeloid leukaemia following FC chemotherapy [Smith et al. 2011]. Third, patients with TP53 deletions and/or mutations do not do well with either FC or R-FC regimens, which is not surprising given that fludarabine depends on an intact p53 pathway to elicit its effects. These patients should be treated with the CD52 MAb alemtuzumab, with the addition of high-dose methylprednisolone if significant lymphadenopathy is present (see also http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=9888). As with R-FC, alemtuzumab-based therapy is not curative and consolidative strategies including allogeneic stem cell transplantation have been used in first remission in this subgroup.

Patients relapsing early within 6 months of R-FC are deemed to be fludarabine refractory [Brown, 2011]. However, overall about 20% of patients will relapse within 24 months and these patients, as well as the fludarabine-refractory subgroup, are very difficult to treat. Full assessment of the p53 pathway, including TP53 deletion, mutation and where possible, functional p53 analysis, should be performed. It is likely that other recently detected mutations (such as SF3B1 mutations) may also play a role in conferring disease resistance to R-FC. How best to treat this group of patients as a whole remains unclear. Patients with TP53 deletion/mutation are often treated with alemtuzumab, although the overall condition of the patient and the immunosuppressive toxicity of alemtuzumab following R-FC may make this option very difficult.

The CD20 MAb, ofatumumab and its possible role in the treatment of CLL

The CD20 antibody ofatumumab (HuMax-CD20) was initially developed by Genmab (see http://www.genmab.com/) and has since been acquired by GSK. Ofatumumab differs from rituximab in a number of potentially clinically important features. First, ofatumumab was generated in human immunoglobulin minilocus transgenic mice and thus the MAb is entirely human. Rituximab on the other hand is a chimeric MAb, containing murine V_H and V_L sequences [Teeling et al. 2004]. Second, ofatumumab recognizes a distinct CD20 epitope comprising both small and larger CD20 loops at the cell surface. Third, and perhaps most importantly, ofatumumab is much more active than rituximab at mediating CDC in vitro, and cell lines and primary clinical samples resistant to rituximab, were sensitive to ofatumumab. This property may be a function of the very slow off rate of ofatumumab. Ofatumumab was cytotoxic to cells expressing very low levels of CD20 as typically seen in CLL.

A large number of clinical studies have been performed with ofatumumab in most subtypes of B-cell malignancy. During the early phases of development of ofatumumab, rituximab did not have a product license in CLL and therefore an obvious and immediate goal was to assess efficacy in this disease. In initial phase I/II studies performed in relapsed and refractory cases between September 2004 and April 2006, four weekly doses of MAb were given, with, at maximal doses, an initial dose of 500 mg being followed by three subsequent doses of 2000 mg (these arbitrary doses and schedule seem to have been heavily influenced by previous rituximab studies) [Coiffier et al. 2008]. Although it is difficult/impossible to disentangle some of the data presented in the paper, it is worth looking at this study in some detail since it influenced subsequent clinical development of ofatumumab.

A total of 33 patients were enrolled into the study, of whom 22 were Binet stage B and 4 stage C at screening. Four exhibited lymph nodes greater than 5 cm in diameter, whilst two had significant splenomegaly. Median number of prior treatments was 3 (range 1–9). Only nine patients had a platelet count less than 125 x 10⁹/l (patients with platelets <75 and neutrophil counts <1.5 x 10⁹/l were excluded from the study). Interphase FISH and IGHV mutational analyses were not reported. However, even with the superficial patient characterization, it is clear that most of the patients enrolled were not suffering with end-stage disease. It is also noteworthy that the primary efficacy end point was response over the period from screening to week 19, i.e. including at least the four weeks of therapy. Overall tumour response was assessed from physical examinations and evaluation of peripheral blood and bone marrow as defined by NCI-WG Guidelines. Responses were confirmed 8 weeks later.

Ofatumumab was well tolerated with the infusional first-dose reactions reminiscent of those seen with rituximab being the most common toxicity. A maximal tolerated dose was not attained. A total of 51% of patients developed infections but this incidence of infectious complications is to be anticipated in CLL patients [Perkins et al. 2002]. A total of 27 patients received the highest doses of ofatumumab; the initial overall response rate assessed at week 19 was 50%. There were no complete remissions. In most, but not all cases, there was a rapid drop in the peripheral blood lymphocyte count; after four MAb infusions, the media reduction from baseline was 97% ranging from 15% to 100%. Prolonged blood lymphocyte depletion was seen in some patients but rapid rebound in others, one patient having a rapid rebound in blood lymphocytes to a total of 240 x 10⁹/l within 12 weeks of starting therapy; such rapid recruitment of cells into the peripheral blood suggests MAb-mediated sequestration within spleen or bone marrow rather than destruction. Whether lymphocyte depletion correlated with improvement in other haematological criteria indicative of improved bone marrow function is not clear from the presented data. Eleven patients underwent repeat bone marrow aspirate and trephine at week 19; three showed a nodular partial response. In terms of lymph nodal responses there was also significant variability; some patients showed marked and sustained reduction in lymph node size, whereas others progressed rapidly. Again, it is impossible from the data to know whether these nodal responses correlated with the maximal size of the lymph node prior to therapy, and whether the nodal responses correlated with responses at other anatomical locations.

So, overall, ofatumumab was well tolerated but had marginal efficacy; certainly, single-agent ofatumumab does not have the activity of alemtuzumab, which is able to induce minimum residual disease (MRD) negative complete remissions in some patients [Moreton et al. 2005]. A striking feature of this study was the rapid rate of progression after completion of therapy with only 2 patients maintaining their responses to week 27. With the benefit of hindsight, a number of criticisms might be levelled at this study. First, ofatumumab should have been continued to maximal response or to time of disease progression, rather than stopping after the fourth infusion. Second, a direct comparison with rituximab should have been introduced from the start. A major problem that has plagued many ofatumumab studies to date has been the lack of direct comparison with its major competitor. Finally, the lack of adequate patient characterization in terms of genetic abnormalities (notably TP53 deletion/mutation, marking a group of patients with significant unmet medical need) and other biological parameters such as levels of CD20 expression, changes in CD20 expression following ofatumumab etc were major flaws. Subsequent compassionate use of ofatumumab in TP53 mutant CLL in the UK has indicated activity in this subgroup [Chowdhury et al. 2011]. Naturally enough, ofatumumab has now been used in combination with FC chemotherapy (O-FC) in a phase II study in the first-line treatment of CLL [Wierda et al. 2011a]. The CR rate in this study (using a dose of 1000 mg of ofatumumab) was 50%, lower than that observed with R-FC in the CLL08 study. An interesting ongoing study assesses the role of maintenance ofatumumab following second-line or third line therapy of CLL [ClinicalTrials.gov Identifier: NCT01039376].

Ofatumumab as single-agent immunotherapy in fludarabine-refractory CLL

As noted above, fludarabine-refractory CLL remains a small but significant unmet medical need. Many patients failing fludarabine-based chemotherapy will be offered alemtuzumab, and some of these may go on to allogeneic stem cell transplantation. This study (Genmab-406), which recruited patients from June 2006 to May 2008, assessed the role of single-agent ofatumumab in patients who had either failed fludarabine and alemtuzumab-based (FAref) therapies or who had failed fludarabine and had bulky lymphadenopathy precluding the use of single-agent alemtuzumab (BFref) [Wierda et al. 2010]. Patients received eight weekly infusions followed by four monthly infusions of ofatumumab, receiving 300 mg at the first infusion and 2000 mg at each subsequent infusion; a later amendment allowed further monthly treatment until disease progression.

A preliminary report focused on an interim analysis of 59 patients with FAref and 79 patients with BFref CLL. These patients had altogether much more aggressive and more advanced disease than those in the initial phase I/II study. A total of 90% of all patients were Binet Stage B or C at screening. Bulky lymphadenopathy (>5 cm on palpation or on CT scan) was present not only in all BFref but also in 65% of FAref patients. Nearly 50% of patients in both subgroups had failed or were refractory to R-FC. A total of 41 of 59 FAref and 36/79 BFref patients exhibited either TP53 deletion or 11q deletion on interphase FISH.

Infusional toxicities were as anticipated from the previous phase I/II study. A total of 59% of all patients received all 12 planned MAb infusions. Again, as anticipated in this disease, and specifically in this subgroup of patients with uncontrolled disease, infections were frequent and often serious. In total, 6 of 59 FAref and 5 of 79 BFref patients died from infection, including one patient with progressive multifocal leukoencephalopathy (PML). Efficacy was assessed at 24 weeks after starting therapy and confirmed 8 weeks later. The overall response rate was 58% in the FAref and 47% in the BFref groups; there was one complete remission in the BFref group with the remainder of patients attaining a partial response. Overall, median progression free survival was short, approximately 6 months in both groups of patients. Some (rare) patients may attain a complete remission with this therapy and others a sufficiently good response to allow allogeneic stem cell transplantation (Professor Steve Devereux, Personal communication, January 2012). However, for the most part, responses are of short duration. Response rates were comparable between patients who had received prior rituximab and those who had not [Wierda et al. 2011b]. A feature noted in many patients is symptomatic improvement with ofatumumab often in the absence of more objective signs of disease control.

Conclusions

The selection of the optimal CD20 MAb for cancer immunotherapy remains fraught with difficulties, especially when MAbs are being used in combination with chemotherapy, since the key parameters for successful tumour lysis and synergy with chemotherapy remain uncertain. Which if any of the MAbs shown in Table 1 might be superior to rituximab clinically is not yet clear. In terms of activation of natural effector mechanisms, enhanced ADCC activity (a feature of most second- and third-generation CD20 MAbs) seems likely to be beneficial. However, the increased depletion of normal B cells will need to be balanced against potential complications of prolonged immunosuppression. Such problems have already been encountered in patients with autoimmune diseases receiving second-generation CD20 MAbs [Rigby et al. 2011].

Carefully designed clinical trials comparing the different CD20 MAbs will need to be performed to assess efficacy and toxicities. How to show superiority of a given CD20 MAb in patients without recourse to large multinational phase III studies costing many millions of dollars is problematic. Sequential use of multiple MAbs in individual patients with bulk disease may allow more rapid and direct comparison for at least proof of principle of enhanced efficacy [Hale et al. 1988; Dyer et al. 1989]. Showing activity in patients deemed to be ‘rituximab refractory’ is more difficult since most patients now receive rituximab in combination with chemotherapy; whether disease progression is due to loss of sensitivity to chemotherapy or rituximab itself is difficult to determine unless the cells lose expression of surface CD20 expression.

Ofatumumab is a CD20 MAb with unique in vitro properties. However, whether ofatumumab can outperform rituximab in vivo remains unclear. In the context of refractory/relapsed clinically aggressive CLL, single-agent ofatumumab at high dose has significant, but for most patients, limited, activity. Ofatumumab is expensive and relatively short-term palliation. Thus, far, it has not been possible to identify prospectively patients who will benefit. Wherever possible, patients failing fludarabine-based immunochemotherapy should be entered into clinical trials. There are currently many clinical trials available worldwide assessing the value of ofatumumab in CLL and other B-cell malignancies (see http://www.clinicaltrials.gov).

CD20 may not be the optimal therapeutic target in CLL. Newer therapies targeting kinases downstream of the B-cell receptor (BCR) may show significant activity in this clinical setting and suggest potentially synergistic therapeutic combinations with ofatumumab [Honigberg et al. 2010].

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The author declares that he is in receipt of research funding from Roche Pharmaceuticals and has acted as a consultant for Roche Pharmaceuticals.

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Safety and efficacy of ofatumumab in patients with fludarabine and alemtuzumab refractory chronic lymphocytic leukaemia

Abstract

Keywords

Introduction

CD20 as a therapeutic target for B-cell malignancies

Current immunochemotherapeutic approaches for CLL

The CD20 MAb, ofatumumab and its possible role in the treatment of CLL

Ofatumumab as single-agent immunotherapy in fludarabine-refractory CLL

Conclusions

Footnotes

Funding

Conflict of interest statement

References