Anti-CD20: tales of identical twins?

In this issue of Blood, Wierda et al show in a retrospective analysis of 206 patients that prior rituximab exposure does not affect the efficacy of subsequent ofatumumab treatment.¹ 

Although these results will have to be confirmed prospectively, they begin to unravel clinically significant differences between these anti-CD20 antibodies. This is important for 2 reasons:

• (1) The addition of the monoclonal anti-CD20 antibody rituximab to the fludarabine and cyclophosphamide chemotherapy backbone in first line therapy²  is the first ever drug combination to have altered the natural history of chronic lymphocytic leukemia (CLL). Besides, the same combination has also shown superior progression-free survival (PFS) in second-line treatment.³  A significant number of CLL patients are therefore treated with rituximab combinations. However, 20% and 40% of patients treated with rituximab, fludarabine, and cyclophosphamide (FCR) in first and second line, respectively, relapsed within 2 years of finishing treatment and are unlikely to benefit from further rounds of FCR. There is, therefore, an urgent need to identify effective modalities for this poor prognosis group of patients.

• (2) The precise mode of action of ofatumumab and indeed rituximab remain poorly understood.⁴  The clinical observations presented by Wierda et al provide clinical evidence that although both are Type I antibodies directed against the same cell-surface molecule, they are likely to act through very different mechanisms. There are striking differences between rituximab and ofatumumab. Whereas rituximab is a chimeric antibody, ofatumumab (HuMax-CD20) is a fully human anti-CD20 monoclonal antibody. Ofatumumab binds to a different epitope than rituximab and is thought to confer greater complement-mediated cellular cytotoxicity with some additional antibody-dependent cellular cytotoxicity.⁵  Ofatumumab is also the only anti-CD20 antibody not to have direct contact with the 3 critical amino acids (170-172) responsible for classic type I and II action.⁶  It shows enhanced activity against CLL cells expressing low levels of CD20. Besides, contrary to ofatumumab, rituximab monotherapy is of limited efficacy.⁴  Although comparison between trials should be made with caution, the recently published phase 2 data on FC-O combination therapy in first line shows inferior overall response rate (ORR) and PFS compared with FCR.⁷ 

In the current study, the authors used follow-up data of the single-arm phase 2 Hx CD20 406 study on safety and efficacy of single-agent ofatumumab in bulky refractory (BF ref) or fludarabine and alemtuzumab refractory (FA ref) disease.⁸  Results of the interim analysis of the first 138 patients led to accelerated FDA approval of ofatumumab for double refractory patients. The ORR in this study was 58% in the FA ref group and 47% in the BF ref group. Perhaps the most significant improvement was in overall survival (OS), which was 13.7 and 15.4 months in the FA ref and BF ref responder groups, respectively, compared with 9.8 and 10.2 months in nonresponders.

Now, Wierda et al proceed with a retrospective analysis of 206 patients from this study: 117 were previously treated with rituximab (98 rituximab-refractory), and 89 were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, ORR was 43%, 44%, and 53%; PFS was 5.3, 5.5, and 5.6 months; and OS was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions or hematologic or infectious adverse events between subgroups.

What do these findings mean for our patients? They are the first attempt to evaluate the impact of prior rituximab exposure on efficacy of a next-generation anti-CD20 antibody. It is important to highlight the weaknesses of the study: this is a retrospective ad-hoc analysis of a study never designed to answer this question. Besides, patient numbers in some of the subgroups are small. These limitations do not allow any definite clinical conclusions to be drawn and ideally, results should be validated in a prospective manner. However, the data clearly tell us that patients with rituximab-treated or rituximab-refractory disease should not be excluded from clinical studies investigating other anti-CD20 antibodies. Importantly, mechanisms of resistance to anti-CD20 antibodies seem to vary between different antibodies. While the German CLL8 data clearly demonstrate that patients with TP53 abnormalities did not benefit from FCR treatment,⁹  there is some evidence from the Hx CD20 406 study that ofatumumab might be effective in at least some of these patients. Furthermore, the United Kingdom analysis of compassionate use ofatumumab included patients with TP53 abnormalities who benefitted from ofatumumab.¹⁰  However, the available data on single-agent ofatumumab in FCR-refractory patients with CLL also demonstrate that responses are generally of short duration and no complete responses were achieved. Therefore, future efforts need to focus on evaluating the role of maintenance and combination therapy with novel targeted agents such as BCR inhibitors.