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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
This agent was approved by the FDA in 2009 for chronic lymphocytic leukemia (CML) refractory to fludarabine and alemtuzumab, and was conditionally approved by the EMA for refractory chronic lymphocytic leukemia in 2010. The results of a Phase III trial were announced in 2013, and later in the same year ofatumumab was granted “Breakthrough Therapy” designation by the FDA for use in combination with chlorambucil for the treatment of patients with chronic lymphocytic leukemia (CLL) who had not received prior treatment and were inappropriate for fludarabine-based therapy. It has also shown potential in treating Diffuse Large B-Cell Lymphoma, Follicular non-Hodgkin’s lymphoma, relapsing remitting multiple sclerosis, and rheumatoid arthritis. It is noteworthy that ofatumumab is the first human monoclonal CD20-targeted antibody available for patients with refractory CLL.
Anti-CD20 Monoclonal Antibody Treatment in Follicular Lymphoma and Chronic Lymphocytic Leukemia
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
The efficacy and safety of ofatumumab was first established in a phase I/II study of single-agent ofatumumab in cases of relapsed or refractory CLL. A response rate of 50% was seen and the maximum tolerated dose was not reached. Adverse events were comparable to those seen with rituximab [88]. Ofatumumab was first approved for use in patients refractory to fludarabine-alemtuzumab (FA) when a multicenter study demonstrated an OR rate of 58%, median PFS of 5.7 months and OS of 13.7 months with single-agent ofatumumab in heavily pretreated patients refractory to FA [89]. Studies of ofatumumab combined with chemotherapy soon followed. Ofatumumab, given at either 500 mg or 1000 mg, combined with standard fludarabine and cyclophosphamide, resulted in an OR rate of 77% and 73%, and CR of 32% and 50% in the 500 mg and 1000 mg groups, respectively. PFS was unable to be estimated due to short follow-up duration, but the response data did not compare favorably to those from rituximab combined with various chemotherapy regimens [80, 86, 90]. A more recent large phase III study found ofatumumab combined with chlorambucil to be superior to chlorambucil alone in terms of OR (82% vs 69%), CR (12% vs 1%), and PFS (22.4 vs 13.1 months). This trial resulted in the approval of ofatumumab plus chlorambucil as first-line treatment of CLL patients who are not candidates for fludarabine-based treatment [91].
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
For patients with CLL who relapse, it is important to establish whether they require treatment at the time of relapse for disease related symptoms or have active disease.160 For patients with an early relapse, defined as those who relapse within 24–36 months following treatment with chemoimmunotherapy, it is reasonable to consider ibrutunib, idelalisib, venetoclax, or duvelisib; for those who relapse after being in remission for 36 months or more, re-treatment with the initial therapy or any of the targeted drugs listed above is reasonable. The long-term efficacy of ibrutinib compared with ofatumab has now been well established.169 Idelalisib is approved for second-line therapy following at least one prior therapy. The drug is effective but associated with significant toxicities, including colitis, pneumonitis, and hepatitis (Figure 28.17). Venetoclax has been found to be remarkably effective in relapsed and/or refractory disease, with responses of about 80%, including 8% complete responses, and is now licensed for patients with relapsed disease and del(17p). The principal adverse effects are neutropenia and tumor lysis syndrome, which can be mitigated by a weekly ramp-up schedule starting at a very low dose. Duvelisib is also effective and approved for all patients with relapsed/refractory disease after they have received at least two lines of prior therapy. Ofatumumab was approved in 2016 to treat relapsed/refractory patients with CLL following two lines of prior therapy.
To wait, or too late? Modeling the effects of delayed ofatumumab treatment in relapsing-remitting multiple sclerosis
Published in Journal of Medical Economics, 2023
Stephen Maxwell Montgomery, Luke Green, Hajer Karoui, Richard Nicholas, Jaclyn Loh
The introduction of time-specific delays to receiving ofatumumab provides further support for the predicted benefits of initiating ofatumumab at an earlier stage. The results demonstrated a trend in which an increased delay was associated with a shorter time to wheelchair for patients with RRMS. Both modeling approaches highlighted a clinical benefit with respect to the proportion of patients with mild disease at later timepoints. In both cases, a smaller proportion of patients were estimated to require a walking aid after 10 years when ofatumumab was provided without a delay. Loss of mobility and requirement for a walking aid or wheelchair are detrimental to quality of life, ability to perform daily activities, and mental wellbeing37–39. By introducing a high-efficacy DMT at an earlier stage of the disease, it may be possible to prolong the time before mobility is decreased, as predicted by the results reported here. In addition, the results may support the need for improved assessments of treatment response which would enable switching of DMTs before a patient experiences a relapse or disease progression and to improve long-term outcomes.
Investigational treatments for chronic lymphocytic leukemia: a focus on phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
The efficacy of ofatumumab in patients with TN and RR CLL has been widely tested [75–78]. Currently, studies of the use of ofatumumab in CLL are focused on its use in combination with other drugs, such as idelalisib [79]. Among the early phase studies performed with ofatumumab, an clinical trial concerning dose-dependent efficacy seems to be particularly interesting. A comparison of two dose levels of ofatumumab induction followed by maintenance therapy (1000 mg vs 2000 mg) in symptomatic, previously untreated CLL patients found the higher dose to be similarly well-tolerated as the lower dose and significantly more active [80]. In the light of these findings, the time of ofatumumab infusion appears to play a more important role in the comfort of the patient. Although the recommended administration requires long infusion times, Donellan et al. report that a rapid infusion of ofatumumab is safe and well tolerated using a stepped-up dosing regimen [81].
B cell depletion in the treatment of multiple sclerosis
Published in Expert Opinion on Biological Therapy, 2019
Kjell-Morten Myhr, Øivind Torkildsen, Andreas Lossius, Lars Bø, Trygve Holmøy
Rituximab, ocrelizumab, and ofatumumab are monoclonal antibodies of the IgG1 kappa isotype (Table 1). They contain two antigen-binding domains and a constant region responsible for effector functions and for recycling by the neonatal Fc receptor (FcRn). Rituximab is a genetically engineered chimeric antibody and contains murine light- and heavy-chain variable region sequences and human constant region sequences. Ocrelizumab is humanized through ‘CDR grafting’, which involves transferring murine complementarity-determining regions (CDR) to the framework regions of a human antibody [44]. Ofatumumab is a fully human antibody. Ocrelizumab has been reported to have a longer half-life than the others, and after intravenous administration the distribution volumes of the three drugs roughly equals that of the adult plasma volume (Table 1) [45].