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The Role of Rituximab in Chronic Lymphocytic Leukemia Treatment and the Potential Utility of Biosimilars.

ABSTRACT: Chronic lymphocytic leukemia (CLL) is managed with observation for asymptomatic or clinically silent disease; pharmacologic intervention is generally required for symptomatic patients with clinically significant adenopathy or cytopenia. In the front-line treatment of CLL, the current standard-of-care includes chemotherapy in combination with an anti-CD20 monoclonal antibody (e.g., rituximab, ofatumumab, or obinutuzumab) or ibrutinib as single agent. Despite the evolving treatment paradigm toward targeted therapy, it is likely that rituximab (plus chemotherapy), with or without targeted agents, will retain a significant role in CLL treatment. However, patents for many biologics, including rituximab, have expired or will expire in the near future. Furthermore, access to rituximab has remained challenging, particularly in countries with restricted resources. Together, these concerns have prompted the development of safe and effective rituximab biosimilars. The term "biosimilar" refers to a biologic that is highly similar to an approved reference (originator) product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in purity, potency, or safety. Biosimilars are developed to treat the same condition(s) using the same treatment regimens as an approved reference biologic and have the potential to increase access to more affordable treatments. We review the importance of rituximab in the current treatment of CLL, the scientific basis of its future role in combination with chemotherapy, and the role of new and emerging agents in the treatment of CLL, which could potentially be used in combination with rituximab biosimilars. We also discuss rituximab biosimilars currently in development.

Implications for practice

Front-line treatments for chronic lymphocytic leukemia (CLL) include chemotherapy in combination with an anti-CD20 monoclonal antibody (e.g., rituximab, ofatumumab, or obinutuzumab) or ibrutinib as single agent. Despite the evolving treatment paradigm, it is likely rituximab (plus chemotherapy) and targeted agents undergoing clinical evaluation will retain a significant role in CLL treatment. However, patents for many biologics, including rituximab, have expired or will expire in the near future and, in many regions, access to rituximab remains challenging. Together, these concerns have prompted the development of safe and effective rituximab biosimilars, with the potential to increase access to more affordable treatments.

SUBMITTER: Brown JR

PROVIDER: S-EPMC5905689 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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The Role of Rituximab in Chronic Lymphocytic Leukemia Treatment and the Potential Utility of Biosimilars.

Brown Jennifer R JR Cymbalista Florence F Sharman Jeff J Jacobs Ira I Nava-Parada Pilar P Mato Anthony A

The oncologist 20171206 3

Chronic lymphocytic leukemia (CLL) is managed with observation for asymptomatic or clinically silent disease; pharmacologic intervention is generally required for symptomatic patients with clinically significant adenopathy or cytopenia. In the front-line treatment of CLL, the current standard-of-care includes chemotherapy in combination with an anti-CD20 monoclonal antibody (e.g., rituximab, ofatumumab, or obinutuzumab) or ibrutinib as single agent. Despite the evolving treatment paradigm toward ...[more]

PMID: 29212732

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Project description:Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness that primarily afflicts the elderly. For many decades, the initial therapy for most patients requiring treatment was limited to single-agent alkylator therapy. Within the last two decades, we have seen remarkable progress in understanding the biology of CLL and the development of more effective treatment strategies that have employed monoclonal antibodies, such as rituximab (anti-CD20). Furthermore, recognition of the synergy between fludarabine, cyclophosphamide, and rituximab (FCR) prompted investigators to explore the clinical activity of FCR in Phase II and III trials in patients with relapsed/refractory or previously untreated CLL. On the basis of these findings, the US Food and Drug Administration (FDA) recently approved rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed/refractory or previously untreated CD20-postive CLL. Recent data from a randomized Phase III trial has confirmed improved overall survival with FCR in patients with previously untreated CLL. However, FCR is not for everyone. More tolerable regimens using rituximab for the elderly and less fit patients are being pursued in clinical trials. Recent Phase II trials have explored potentially less myelosuppressive approaches by using lower doses of fludarabine and cyclophosphamide, replacing fludarabine with pentostatin, and combining rituximab with chlorambucil. Furthermore new biomarkers predictive of early disease progression have prompted investigators to explore the benefits of early treatment with rituximab combined with other agents. In addition to the proven utility of rituximab as a frontline agent for CLL, rituximab has a favorable toxicity profile both as a single agent and in combination with chemotherapy. The majority of adverse events are Grade 1 and 2 infusion-related reactions (fevers, chills, and rigors) and occur with the first dose of rituximab. The improved tolerability observed with second and subsequent infusions allows for shorter infusion times. Rituximab's proven activity and favorable toxicity profile has made it an ideal agent for expanding treatment options for patients with CLL, the majority of whom are elderly.

Project description:BackgroundData regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.MethodsIn a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.ResultsA total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).ConclusionsThe ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Dataset Information

The Role of Rituximab in Chronic Lymphocytic Leukemia Treatment and the Potential Utility of Biosimilars.

Implications for practice

Publications

The Role of Rituximab in Chronic Lymphocytic Leukemia Treatment and the Potential Utility of Biosimilars.

Similar Datasets

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