Ofatumumab as Front-Line Therapy in Untreated CLL
Ofatumumab as Front-Line Therapy in Untreated CLL
A series of drugs are currently US FDA-approved for the treatment of CLL. Chlorambucil (Leukeran®; CHL), fludarabine (Fludara®), alemtuzumab (Campath®), bendamustine (Treanda®), ofatumumab (Arzerra®) and ibrutinib (Imbruvica™) have been approved as single-agent therapies. CHL is an alkylating agent that has shown to induce responses lasting from 1 to 2 years in patients with CLL. Fludarabine, alemtuzumab and bendamustine were approved based on randomized controlled trials (RCTs) showing higher response rates and longer PFS than CHL. Fludarabine is an antimetabolite agent that has been associated with higher rates of severe infections and neutropenia. Alemtuzumab, an anti-CD52 monoclonal antibody (mAb), has shown efficacy in high-risk patients carrying 17p deletions, but it is associated with profound immunosuppression, an increased rate of cytomegalovirus reactivation and presence of cytopenias. Bendamustine, an alkylator, has an acceptable toxicity profile although with potential long-term stem cell-damaging effects. Based on a multicenter open label Phase Ib–II study, ibrutinib was recently approved by the FDA for single- agent use in relapsed and refractory CLL. Ibrutinib is an oral BTK inhibitor that has induced responses in 71% of patients with relapsed/refractory CLL; the most common adverse events (AEs) were transient diarrhea, fatigue and upper respiratory infections. Importantly, ibrutinib has shown single-agent activity in patients with 11q and 17p deletions.
The combination of the antimetabolite fludarabine, the alkylator cyclophosphamide (Cytoxan®) and the chimeric anti-CD20 mAb rituximab (Rituxan®; FCR) has been approved as combination therapy in untreated and previously treated patients with CLL. FCR has shown in two separate RCTs, one in untreated and one in previously treated patients, to be superior to fludarabine plus cyclophosphamide (FC) by significantly prolonging PFS. However, the rates of AEs such as neutropenia, febrile neutropenia, thrombocytopenia, hypotension, hepatitis B and pancytopenia were higher in patients who received FCR compared with FC. Furthermore, the patients included in these studies were younger than the general population diagnosed with CLL. Recently, the combination of obinutuzumab (Gazyva®), a glycoengineered type II anti-CD20 mAb, and CHL has been approved for the front-line treatment of CLL patients based on an RCT in which the combination showed higher response rates and longer PFS than patients treated with CHL alone. The most common AEs associated with the combination were infusion reactions, thrombocytopenia, neutropenia, musculoskeletal pain and fever.
Newer agents that have shown efficacy and that are likely to be approved in CLL are lenalidomide (Revlimid®) and idelalisib (formerly GS-1101 and CAL-101), among others. Lenalidomide is an oral immunomodulator that in a Phase II study has shown to induce responses in 47% of relapsed/refractory CLL patients with neutropenia, thrombocytopenia and flare reaction as the most common AEs. Idelalisib is an oral PI3K inhibitor that is associated with 56% response rate in relapsed/refractory CLL patients; the most common AEs are liver enzyme elevation, pneumonia, diarrhea and fever. Like ibrutinib, idelalisib has shown efficacy against patients with high-risk cytogenetic anomalies.
Overview of the Market
A series of drugs are currently US FDA-approved for the treatment of CLL. Chlorambucil (Leukeran®; CHL), fludarabine (Fludara®), alemtuzumab (Campath®), bendamustine (Treanda®), ofatumumab (Arzerra®) and ibrutinib (Imbruvica™) have been approved as single-agent therapies. CHL is an alkylating agent that has shown to induce responses lasting from 1 to 2 years in patients with CLL. Fludarabine, alemtuzumab and bendamustine were approved based on randomized controlled trials (RCTs) showing higher response rates and longer PFS than CHL. Fludarabine is an antimetabolite agent that has been associated with higher rates of severe infections and neutropenia. Alemtuzumab, an anti-CD52 monoclonal antibody (mAb), has shown efficacy in high-risk patients carrying 17p deletions, but it is associated with profound immunosuppression, an increased rate of cytomegalovirus reactivation and presence of cytopenias. Bendamustine, an alkylator, has an acceptable toxicity profile although with potential long-term stem cell-damaging effects. Based on a multicenter open label Phase Ib–II study, ibrutinib was recently approved by the FDA for single- agent use in relapsed and refractory CLL. Ibrutinib is an oral BTK inhibitor that has induced responses in 71% of patients with relapsed/refractory CLL; the most common adverse events (AEs) were transient diarrhea, fatigue and upper respiratory infections. Importantly, ibrutinib has shown single-agent activity in patients with 11q and 17p deletions.
The combination of the antimetabolite fludarabine, the alkylator cyclophosphamide (Cytoxan®) and the chimeric anti-CD20 mAb rituximab (Rituxan®; FCR) has been approved as combination therapy in untreated and previously treated patients with CLL. FCR has shown in two separate RCTs, one in untreated and one in previously treated patients, to be superior to fludarabine plus cyclophosphamide (FC) by significantly prolonging PFS. However, the rates of AEs such as neutropenia, febrile neutropenia, thrombocytopenia, hypotension, hepatitis B and pancytopenia were higher in patients who received FCR compared with FC. Furthermore, the patients included in these studies were younger than the general population diagnosed with CLL. Recently, the combination of obinutuzumab (Gazyva®), a glycoengineered type II anti-CD20 mAb, and CHL has been approved for the front-line treatment of CLL patients based on an RCT in which the combination showed higher response rates and longer PFS than patients treated with CHL alone. The most common AEs associated with the combination were infusion reactions, thrombocytopenia, neutropenia, musculoskeletal pain and fever.
Newer agents that have shown efficacy and that are likely to be approved in CLL are lenalidomide (Revlimid®) and idelalisib (formerly GS-1101 and CAL-101), among others. Lenalidomide is an oral immunomodulator that in a Phase II study has shown to induce responses in 47% of relapsed/refractory CLL patients with neutropenia, thrombocytopenia and flare reaction as the most common AEs. Idelalisib is an oral PI3K inhibitor that is associated with 56% response rate in relapsed/refractory CLL patients; the most common AEs are liver enzyme elevation, pneumonia, diarrhea and fever. Like ibrutinib, idelalisib has shown efficacy against patients with high-risk cytogenetic anomalies.
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