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Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Hill BT, Kalaycio M - Onco Targets Ther (2015)

Bottom Line: This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities.Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL.Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional therapeutic option.

No MeSH data available.


Related in: MedlinePlus

Pharmacokinetics of obinutuzumab.Notes: Serum concentrations of obinutuzumab based on two loading doses of 1,600 mg followed by doses of 800 mg every 2 weeks (blue line) vs continuous dosing with 400 mg every 2 weeks (yellow line), for patients with relapsed/refractory NHL. Reprinted with permission. ©2013 American Society of Clinical Oncology. all rights reserved. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–2919.21Abbreviation: NHL, non-Hodgkin lymphoma.
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f2-ott-8-2391: Pharmacokinetics of obinutuzumab.Notes: Serum concentrations of obinutuzumab based on two loading doses of 1,600 mg followed by doses of 800 mg every 2 weeks (blue line) vs continuous dosing with 400 mg every 2 weeks (yellow line), for patients with relapsed/refractory NHL. Reprinted with permission. ©2013 American Society of Clinical Oncology. all rights reserved. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–2919.21Abbreviation: NHL, non-Hodgkin lymphoma.

Mentions: The activity of obinutuzumab was evaluated in a Phase I/II trial in patients with relapsed/refractory indolent NHL or aggressive NHL (diffuse large B-cell lymphoma and mantle cell lymphoma) most of whom were previously treated with rituximab.21,22 There appeared to be a dose-dependent response with ORR of 55% for subjects with indolent NHL and 37% for patients with aggressive NHL receiving two loading doses of 1,600 mg, followed by doses of 800 mg every 2 weeks. The therapy was well tolerated, with a high frequency of infusion-related reactions (IRRs) that were predominantly grade 1–2. Premedication with acetaminophen and antihistamine was required, and glucocorticoid was given to high-risk patients. Serum concentrations of obinutuzumab were significantly higher, earlier in the course of therapy, for patients treated with loading doses rather than continuous dosing at 400 mg every 2 weeks (Figure 2). This is particularly important, as it provided direct clinical evidence for the pharmacodynamic and pharmacokinetic models in which early doses of monoclonal antibody do not necessarily reach their target, as the initial drug is absorbed by both target cells and off-target immune effector cells.


Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Hill BT, Kalaycio M - Onco Targets Ther (2015)

Pharmacokinetics of obinutuzumab.Notes: Serum concentrations of obinutuzumab based on two loading doses of 1,600 mg followed by doses of 800 mg every 2 weeks (blue line) vs continuous dosing with 400 mg every 2 weeks (yellow line), for patients with relapsed/refractory NHL. Reprinted with permission. ©2013 American Society of Clinical Oncology. all rights reserved. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–2919.21Abbreviation: NHL, non-Hodgkin lymphoma.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562745&req=5

f2-ott-8-2391: Pharmacokinetics of obinutuzumab.Notes: Serum concentrations of obinutuzumab based on two loading doses of 1,600 mg followed by doses of 800 mg every 2 weeks (blue line) vs continuous dosing with 400 mg every 2 weeks (yellow line), for patients with relapsed/refractory NHL. Reprinted with permission. ©2013 American Society of Clinical Oncology. all rights reserved. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–2919.21Abbreviation: NHL, non-Hodgkin lymphoma.
Mentions: The activity of obinutuzumab was evaluated in a Phase I/II trial in patients with relapsed/refractory indolent NHL or aggressive NHL (diffuse large B-cell lymphoma and mantle cell lymphoma) most of whom were previously treated with rituximab.21,22 There appeared to be a dose-dependent response with ORR of 55% for subjects with indolent NHL and 37% for patients with aggressive NHL receiving two loading doses of 1,600 mg, followed by doses of 800 mg every 2 weeks. The therapy was well tolerated, with a high frequency of infusion-related reactions (IRRs) that were predominantly grade 1–2. Premedication with acetaminophen and antihistamine was required, and glucocorticoid was given to high-risk patients. Serum concentrations of obinutuzumab were significantly higher, earlier in the course of therapy, for patients treated with loading doses rather than continuous dosing at 400 mg every 2 weeks (Figure 2). This is particularly important, as it provided direct clinical evidence for the pharmacodynamic and pharmacokinetic models in which early doses of monoclonal antibody do not necessarily reach their target, as the initial drug is absorbed by both target cells and off-target immune effector cells.

Bottom Line: This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities.Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL.Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional therapeutic option.

No MeSH data available.


Related in: MedlinePlus