Ibrutinib: A New Targeted Therapy for Hematologic Cancers
Ibrutinib: A New Targeted Therapy for Hematologic Cancers
Multiple studies have shown that ibrutinib is a groundbreaking approach for management of hematologic malignancies by inducing durable remissions (Chustecka, 2014), which is significant because multiple hematologic cancers (e.g., CLL, MM, follicular lymphoma) are incurable (Manson & Porter, 2011). Cure is rare in MCL (Manson & Porter, 2011). Optimizing remissions helps to give patients with hematologic malignancies longer overall survival and improved quality of life. See Figure 1 for definitions of responses in CLL and MCL.
(Enlarge Image)
Figure 1.
Definitions of Responses in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma
Note. Based on information from the National Comprehensive Cancer Network, 2015.
A phase I study was conducted by Advani et al. (2013) with 56 patients with six different kinds of B-cell malignancies. The median participant age was 65 years, and the median number of prior therapies was three. Sixty percent (n = 30) of the 50 participants evaluated for tumor response had achieved complete or partial remission; most responses lasted 10 months or more, and the best responses were in patients with MCL, CLL, and WM (Advani et al., 2013).
A phase II study by Wang et al. (2013) involving 111 patients with relapsed MCL showed that 21% (n = 23) of the participants had achieved complete response, and 47% (n = 52) had achieved partial response. The median response duration of decreased or undetectable tumor load lasted 19.6 months (Wang et al., 2013). This pivotal trial helped to accelerate the FDA's approval for ibrutinib's use in patients with MCL (FDA, 2013a).
A phase Ib/II study by O'Brien et al. (2014) investigated ibrutinib as initial therapy in 31 older adults with CLL. Twenty-two of the participants achieved an objective response, four had a partial response with lymphocytosis, and three patients had stable disease. Ninety-six percent (n = 30) of the 31 participants had a progression-free survival at 24 months (O'Brien et al., 2014). The median time to initial response was 1.9 months, and the median time to best response was 5.9 months (O'Brien et al., 2014).
Another phase II study, conducted by the University of Texas MD Anderson Cancer Center (2013), included 40 patients with CLL who were treated with ibrutinib and rituximab. This combination induced a response in 95% (n = 38) of the participants, with 78% (n = 31) showing no evidence of disease progression at 18 months (University of Texas MD Anderson Cancer Center, 2013). In addition, 20 of the 40 participants had mutations of the tumor-suppressing gene TP53 or chromosome 17p deletions, which are associated with poor prognosis; 90% (n = 18) of these patients had a response (University of Texas MD Anderson Cancer Center, 2013).
Full FDA approval was obtained for ibrutinib in patients with CLL in July 2014 based on results from the RESONATE (PCYC-1112) trial (FDA, 2014b). This phase III trial enrolled 391 patients with CLL who had received at least one prior therapy. The trial compared ibrutinib and ofatumumab, a standard therapy in CLL; ibrutinib was found to prolong the duration of progression-free survival and overall survival (Byrd et al., 2014). Patients receiving ibrutinib had progression-free survival at a median of 9.4 months, compared to a median of 8.1 months for those receiving ofatumumab (Byrd et al., 2014). At one year, 90% of the ibrutinib group were still living, compared to 81% of the ofatumumab group (Byrd et al., 2014). Similar results were found in 127 of the 391 participants who had chromosome 17p deletions (Byrd et al., 2014).
FDA approval was granted for ibrutinib in patients with WM following a phase II study by Treon et al. (2015) consisting of 63 previously treated patients with WM. Treon et al. (2015) found that 91% (n = 57) of the participants had an overall response to ibrutinib, with 16% (n = 10) of the participants having a very good partial response. The estimated two-year progression-free survival rate was 69%; among patients with progressive disease, the median time to progression was 9.6 months (Treon et al., 2015).
Multiple clinical trials that examine the effects of ibrutinib alone and with additional therapies are underway, with the objective of gaining FDA approval for the drug's use in patients with different hematologic malignancies (Wiestner, 2013). Phase III trials involving ibrutinib use in patients with CLL, WM, and DLBCL are also ongoing, as are phase II studies examining the drug's use in patients with MM, follicular lymphoma, and central nervous system lymphoma (National Cancer Institute [NCI], 2015). Ibrutinib is also being studied as an initial therapy for patients with newly diagnosed MCL and CLL and is under investigation for treatment of acute myeloid and acute lymphocytic leukemias (NCI, 2015).
B-cell malignancies typically affect older adults with comorbidities and reduced bone marrow reserve (O'Brien et al., 2014). Older adults who receive traditional cytotoxic chemotherapy are at greater risk for myelosuppression and infections (O'Brien et al., 2014). Ibrutinib has been shown to be well tolerated and to have low toxicity with less myelosuppression and subsequent infections, making it a fitting therapeutic option for older adults (Chustecka, 2014). However, ibrutinib is also an option for all patients with MCL, CLL, and WM as indicated, regardless of age or health status. Ibrutinib received accelerated FDA approval for MCL and CLL in part because of its low toxicity profile. This early approval is given because a drug demonstrates "the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition" (FDA, 2013a, para. 6).
Although ibrutinib is well tolerated, adverse reactions have been reported (FDA, 2014a). Most are grade 1–2 in severity and are easily managed or reversible (Advani et al., 2013) (see Figure 2). The most common side effect is diarrhea, but it usually is self-limited (O'Brien et al., 2014). The next most common adverse reactions are nausea and fatigue (O'Brien et al., 2014). Grade 1–2 side effects of diarrhea, nausea, fatigue, upper respiratory infection, peripheral edema, dyspnea, decreased appetite, rash, and arthralgia occurred in 19%–44% of patients (Chavez, Sahakian, & Pinilla-Ibarz, 2013; Wang et al., 2013). Fever, dizziness, sinusitis, stomatitis, bruising, constipation, abdominal pain, and musculoskeletal pain are also common adverse effects (Pharmacyclics, Inc., 2015).
(Enlarge Image)
Figure 2.
Common Grade 1–2 Adverse Events With Ibrutinib as Monotherapy in Patients With CLL and MCL
Note. Based on information from Chavez et al., 2013; Wang et al., 2013.
Grade 3–4 toxicities are infrequent with ibrutinib (Wang et al., 2013) (see Figure 3). Healthcare providers should note that the incidence of serious adverse reactions is two times more likely in patients who have had prior therapy (Berkrot, 2013). Neutropenia, thrombocytopenia, and anemia were the most common grade 3–4 toxicities, affecting 7%–13% of patients (Advani et al., 2013). Grade 3–5 pneumonia occurred in 6% of patients (Wang et al., 2013). Grade 3 bleeding occurred in about 5% of patients (Wang et al., 2013). Adverse events led to a discontinuation of therapy in 6% (Chavez et al., 2013), 7% (Wang et al., 2013), and 14% (Advani et al., 2013) of participants in three different studies. Ibrutinib is not known to cause significant liver or renal toxicities or cumulative toxicities with prolonged therapy (Advani et al., 2013).
(Enlarge Image)
Figure 3.
Common Grade 3–4 AEs With Ibrutinib as Monotherapy in Patients With MCL (N = 111)
Note. Based on information from Wang et al., 2013.
If a patient experiences grade 3–4 toxicities, the drug should be stopped. The drug can be reinitiated at the starting dose if the patient returns to grade 1 toxicity or baseline (Pharmacyclics, Inc., 2015). However, if the toxicity reoccurs, the patient's daily dose should be dose-reduced by one capsule (140 mg per day) (Pharmacyclics, Inc., 2015). The drug can be dose-reduced twice, but if toxicities continue after two dose reductions, the drug should be discontinued (Pharmacyclics, Inc., 2015). A dose reduction will be required in 6%–14% of patients with MCL, CLL, and WM (Pharmacyclics, Inc., 2015). In addition, ibrutinib can cause fetal harm when administered to a pregnant woman (Pharmacyclics, Inc., 2015). Therefore, women should avoid becoming pregnant and breastfeeding while taking ibrutinib (Pharmacyclics, Inc., 2015).
Ibrutinib has the potential to greatly improve patient quality of life. In the University of Texas MD Anderson Cancer Center (2013) study, patients reported improvement in their overall health and quality of life (QOL) six months after starting ibrutinib and rituximab. The study used the European Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire–Core 30. This questionnaire, used to assess the QOL of patients with cancer, includes questions pertaining to activities of daily living, symptoms, and psychosocial health (EORTC Quality of Life Group, 1995). After six months of ibrutinib combination treatment, the percentage of patients with a high QOL rating rose from 46% to 89% (University of Texas MD Anderson Cancer Center, 2013).
Clinical Trial Results
Multiple studies have shown that ibrutinib is a groundbreaking approach for management of hematologic malignancies by inducing durable remissions (Chustecka, 2014), which is significant because multiple hematologic cancers (e.g., CLL, MM, follicular lymphoma) are incurable (Manson & Porter, 2011). Cure is rare in MCL (Manson & Porter, 2011). Optimizing remissions helps to give patients with hematologic malignancies longer overall survival and improved quality of life. See Figure 1 for definitions of responses in CLL and MCL.
(Enlarge Image)
Figure 1.
Definitions of Responses in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma
Note. Based on information from the National Comprehensive Cancer Network, 2015.
A phase I study was conducted by Advani et al. (2013) with 56 patients with six different kinds of B-cell malignancies. The median participant age was 65 years, and the median number of prior therapies was three. Sixty percent (n = 30) of the 50 participants evaluated for tumor response had achieved complete or partial remission; most responses lasted 10 months or more, and the best responses were in patients with MCL, CLL, and WM (Advani et al., 2013).
A phase II study by Wang et al. (2013) involving 111 patients with relapsed MCL showed that 21% (n = 23) of the participants had achieved complete response, and 47% (n = 52) had achieved partial response. The median response duration of decreased or undetectable tumor load lasted 19.6 months (Wang et al., 2013). This pivotal trial helped to accelerate the FDA's approval for ibrutinib's use in patients with MCL (FDA, 2013a).
A phase Ib/II study by O'Brien et al. (2014) investigated ibrutinib as initial therapy in 31 older adults with CLL. Twenty-two of the participants achieved an objective response, four had a partial response with lymphocytosis, and three patients had stable disease. Ninety-six percent (n = 30) of the 31 participants had a progression-free survival at 24 months (O'Brien et al., 2014). The median time to initial response was 1.9 months, and the median time to best response was 5.9 months (O'Brien et al., 2014).
Another phase II study, conducted by the University of Texas MD Anderson Cancer Center (2013), included 40 patients with CLL who were treated with ibrutinib and rituximab. This combination induced a response in 95% (n = 38) of the participants, with 78% (n = 31) showing no evidence of disease progression at 18 months (University of Texas MD Anderson Cancer Center, 2013). In addition, 20 of the 40 participants had mutations of the tumor-suppressing gene TP53 or chromosome 17p deletions, which are associated with poor prognosis; 90% (n = 18) of these patients had a response (University of Texas MD Anderson Cancer Center, 2013).
Full FDA approval was obtained for ibrutinib in patients with CLL in July 2014 based on results from the RESONATE (PCYC-1112) trial (FDA, 2014b). This phase III trial enrolled 391 patients with CLL who had received at least one prior therapy. The trial compared ibrutinib and ofatumumab, a standard therapy in CLL; ibrutinib was found to prolong the duration of progression-free survival and overall survival (Byrd et al., 2014). Patients receiving ibrutinib had progression-free survival at a median of 9.4 months, compared to a median of 8.1 months for those receiving ofatumumab (Byrd et al., 2014). At one year, 90% of the ibrutinib group were still living, compared to 81% of the ofatumumab group (Byrd et al., 2014). Similar results were found in 127 of the 391 participants who had chromosome 17p deletions (Byrd et al., 2014).
FDA approval was granted for ibrutinib in patients with WM following a phase II study by Treon et al. (2015) consisting of 63 previously treated patients with WM. Treon et al. (2015) found that 91% (n = 57) of the participants had an overall response to ibrutinib, with 16% (n = 10) of the participants having a very good partial response. The estimated two-year progression-free survival rate was 69%; among patients with progressive disease, the median time to progression was 9.6 months (Treon et al., 2015).
Future Directions
Multiple clinical trials that examine the effects of ibrutinib alone and with additional therapies are underway, with the objective of gaining FDA approval for the drug's use in patients with different hematologic malignancies (Wiestner, 2013). Phase III trials involving ibrutinib use in patients with CLL, WM, and DLBCL are also ongoing, as are phase II studies examining the drug's use in patients with MM, follicular lymphoma, and central nervous system lymphoma (National Cancer Institute [NCI], 2015). Ibrutinib is also being studied as an initial therapy for patients with newly diagnosed MCL and CLL and is under investigation for treatment of acute myeloid and acute lymphocytic leukemias (NCI, 2015).
Adverse Reactions
B-cell malignancies typically affect older adults with comorbidities and reduced bone marrow reserve (O'Brien et al., 2014). Older adults who receive traditional cytotoxic chemotherapy are at greater risk for myelosuppression and infections (O'Brien et al., 2014). Ibrutinib has been shown to be well tolerated and to have low toxicity with less myelosuppression and subsequent infections, making it a fitting therapeutic option for older adults (Chustecka, 2014). However, ibrutinib is also an option for all patients with MCL, CLL, and WM as indicated, regardless of age or health status. Ibrutinib received accelerated FDA approval for MCL and CLL in part because of its low toxicity profile. This early approval is given because a drug demonstrates "the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition" (FDA, 2013a, para. 6).
Although ibrutinib is well tolerated, adverse reactions have been reported (FDA, 2014a). Most are grade 1–2 in severity and are easily managed or reversible (Advani et al., 2013) (see Figure 2). The most common side effect is diarrhea, but it usually is self-limited (O'Brien et al., 2014). The next most common adverse reactions are nausea and fatigue (O'Brien et al., 2014). Grade 1–2 side effects of diarrhea, nausea, fatigue, upper respiratory infection, peripheral edema, dyspnea, decreased appetite, rash, and arthralgia occurred in 19%–44% of patients (Chavez, Sahakian, & Pinilla-Ibarz, 2013; Wang et al., 2013). Fever, dizziness, sinusitis, stomatitis, bruising, constipation, abdominal pain, and musculoskeletal pain are also common adverse effects (Pharmacyclics, Inc., 2015).
(Enlarge Image)
Figure 2.
Common Grade 1–2 Adverse Events With Ibrutinib as Monotherapy in Patients With CLL and MCL
Note. Based on information from Chavez et al., 2013; Wang et al., 2013.
Grade 3–4 toxicities are infrequent with ibrutinib (Wang et al., 2013) (see Figure 3). Healthcare providers should note that the incidence of serious adverse reactions is two times more likely in patients who have had prior therapy (Berkrot, 2013). Neutropenia, thrombocytopenia, and anemia were the most common grade 3–4 toxicities, affecting 7%–13% of patients (Advani et al., 2013). Grade 3–5 pneumonia occurred in 6% of patients (Wang et al., 2013). Grade 3 bleeding occurred in about 5% of patients (Wang et al., 2013). Adverse events led to a discontinuation of therapy in 6% (Chavez et al., 2013), 7% (Wang et al., 2013), and 14% (Advani et al., 2013) of participants in three different studies. Ibrutinib is not known to cause significant liver or renal toxicities or cumulative toxicities with prolonged therapy (Advani et al., 2013).
(Enlarge Image)
Figure 3.
Common Grade 3–4 AEs With Ibrutinib as Monotherapy in Patients With MCL (N = 111)
Note. Based on information from Wang et al., 2013.
If a patient experiences grade 3–4 toxicities, the drug should be stopped. The drug can be reinitiated at the starting dose if the patient returns to grade 1 toxicity or baseline (Pharmacyclics, Inc., 2015). However, if the toxicity reoccurs, the patient's daily dose should be dose-reduced by one capsule (140 mg per day) (Pharmacyclics, Inc., 2015). The drug can be dose-reduced twice, but if toxicities continue after two dose reductions, the drug should be discontinued (Pharmacyclics, Inc., 2015). A dose reduction will be required in 6%–14% of patients with MCL, CLL, and WM (Pharmacyclics, Inc., 2015). In addition, ibrutinib can cause fetal harm when administered to a pregnant woman (Pharmacyclics, Inc., 2015). Therefore, women should avoid becoming pregnant and breastfeeding while taking ibrutinib (Pharmacyclics, Inc., 2015).
Patient Quality of Life
Ibrutinib has the potential to greatly improve patient quality of life. In the University of Texas MD Anderson Cancer Center (2013) study, patients reported improvement in their overall health and quality of life (QOL) six months after starting ibrutinib and rituximab. The study used the European Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire–Core 30. This questionnaire, used to assess the QOL of patients with cancer, includes questions pertaining to activities of daily living, symptoms, and psychosocial health (EORTC Quality of Life Group, 1995). After six months of ibrutinib combination treatment, the percentage of patients with a high QOL rating rose from 46% to 89% (University of Texas MD Anderson Cancer Center, 2013).
Source...