SINGLE-AGENT IBRUTINIB DEMONSTRATES LONG-TERM ACTIVITY AND SAFETY IN PATIENTS WITH RELAPSED/REFRACTORY WALDENSTR
(Abstract release date: 05/21/15)
EHA Library. Furman R. 06/12/15; 102682; PB1786
Disclosure(s): Weill Cornell Medical College
Dr. Richard Furman
Contributions
Contributions
Abstract
Abstract: PB1786
Type: Publication Only
Background
Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor pathway and functions via the activation of downstream signals mediating B-cell growth, adhesion, and survival. Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, has emerged as an attractive treatment option for patients with Waldenström’s macroglobulinemia (WM). Recently, ibrutinib was approved by the FDA for the treatment of WM, representing the first FDA-approved agent in WM. The first-in-human trial of ibrutinib was an open-label, phase 1 study in patients with relapsed/refractory (R/R) B-cell malignancies including WM (Advani, J Clin Oncol. 2013) and demonstrated encouraging activity of ibrutinib (75% overall response rate) in WM, thus initiating further studies.
Aims
To report long-term activity and safety outcomes of ibrutinib in 4 patients with R/R WM who enrolled in this phase 1 study and then continued into an extension study.
Methods
All patients provided written informed consent before enrollment. Four patients with R/R, histologically confirmed WM and adequate hematologic, renal, and hepatic function received oral ibrutinib between 560 mg/day and 12.5 mg/kg/day until progressive disease or unacceptable toxicity. Patients were required to have IgM levels ≥1000 mg/dL with bone marrow infiltration. After 6 months of therapy, patients with objective response or stable disease were rolled over from the parent study (PCYC-04753) into the extension study (PCYC-1103-CA) at a fixed dose of ibrutinib 560 mg daily. Adverse events (AEs) were assessed by NCI CTCAE v3.0. In the 1103 study, only data on AEs grade ≥3, serious AEs (SAEs), and AEs leading to dose modification or discontinuation were captured. Disease response assessments included laboratory assessments (serum IgM) and radiographic imaging when applicable. Best clinical response was assessed per the 3rd International Workshop of WM (IWWM).
Results
Three of 4 WM patients achieved durable partial responses accompanied by ≥50% reductions from baseline in IgM levels (~80% to 90%), which reached a plateau after 1 year of therapy. Responses are ongoing after 4 years of therapy with no evidence of progression in other clinical features attributed to WM. Additional clinical improvements included sustained increases or stabilization in hemoglobin levels (without the use of erythropoietic growth factors or transfusion); reduction in lymphadenopathy (present in 3 of 4 patients at baseline); and improvement in hematocrit over time. Grade 3/4 AEs included neutropenia (1 patient) and thrombocytopenia (1 patient), and SAEs included febrile neutropenia (2 patients), pneumonia and pneumonitis (1 patient), and atrial fibrillation (1 patient). In addition, the same patient experienced a second episode of grade 2 atrial fibrillation (not an SAE), leading to dose modification to ibrutinib 420 mg daily. All grade 3/4 AEs and SAEs were resolved without sequelae and were assessed by the investigator as unrelated to ibrutinib.
Summary
This case series is the first to demonstrate extended activity and tolerability of ibrutinib in R/R WM, accompanied by early and rapid decline in IgM levels and increase in hemoglobin levels. Single-agent ibrutinib induced profound and durable responses, with a favorable safety profile, in this difficult-to-treat patient population—consistent with findings of a phase 2 trial (Treon, IWWM, 2014).
Keyword(s): Waldenstrom's macroglobulinemia
Type: Publication Only
Background
Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor pathway and functions via the activation of downstream signals mediating B-cell growth, adhesion, and survival. Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, has emerged as an attractive treatment option for patients with Waldenström’s macroglobulinemia (WM). Recently, ibrutinib was approved by the FDA for the treatment of WM, representing the first FDA-approved agent in WM. The first-in-human trial of ibrutinib was an open-label, phase 1 study in patients with relapsed/refractory (R/R) B-cell malignancies including WM (Advani, J Clin Oncol. 2013) and demonstrated encouraging activity of ibrutinib (75% overall response rate) in WM, thus initiating further studies.
Aims
To report long-term activity and safety outcomes of ibrutinib in 4 patients with R/R WM who enrolled in this phase 1 study and then continued into an extension study.
Methods
All patients provided written informed consent before enrollment. Four patients with R/R, histologically confirmed WM and adequate hematologic, renal, and hepatic function received oral ibrutinib between 560 mg/day and 12.5 mg/kg/day until progressive disease or unacceptable toxicity. Patients were required to have IgM levels ≥1000 mg/dL with bone marrow infiltration. After 6 months of therapy, patients with objective response or stable disease were rolled over from the parent study (PCYC-04753) into the extension study (PCYC-1103-CA) at a fixed dose of ibrutinib 560 mg daily. Adverse events (AEs) were assessed by NCI CTCAE v3.0. In the 1103 study, only data on AEs grade ≥3, serious AEs (SAEs), and AEs leading to dose modification or discontinuation were captured. Disease response assessments included laboratory assessments (serum IgM) and radiographic imaging when applicable. Best clinical response was assessed per the 3rd International Workshop of WM (IWWM).
Results
Three of 4 WM patients achieved durable partial responses accompanied by ≥50% reductions from baseline in IgM levels (~80% to 90%), which reached a plateau after 1 year of therapy. Responses are ongoing after 4 years of therapy with no evidence of progression in other clinical features attributed to WM. Additional clinical improvements included sustained increases or stabilization in hemoglobin levels (without the use of erythropoietic growth factors or transfusion); reduction in lymphadenopathy (present in 3 of 4 patients at baseline); and improvement in hematocrit over time. Grade 3/4 AEs included neutropenia (1 patient) and thrombocytopenia (1 patient), and SAEs included febrile neutropenia (2 patients), pneumonia and pneumonitis (1 patient), and atrial fibrillation (1 patient). In addition, the same patient experienced a second episode of grade 2 atrial fibrillation (not an SAE), leading to dose modification to ibrutinib 420 mg daily. All grade 3/4 AEs and SAEs were resolved without sequelae and were assessed by the investigator as unrelated to ibrutinib.
Summary
This case series is the first to demonstrate extended activity and tolerability of ibrutinib in R/R WM, accompanied by early and rapid decline in IgM levels and increase in hemoglobin levels. Single-agent ibrutinib induced profound and durable responses, with a favorable safety profile, in this difficult-to-treat patient population—consistent with findings of a phase 2 trial (Treon, IWWM, 2014).
Keyword(s): Waldenstrom's macroglobulinemia
Abstract: PB1786
Type: Publication Only
Background
Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor pathway and functions via the activation of downstream signals mediating B-cell growth, adhesion, and survival. Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, has emerged as an attractive treatment option for patients with Waldenström’s macroglobulinemia (WM). Recently, ibrutinib was approved by the FDA for the treatment of WM, representing the first FDA-approved agent in WM. The first-in-human trial of ibrutinib was an open-label, phase 1 study in patients with relapsed/refractory (R/R) B-cell malignancies including WM (Advani, J Clin Oncol. 2013) and demonstrated encouraging activity of ibrutinib (75% overall response rate) in WM, thus initiating further studies.
Aims
To report long-term activity and safety outcomes of ibrutinib in 4 patients with R/R WM who enrolled in this phase 1 study and then continued into an extension study.
Methods
All patients provided written informed consent before enrollment. Four patients with R/R, histologically confirmed WM and adequate hematologic, renal, and hepatic function received oral ibrutinib between 560 mg/day and 12.5 mg/kg/day until progressive disease or unacceptable toxicity. Patients were required to have IgM levels ≥1000 mg/dL with bone marrow infiltration. After 6 months of therapy, patients with objective response or stable disease were rolled over from the parent study (PCYC-04753) into the extension study (PCYC-1103-CA) at a fixed dose of ibrutinib 560 mg daily. Adverse events (AEs) were assessed by NCI CTCAE v3.0. In the 1103 study, only data on AEs grade ≥3, serious AEs (SAEs), and AEs leading to dose modification or discontinuation were captured. Disease response assessments included laboratory assessments (serum IgM) and radiographic imaging when applicable. Best clinical response was assessed per the 3rd International Workshop of WM (IWWM).
Results
Three of 4 WM patients achieved durable partial responses accompanied by ≥50% reductions from baseline in IgM levels (~80% to 90%), which reached a plateau after 1 year of therapy. Responses are ongoing after 4 years of therapy with no evidence of progression in other clinical features attributed to WM. Additional clinical improvements included sustained increases or stabilization in hemoglobin levels (without the use of erythropoietic growth factors or transfusion); reduction in lymphadenopathy (present in 3 of 4 patients at baseline); and improvement in hematocrit over time. Grade 3/4 AEs included neutropenia (1 patient) and thrombocytopenia (1 patient), and SAEs included febrile neutropenia (2 patients), pneumonia and pneumonitis (1 patient), and atrial fibrillation (1 patient). In addition, the same patient experienced a second episode of grade 2 atrial fibrillation (not an SAE), leading to dose modification to ibrutinib 420 mg daily. All grade 3/4 AEs and SAEs were resolved without sequelae and were assessed by the investigator as unrelated to ibrutinib.
Summary
This case series is the first to demonstrate extended activity and tolerability of ibrutinib in R/R WM, accompanied by early and rapid decline in IgM levels and increase in hemoglobin levels. Single-agent ibrutinib induced profound and durable responses, with a favorable safety profile, in this difficult-to-treat patient population—consistent with findings of a phase 2 trial (Treon, IWWM, 2014).
Keyword(s): Waldenstrom's macroglobulinemia
Type: Publication Only
Background
Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor pathway and functions via the activation of downstream signals mediating B-cell growth, adhesion, and survival. Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, has emerged as an attractive treatment option for patients with Waldenström’s macroglobulinemia (WM). Recently, ibrutinib was approved by the FDA for the treatment of WM, representing the first FDA-approved agent in WM. The first-in-human trial of ibrutinib was an open-label, phase 1 study in patients with relapsed/refractory (R/R) B-cell malignancies including WM (Advani, J Clin Oncol. 2013) and demonstrated encouraging activity of ibrutinib (75% overall response rate) in WM, thus initiating further studies.
Aims
To report long-term activity and safety outcomes of ibrutinib in 4 patients with R/R WM who enrolled in this phase 1 study and then continued into an extension study.
Methods
All patients provided written informed consent before enrollment. Four patients with R/R, histologically confirmed WM and adequate hematologic, renal, and hepatic function received oral ibrutinib between 560 mg/day and 12.5 mg/kg/day until progressive disease or unacceptable toxicity. Patients were required to have IgM levels ≥1000 mg/dL with bone marrow infiltration. After 6 months of therapy, patients with objective response or stable disease were rolled over from the parent study (PCYC-04753) into the extension study (PCYC-1103-CA) at a fixed dose of ibrutinib 560 mg daily. Adverse events (AEs) were assessed by NCI CTCAE v3.0. In the 1103 study, only data on AEs grade ≥3, serious AEs (SAEs), and AEs leading to dose modification or discontinuation were captured. Disease response assessments included laboratory assessments (serum IgM) and radiographic imaging when applicable. Best clinical response was assessed per the 3rd International Workshop of WM (IWWM).
Results
Three of 4 WM patients achieved durable partial responses accompanied by ≥50% reductions from baseline in IgM levels (~80% to 90%), which reached a plateau after 1 year of therapy. Responses are ongoing after 4 years of therapy with no evidence of progression in other clinical features attributed to WM. Additional clinical improvements included sustained increases or stabilization in hemoglobin levels (without the use of erythropoietic growth factors or transfusion); reduction in lymphadenopathy (present in 3 of 4 patients at baseline); and improvement in hematocrit over time. Grade 3/4 AEs included neutropenia (1 patient) and thrombocytopenia (1 patient), and SAEs included febrile neutropenia (2 patients), pneumonia and pneumonitis (1 patient), and atrial fibrillation (1 patient). In addition, the same patient experienced a second episode of grade 2 atrial fibrillation (not an SAE), leading to dose modification to ibrutinib 420 mg daily. All grade 3/4 AEs and SAEs were resolved without sequelae and were assessed by the investigator as unrelated to ibrutinib.
Summary
This case series is the first to demonstrate extended activity and tolerability of ibrutinib in R/R WM, accompanied by early and rapid decline in IgM levels and increase in hemoglobin levels. Single-agent ibrutinib induced profound and durable responses, with a favorable safety profile, in this difficult-to-treat patient population—consistent with findings of a phase 2 trial (Treon, IWWM, 2014).
Keyword(s): Waldenstrom's macroglobulinemia
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