Ibrutinib highly active against refractory Waldenstrom’s macroglobulinemia

Ibrutinib proved to be “highly active” against refractory Waldenstrom’s macroglobulinemia in the first clinical trial to assess the agent’s safety and efficacy in this patient population, producing an overall response rate of 90.5% and a major response rate of 73.0% in a series of 63 consecutive patients, according to a report published online April 9 in the New England Journal of Medicine.

Waldenstrom’s macroglobulinemia is a malignant B-cell lymphoma in which whole-genome sequencing has revealed several activating mutations. Ibrutinib – an oral inhibitor of Bruton’s tyrosine kinase (BTK), which is activated in tumor cells by some of these mutations – was found to trigger apoptosis of Waldenstrom’s macroglobulinemia cells in vitro and to show clinical activity in a phase I study. Investigators now report their findings from a prospective, industry-sponsored study of adults enrolled at the Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and Stanford University Medical Center during a 1-year period and followed up for another 18 months.

All the participants had progressive disease at baseline despite receiving previous treatments including monoclonal antibodies, glucocorticoids, proteasome inhibitors, alkylators, immunomodulators, anthracyclines, and experimental therapies. Ibrutinib was taken orally every day for 26 4-week cycles until disease progressed or unacceptable toxic effects developed; treatment responders were permitted to continue the therapy after that time, if they wished, said Dr. Steven P. Treon of the Bing Center for Waldenstrom’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, and his associates.

The primary objective of the study was to determine the overall rate of any treatment response (it was 90.5%) and the rate of major treatment response, defined as a 50% or greater decline in serum IgM levels (it was 73.0%). In addition, at 24 months, the progression-free survival was 69.1% and the overall survival was 95.2%. In comparison, previous studies of other monotherapies have shown overall response rates of only 40%-80% and median progression-free survival of only 8-20 months, the investigators said (N. Engl. J. Med. 2015 April 9 [doi:10.1056/NEJMoa1501548]).

Treatment response was rapid, with a median onset at 4 weeks, and both serum IgM and hemoglobin levels improved even in patients who showed modest or no changes in bone marrow disease burden. “This suggests that a mechanism other than tumor debulking could contribute to the clinical benefit with ibrutinib,” they added.

On CT imaging, 68% of patients showed decreased or resolved adenopathy and 57% showed decreased splenomegaly. Malignant pleural effusions resolved in two of three patients who had them, and peripheral neuropathy stabilized or improved in all nine who were affected. The latter result is “particularly encouraging given the challenging nature of treating IgM-related peripheral neuropathy in Waldenstrom’s macroglobulinemia,” Dr. Treon and his associates noted.

The toxic effects of treatment were moderate in these heavily pretreated patients and included neutropenia (22% of patients), thrombocytopenia (14%), bleeding events (3%), and reversible atrial fibrillation (5%) in patients with a history of arrhythmia. There were few infections, and no unexpected toxicities occurred, the investigators reported.

This study was supported by Pharmacyclics and Janssen Pharmaceuticals; with additional funding by Peter S. Bing, M.D.; the International Waldenstrom’s Macroglobulinemia Foundation; the Leukemia and Lymphoma Society; the Linda and Edward Nelson Fund for Waldenstrom’s Macroglobulinemia Research; the D’Amato Family Fund for Genomic Discovery; the Coyote Fund; and the Bauman Family Foundation. Dr. Treon reported ties to Pharmacyclics and Janssen; his associates reported ties to several industry sources.

Ibrutinib proved to be “highly active” against refractory Waldenstrom’s macroglobulinemia in the first clinical trial to assess the agent’s safety and efficacy in this patient population, producing an overall response rate of 90.5% and a major response rate of 73.0% in a series of 63 consecutive patients, according to a report published online April 9 in the New England Journal of Medicine.

Waldenstrom’s macroglobulinemia is a malignant B-cell lymphoma in which whole-genome sequencing has revealed several activating mutations. Ibrutinib – an oral inhibitor of Bruton’s tyrosine kinase (BTK), which is activated in tumor cells by some of these mutations – was found to trigger apoptosis of Waldenstrom’s macroglobulinemia cells in vitro and to show clinical activity in a phase I study. Investigators now report their findings from a prospective, industry-sponsored study of adults enrolled at the Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and Stanford University Medical Center during a 1-year period and followed up for another 18 months.

All the participants had progressive disease at baseline despite receiving previous treatments including monoclonal antibodies, glucocorticoids, proteasome inhibitors, alkylators, immunomodulators, anthracyclines, and experimental therapies. Ibrutinib was taken orally every day for 26 4-week cycles until disease progressed or unacceptable toxic effects developed; treatment responders were permitted to continue the therapy after that time, if they wished, said Dr. Steven P. Treon of the Bing Center for Waldenstrom’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, and his associates.

The primary objective of the study was to determine the overall rate of any treatment response (it was 90.5%) and the rate of major treatment response, defined as a 50% or greater decline in serum IgM levels (it was 73.0%). In addition, at 24 months, the progression-free survival was 69.1% and the overall survival was 95.2%. In comparison, previous studies of other monotherapies have shown overall response rates of only 40%-80% and median progression-free survival of only 8-20 months, the investigators said (N. Engl. J. Med. 2015 April 9 [doi:10.1056/NEJMoa1501548]).

Treatment response was rapid, with a median onset at 4 weeks, and both serum IgM and hemoglobin levels improved even in patients who showed modest or no changes in bone marrow disease burden. “This suggests that a mechanism other than tumor debulking could contribute to the clinical benefit with ibrutinib,” they added.

On CT imaging, 68% of patients showed decreased or resolved adenopathy and 57% showed decreased splenomegaly. Malignant pleural effusions resolved in two of three patients who had them, and peripheral neuropathy stabilized or improved in all nine who were affected. The latter result is “particularly encouraging given the challenging nature of treating IgM-related peripheral neuropathy in Waldenstrom’s macroglobulinemia,” Dr. Treon and his associates noted.

The toxic effects of treatment were moderate in these heavily pretreated patients and included neutropenia (22% of patients), thrombocytopenia (14%), bleeding events (3%), and reversible atrial fibrillation (5%) in patients with a history of arrhythmia. There were few infections, and no unexpected toxicities occurred, the investigators reported.

This study was supported by Pharmacyclics and Janssen Pharmaceuticals; with additional funding by Peter S. Bing, M.D.; the International Waldenstrom’s Macroglobulinemia Foundation; the Leukemia and Lymphoma Society; the Linda and Edward Nelson Fund for Waldenstrom’s Macroglobulinemia Research; the D’Amato Family Fund for Genomic Discovery; the Coyote Fund; and the Bauman Family Foundation. Dr. Treon reported ties to Pharmacyclics and Janssen; his associates reported ties to several industry sources.

Ibrutinib proved to be “highly active” against refractory Waldenstrom’s macroglobulinemia in the first clinical trial to assess the agent’s safety and efficacy in this patient population, producing an overall response rate of 90.5% and a major response rate of 73.0% in a series of 63 consecutive patients, according to a report published online April 9 in the New England Journal of Medicine.

Waldenstrom’s macroglobulinemia is a malignant B-cell lymphoma in which whole-genome sequencing has revealed several activating mutations. Ibrutinib – an oral inhibitor of Bruton’s tyrosine kinase (BTK), which is activated in tumor cells by some of these mutations – was found to trigger apoptosis of Waldenstrom’s macroglobulinemia cells in vitro and to show clinical activity in a phase I study. Investigators now report their findings from a prospective, industry-sponsored study of adults enrolled at the Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and Stanford University Medical Center during a 1-year period and followed up for another 18 months.

All the participants had progressive disease at baseline despite receiving previous treatments including monoclonal antibodies, glucocorticoids, proteasome inhibitors, alkylators, immunomodulators, anthracyclines, and experimental therapies. Ibrutinib was taken orally every day for 26 4-week cycles until disease progressed or unacceptable toxic effects developed; treatment responders were permitted to continue the therapy after that time, if they wished, said Dr. Steven P. Treon of the Bing Center for Waldenstrom’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, and his associates.

The primary objective of the study was to determine the overall rate of any treatment response (it was 90.5%) and the rate of major treatment response, defined as a 50% or greater decline in serum IgM levels (it was 73.0%). In addition, at 24 months, the progression-free survival was 69.1% and the overall survival was 95.2%. In comparison, previous studies of other monotherapies have shown overall response rates of only 40%-80% and median progression-free survival of only 8-20 months, the investigators said (N. Engl. J. Med. 2015 April 9 [doi:10.1056/NEJMoa1501548]).

Treatment response was rapid, with a median onset at 4 weeks, and both serum IgM and hemoglobin levels improved even in patients who showed modest or no changes in bone marrow disease burden. “This suggests that a mechanism other than tumor debulking could contribute to the clinical benefit with ibrutinib,” they added.

On CT imaging, 68% of patients showed decreased or resolved adenopathy and 57% showed decreased splenomegaly. Malignant pleural effusions resolved in two of three patients who had them, and peripheral neuropathy stabilized or improved in all nine who were affected. The latter result is “particularly encouraging given the challenging nature of treating IgM-related peripheral neuropathy in Waldenstrom’s macroglobulinemia,” Dr. Treon and his associates noted.

The toxic effects of treatment were moderate in these heavily pretreated patients and included neutropenia (22% of patients), thrombocytopenia (14%), bleeding events (3%), and reversible atrial fibrillation (5%) in patients with a history of arrhythmia. There were few infections, and no unexpected toxicities occurred, the investigators reported.

This study was supported by Pharmacyclics and Janssen Pharmaceuticals; with additional funding by Peter S. Bing, M.D.; the International Waldenstrom’s Macroglobulinemia Foundation; the Leukemia and Lymphoma Society; the Linda and Edward Nelson Fund for Waldenstrom’s Macroglobulinemia Research; the D’Amato Family Fund for Genomic Discovery; the Coyote Fund; and the Bauman Family Foundation. Dr. Treon reported ties to Pharmacyclics and Janssen; his associates reported ties to several industry sources.