Potential treatment for cGVHD after steroid failure

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.

Attendees at the

2016 ASH Annual Meeting

SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.

At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.

The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.

David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.

This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.

“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.

In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.

“So this dose was carried forward into the phase 2 study,” Dr Miklos said.

He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).

Study design

Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.

They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.

Patients with cGVHD had to have failed frontline therapy.

They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.

The primary endpoint was cGVHD response per NIH 2005 response criteria.

Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.

Investigators enrolled 42 patients, the first of whom was dosed in July 2014.

Patient demographics

Patients were a median age of 56 (range, 19–74), and 52% were male.

The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).

Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.

And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.

“This was a heavily treated patient population,” Dr Miklos said.

They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.

Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).

Results

The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.

Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.

Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.

Five responders discontinued all corticosteroid treatment.

Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.

And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.

Discontinuation and toxicity

At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.

“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.

Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).

“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”

Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.

Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).

Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.

Exploratory endpoints

Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.

“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.

These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.

“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of  chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.

The current study was sponsored by Pharmacyclics, Inc.