Drug may improve outcomes of VOD with MOF after HSCT

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.