User login
Photo courtesy of ASH
ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.
In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.
The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.
Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*
Study design and patient demographics
Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.
The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.
“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”
The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.
Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.
The patients received no prior therapies.
Results
The trial is currently ongoing.
The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.
“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.
In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.
Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.
Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”
Dr Lampson noted that toxicities resolved rapidly with steroids.
“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”
Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.
Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.
“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.
Comparison with earlier studies
The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).
They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.
Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.
The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.
The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.
“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”
He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.
Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.
Decrease in regulatory T cells
Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.
This, they say, could provide a possible explanation for the development of early hepatotoxicity.
The trial is investigator-initiated and funded by Gilead Sciences. 
*Data in the presentation differs from the abstract.
Photo courtesy of ASH
ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.
In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.
The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.
Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*
Study design and patient demographics
Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.
The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.
“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”
The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.
Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.
The patients received no prior therapies.
Results
The trial is currently ongoing.
The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.
“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.
In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.
Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.
Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”
Dr Lampson noted that toxicities resolved rapidly with steroids.
“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”
Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.
Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.
“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.
Comparison with earlier studies
The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).
They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.
Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.
The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.
The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.
“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”
He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.
Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.
Decrease in regulatory T cells
Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.
This, they say, could provide a possible explanation for the development of early hepatotoxicity.
The trial is investigator-initiated and funded by Gilead Sciences.
*Data in the presentation differs from the abstract.
Photo courtesy of ASH
ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.
In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.
The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.
Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*
Study design and patient demographics
Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.
The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.
“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”
The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.
Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.
The patients received no prior therapies.
Results
The trial is currently ongoing.
The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.
“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.
In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.
Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.
Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”
Dr Lampson noted that toxicities resolved rapidly with steroids.
“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”
Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.
Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.
“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.
Comparison with earlier studies
The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).
They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.
Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.
The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.
The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.
“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”
He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.
Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.
Decrease in regulatory T cells
Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.
This, they say, could provide a possible explanation for the development of early hepatotoxicity.
The trial is investigator-initiated and funded by Gilead Sciences.
*Data in the presentation differs from the abstract.