Neil Osterweil

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“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.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“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 eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“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.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“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 eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – Idelalisib given as first-line therapy for patients with chronic lymphocytic leukemia carries a high risk of early fulminant hepatotoxicity requiring drug interruption and steroids, investigators reported.

Among 24 patients who received idelalisib (Zydelig) monotherapy in a phase II trial of a combination of idelalisib followed by idelalisib concurrent with ofatumumab (Arzerra) as first-line therapy for chronic lymphocytic leukemia (CLL), 12 patients developed acute hepatotoxicity, marked by rapidly soaring levels of transaminase within about 28 days of starting therapy. An additional four patients developed hepatotoxicity at around 130 days, noted Dr. Benjamin L. Lampson, a clinical fellow in medicine at the Dana-Farber Cancer Institute in Boston.

“Multiple lines of evidence suggest that this early hepatotoxicity is immune mediated. The proportion of regulatory T cells in the peripheral blood decrease on idelalisib therapy, providing a possible explanation for the development of early hepatotoxicity,” he said at the annual meeting of the American Society of Hematology.

The toxicities occur more frequently among younger and less heavily pretreated patients, and are likely due to on-target, immune-mediated effects, he noted.

Dr. Lampson presented data on the first 24 patients in an ongoing phase II trial. Patients with previously untreated CLL receive idelalisib 150 mg twice daily for 56 days, in an attempt to mobilize neoplastic B cells from the peripheral lymphoid tissues and into the bloodstream.

Following the monotherapy phase, patients are given ofatumumab in an attempt to clear the disease from peripheral blood.

“This dosing strategy is slightly different than what has been previously been used in trials combining these particular drugs. Specifically, previously reported trials have started these agents simultaneously without a lead-in period of monotherapy,” Dr. Lampson explained.

When the lead-in phase is completed, patients receive idelalisib plus ofatumumab infusions once weekly for 8 weeks, followed by once-monthly infusions for 4 months. Patients then continue on idelalisib indefinitely. The primary endpoint is the overall response rate assessed 2 months after the completion of the combination therapy.

For the first 24 patients treated as of Nov. 9, 2015, the median time on therapy was 7.7 months and median follow-up was 14.7 months.

The median patient age was 67.4 years (range 57.6-84.9). CLL genetics showed that 13 patients had unmutated immunoglobulin heavy chain variable region (IgHV) disease, 4 had the 17p deletion and TP53 mutation, 1 had deletion 11q, and 13 had deletion 13q; some patients had more than one mutation.

“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.

He presented one case, a 58-year-old man who was in the idelalisib monotherapy phase of the study. He developed grade 3 hepatotoxicity 28 days after starting the drug, despite having a normal liver function test just 1 day earlier. The drug was stopped, but his liver function tests continued to rise, suggesting a self-perpetuating or self-sustaining process.

On day 32, the patient was admitted to the hospital, and on day 33 he was started on steroids, based on the hypothesis that the hepatotoxicity might have been immune mediated. Two days after initiation of steroids, his liver function tests continued to rise, whereupon he was started on mycophenolate mofetil.

“With these two forms of immunosuppression, the [liver function tests] did eventually normalize, although the steroids and mycophenolate had to be tapered over a period of many weeks. And this patient was not the only patient to experience toxicity; in fact, hepatotoxicity was frequent and often severe,” he said.

At the time of maximum incidence, week 4, the percentage of patients with any hepatotoxicity was 46%, with 13% at grade 4, and 21% at grade 3.

“The median time to initial development of hepatotoxicity is 28 days. This suggests that the mechanism of hepatotoxicity is not immediate, but takes time to develop, consistent with an adaptive immune response. Furthermore, hepatotoxicity is typically occurring before the first dose of ofatumumab is occurring at week 8, suggesting idelalisib alone is the cause of the hepatotoxicity,” Dr. Lampson said.

A comparison of data from the ongoing study and from three previous studies – two with idelalisib in relapsed refractory disease, and one as first-line therapy in patients 65 and older – showed that grade 3 or greater hepatotoxicity was lowest in a phase I trial of idelalisib in which patients had received a median of five prior lines of therapy, occurring in only 1.9% of patients. In contrast, in the current study, 52% of patients experienced grade 3 or 4 transaminitis at some point in the trial.

Evidence for the hepatotoxicity being an on-target immune-mediated effect comes from lymphocytic infiltrate on liver biopsy and lymphocytic colitis in idelalisib-treated patients. Additional evidence comes from the fact that the toxicity is both treatable and preventable with steroids, he said.

He cautioned that hepatotoxicity can recur rapidly when the drug is reintroduced.

“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 eventually can be tapered off steroids,” he said.

Asked by an audience member whether patients who are receiving idelalisib in the first-line setting should also receive steroids, Dr. Lampson said that they closely monitor patient liver enzymes around 28 days, and if grade 1 transaminitis is detected, patients are automatically started on low-dose steroids.

The study is sponsored by the Dana-Farber Cancer Institute in collaboration with Gilead Sciences and GlaxoSmithKline. Dr. Lampson and colleagues declared no relevant conflicts of interest.

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.