User login
European Hematology Association (EHA): Annual Congress
Approach can reduce drug-induced TLS
Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg. 
Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.
Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.
Eltrombopag reduces bleeding in children with chronic immune thrombocytopenia
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
AT THE EHA CONGRESS
Key clinical point: Eltrombopag may soon be a treatment option for children with chronic immune thrombocytopenia.
Major finding: Platelet response was durable at 6-8 weeks in 40% of children on eltrombopag versus 3.4% of children on placebo (P less than .001).
Data source: A phase III randomized study in 92 children.
Disclosures: GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
Cream provides relief for leg ulcers in SCD
MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).
The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.
A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.
But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.
She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.
“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . . remains a clinical and economic burden,” Dr Minniti noted.
“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”
With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.
Patient characteristics and treatment
The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).
Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm2 (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm2 (range, 2.51-14.66).
The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).
For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.
Adverse events
There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.
Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.
For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.
Effects on ulcer size
Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).
Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.
One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.
The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.
Effects on pain and blood flow
One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.
There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).
Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).
“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”
Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).
Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients. 
MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).
The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.
A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.
But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.
She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.
“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . . remains a clinical and economic burden,” Dr Minniti noted.
“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”
With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.
Patient characteristics and treatment
The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).
Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm2 (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm2 (range, 2.51-14.66).
The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).
For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.
Adverse events
There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.
Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.
For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.
Effects on ulcer size
Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).
Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.
One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.
The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.
Effects on pain and blood flow
One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.
There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).
Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).
“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”
Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).
Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.
MILAN—Results of a phase 1 study indicate that topical sodium nitrate is safe and effective for treating leg ulcers in patients with sickle cell disease (SCD).
The cream significantly decreased the size of leg ulcers overall, healed ulcers in 6 of the 18 patients studied, and reduced pain levels, seemingly independent of wound healing.
A few patients did experience short-lived burning at the treatment site, and some experienced a temporary, asymptomatic drop in blood pressure that resolved without intervention.
But the treatment was generally well-tolerated, according to study investigator Caterina P. Minniti, MD, of the National Heart, Lung and Blood Institute in Bethesda, Maryland.
She presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S663.
“The morbidity from chronic and recurrent leg ulcers in sickle cell disease and other hematologic disorders . . . remains a clinical and economic burden,” Dr Minniti noted.
“[C]urrent therapies have limited efficacy and usually are borrowed from the treatment of venous ulcers and diabetic ulcers. There isn’t really a concerted effort to treat sickle cell leg ulcers.”
With that in mind, she and her colleagues initiated a phase 1 dose-escalation trial of topical sodium nitrate in SCD patients.
Patient characteristics and treatment
The researchers enrolled 18 patients with a median age of 39 ± 12 (range, 20-59). The median number of ulcers per patient was 1.5 (range, 1-10), and the median ulcer age was 10 months (range, 2-300).
Manual assessment suggested the median ulcer size was 7.50 ± 4.65 cm2 (range, 2.09-16.50). Digital assessment suggested the median ulcer size was 5.97± 3.40 cm2 (range, 2.51-14.66).
The mean number of prior ulcer therapies was 8. This included surgical/sharp debridement (n=18), hyperbaric chamber (n=7), skin graft (n=6), MIST therapy (n=4), and oral/parenteral antibiotics (n=11).
For this study, patients had sodium nitrate cream applied twice a week for 4 weeks on 1 leg ulcer per subject. There were 5 cohorts of escalating treatment concentrations: 0.5%, 1%, 1.5%, 1.8%, and 2%.
Adverse events
There were no serious adverse events, and none of the patients discontinued treatment. One adverse event that was likely related to treatment was short-lived burning after cream application in 4 patients. But this resolved without intervention.
Another event that may have been related to treatment was asymptomatic, short-lived, diastolic blood pressure less than 50 mmHg in 5 subjects who received treatment at the highest concentrations (2 in the 2% cohort and 3 in the 1.8% cohort). On the other hand, 3 of these 5 subjects had documented diastolic blood pressure less than 50 mmHg prior to starting the treatment.
For the most part, there were no changes in laboratory or clinical parameters before and after the trial. However, the researchers did observe a significant decrease in white blood cell counts.
Effects on ulcer size
Among all patients, there was a significant decrease in ulcer size from the first treatment application to the end of the study, both according to digital photography and assessment by wound-care nurses (P<0.001 and P<0.0001, respectively).
Although patients in all of the treatment groups experienced a decrease in wound size, there was a correlation between the decrease and the concentration of treatment.
One patient in the 1%-concentration cohort had an ulcer that progressed, but all other patients saw improvements. The 4 patients who received the 1.8% concentration had a 69.7% decrease in ulcer size at week 5, and 1 ulcer had healed by the end of treatment.
The 3 patients who received the 2% concentration had an 88.3% decrease in ulcer size at week 5, and 2 ulcers had healed by that time. An additional 3 ulcers healed within weeks or months of the study end.
Effects on pain and blood flow
One of the most interesting findings of this study, according to Dr Minniti, was the effect of the cream on patients’ pain.
There was a significant decrease in patient-reported pain for treated ulcers (P<0.006) but not for untreated ulcers (P=0.38). And there was a significant correlation with pain score and nitrate concentration (P=0.006).
Patients’ weekly total usage of opioids decreased from baseline to the end of the study, but this difference was not significant (P=0.26).
“There was a trend toward significance,” Dr Minniti noted. “It’s very hard, in 1 month, to get off your long-acting opioid.”
Finally, Dr Minniti and her colleagues found that blood flow to the wound area changed before and after treatment. According to laser speckle contrast imaging, there was a significant increase in blood flow after treatment (P<0.0002).
Based on these results, the researchers have initiated a phase 1/2, randomized trial comparing topical sodium nitrate to placebo in SCD patients.