ASH 2011

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.