Leukemia, Myelodysplasia, Transplantation

NEW ORLEANS – Adding dasatinib to standard first-line chemotherapy and continuing the KIT inhibitor as maintenance therapy are tolerable in core binding factor acute myeloid leukemia, even for older patients, a phase II study shows.

There were no unexpected toxicities, and clinical outcomes were at least comparable to those historically achieved in this population, Dr. Guido Marcucci said at the annual meeting of the American Society of Hematology.

Core binding factor (CBL) acute myeloid leukemia (AML) has a relatively favorable prognosis, though about 40% of patients will eventually relapse.

The Cancer and Leukemia Group B (CALGB) 10801 study investigators hypothesized that adding dasatinib (Sprycel) to chemotherapy would improve patient outcomes, because KIT mutations are present in about 25%-30% of CBL AML patients and are associated with a higher frequency of relapse, said Dr. Marcucci, professor of hematology at the Ohio State University, Columbus.

Molecular screening confirmed CBF AML in 69 patients, with 61 starting induction therapy with daunorubicin 60 mg/m² per day on days 1-3, cytarabine 200 mg/m² per day on days 1-7, and oral dasatinib 100 mg/day on days 8-21. Patients with residual disease on day 21 underwent reinduction chemotherapy, while those achieving complete remission received consolidation therapy with high-dose cytarabine and dasatinib for four cycles. Patients remaining in remission were maintained on dasatinib at 100 mg/day for 12 months.

The median age in the study was 51 years (range, 20-85 years), 65% were positive for the CBFB-MYH11 gene fusion, and 35% were positive for the RUNX1-RUNX1T1 gene fusion.

After a median follow-up of 14 months, 30-day survival was 97%. The complete remission rate was 89% overall – 91% for patients younger than 60 years, and 80% for those older than 60 years – Dr. Marcucci said.

To date, 20 patients remain on treatment and only 2 have relapsed. Four patients died during induction/consolidation therapy, and four died during follow-up (two after relapse).

Among 58 patients evaluable for toxicity, the most common grade 4 toxicities were sepsis (6 cases), increased alanine aminotransferase (3 cases), and 2 events each of pleural effusion, lung infection, elevated aspartate aminotransferase, hypocalcemia, and dyspnea. Grade 5 toxicities included sepsis in two patients and one respiratory failure. Nine patients discontinued treatment due to adverse events.

"We did not really see any adverse events that have not been seen before with chemotherapy or dasatinib," Dr. Marcucci said.

By 12 months, event-free survival was 85% and overall survival was 89%. So far, no survival difference has been seen between patients with chromosome 21 translocations and those with chromosome 16 inversions; however, younger patients seem to have better outcomes than older patients, he said.

The KIT inhibition strategy makes sense scientifically, but the follow-up is too short to enable investigators to draw conclusions, since the bulk of AML patients will relapse within 2 years, said Dr. Peter D. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas, Little Rock.

"At least so far, in early follow-up, it looks like they haven’t done any damage and time will tell if they’ve done good or not," he said in an interview.

Dr. Marcucci concluded that rapid screening for CBF AML is feasible within a cooperative group, noting that patients entered the trial at a median of just 4 days from diagnosis. This may not be feasible, just yet, in clinical practice.

"Most private practice hem/oncs send off the chromosomes from the bone marrow, and you’ll be way into induction chemo by the time you get those results back," Dr. Emanuel observed. "It’s got to be ramped up so it’s in a real-world setting beyond the university setting. I think we’ll get there because there are more and more labs capable of doing this."

The National Cancer Institute sponsored CALGB 10801. Dr. Marcucci reported research funding from Boehringer Ingelheim.

pwendling@frontlinemedcom.com

NEW ORLEANS – Adding dasatinib to standard first-line chemotherapy and continuing the KIT inhibitor as maintenance therapy are tolerable in core binding factor acute myeloid leukemia, even for older patients, a phase II study shows.

There were no unexpected toxicities, and clinical outcomes were at least comparable to those historically achieved in this population, Dr. Guido Marcucci said at the annual meeting of the American Society of Hematology.

Core binding factor (CBL) acute myeloid leukemia (AML) has a relatively favorable prognosis, though about 40% of patients will eventually relapse.

The Cancer and Leukemia Group B (CALGB) 10801 study investigators hypothesized that adding dasatinib (Sprycel) to chemotherapy would improve patient outcomes, because KIT mutations are present in about 25%-30% of CBL AML patients and are associated with a higher frequency of relapse, said Dr. Marcucci, professor of hematology at the Ohio State University, Columbus.

Molecular screening confirmed CBF AML in 69 patients, with 61 starting induction therapy with daunorubicin 60 mg/m² per day on days 1-3, cytarabine 200 mg/m² per day on days 1-7, and oral dasatinib 100 mg/day on days 8-21. Patients with residual disease on day 21 underwent reinduction chemotherapy, while those achieving complete remission received consolidation therapy with high-dose cytarabine and dasatinib for four cycles. Patients remaining in remission were maintained on dasatinib at 100 mg/day for 12 months.

The median age in the study was 51 years (range, 20-85 years), 65% were positive for the CBFB-MYH11 gene fusion, and 35% were positive for the RUNX1-RUNX1T1 gene fusion.

After a median follow-up of 14 months, 30-day survival was 97%. The complete remission rate was 89% overall – 91% for patients younger than 60 years, and 80% for those older than 60 years – Dr. Marcucci said.

To date, 20 patients remain on treatment and only 2 have relapsed. Four patients died during induction/consolidation therapy, and four died during follow-up (two after relapse).

Among 58 patients evaluable for toxicity, the most common grade 4 toxicities were sepsis (6 cases), increased alanine aminotransferase (3 cases), and 2 events each of pleural effusion, lung infection, elevated aspartate aminotransferase, hypocalcemia, and dyspnea. Grade 5 toxicities included sepsis in two patients and one respiratory failure. Nine patients discontinued treatment due to adverse events.

"We did not really see any adverse events that have not been seen before with chemotherapy or dasatinib," Dr. Marcucci said.

By 12 months, event-free survival was 85% and overall survival was 89%. So far, no survival difference has been seen between patients with chromosome 21 translocations and those with chromosome 16 inversions; however, younger patients seem to have better outcomes than older patients, he said.

The KIT inhibition strategy makes sense scientifically, but the follow-up is too short to enable investigators to draw conclusions, since the bulk of AML patients will relapse within 2 years, said Dr. Peter D. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas, Little Rock.

"At least so far, in early follow-up, it looks like they haven’t done any damage and time will tell if they’ve done good or not," he said in an interview.

Dr. Marcucci concluded that rapid screening for CBF AML is feasible within a cooperative group, noting that patients entered the trial at a median of just 4 days from diagnosis. This may not be feasible, just yet, in clinical practice.

"Most private practice hem/oncs send off the chromosomes from the bone marrow, and you’ll be way into induction chemo by the time you get those results back," Dr. Emanuel observed. "It’s got to be ramped up so it’s in a real-world setting beyond the university setting. I think we’ll get there because there are more and more labs capable of doing this."

The National Cancer Institute sponsored CALGB 10801. Dr. Marcucci reported research funding from Boehringer Ingelheim.

pwendling@frontlinemedcom.com

NEW ORLEANS – Adding dasatinib to standard first-line chemotherapy and continuing the KIT inhibitor as maintenance therapy are tolerable in core binding factor acute myeloid leukemia, even for older patients, a phase II study shows.

There were no unexpected toxicities, and clinical outcomes were at least comparable to those historically achieved in this population, Dr. Guido Marcucci said at the annual meeting of the American Society of Hematology.

Core binding factor (CBL) acute myeloid leukemia (AML) has a relatively favorable prognosis, though about 40% of patients will eventually relapse.

The Cancer and Leukemia Group B (CALGB) 10801 study investigators hypothesized that adding dasatinib (Sprycel) to chemotherapy would improve patient outcomes, because KIT mutations are present in about 25%-30% of CBL AML patients and are associated with a higher frequency of relapse, said Dr. Marcucci, professor of hematology at the Ohio State University, Columbus.

Molecular screening confirmed CBF AML in 69 patients, with 61 starting induction therapy with daunorubicin 60 mg/m² per day on days 1-3, cytarabine 200 mg/m² per day on days 1-7, and oral dasatinib 100 mg/day on days 8-21. Patients with residual disease on day 21 underwent reinduction chemotherapy, while those achieving complete remission received consolidation therapy with high-dose cytarabine and dasatinib for four cycles. Patients remaining in remission were maintained on dasatinib at 100 mg/day for 12 months.

The median age in the study was 51 years (range, 20-85 years), 65% were positive for the CBFB-MYH11 gene fusion, and 35% were positive for the RUNX1-RUNX1T1 gene fusion.

After a median follow-up of 14 months, 30-day survival was 97%. The complete remission rate was 89% overall – 91% for patients younger than 60 years, and 80% for those older than 60 years – Dr. Marcucci said.

To date, 20 patients remain on treatment and only 2 have relapsed. Four patients died during induction/consolidation therapy, and four died during follow-up (two after relapse).

Among 58 patients evaluable for toxicity, the most common grade 4 toxicities were sepsis (6 cases), increased alanine aminotransferase (3 cases), and 2 events each of pleural effusion, lung infection, elevated aspartate aminotransferase, hypocalcemia, and dyspnea. Grade 5 toxicities included sepsis in two patients and one respiratory failure. Nine patients discontinued treatment due to adverse events.

"We did not really see any adverse events that have not been seen before with chemotherapy or dasatinib," Dr. Marcucci said.

By 12 months, event-free survival was 85% and overall survival was 89%. So far, no survival difference has been seen between patients with chromosome 21 translocations and those with chromosome 16 inversions; however, younger patients seem to have better outcomes than older patients, he said.

The KIT inhibition strategy makes sense scientifically, but the follow-up is too short to enable investigators to draw conclusions, since the bulk of AML patients will relapse within 2 years, said Dr. Peter D. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas, Little Rock.

"At least so far, in early follow-up, it looks like they haven’t done any damage and time will tell if they’ve done good or not," he said in an interview.

Dr. Marcucci concluded that rapid screening for CBF AML is feasible within a cooperative group, noting that patients entered the trial at a median of just 4 days from diagnosis. This may not be feasible, just yet, in clinical practice.

"Most private practice hem/oncs send off the chromosomes from the bone marrow, and you’ll be way into induction chemo by the time you get those results back," Dr. Emanuel observed. "It’s got to be ramped up so it’s in a real-world setting beyond the university setting. I think we’ll get there because there are more and more labs capable of doing this."

The National Cancer Institute sponsored CALGB 10801. Dr. Marcucci reported research funding from Boehringer Ingelheim.

pwendling@frontlinemedcom.com

NEW ORLEANS – Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to results from Study 116.

The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).

The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).

New therapies are needed for relapsed chronic lymphocytic leukemia patients (CLL), especially those who are unfit for chemoimmunotherapy, observed Dr. Furman, head of the CLL and Waldenström’s macroglobulinemia program at Cornell University, New York

Relapsed CLL responds poorly to available therapies, and older patients and those with comorbidities or poor renal/bone marrow function often cannot tolerate standard chemoimmunotherapy.

A new drug application for refractory indolent non-Hodgkin lymphoma was submitted in September for idelalisib and the oral phosphoinositide 3-kinase–delta inhibitor was subsequently granted breakthrough therapy status for relapsed CLL based on the Study 116 findings.

The positive findings also prompted the phase III trial to be halted early in November.

Idelalisib had an acceptable safety profile, with adverse events leading 9 patients to stop idelalisib combination therapy vs. 11 controls, Dr. Furman said.

Infusion-related reactions were also lower, possibly because idelalisib had an impact on the tolerability of rituximab, he said. No patient on idelalisib had a grade 3 or higher infusion reaction vs. four on rituximab alone.

As seen in another idelalisib trial reported at the meeting, grade 3/4 transaminase elevations were more common with the addition of idelalisib to rituximab (six patients vs. one patient). Four of the six idelalisib patients with this event were successfully rechallenged, he said.

Concerns were raised by the audience, however, about whether single-agent rituximab was an appropriate comparator since 88% of controls had already been treated with rituximab.

In response to the criticism, Dr. Furman reminded the audience that all patients were unfit for chemotherapy and that physicians had to be comfortable with the protocol in order to enroll patients.

"You have to remember rituximab is actually, in practice, the most commonly used agent for these patients and by giving sort of a stepped-up dosing, they’d hopefully be getting sufficient therapy to better the patients’ outcome," he added.

Commenting on the results, Dr. Wendy Stock of the University of Chicago, who was a session co-moderator, said the choice of the control arm was her one concern, but that the study design would likely have not been improved if the previous standard, chlorambucil chemotherapy, had been used as the control.

"I think the data are very compelling in terms of the efficacy of this new agent, and we’ll have to see now how it gets incorporated with other novel agents and/or moved into the United States and Europe evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m² in week 1, 500 mg/m² every 2 weeks for four doses, followed by 500 mg/m² every 4 weeks for three more doses.

Patients had received a median of three prior therapies, a median Cumulative Illness Rating Scale score of 8, and a median age of 71 years.

The addition of idelalisib to rituximab increased the overall response rate from 13% to 81% (P less than .0001) and the number of patients achieving at least a 50% reduction in lymph nodes from 4% to 93% (P less than .0001), Dr. Furman said.

Idelalisib is currently being evaluated in more than a dozen studies including a phase II study of combination therapy with the experimental spleen tyrosine kinase inhibitor GS-9973 in a variety of relapsed or refractory hematologic malignancies.

Dr. Furman reported research funding from and board of directors or advisory committee membership with Gilead Sciences, which is developing idelalisib.

pwendling@frontlinemedcom.com

NEW ORLEANS – Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to results from Study 116.

The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).

The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).

New therapies are needed for relapsed chronic lymphocytic leukemia patients (CLL), especially those who are unfit for chemoimmunotherapy, observed Dr. Furman, head of the CLL and Waldenström’s macroglobulinemia program at Cornell University, New York

Relapsed CLL responds poorly to available therapies, and older patients and those with comorbidities or poor renal/bone marrow function often cannot tolerate standard chemoimmunotherapy.

A new drug application for refractory indolent non-Hodgkin lymphoma was submitted in September for idelalisib and the oral phosphoinositide 3-kinase–delta inhibitor was subsequently granted breakthrough therapy status for relapsed CLL based on the Study 116 findings.

The positive findings also prompted the phase III trial to be halted early in November.

Idelalisib had an acceptable safety profile, with adverse events leading 9 patients to stop idelalisib combination therapy vs. 11 controls, Dr. Furman said.

Infusion-related reactions were also lower, possibly because idelalisib had an impact on the tolerability of rituximab, he said. No patient on idelalisib had a grade 3 or higher infusion reaction vs. four on rituximab alone.

As seen in another idelalisib trial reported at the meeting, grade 3/4 transaminase elevations were more common with the addition of idelalisib to rituximab (six patients vs. one patient). Four of the six idelalisib patients with this event were successfully rechallenged, he said.

Concerns were raised by the audience, however, about whether single-agent rituximab was an appropriate comparator since 88% of controls had already been treated with rituximab.

In response to the criticism, Dr. Furman reminded the audience that all patients were unfit for chemotherapy and that physicians had to be comfortable with the protocol in order to enroll patients.

"You have to remember rituximab is actually, in practice, the most commonly used agent for these patients and by giving sort of a stepped-up dosing, they’d hopefully be getting sufficient therapy to better the patients’ outcome," he added.

Commenting on the results, Dr. Wendy Stock of the University of Chicago, who was a session co-moderator, said the choice of the control arm was her one concern, but that the study design would likely have not been improved if the previous standard, chlorambucil chemotherapy, had been used as the control.

"I think the data are very compelling in terms of the efficacy of this new agent, and we’ll have to see now how it gets incorporated with other novel agents and/or moved into the United States and Europe evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m² in week 1, 500 mg/m² every 2 weeks for four doses, followed by 500 mg/m² every 4 weeks for three more doses.

Patients had received a median of three prior therapies, a median Cumulative Illness Rating Scale score of 8, and a median age of 71 years.

The addition of idelalisib to rituximab increased the overall response rate from 13% to 81% (P less than .0001) and the number of patients achieving at least a 50% reduction in lymph nodes from 4% to 93% (P less than .0001), Dr. Furman said.

Idelalisib is currently being evaluated in more than a dozen studies including a phase II study of combination therapy with the experimental spleen tyrosine kinase inhibitor GS-9973 in a variety of relapsed or refractory hematologic malignancies.

Dr. Furman reported research funding from and board of directors or advisory committee membership with Gilead Sciences, which is developing idelalisib.

pwendling@frontlinemedcom.com

NEW ORLEANS – Adding idelalisib to rituximab significantly extends survival in patients with heavily pretreated relapsed chronic lymphocytic leukemia unsuitable for chemotherapy, according to results from Study 116.

The primary endpoint of median progression-free survival (PFS) was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab plus idelalisib (hazard ratio, 0.15; P less than .0001).

The PFS advantage was seen across all subgroups including patients with the 17p deletion and TP53 mutations, Dr. Richard R. Furman reported during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Overall survival was not reached in either group, but was also significantly longer with idelalisib (HR, 0.28; P = .018).

New therapies are needed for relapsed chronic lymphocytic leukemia patients (CLL), especially those who are unfit for chemoimmunotherapy, observed Dr. Furman, head of the CLL and Waldenström’s macroglobulinemia program at Cornell University, New York

Relapsed CLL responds poorly to available therapies, and older patients and those with comorbidities or poor renal/bone marrow function often cannot tolerate standard chemoimmunotherapy.

A new drug application for refractory indolent non-Hodgkin lymphoma was submitted in September for idelalisib and the oral phosphoinositide 3-kinase–delta inhibitor was subsequently granted breakthrough therapy status for relapsed CLL based on the Study 116 findings.

The positive findings also prompted the phase III trial to be halted early in November.

Idelalisib had an acceptable safety profile, with adverse events leading 9 patients to stop idelalisib combination therapy vs. 11 controls, Dr. Furman said.

Infusion-related reactions were also lower, possibly because idelalisib had an impact on the tolerability of rituximab, he said. No patient on idelalisib had a grade 3 or higher infusion reaction vs. four on rituximab alone.

As seen in another idelalisib trial reported at the meeting, grade 3/4 transaminase elevations were more common with the addition of idelalisib to rituximab (six patients vs. one patient). Four of the six idelalisib patients with this event were successfully rechallenged, he said.

Concerns were raised by the audience, however, about whether single-agent rituximab was an appropriate comparator since 88% of controls had already been treated with rituximab.

In response to the criticism, Dr. Furman reminded the audience that all patients were unfit for chemotherapy and that physicians had to be comfortable with the protocol in order to enroll patients.

"You have to remember rituximab is actually, in practice, the most commonly used agent for these patients and by giving sort of a stepped-up dosing, they’d hopefully be getting sufficient therapy to better the patients’ outcome," he added.

Commenting on the results, Dr. Wendy Stock of the University of Chicago, who was a session co-moderator, said the choice of the control arm was her one concern, but that the study design would likely have not been improved if the previous standard, chlorambucil chemotherapy, had been used as the control.

"I think the data are very compelling in terms of the efficacy of this new agent, and we’ll have to see now how it gets incorporated with other novel agents and/or moved into the United States and Europe evenly randomized 220 patients to eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo twice daily until disease progression. Rituximab was dosed at 375 mg/m² in week 1, 500 mg/m² every 2 weeks for four doses, followed by 500 mg/m² every 4 weeks for three more doses.

Patients had received a median of three prior therapies, a median Cumulative Illness Rating Scale score of 8, and a median age of 71 years.

The addition of idelalisib to rituximab increased the overall response rate from 13% to 81% (P less than .0001) and the number of patients achieving at least a 50% reduction in lymph nodes from 4% to 93% (P less than .0001), Dr. Furman said.

Idelalisib is currently being evaluated in more than a dozen studies including a phase II study of combination therapy with the experimental spleen tyrosine kinase inhibitor GS-9973 in a variety of relapsed or refractory hematologic malignancies.

Dr. Furman reported research funding from and board of directors or advisory committee membership with Gilead Sciences, which is developing idelalisib.

pwendling@frontlinemedcom.com

NEW ORLEANS – Available medications to treat CML are giving rise to new questions. For instance, why do some patients respond to some medications better than others? How can side effects best be managed? And how can treatment be stopped safely?

In an exclusive interview at the American Society of Hematology's annual meeting, Dr. Richard E. Clark of Royal Liverpool University Hospital, Liverpool, United Kingdom, provides an overview of the field and its future.

NEW ORLEANS – Available medications to treat CML are giving rise to new questions. For instance, why do some patients respond to some medications better than others? How can side effects best be managed? And how can treatment be stopped safely?

In an exclusive interview at the American Society of Hematology's annual meeting, Dr. Richard E. Clark of Royal Liverpool University Hospital, Liverpool, United Kingdom, provides an overview of the field and its future.

NEW ORLEANS – Available medications to treat CML are giving rise to new questions. For instance, why do some patients respond to some medications better than others? How can side effects best be managed? And how can treatment be stopped safely?

In an exclusive interview at the American Society of Hematology's annual meeting, Dr. Richard E. Clark of Royal Liverpool University Hospital, Liverpool, United Kingdom, provides an overview of the field and its future.

The American Society of Hematology introduced its Choosing Wisely list during its annual meeting in New Orleans, highlighting five hematologic tests and treatments that physician should question.

The list was published earlier this month in the Blood journal.

“The initiative is about encouraging hematologists to stop for a moment, take a step back, and reconsider some of the tests and procedures we order, and see if they are necessary,” said Dr. Lisa Hicks, chair of the ASH Choosing Wisely Task Force. It’s also about starting conversations about cost, quality and value, said Dr. Hicks.

In a video interview, Dr. Hicks reviews the list and discusses the implications.

The real challenge, the authors wrote in the Blood journal, is determining whether the Choosing Wisely campaigns contributed to positive change in patient care. Dr. Hicks and colleagues said that the society is working on developing toolkits and metrics to measure the impact.

Choosing Wisely is a campaign led by the ABIM Foundation in collaboration with leading medical societies. Several societies have released their lists during the past two years.

You can download ASH’s list here.

The American Society of Hematology introduced its Choosing Wisely list during its annual meeting in New Orleans, highlighting five hematologic tests and treatments that physician should question.

The list was published earlier this month in the Blood journal.

“The initiative is about encouraging hematologists to stop for a moment, take a step back, and reconsider some of the tests and procedures we order, and see if they are necessary,” said Dr. Lisa Hicks, chair of the ASH Choosing Wisely Task Force. It’s also about starting conversations about cost, quality and value, said Dr. Hicks.

In a video interview, Dr. Hicks reviews the list and discusses the implications.

The real challenge, the authors wrote in the Blood journal, is determining whether the Choosing Wisely campaigns contributed to positive change in patient care. Dr. Hicks and colleagues said that the society is working on developing toolkits and metrics to measure the impact.

Choosing Wisely is a campaign led by the ABIM Foundation in collaboration with leading medical societies. Several societies have released their lists during the past two years.

You can download ASH’s list here.

The American Society of Hematology introduced its Choosing Wisely list during its annual meeting in New Orleans, highlighting five hematologic tests and treatments that physician should question.

The list was published earlier this month in the Blood journal.

“The initiative is about encouraging hematologists to stop for a moment, take a step back, and reconsider some of the tests and procedures we order, and see if they are necessary,” said Dr. Lisa Hicks, chair of the ASH Choosing Wisely Task Force. It’s also about starting conversations about cost, quality and value, said Dr. Hicks.

In a video interview, Dr. Hicks reviews the list and discusses the implications.

The real challenge, the authors wrote in the Blood journal, is determining whether the Choosing Wisely campaigns contributed to positive change in patient care. Dr. Hicks and colleagues said that the society is working on developing toolkits and metrics to measure the impact.

Choosing Wisely is a campaign led by the ABIM Foundation in collaboration with leading medical societies. Several societies have released their lists during the past two years.

You can download ASH’s list here.

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.