Resurrected gemtuzumab shows benefit against pediatric AML

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute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The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete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.