Elderly AML patients respond to first-line azacitidine

MILAN – The phase III AML-001 study of azacitidine failed to achieve its primary overall survival endpoint in elderly patients with newly diagnosed acute myeloid leukemia and more than 30% bone marrow blasts, but the drug did provide a clinically meaningful 4-month improvement in median survival from 6.5 months with conventional regimens to 10.4 months, according to Dr. Hervé Dombret.

The hazard ratio was 0.84 in unstratified analysis (P = .0829) and 0.85 after stratification by ECOG performance status and cytogenetic risk (P = .1009).

The lack of statistical significance likely came from a convergence of the survival curves at approximately 2 years, suggested Dr. Dombret of Hôpital Saint Louis, Paris.

At 1 year, survival was 46.5% with azacitidine vs. 34.2% with conventional care regimens (95% confidence interval, 3.5%-21%).

Further, a preplanned sensitivity analysis that censored for subsequent acute myeloid leukemia (AML) treatment demonstrated a statistically significant overall survival benefit for azacitidine (median, 12.1 months vs. 6.9 months; HR, 0.75; P = .0147, unstratified; HR, 0.76; P = .0190, stratified), Dr. Dombret said in a late-breaking abstract session at the annual congress of the European Hematology Association.

In an earlier phase III study, azacitidine (Vidaza) showed a significant survival advantage over conventional care regimens in older AML patients with low blast counts of 20%-30% (J. Clin. Oncol. 2010;28:562-9).

Older AML patients have a poor prognosis and a median overall survival of only about 2-8 months. Therapeutic options include best supportive care, intensive chemotherapy, and low-dose cytarabine, but intensive chemotherapy is not suitable for many because of high toxicity, especially in those with significant comorbidity and adverse risk factors, Dr. Dombret said.

The 488 patients, aged 65 years and older, enrolled in the AML-001 study had a median age of 75 years (range, 64-91 years), a third had poor-risk cytogenetics, and a third had myelodysplasia-related changes present at baseline. The median bone marrow blasts was 70% in azacitidine-treated patients and 74% in those given conventional care.

Prior to randomization, investigators preselected patients for one of three conventional care regimens: best supportive care (BSC) only until study end (n = 89), low-dose cytarabine (LDAC) 20 mg twice daily for 10 days in 28-day cycles plus BSC until disease progression or unacceptable toxicity (n = 312), or intensive chemotherapy with cytarabine 100-200 mg/m² continuous IV infusion for 7 days plus anthracycline IV for 3 days (induction with up to two consolidation cycles) plus BSC (n = 87).

The patients were then evenly randomized to remain on their assigned conventional care regimen or to receive azacitidine 75 mg/m² subcutaneous daily for 7 days every 28 days plus BSC, ideally for at least six cycles.

The median exposure to randomized treatment was six cycles of azacitidine, 65 days of BSC, four cycles of LDAC, and two cycles of intensive chemotherapy.

The overall survival benefit with azacitidine was obtained despite similar response rates and response duration in the conventional arms, Dr. Dombret said. Data were not presented, but overall survival was similar for the three conventional regimens, he said.

Azacitidine had an effect on overall survival among all patients; nevertheless, lower hazard ratios were observed for younger patients aged less than 75 years, females, and importantly, patients with AML with myelodysplasia-related changes and those with poor-risk cytogenetics, Dr. Dombret said.

He urged caution in interpreting the subgroup analysis, but said the lower hazard ratios for poor-risk cytogenetic patients were "a really interesting clinical observation."

The safety profile was consistent with that previously observed with azacitidine. Grade 3/4 hematologic adverse events in the azacitidine group were anemia in 16%, neutropenia in 26%, febrile neutropenia in 28%, and thrombocytopenia in 24%. These findings compare with rates of 5%, 5%, 28%, and 5% in the BSC-only group; 23%, 25%, 30%, and 28% in the LDAC group; and 14%, 33%, 31%, and 21% in the intensive chemotherapy group, Dr. Dombret reported.

Celgene, maker of azacitidine, is currently recruiting patients for a phase III study evaluating azacitidine plus BSC as maintenance therapy in patients, aged 55 years or older, with AML in complete remission.

Dr. Dombret reported consulting for and honoraria from the study sponsor, Celgene. Several coauthors also reported financial ties, including employment, with Celgene.

[email protected]

MILAN – The phase III AML-001 study of azacitidine failed to achieve its primary overall survival endpoint in elderly patients with newly diagnosed acute myeloid leukemia and more than 30% bone marrow blasts, but the drug did provide a clinically meaningful 4-month improvement in median survival from 6.5 months with conventional regimens to 10.4 months, according to Dr. Hervé Dombret.

The hazard ratio was 0.84 in unstratified analysis (P = .0829) and 0.85 after stratification by ECOG performance status and cytogenetic risk (P = .1009).

The lack of statistical significance likely came from a convergence of the survival curves at approximately 2 years, suggested Dr. Dombret of Hôpital Saint Louis, Paris.

At 1 year, survival was 46.5% with azacitidine vs. 34.2% with conventional care regimens (95% confidence interval, 3.5%-21%).

Further, a preplanned sensitivity analysis that censored for subsequent acute myeloid leukemia (AML) treatment demonstrated a statistically significant overall survival benefit for azacitidine (median, 12.1 months vs. 6.9 months; HR, 0.75; P = .0147, unstratified; HR, 0.76; P = .0190, stratified), Dr. Dombret said in a late-breaking abstract session at the annual congress of the European Hematology Association.

In an earlier phase III study, azacitidine (Vidaza) showed a significant survival advantage over conventional care regimens in older AML patients with low blast counts of 20%-30% (J. Clin. Oncol. 2010;28:562-9).

Older AML patients have a poor prognosis and a median overall survival of only about 2-8 months. Therapeutic options include best supportive care, intensive chemotherapy, and low-dose cytarabine, but intensive chemotherapy is not suitable for many because of high toxicity, especially in those with significant comorbidity and adverse risk factors, Dr. Dombret said.

The 488 patients, aged 65 years and older, enrolled in the AML-001 study had a median age of 75 years (range, 64-91 years), a third had poor-risk cytogenetics, and a third had myelodysplasia-related changes present at baseline. The median bone marrow blasts was 70% in azacitidine-treated patients and 74% in those given conventional care.

Prior to randomization, investigators preselected patients for one of three conventional care regimens: best supportive care (BSC) only until study end (n = 89), low-dose cytarabine (LDAC) 20 mg twice daily for 10 days in 28-day cycles plus BSC until disease progression or unacceptable toxicity (n = 312), or intensive chemotherapy with cytarabine 100-200 mg/m² continuous IV infusion for 7 days plus anthracycline IV for 3 days (induction with up to two consolidation cycles) plus BSC (n = 87).

The patients were then evenly randomized to remain on their assigned conventional care regimen or to receive azacitidine 75 mg/m² subcutaneous daily for 7 days every 28 days plus BSC, ideally for at least six cycles.

The median exposure to randomized treatment was six cycles of azacitidine, 65 days of BSC, four cycles of LDAC, and two cycles of intensive chemotherapy.

The overall survival benefit with azacitidine was obtained despite similar response rates and response duration in the conventional arms, Dr. Dombret said. Data were not presented, but overall survival was similar for the three conventional regimens, he said.

Azacitidine had an effect on overall survival among all patients; nevertheless, lower hazard ratios were observed for younger patients aged less than 75 years, females, and importantly, patients with AML with myelodysplasia-related changes and those with poor-risk cytogenetics, Dr. Dombret said.

He urged caution in interpreting the subgroup analysis, but said the lower hazard ratios for poor-risk cytogenetic patients were "a really interesting clinical observation."

The safety profile was consistent with that previously observed with azacitidine. Grade 3/4 hematologic adverse events in the azacitidine group were anemia in 16%, neutropenia in 26%, febrile neutropenia in 28%, and thrombocytopenia in 24%. These findings compare with rates of 5%, 5%, 28%, and 5% in the BSC-only group; 23%, 25%, 30%, and 28% in the LDAC group; and 14%, 33%, 31%, and 21% in the intensive chemotherapy group, Dr. Dombret reported.

Celgene, maker of azacitidine, is currently recruiting patients for a phase III study evaluating azacitidine plus BSC as maintenance therapy in patients, aged 55 years or older, with AML in complete remission.

Dr. Dombret reported consulting for and honoraria from the study sponsor, Celgene. Several coauthors also reported financial ties, including employment, with Celgene.

[email protected]

MILAN – The phase III AML-001 study of azacitidine failed to achieve its primary overall survival endpoint in elderly patients with newly diagnosed acute myeloid leukemia and more than 30% bone marrow blasts, but the drug did provide a clinically meaningful 4-month improvement in median survival from 6.5 months with conventional regimens to 10.4 months, according to Dr. Hervé Dombret.

The hazard ratio was 0.84 in unstratified analysis (P = .0829) and 0.85 after stratification by ECOG performance status and cytogenetic risk (P = .1009).

The lack of statistical significance likely came from a convergence of the survival curves at approximately 2 years, suggested Dr. Dombret of Hôpital Saint Louis, Paris.

At 1 year, survival was 46.5% with azacitidine vs. 34.2% with conventional care regimens (95% confidence interval, 3.5%-21%).

Further, a preplanned sensitivity analysis that censored for subsequent acute myeloid leukemia (AML) treatment demonstrated a statistically significant overall survival benefit for azacitidine (median, 12.1 months vs. 6.9 months; HR, 0.75; P = .0147, unstratified; HR, 0.76; P = .0190, stratified), Dr. Dombret said in a late-breaking abstract session at the annual congress of the European Hematology Association.

In an earlier phase III study, azacitidine (Vidaza) showed a significant survival advantage over conventional care regimens in older AML patients with low blast counts of 20%-30% (J. Clin. Oncol. 2010;28:562-9).

Older AML patients have a poor prognosis and a median overall survival of only about 2-8 months. Therapeutic options include best supportive care, intensive chemotherapy, and low-dose cytarabine, but intensive chemotherapy is not suitable for many because of high toxicity, especially in those with significant comorbidity and adverse risk factors, Dr. Dombret said.

The 488 patients, aged 65 years and older, enrolled in the AML-001 study had a median age of 75 years (range, 64-91 years), a third had poor-risk cytogenetics, and a third had myelodysplasia-related changes present at baseline. The median bone marrow blasts was 70% in azacitidine-treated patients and 74% in those given conventional care.

Prior to randomization, investigators preselected patients for one of three conventional care regimens: best supportive care (BSC) only until study end (n = 89), low-dose cytarabine (LDAC) 20 mg twice daily for 10 days in 28-day cycles plus BSC until disease progression or unacceptable toxicity (n = 312), or intensive chemotherapy with cytarabine 100-200 mg/m² continuous IV infusion for 7 days plus anthracycline IV for 3 days (induction with up to two consolidation cycles) plus BSC (n = 87).

The patients were then evenly randomized to remain on their assigned conventional care regimen or to receive azacitidine 75 mg/m² subcutaneous daily for 7 days every 28 days plus BSC, ideally for at least six cycles.

The median exposure to randomized treatment was six cycles of azacitidine, 65 days of BSC, four cycles of LDAC, and two cycles of intensive chemotherapy.

The overall survival benefit with azacitidine was obtained despite similar response rates and response duration in the conventional arms, Dr. Dombret said. Data were not presented, but overall survival was similar for the three conventional regimens, he said.

Azacitidine had an effect on overall survival among all patients; nevertheless, lower hazard ratios were observed for younger patients aged less than 75 years, females, and importantly, patients with AML with myelodysplasia-related changes and those with poor-risk cytogenetics, Dr. Dombret said.

He urged caution in interpreting the subgroup analysis, but said the lower hazard ratios for poor-risk cytogenetic patients were "a really interesting clinical observation."

The safety profile was consistent with that previously observed with azacitidine. Grade 3/4 hematologic adverse events in the azacitidine group were anemia in 16%, neutropenia in 26%, febrile neutropenia in 28%, and thrombocytopenia in 24%. These findings compare with rates of 5%, 5%, 28%, and 5% in the BSC-only group; 23%, 25%, 30%, and 28% in the LDAC group; and 14%, 33%, 31%, and 21% in the intensive chemotherapy group, Dr. Dombret reported.

Celgene, maker of azacitidine, is currently recruiting patients for a phase III study evaluating azacitidine plus BSC as maintenance therapy in patients, aged 55 years or older, with AML in complete remission.

Dr. Dombret reported consulting for and honoraria from the study sponsor, Celgene. Several coauthors also reported financial ties, including employment, with Celgene.

[email protected]