Secondary acute myeloid leukemia (sAML) usually develops within 10 years of treatment for a first cancer, has a poorer prognosis, and is strongly associated with multidrug resistance. Standard treatment involves intensive chemotherapy with cytotoxic agents such as the anthracycline daunorubicin in combination with cytarabine.

The ACCEDE trial compared this sAML treatment with a novel DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organization independently of ATP, Amonafide L-malate (AS1413) from London-based Antisoma. The compound has also demonstrated that it is able to evade P-glycoprotein and related transporters that contribute to multidrug resistance.

“There was hope that Amonafide, in combination with a standard protocol of cytarabine, might be better than the usual combination of drugs used to treat sAML patients, which is daunorubicin plus cytarabine,” said Richard M. Stone, MD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute in Boston.

Stone and colleagues unveiled a poster presentation of their ACCEDE findings at the American Society of Clinical Oncology conference on Friday. In the phase III, multicenter, open-label study, patients aged ≥ 18 years with newly diagnosed sAML were randomized to cytarabine 200 mg/m2 continuous IV infusion daily on days 1—7 plus either AS1413 600 mg/m2 IV over 4 hours daily on days 1–5 (Arm A) or daunorubicin 45 mg/m2 IV over 30 minutes daily on days 1–3 (Arm B), according to the researchers.

“The primary endpoint of the trial was to determine if the complete remission [CR] rate, or the likelihood of a major response, was higher in the group that got the investigative combination drug compared with the group that got the standard treatment combination,” he said in an interview with 

The planned sample size of 420 patients provided 89% power to detect a 15% difference at the 

=0.05 level (two-tailed) between anticipated CR rates, they noted. The researchers reported that 564 sAML patients were screened and 433 were randomized; 216 to arm A and 217 to arm B. In addition, disease etiology, cytogenetics, and age were balanced among both arms.

“Sadly, there was no improvement in the CR rate of the patients who were randomized to Arm A, compared with those who were randomized to Arm B,” Stone observed. “Actually, the newer regimen did as well as expected, but the older regimen did better than expected.”

The researchers wrote that CR + CR with incomplete blood count recovery was 94/216 (43.5%) in Arm A and 94/217 in Arm B (43.3%) with a 

 value of 0.966. Also, 30-day mortality was 20.4% in arm A and 12.4% in arm B. Serious adverse events were balanced between the two arms, they noted, and no event occurred in more than 6% of patients in either arm.

Although conventional sAML treatment performed better than expected in the ACCEDE trial, it is still not very good, according to Stone.

“We still need better therapies for patients with this type of intrinsically resistant AML,” he stated.

Stone RM, Allen SL, and Pigneux, et al. A phase III, open-label, randomized comparison of AS1413 (amonafide L-malate) plus cytarabine with daunorubicin plus cytarabine in secondary acute myeloid leukemia (ACCEDE). 

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Amonafide+Cytarabine may not be effective for secondary acute myeloid leukemia, according to ACCEDE trial data

Amonafide Plus Cytarabine Fails To Meet Primary Endpoint

Methotrexate has been a go-to treatment for high-risk acute lymphoblastic leukemia (HR-ALL) for more than 60 years, but its full potential is still being mined. Research presented at the Annual Meeting of the American Society of Clinical Oncology on Friday demonstrated that higher doses of this drug delivers superior event free survival (EFS), with no increase in acute toxicity, for children and young adults with the disease.

The drug has enjoyed a long history as a staged treatment, also known as the Capizzi regimen, for children and young adults with HR-ALL, delivering an average 75% EFS to patients, according to Eric C. Larsen, MD, medical director of the Maine Children's Cancer Program at the Barbara Bush Children's Hospital at Maine Medical Center in Portland.

Larsen and colleagues in the Children's Oncology Group (COG) Study AALL02332 conducted a randomized trial that delivered higher doses of methotrexate (approximately 50 times the initial dose of conventional treatment) to 1209 HR-ALL patients in one study arm. They compared this with the standard method, Capizzi escalating methotrexate plus PEG asparaginase, in the other study arm (1217 patients) of the trial.

The protocol, which began in 2004, was closed early (January 2011) due to positive results of the investigative therapy in 5-year interim monitoring.

“Planned interim analysis demonstrated that the high-dose methotrexate treatment was clearly superior to the standard Capizzi methotrexate treatment,” stated Larsen.

He reported that the 5-year EFS rates were 82% for the high-dose methotrexate treatment, compared with 75.4% for the Capizzi treatment. Patients in the Capizzi arm were offered the high-dose treatment at protocol close, Larsen noted.

There were fewer marrow and CNS relapses in the high-dose versus Capizzi arms (42 and 22 vs 68 and 32), he said. In addition, the incidence of febrile neutropenia was lower with high-dose methotrexate compared with the Capizzi treatment; 5.2% vs 8.2%, respectively, with a 

“Pediatric oncologists have recognized that to get optimal results in treating cancer, you have to optimize the way cancer treatment is given,” commented Richard Schilsky, MD, of the University of Chicago Pritzker School of Medicine, who moderated the press conference at which the COG study was presented. “Many of the major results in pediatric oncology, including this one, have really come without introducing any new drugs at all; they've come from optimizing the way available therapies are used.”

Larsen EC, Salzer WL, Devidas M, et al. Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. 

High doses of methotrexate increases EFS for children and young adults

By Jonathan S. Batchelor

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Amonafide Plus Cytarabine Fails To Meet Primary Endpoint

High-Dose Methotrexate Better for ALL