This protocol has been superseded due to the availability of superior alternatives. The preferred regimen is ID 4285 Acute myeloid leukaemia consolidation cytarabine (age under 60 years) or ID 4354 Acute myeloid leukaemia consolidation cytarabine (age 60 years and over).
Consolidation chemotherapy post-induction has been proven to increase the duration of remission in patients with Acute Myeloid Leukaemia (AML). Cytarabine at higher doses has been suggested to improve the efficacy of the drug despite reaching intracellular saturation point at 0.5-1 g/m2.r
The evidence supporting this protocol is provided by a phase 3 multicentre randomised trial. For this study 1088 adults with newly diagnosed de novo AML were analysed. Of these, 596 patients achieved morphological remission (less than 5% blasts on bone marrow) with no central nervous system (CNS) involvement after induction with daunorubicin and cytarabine. These 596 patients in remission were randomised to receive four cycles of cytarabine at 100 mg/m2 per day for 5 days (203 patients), 400 mg/m2 per day for 5 days (206 patients) and 3 g/m2 every 12 hours on days 1, 3 and 5 (187 patients).r
The primary endpoints were overall and disease free survival and secondary endpoints were tolerance and toxicity of post-remission cytarabine. The trial demonstrated that patients aged 60 years and younger who received high-dose cytarabine were more likely to remain in remission and survive longer compared to lower doses of cytarabine, with disease-free survival (DFS) of 24% (100 mg/m2 group), 29% (400 mg/m2 group) and 44% (3 g/m2 group), p=0.002.r
Another study by Bloomfield et al. found that the benefit was most marked for core-binding factor (CBF) positive patients with 5 year survival of 78% compared to 16% in conventional dose arm and to a lesser extent normal karyotype patients with 5 year survival of 40% compared to 20% in conventional dose arm. There was no benefit seen in the abnormal karyotype group with 5 year survival of 21% as compared to 13% in conventional dose arm.r
A subsequent Cancer and Leukaemia Group B (CALGB) study (CALGB 9222) did not demonstrate improvement in outcome with sequential multiagent chemotherapy (which included 1 cycle of HiDAC) with median DFS survival 1 year, 5 year DFS 30% and 5 year overall survival (OS) 46% as post-remission therapy compared to HiDAC (6 doses) x 3 cycles with median DFS 1.1 years, 5 year DFS 35% and 5 year OS 44%.r
An intergroup study comparing post-remission therapy with HiDAC x 12 doses in a single course versus autologous stem cell transplant versus allogeneic stem cell transplant demonstrated better OS at 4 years and median survival in the chemotherapy arm of 52% and 60 months respectively compared to allogeneic transplant (46% and 35 months) and autologous transplant arms (43% and 27 months) despite more relapses in the chemotherapy arm.r
Efficacy
In the Mayer study, after a follow up of 4 years, the probability of survival was 31% in the 100 mg/m2 group (CI 95%; 24% to 37%), 35% for the 400 mg/m2 group (CI 95%; 27% to 42%) and 46% in the 3 g/m2 group (CI 95%; 38% to 53%) (p=0.04). For patients aged 60 years and younger the probability of survival after 4 years was 35% in the 100 mg/m2 group (CI 95%; 27% to 43%), 40% for the 400 mg/m2 group (CI 95%; 32% to 49%) and 52% in the 3 g/m2 group (CI 95%; 44% to 60%) (p=0.02).r
Figure 1: Probability of survival according to dose of cytarabine.r
© New England Journal of Medicine 1994
After a follow-up of 4 years, the probability of disease-free survival (DFS) was 21% in the 100 mg/m2 group (CI 95%; 15% to 26%), 25% for the 400 mg/m2 group (CI 95%; 19% to 32%) and 39% in the 3 g/m2 group (CI 95%; 32% to 46%) (p=0.003). This was statistically significant in the below 60 year group (P=0.002) but not in the over 60 year group (P=0.19).r
Figure 2: Probability of DFS in all patients. r
© New England Journal of Medicine 1994
Quality of Life data was not assessed in this study.
Toxicity
High-dose cytarabine chemotherapy was much more poorly tolerated compared to the lower doses in the above 60 years of age group. The proportion of patients requiring hospitalisation for fever, neutropenia and platelet transfusion was significantly higher with an increased dose of cytarabine. Serious CNS toxicity was reported only in the high-dose cytarabine arm and was found to be more common in the above 60 age group (32%). Permanent neurological disability was noted in 40% of patients affected by CNS toxicity. Treatment related deaths were higher in the 400 mg/m2 and 3 g/m2 (6% and 5% respectively). Transient rise in hepatic enzymes (aminotransferase) was noted.rrr
Table 1: Tolerance and toxicity of post-remission cytarabine.r
© New England Journal of Medicine 1994