Despite second remission induction in over one-half of children with acute myeloid leukemia (AML) treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[1,2] Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis. The vast majority of relapses occur in the bone marrow, with central nervous system (CNS) relapse being very uncommon. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of remission than children whose first remission is greater than 1 year (50%-60% vs. 70%-90%, respectively).[2,3,4] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[2,3,4,5]
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with other agents, such as mitoxantrone, fludarabine and idarubicin,[6,7,8], L-asparaginase, etoposide, and clofarabine and etoposide. Regimens built upon clofarabine have also been used;[10,11,12][Level of evidence: 2Div] as have regimens of 2-chloroadenosine. The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council AML 10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.
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In a report of 379 children with AML who relapsed after initial treatment on the German Berlin-Frankfurt-Münster (BFM) group protocols, a second complete remission rate was 63% and overall survival (OS) was 23%.[Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)). A subsequent study by the BFM group compared fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) with FLAG plus liposomal daunorubicin. Four-year OS was 38%, with no difference in survival for the total group; however, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core binding factor mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[Level of evidence: 1iiA] The Therapeutic Advances in Childhood Leukemia and Lymphoma Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration and 19% ± 6% for patients with shorter periods of first remission. A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who went to hematopoietic stem cell transplantation (HSCT) after achieving a second complete remission (66%) than in patients not in remission (17%).