Leukemia (2005) 19, 2101–2116 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000 Y Ravindranath1, M Chang2, CP Steuber3, D Becton4, G Dahl5, C Civin6, B Camitta7, A Carroll8, SC Raimondi9 and HJ Weinstein10, for the Pediatric Oncology Group 1Department of Pediatrics, Children’s Hospital of Michigan and Wayne State University, Detroit, MI, USA; 2Department of Statistics, University of Florida, Gainesville, FL, USA; 3Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; 4Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 5Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; 6Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 7Department of Pediatrics, Midwest Children’s Hospital and Medical College of Wisconsin, Milwaukee, WI, USA; 8Department of Genetics, University of Alabama, Birmingham, AL, USA; 9Department of Pathology, St Jude Children’s Hospital, Memphis, TN, USA; and 10Division of Pediatric Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA From 1981 to 2000, a total of 1823 children with acute myeloid Introduction leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the The general focus of the Pediatric Oncology Group (POG) induction rate associated with the 3 þ 7 þ 7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than acute myeloid leukemia (AML) studies was to explore the that associated with an induction regimen used to treat acute use of cytarabine dose intensification in the treatment for lymphoblastic leukemia (82 vs 61%; P ¼ 0.02). Designed as a childhood AML. In this paper, we review four successive POG pilot study to determine the feasibility of administration of AML studies in which a stepwise dose intensification of noncross-resistant drug pairs and later modified to assess the cytarabine was introduced along with anthracyclines. During effect of dose intensification of Ara-C during the second these studies, we also evaluated the role of autologous and induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of allogeneic bone marrow transplantation (BMT) in first remission Ara-C during the second induction course resulted in a trend in the treatment of childhood AML. Further centralized, toward higher event-free survival (EFS) estimates than did morphology review immunophenotyping and cytogenetic standard-dose DAT (2 þ 5) during the second induction course evaluation was incorporated in successive, thus allowing for (5 year EFS estimates, 22 vs 27%; P ¼ 0.33). Age o2 years and evaluation of prognostic features in large cohorts of childhood leukocyte count o100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the AML cases. POG 8498 study was the markedly superior outcome of children Since 1981, four consecutive AML trials have been perfor- with Down’s syndrome who were treated on the high-dose Ara-C med by the POG. Table 1 gives an overview of the number regimen. POG 8821 compared the efficacy of autologous bone of centers involved in three of the four trials, the average marrow transplantation (BMT) with that of intensive consolida- numbers of patients, and the distribution of patients by age at tion chemotherapy. Intent-to-treat analysis revealed similar 5- diagnosis. year EFS estimates for the group that underwent autologous BMT (3674.7%) and for the group that received only intensive Before 1981, patients with AML were treated with regimens chemotherapy (3574.5%) (P ¼ 0.25). There was a high rate of similar to those used to treat childhood acute lymphoblastic treatment-related mortality in the autologous transplantation leukemia (ALL), and the results of the AML treatment were group. The study demonstrated superior results of allogeneic relatively poor. Clinical trials of more intensive regimens BMT for patients with histocompatible related donors (5-year consisting of cytarabine (Ara-C) and anthracycline started with 7 EFS estimate 63 5.4%) and of children with Down’s syndrome the POG 8101 study.1–3 In POG 8101 patients were randomly (5-year EFS estimate, 6678.6%). The POG 9421 AML study þ þ evaluated high-dose Ara-C as part of the first induction course assigned to receive either the 3 7 7 regimen of DAT and the use of the multidrug resistance modulator cyclosporine. (daunorubicin, Ara-C, and 6-thioguinine) or a regimen that Preliminary results showed that patients receiving both high- had been used to treat ALL and included vincristine, dexa- dose Ara-C for remission induction and the MDR modulator for methasone, and Ara-C. The therapy given after remission consolidation had a superior outcome (5-year EFS estimate, induction included a long maintenance phase given over 7 42 8.2%) than did patients receiving other treatment; however, 2 years. the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of The POG 8498 pilot study evaluated the efficacy and toxicity Ara-C in the treatment of childhood AML; cytogenetics as the of high-dose Ara-C given both as a second induction course after single most prognostic factor and the unique curability of AML DAT and as consolidation therapy immediately after the in children with Down’s syndrome. completion of remission induction therapy. Multiagent che- Leukemia (2005) 19, 2101–2116. doi:10.1038/sj.leu.2403927; motherapy after remission induction was modeled after the published online 1 September 2005 VAPA regimen of Weinstein et al.4 The results clearly confirmed Keywords: AML; childhood; treatment; bone marrow the efficacy of the DAT regimen as part of initial induction transplantation; daunorubicin dosing; high-dose cytarabine therapy and established a toxicity profile for high-dose Ara-C in childhood AML.4 In addition, the immunophenotypic charac- Correspondence: Dr Y Ravindranath, Georgie Ginopolis Chair for teristics of childhood AML were analyzed in detail.5 Finally, the Pediatric Cancer and Hematology, Wayne State University School of superior outcome of children with Down’s syndrome treated on Medicine, Children’s Hospital of Michigan-2M34, 3901 Beaubien high-dose Ara-C-containing regimens was first recognized.6 Boulevard, Detroit, MI 48201, USA; Fax: þ 313 745 5237; E-mail: [email protected] POG 8821 compared the efficacy of autologous BMT during Received 8 February 2005; accepted 14 April 2005; published online early remission with that of intensive chemotherapy alone. 1 September 2005 Patients with matched family donors were eligible to proceed Pediatric Oncology Group studies of acute myeloid leukemia Y Ravindranath et al 2102 Table 1 Accrual and follow-up of all patients Trial Period of No. of patients/No. of eligible No. of participating Average no. of patients Average No. of patients accrual patients/No. of eligible patients centers without DS enrolled at each without DS enrolled except those with DS center (range) each year 8101 7/81–1/86 267/264/257 52 4.9 (1–21) 57 8498 7/84–7/88 294/288/274 56 4.9 (1–21) 68 8821 6/88–3/93 666/649/615 88 7.0 (1–22) 130 to allogeneic BMT.7 The outcome of patients who underwent a POG AML protocols- Treatment Schemas autologous BMT as given in this study was not superior to that of Ara-C/TG patients who received only intensive chemotherapy.7 8101-II DAT (3+7)* DAT (2+5) TG/Ara-C/AZ DA The POG 9421 study compared the results of treatment using standard-dose DAT as a first induction course with 8498- I DAT (3+7)* DAT (2+5) HdA+L-Asp (4courses) those of treatment using high-dose Ara-C (1 g/m2 per dose; total, 14 doses), daunorubicin (45 mg/m2 daily for 3 days), and 8498- II DAT (3+7)* HdA HdA X 1 course 6-thioguanine (for 7 days) given as a first induction course. The 6 6 safety and efficacy of an MDR modulator administered during intensification therapy was also investigated. Preliminary results Vp/AZ*- 4 courses of this trial are presented in this paper. POMP*- 4 courses Patients and methods Ara-C Daily x5- 4 courses D = Daunorubicin; A and Ara-C = cytarabine; T, TG = Thioguanine ; AZ = Azacytidine; POMP = Eligibility Mercaptopurine, Oncovin (vincristine), Methotrexate, Prednisolone The main entry criteria of studies 8101, 8498, and 8821 were b Chemotherapy vs ABMT for Childhood AML: POG 8821 age p21 years and previously untreated AML (patients with Treatment Schema secondary AML were eligible if the treatment was for another DAT* type of malignancy); patients with an isolated chloroma were eligible. Patients with myelodysplastic syndrome were not HdA6 eligible, and starting with the POG 8498 study, data of patients Remission (M1 + M2a <15% blasts) with Down’s syndrome were analyzed separately from those of the other patient groups. Randomize For POG 9421, patients with APL were not eligible, and patients with Down’s syndrome were not eligible for random VP/AZ* VP/AZ* VP/AZ* assignment to the groups that received high-dose DAT or cyclosporine (CsA); instead, patients with Down’s syndrome Chemo ABMT AlloBMT were treated with the standard chemotherapy regimen. Chemo = D+ HdA6 DAT VP/AZHdA6 DAT VP/AZ Diagnosis * = IT ara-c X 2 D = Daunorubicin; A = cytarabine; had = high dose cytarabine ; T = Thioguanine ; AZ = Standard French–American–British (FAB) criteria were used in Azacytidine; ABMT= autologous bone marrow transplantation: AlloBMT = allogeneic BMT. IT = the initial diagnosis of AML and its subtypes. Central pathology intrathecal review occurred in all studies. Diagnosis of M0 and M7 subtypes required confirmation by immunologic methods.