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© 2002 American Society for Clinical Oncology Interim Comparison of a Continuous Infusion Versus a Short Daily Infusion of Cytarabine Given in Combination With Cladribine for Pediatric Acute Myeloid LeukemiaByFrom the Departments of Pharmaceutical Sciences, Biostatistics, Hematology-Oncology, and Pathology, St Jude Children’s Research Hospital, Memphis, TN, and Departments of Experimental Therapeutics and Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Kristine R. Crews, Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; email: kristine.crews{at}stjude.org
PURPOSE: To identify the optimal schedule for infusion of cytarabine (ara-C) given with cladribine (2-CdA) to pediatric patients with acute myeloid leukemia (AML), and to compare the effects of the two schedules on the pharmacokinetics of ara-C triphosphate (ara-CTP) in leukemic cells. PATIENTS AND METHODS: Forty-nine pediatric patients with newly diagnosed primary AML received a 5-day course of ara-C 500 mg/m2/d and 2-CdA 9 mg/m2/d. They were randomly assigned to receive ara-C as either a 2-hour daily infusion (arm A) or a continuous infusion (arm B). Cellular pharmacokinetics were studied on days 1 and 2. All patients then received two courses of remission induction chemotherapy with daunorubicin, ara-C, and etoposide (DAV). RESULTS: Thirty-two percent of patients (seven of 22) in arm A and 63% (17 of 27) in arm B entered complete remission (P = .045) after ara-C and 2-CdA therapy. Coadministration of 2-CdA increased the intracellular concentration of ara-CTP in 20 of 36 patients, although we found no statistically significant difference between the treatment arms in this effect (P = .63). The incidence of toxicity did not differ significantly between the two treatment arms (P = .53). After two courses of DAV, the rate of complete remission was 91% in arm A and 96% in arm B (P = .58). CONCLUSION: Intracellular accumulation of ara-CTP is increased when 2-CdA is given with ara-C, but no schedule-dependent differences in this effect were seen. The combination of 2-CdA and ara-C seems to be effective therapy for pediatric AML.
THE LONG-TERM prognosis of children and adolescents with acute myeloid leukemia (AML) remains poor.1-4 Despite the dose intensification of therapy with available agents and the use of hematopoietic stem-cell transplantation, only approximately half of the children with AML now experience long-term disease-free survival.5-7 An alternative strategy to dose intensification may be the rational combination of active chemotherapy agents to enhance their efficacy. Cytarabine (ara-C) is one of the most effective agents for the treatment of AML. Ara-C is converted to its active form, ara-C 5'-triphosphate (ara-CTP), by a series of intracellular enzyme-dependent phosphorylation steps. The first of these, which is mediated by deoxycytidine (dCyd) kinase, is rate limiting. The activity of dCyd kinase is inhibited by the product dCyd triphosphate through a feedback mechanism.8 Biochemical modulation of ara-CTP metabolism has been shown to be feasible in clinical studies of adult AML9 and pediatric acute leukemias.10 These studies were based on the results of in vitro investigations in leukemic cell lines,11 ex vivo observations in primary leukemic cells,12 and in vivo results in patients with chronic lymphocytic leukemia13 or AML.9 In these studies, fludarabine was used to modulate the metabolism of ara-CTP. Addition of fludarabine increased the accumulation of ara-CTP in the circulating blast cells in both adult AML9 and pediatric AML.10 Although not studied as extensively as ara-C, cladribine (2-CdA) has shown efficacy against pediatric acute leukemias, especially French-American-British M5 AML, when given as a single agent.4,14,15 In one study of 17 pediatric patients with relapsed AML,14 2-CdA as a single agent induced complete hematologic remission in eight patients (47%); in four of these patients, remission occurred after only one course. Because of these favorable responses, 2-CdA was given before daunorubicin, ara-C, and etoposide (DAV) remission induction therapy in the St Jude AML-91 protocol. Overall, 57 of 72 children (78%) entered complete hematologic remission after 2-CdA therapy plus at least one course of induction therapy.4 Like ara-C, 2-CdA is converted to its triphosphate (2-CdATP) after initial phosphorylation by dCyd kinase. However, unlike ara-CTP, 2-CdATP is an inhibitor of ribonucleotide reductase (as is fludarabine), the enzyme responsible for de novo synthesis of deoxynucleotides. Inhibition of this enzyme is thought to reduce pools of cellular deoxynucleotides, including dCyd triphosphate, thus lessening the feedback inhibition of dCyd kinase. This postulate is supported by the results of in vitro studies showing that intracellular ara-CTP accumulation is increased when 2-CdA is given with ara-C.16 On the basis of these findings, ara-C and 2-CdA were combined in a protocol for relapsed or refractory adult AML; the results showed that 2-CdA increases the intracellular concentration of ara-CTP in vivo.16,17 The two-drug combination seemed to be well tolerated.16 These clinical findings prompted us to design a study for newly diagnosed pediatric AML in which 2-CdA is given with ara-C before DAV remission induction therapy. In this interim analysis, we compared the clinical benefit of two schedules of ara-C administration (a short infusion v a continuous infusion) in a combination regimen with 2-CdA. We also investigated which infusion schedule in this regimen better promotes the intracellular accumulation of ara-CTP.
Patients Between March 1997 and February 2000, 49 children with newly diagnosed, untreated primary AML were enrolled onto the St Jude AML-97 protocol. All patients were  21 years of age and had a serum bilirubin 3 mg/dL and a serum creatinine two times the normal for their age. Patients with all subtypes of AML except acute promyelocytic leukemia with the t(15;17) (PML-RARa fusion) were eligible for enrollment. Patients with AML that expressed lymphoid-associated antigens were eligible for enrollment, but cases of mixed-lineage dimorphic acute leukemia (expressing the lineage-specific markers cCD3 and cCD79a) were excluded. Patients with Down’s syndrome, secondary AML, or myelodysplastic syndrome were excluded from this analysis.
Chemotherapy
After one course of ara-C and 2-CdA, all patients received two courses of DAV remission induction chemotherapy (daunorubicin 30 mg/m2/d given by continuous 72-hour IV infusion days 1 to 3, ara-C 250 mg/m2/d given by continuous 120-hour IV infusion days 1 to 5, and etoposide 200 mg/m2/d given by continuous 48-hour IV infusion days 4 and 5). The study design and pharmacologic investigations were approved by the St Jude Children’s Research Hospital institutional review board. Written informed consent was obtained from patients, parents, or guardians, as appropriate, before enrollment onto the study.
Assessment of Response
Bone Marrow Samples for Pharmacologic Studies
Cellular Pharmacology
Inhibition of DNA Synthesis
Statistical Analysis
Patient Characteristics The median age of the 49 patients at the time of diagnosis was 9.8 years (range, 0.4 to 20.2 years). Table 1 lists their clinical and demographic features by treatment arm. No significant differences were seen between the treatment arms in age, WBC count, or percentage of bone marrow blast cells at the time of diagnosis (all P values  .07). French-American-British subtypes and cytogenetic features were distributed similarly in the two arms.
Clinical Response to Therapy On day 7 of therapy, the circulating blast cells had decreased in 19 (86%) of 22 patients and completely cleared from 18 patients (82%) in arm A. In arm B, the circulating blast cells had decreased in all patients by day 7, and no circulating blast cells were seen in 23 (85%) of 27 patients. The median WBC counts on day 7 were 0.9 x 109/L (range, 0.4 to 3.2 x 109/L) in arm A and 0.9 x 109/L (range, 0.1 to 4.2 x 109/L) in arm B. Bone marrow samples were obtained 15 days after the start of therapy to assess responses (Table 2). A CR was documented in seven (32%) of 22 patients in arm A and in 17 (63%) of 27 patients in arm B after one course of ara-C plus 2-CdA (P = .045). Median bone marrow cellularity decreased from 99% (range, 20% to 100%) at diagnosis to 22% (range, 0% to 100%) on day 15 in arm A and from 100% (range, 12% to 100%) at diagnosis to 10% (range, 0% to 100%) on day 15 in arm B.
Responses were again evaluated after DAV induction therapy. After two courses of DAV, 96% of patients in arm B and 91% of patients in arm A were in CR (P = .58).
Effect of 2-CdA on Accumulation of ara-CTP
Inhibition of DNA Synthesis The DNA synthesis values for days 1 and 2 were expressed as percentages of the DNA synthesis values of cells collected from the respective patients before therapy began. Sufficient numbers of cells were obtained from 35 patients (18 in arm A and 17 in arm B) for this analysis. Figure 2 shows proportional changes in DNA synthesis in bone marrow cells after ara-C alone (day 1) and after ara-C and 2-CdA (day 2), according to treatment arm. In arm A, mean DNA synthesis was inhibited 87% ± 15% on day 1 (after ara-C alone) and 94% ± 7% on day 2 (after ara-C plus 2-CdA) (P = .02). In arm B, mean DNA synthesis was inhibited 76% ± 34% on day 1 and 88% ± 14% on day 2 (P = .08). Inhibition of DNA synthesis did not differ significantly between the treatment arms on day 1 (P = .21) or on day 2 (P = .14).
Toxicity of ara-C and 2-CdA Eighteen episodes of grade 3 or 4 toxicity were reported in 14 patients. The most common grade 3 or 4 toxic effects were febrile neutropenia in five (10%) of 49 patients and infection in five (10%) of 49 patients. The incidence of grade 3 or 4 toxicity was 33% in arm B and 23% in arm A (P = .53). Patients in arm A began DAV induction therapy a median period of 18.5 days (range, 14 to 33 days), and those in arm B began DAV therapy a median period of 24 days (range, 15 to 57 days), after the end of ara-C and 2-CdA therapy (P = .033).
The efficacy of ara-C, one of the most effective agents for the treatment of pediatric AML, is correlated with intracellular exposure to its active form, ara-CTP.20,21 Intracellular exposure to ara-CTP cannot be enhanced simply by increasing the dosage of ara-C because the phosphorylation of ara-C by dCyd kinase, the rate-limiting step in its metabolism, is saturated at plasma concentrations (7 to 10 µmol/L) routinely achieved at intermediate dose rates of ara-C (500 mg/m2 infused over 2 hours).20-23 Therefore, biochemical modulation of the rate-limiting step is a rational alternative strategy to increase the intracellular accumulation of ara-CTP.11,13,24,25 By inhibiting ribonucleotide reductase, 2-CdA reduces the feedback inhibition of deoxycytidine kinase, the enzyme that catalyzes the rate-limiting monophosphorylation. Administration of 2-CdA with ara-C has been shown to increase the rate of ara-CTP accumulation in leukemic cells by 40%.17 The successful biochemical modulation of ara-CTP in AML blast cells and the efficacy of 2-CdA for treating pediatric AML4,14,15,26 provided a compelling rationale for combining the two agents. Although 2-CdA has previously been administered by continuous infusion when given as a single agent14,15,26 or when combined with ara-C,17 pharmacokinetic studies have shown that an intermittent infusion schedule produces a comparable systemic exposure.27,28 This finding may reflect the fact that the 2-CdA nucleotides are retained in leukemic cells for as long as 30 hours.29 In addition, a short infusion schedule has been shown to produce a high peak concentration of 2-CdA29 that may allow 2-CdA to compete favorably with ara-C for phosphorylation. A bolus infusion of the modulator fludarabine has also been shown to increase steady-state ara-CTP concentration in leukemic cells in adults with AML.9 We selected a short infusion schedule of 2-CdA on the basis of these pharmacologic features, which suggested that such a schedule would produce a high peak plasma concentration of 2-CdA. This interim analysis compared two schedules of ara-C administration in a combination regimen with 2-CdA to determine which would result in greater ara-CTP accumulation and greater efficacy. The dosing schedule for arm A (500 mg/m2/d over 2 hours) was selected because at this dose rate (250 mg/m2/h), the plasma concentration is predicted to be more than 10 µmol/L at the end of the infusion. At this plasma concentration, the phosphorylation of ara-C is saturated.23 In a study of ara-C combined with 2-CdA in adults with AML, the rate of intracellular ara-CTP accumulation remained linear throughout a 2-hour ara-C infusion.17 This finding suggested that a longer infusion of ara-C given in combination with 2-CdA might allow increased intracellular accumulation of ara-CTP. For this reason, the dosing schedule for arm B (500 mg/m2/d given as a continuous infusion) was selected to deliver the same cumulative ara-C dose as arm A to test whether a longer infusion of ara-C combined with 2-CdA allows increased accumulation of ara-CTP. We used blast cells from bone marrow aspirates for the intracellular pharmacokinetic studies because in our previous experience, serial sampling of peripheral-blood blast cells was precluded by the rapid cytoreductive effect of ara-C in pediatric patients.30 Additionally, ara-CTP pharmacokinetic profiles are similar in blast cells obtained from peripheral blood and from bone marrow.22 Previous investigations in which single-agent ara-C was infused at 12- and 24-hour intervals demonstrated equivalent ara-CTP accumulation, elimination rates, and area under the concentration-time curve values in AML blast cells on successive days.20,22,23 In contrast, infusion of ara-C alone on the first day and fludarabine before ara-C on the second day increased ara-CTP accumulation by two-fold in AML blast cells.9 These results suggest that comparison of ara-CTP pharmacokinetics on successive days during therapy is a feasible method of evaluating biochemical modulation by agents such as fludarabine or cladribine. To minimize the number of bone marrow procedures, we based our sampling schedule for patients in arm A (short daily infusion) on the pharmacokinetics of ara-CTP in peripheral blast cells in adult patients in which the peak ara-CTP concentrations occurred 2 hours after the start of an ara-C infusion.17 For patients receiving ara-C by continuous infusion, we chose a sampling time of 10 hours after the start of infusion, which allowed an intracellular steady-state concentration of ara-CTP to be reached.31 The day 1 ara-CTP concentration did not differ significantly between patients receiving short daily infusions (in whom the samples were timed to be peak concentrations) and patients receiving continuous infusions (in whom the samples were steady-state concentrations). In this study, administration of ara-C in combination with 2-CdA by short daily infusion and by continuous infusion resulted in comparable increases in intracellular ara-CTP accumulation. This result suggests that the duration of ara-C infusion does not influence the degree to which ara-C is biochemically modulated by 2-CdA. Overall, 56% of patients had a greater intracellular ara-CTP concentration on day 2 after the addition of 2-CdA than on day 1 when ara-C was given alone. There was a rapid decrease in DNA synthesis in patients’ leukemic cells on day 1 of therapy. The addition of 2-CdA to ara-C on day 2 further inhibited DNA synthesis in both treatment arms, demonstrating the efficacy of this combination, although a statistically significant effect was seen only in patients who received short daily infusions of ara-C. The ara-CTP concentrations in arm B were steady-state values expected to be maintained throughout the 5-day ara-C infusion.32 Thus, ara-CTP–mediated inhibition of DNA synthesis should be sustained in patients receiving the continuous infusion.32 In contrast, the values in arm A reflect the peak ara-CTP concentration after each intermittent infusion. These concentrations could be expected to decrease before the next infusion, allowing recovery of DNA synthesis.9 We assessed bone marrow response on day 15 of window therapy because in the AML-Berlin-Frankfurt-Münster 83 and 87 studies, patients who had more than 5% bone marrow blast cells on day 15 of induction therapy had a significantly decreased rate of CR after consolidation and a significantly smaller probability of 5-year event-free survival and disease-free survival than did patients with 5% or fewer blast cells.33 In this interim analysis, patients receiving ara-C as a continuous infusion with 2-CdA (arm B) had a higher rate of CR on day 15 than did patients in arm A. Therefore, a regimen that combines 2-CdA with ara-C given as a continuous infusion may offer a survival benefit over a comparable regimen in which ara-C is given as a short daily infusion, although the rates of CR in the two groups were similar (91% in arm A and 96% in arm B) after the completion of DAV remission induction therapy. Analysis of additional data from this ongoing study is needed to conclusively compare the long-term disease-free survival and overall toxicity of the two treatment arms. The rate of CR observed in arm A after one course of ara-C and 2-CdA (32%) is comparable to that observed in similar groups of patients given 2-CdA as a single agent. For example, Krance et al4 reported a CR rate of 24% after one course of 2-CdA (8.9 mg/m2/d by 120-hour infusion) and 40% after two courses in 72 pediatric patients with primary AML. The initial rate of CR in arm B (63%) was superior to these results. Therefore, a regimen that combines 2-CdA with ara-C given as a continuous infusion may offer a greater benefit than single-agent therapy with 2-CdA. Additional investigation will be needed to substantiate this possibility. The CR rates we observed after ara-C/2-CdA and DAV remission induction therapy (91% in arm A and 96% in arm B) compare favorably with those reported in recent pediatric AML studies. In the St Jude AML-91 study, 2-CdA therapy followed by DAV produced a 78% overall rate of CR.4 In the AML-Berlin-Frankfurt-Münster 93 study, the day 15 proportion of bone marrow blast cells was reduced to less than 5% in 83% of patients who received ara-C, idarubicin, and etoposide induction therapy and in 69% of patients who received ara-C, daunorubicin, and etoposide induction therapy.34 In the United Kingdom’s Medical Research Council’s AML10 trial, the rate of CR was 83% after two courses of remission induction therapy with daunorubicin, ara-C (twice-daily bolus infusion), and either etoposide or thioguanine.5 In conclusion, this interim analysis suggests that combination chemotherapy with ara-C and 2-CdA is effective in the treatment of pediatric AML and that response rates are favorable when this combination is followed by DAV induction therapy. Patients who received a continuous infusion of ara-C had a better rate of response on day 15 than did patients who received short daily infusions of ara-C. The study’s final analysis will compare toxicity, response, and event-free survival in the two treat-ment arms.
Supported in part by grants nos. CA 57629 and CA 21765 from the National Institutes of Health, United States Department of Health and Human Services, and by the American Lebanese Syrian Associated Charities. We thank the following for their expert technical assistance: Feng Bai, Kathryn Brown, YaQin Chu, Cong Ding, Min Du, Leigh Hankins, Suzan Hanna, Markos Leggas, Natasha Lenchik, Geeta Nair, Thandranese Owens, and Miriam de Tamano. We thank Sharon Naron for editorial assistance.
1. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children’s Cancer Group. Blood 87: 4979-4989, 1996
2. Ravindranath Y, Yeager AM, Chang MN, et al: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood: Pediatric Oncology Group. N Engl J Med 334: 1428-1434, 1996 3. Arnaout MK, Radomski KM, Srivastava DK, et al: Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: Short- and long-term effects. Leukemia 14: 1736-1742, 2000[CrossRef][Medline]
4. Krance RA, Hurwitz CA, Head DR, et al: Experience with 2-chlorodeoxyadenosine in previously untreated children with newly diagnosed acute myeloid leukemia and myelodysplastic diseases. J Clin Oncol 19: 2804-2811, 2001 5. Stevens RF, Hann IM, Wheatley K, et al: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: Results of the United Kingdom Medical Research Council’s 10th AML trial—MRC Childhood Leukaemia Working Party. Br J Haematol 101: 130-140, 1998[CrossRef][Medline]
6. Creutzig U, Ritter J, Zimmermann M, et al: Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: Results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 93. J Clin Oncol 19: 2705-2713, 2001
7. Woods WG, Neudorf S, Gold S, et al: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97: 56-62, 2001
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13. Gandhi V, Kemena A, Keating MJ, et al: Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 52: 897-903, 1992
14. Santana VM, Mirro J Jr, Kearns C, et al: 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 10: 364-370, 1992
15. Santana VM, Hurwitz CA, Blakley RL, et al: Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia. Blood 84: 1237-1242, 1994 16. Kornblau SM, Gandhi V, Andreeff HM, et al: Clinical and laboratory studies of 2-chlorodeoxyadenosine +/- cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 10: 1563-1569, 1996[Medline]
17. Gandhi V, Estey E, Keating MJ, et al: Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: Pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 87: 256-264, 1996
18. Plunkett W, Hug V, Keating MJ, et al: Quantitation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-beta-D-arabinofuranosylcytosine therapy. Cancer Res 40: 588-591, 1980 19. Gandhi V, Danhauser L, Plunkett W: Separation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate and 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate in human leukemia cells by high-performance liquid chromatography. J Chromatogr 413: 293-299, 1987[Medline] 20. Estey E, Plunkett W, Dixon D, et al: Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia. Leukemia 1: 580-583, 1987[Medline] 21. Plunkett W, Nowak B, Keating MJ: Effect of amsacrine on ara-CTP cellular pharmacology in human leukemia cells during high-dose cytarabine therapy. Cancer Treat Rep 71: 479-483, 1987[Medline] 22. Plunkett W, Iacoboni S, Estey E, et al: Pharmacologically directed ara-C therapy for refractory leukemia. Semin Oncol 12: 20-30, 1985[Medline]
23. Plunkett W, Liliemark JO, Adams TM, et al: Saturation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation in leukemia cells during high-dose 1-beta-D- arabinofuranosylcytosine therapy. Cancer Res 47: 3005-3011, 1987
24. Gandhi V, Nowak B, Keating MJ, et al: Modulation of arabinosylcytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: Implications for combination therapy. Blood 74: 2070-2075, 1989 25. Gandhi V, Estey E, Keating MJ, et al: Biochemical modulation of arabinosylcytosine for therapy of leukemias. Leuk Lymphoma 10: 109-114, 1993 (suppl) 26. Santana VM, Mirro J Jr, Harwood FC, et al: A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 9: 416-422, 1991[Abstract]
27. Liliemark J, Juliusson G: On the pharmacokinetics of 2-chloro-2'-deoxyadenosine in humans. Cancer Res 51: 5570-5572, 1991
28. Liliemark J, Juliusson G: Cellular pharmacokinetics of 2-chloro-2'-deoxyadenosine nucleotides: Comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients. Clin Cancer Res 1: 385-390, 1995 29. Larson RA, Mick R, Spielberger RT, et al: Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies. J Clin Oncol 14: 188-195, 1996[Abstract] 30. Arnaout MK, Radomski KM, Srivastava DK, et al: Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: Short- and long-term effects. Leukemia 14: 1736-1742, 2000[CrossRef][Medline]
31. Liliemark JO, Plunkett W, Dixon DO: Relationship of 1-beta-D-arabinofuranosylcytosine in plasma to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate levels in leukemic cells during treatment with high-dose 1-beta-D-arabinofuranosylcytosine. Cancer Res 45: 5952-5957, 1985 32. Heinemann V, Estey E, Keating MJ, et al: Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. J Clin Oncol 7: 622-628, 1989[Abstract] 33. Creutzig U, Zimmermann M, Ritter J, et al: Definition of a standard-risk group in children with AML. Br J Haematol 104: 630-639, 1999[CrossRef][Medline] 34. Creutzig U, Ritter J, Zimmermann M, et al: Idarubicin improves blast cell clearance during induction therapy in children with AML: Results of study AML-BFM 93—AML-BFM Study Group. Leukemia 15: 348-354, 2001[CrossRef][Medline] Submitted October 1, 2001; accepted June 28, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
Induction Therapy
