Induction chemotherapy
Central nervous system prophylaxis for acute myeloid leukemia
Granulocytic sarcoma/chloroma

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with acute promyelocytic leukemia (APL), Down syndrome, myelodysplastic syndromes (MDS), and juvenile myelomonocytic leukemia (JMML).

Because of the intensity of therapy used to treat children with AML, patients should have their care coordinated by specialists in pediatric oncology, and should be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support).

Contemporary effective pediatric AML protocols result in 75% to 90% complete remission rates.[1-3] Of those patients who do not go into remission, about one half have resistant leukemia and one half die from the complications of the disease or its treatment. To achieve a complete remission, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.

The 2 most effective drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[1-3] For example, the Children’s Cancer Group (CCG) intensively-timed dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin (DCTER) and idarubicin (IDA)-DCTER regimens utilized cytarabine, daunorubicin or idarubicin, dexamethasone, etoposide, and thioguanine given as 2, 4-day treatments separated by 6 days.[3,4] The German Berlin-Frankfurt-Munster (BFM) Group studied cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) given over 8 days.[2,5,6] The United Kingdom Medical Research Council (MRC) 10 Trial compared induction with ADE versus cytarabine and daunorubicin given with thioguanine (DAT); the results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.[7] The MRC also studied cytarabine, mitoxantrone, and etoposide (MAE).[1,7,8]

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[1-3] though idarubicin and the anthracenedione, mitoxantrone, have also been used.[5] A randomized study in children with newly diagnosed AML comparing daunorubicin and idarubicin (each given with cytarabine and etoposide) observed a trend favoring idarubicin, but the small benefit for idarubicin in terms of remission rate and event-free survival (EFS) was not statistically significant.[5] Similarly, studies comparing idarubicin and daunorubicin in adults with AML have not produced compelling evidence that idarubicin is more efficacious than daunorubicin.[2] Excessive toxicity from IDA-DCTER compared with historical data from DCTER was reported in a CCG pilot study.[4] Preliminary results of the randomized comparison of daunorubicin or mitoxantrone combined with cytarabine and etoposide showed similar induction deaths and resistant disease percentages.[8] In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome to daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.

The intensity of induction therapy influences the overall outcome of therapy. The CCG 2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better event-free survival (EFS) than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[3] The MRC Group has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[1] Another way of intensifying induction therapy is by the use of high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2-3 g/m²/dose) compared with standard-dose cytarabine,[9,10] a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m² given twice daily for 7 days with daunorubicin and thioguanine.[11]

Randomized trials evaluating hematopoietic growth factors during induction therapy for patients with AML have not been reported in children, and so the potential benefit of these agents for children with AML must be extrapolated from the adult experience. Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in attempts to reduce the toxicity associated with prolonged myelosuppression.[12,13] Treatment with hematopoietic growth factor generally begins within a day or 2 following the completion of cytotoxic therapy and continues until granulocyte recovery. A reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF has been observed.[12] Most, but not all, randomized studies showed statistically significant reductions in the duration of hospitalization and antibiotic use in patients receiving hematopoietic growth factors.[12] Significant effects on treatment-related mortality or overall survival, however, were rarely observed.[12]

Although the presence of central nervous system (CNS) leukemia at diagnosis (i.e., clinical neurologic features and/or leukemic cells in cerebral spinal fluid on cytocentrifuge preparation) is more common in childhood AML than in childhood acute lymphoblastic leukemia (ALL), reduction in overall survival directly attributable to CNS involvement has not been convincingly demonstrated in childhood AML. This finding is perhaps related to both the higher doses of chemotherapy used in AML (with potential crossover to the CNS) and the fact that marrow disease has not yet been as effectively brought under long-term control in AML as in ALL. Children with M4 and M5 AML have the highest incidence of CNS leukemia (especially those with inv(16) or 11q23 chromosomal abnormalities). The use of some form of CNS treatment (intrathecal chemotherapy with or without cranial irradiation) is now incorporated into most protocols for the treatment of childhood AML and is considered a standard part of the treatment for AML.[14]

Granulocytic sarcoma (GS) (chloroma), describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of 3 AML studies conducted by the former Children's Cancer Group, <1% of patients had isolated GS, and 11% had GS along with marrow disease at the time of diagnosis.[15] Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated GS have a good prognosis if treated with current AML therapy. For those patients who have GS in addition to marrow involvement, the patients with disease limited to the skin do worse than those without GS; those with AML that involves sites other than skin (e.g., orbit, head, and neck), have a similar prognosis to patients with medullary leukemia alone. Many of these patients have t(8;21) with orbital myeloblastomas. The use of radiation therapy does not improve survival in patients with GS who have a complete response to chemotherapy, but may be necessary if the site(s) of GS do not show complete response to chemotherapy.[15]

References

1. 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 (1): 130-40, 1998.  [PUBMED Abstract]
   
   
2. 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-Münster 93. J Clin Oncol 19 (10): 2705-13, 2001.  [PUBMED Abstract]
   
   
3. 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 (12): 4979-89, 1996.  [PUBMED Abstract]
   
   
4. Lange BJ, Dinndorf P, Smith FO, et al.: Pilot study of idarubicin-based intensive-timing induction therapy for children with previously untreated acute myeloid leukemia: Children's Cancer Group Study 2941. J Clin Oncol 22 (1): 150-6, 2004.  [PUBMED Abstract]
   
   
5. 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 (3): 348-54, 2001.  [PUBMED Abstract]
   
   
6. Creutzig U, Zimmermann M, Reinhardt D, et al.: Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol 22 (21): 4384-93, 2004.  [PUBMED Abstract]
   
   
7. Hann IM, Stevens RF, Goldstone AH, et al.: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 89 (7): 2311-8, 1997.  [PUBMED Abstract]
   
   
8. Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.  [PUBMED Abstract]
   
   
9. Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.  [PUBMED Abstract]
   
   
10. Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996.  [PUBMED Abstract]
    
    
11. Becton D, Ravindranath Y, Dahl GV, et al.: A phase III study of intensive cytarabine (Ara-C) induction followed by cyclosporine (CSA) modulation of drug resistance in de novo pediatric AML; POG 9421. [Abstract] Blood 98 (11 Pt 1): A-1929, 461a, 2001. 
    
    
12. Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000.  [PUBMED Abstract]
    
    
13. Creutzig U, Zimmermann M, Lehrnbecher T, et al.: Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 24 (27): 4499-506, 2006.  [PUBMED Abstract]
    
    
14. Pui CH, Dahl GV, Kalwinsky DK, et al.: Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 66 (5): 1062-7, 1985.  [PUBMED Abstract]
    
    
15. Dusenbery KE, Howells WB, Arthur DC, et al.: Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (10): 760-8, 2003.  [PUBMED Abstract]
    
    

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