Treatment Options Under Clinical Evaluation
Current Clinical Trials

A major challenge in the treatment of children with acute myeloid leukemia (AML) is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT). In practice, most patients are treated with intensive chemotherapy after remission is achieved, as only a small subset have a matched-family donor (MFD). Such therapy includes the drugs used in induction and often includes high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[1,2] Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.[3-5] The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy, including the induction course.[6] As noted above, the United Kingdom Medical Research Council (MRC) studies have randomized patients to four versus five courses of intensive therapy.

The use of HSCT in first remission has been under evaluation since the late 1970s, and an evidence-based appraisal concerning indications for autologous and allogeneic HSCT has been published.[7] Prospective trials of transplantation in children with AML suggest that 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions.[8,9] Prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT have demonstrated a superior outcome for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor.[8-13] In theMRC trials, the difference (70% vs. 60%) did not reach statistical significance but the numbers of patients enrolled did not give the study the power to demonstrate this difference.[9] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[8-10,12]

Because of the improved outcome in patients with favorable prognostic features receiving contemporary regimens, it is now recommended that this group of patients receive an MFD HSCT only after first relapse and the achievement of a second complete remission (CR).[14] The Berlin-Frankfurt-Munster Group uses a combination of day-15 marrow response (<5% blasts) and French-American-British (FAB) subtypes M1 and M2 with Auer rods, M3, or M4Eo to define a good-risk group.[15] The MRC has identified a group of good-risk patients with a 7-year survival from CR of 78% and a disease-free survival (DFS) of 59%. The patients in this group primarily include those with t(8;21), t(15;17), FAB M3, and inv(16).[9] A retrospective analysis of 1,464 children with AML treated on Children's Cancer Group trials suggests that allogeneic HSCT improves overall survival and DFS for patients with low or high white blood cell counts with all subtypes except those with inv(16);[16] however, the ability of patients with t(8;21) treated with chemotherapy to be successfully cured following achievement of a second CR and MFD HSCT has led the Children's Oncology Group (COG) to not recommend transplantation in first CR for patients with t(8;21) and inv(16). A large intent-to-treat analysis of 472 young adults treated on Bordeaux-Grenoble-Marseille-Toulouse studies did not show benefit from allogeneic HSCT in high-risk or low-risk patients but did show a benefit in intermediate-risk patients.[17] Further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials. Based on a published retrospective study of 95 children who received unrelated cord blood (UCB) transplantation for AML, the Eurocord Group is recommending UCB transplantation for children who have very poor-prognosis AML and who lack an HLA-identical sibling. Poor-risk AML was defined as that having cytogenetics with any of the following abnormalities: monosomy 7 and 5, 5q-, 11q23 abnormalities other than t(9;11), abnormal 3q, t(y:9), or complex karyotypes.[18]

Maintenance chemotherapy has been shown to be effective in the treatment of acute promyelocytic leukemia (APL).[19] In other subtypes, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration with two randomized studies failing to show benefit for maintenance therapy with interleukin-2.[3,6,20]

The following are examples of national and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• COG is conducting a randomized study (AAML0531) of the MRC backbone [21] with or without the addition of gemtuzumab ozogamicin (GMTZ) in both induction and postremission treatment blocks. GMTZ is a recombinant humanized anti-CD33 monoclonal antibody linked to NAC-gamma calicheamicin, a potent antitumor antibiotic. Patients are assigned to low-risk, intermediate-risk and high-risk groups based on cytogenetics, FLT3 ITD status, and response to induction chemotherapy. All risk groups participate in the GMTZ randomization. Low-risk patients are treated with five cycles of chemotherapy and no stem cell transplant (SCT). Intermediate risk patients receive MFD SCT after three cycles. If there is no MFD, these patients receive five cycles of chemotherapy. High-risk patients (defined by presence of monosomy 7, monosomy 5/del[5q], FLT3 ITD with high allelic ratio, or elevated levels of persistent disease after course one) receive MFD or alternative donor SCT if a suitable donor is available after three cycles of chemotherapy; if a suitable donor is not available, they complete the five cycles of chemotherapy. The study includes patients aged 4 years or older with Down syndrome and excludes patients with APL.



• St. Jude Children’s Research Hospital is currently conducting a randomized trial (AML08) for children with newly diagnosed AML in which the efficacy of postchemotherapy NK cell transplantation is being assessed after five cycles of chemotherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute myeloid leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994.  [PUBMED Abstract]
   
   
2. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.  [PUBMED Abstract]
   
   
3. Wells RJ, Woods WG, Buckley JD, et al.: Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol 12 (11): 2367-77, 1994.  [PUBMED Abstract]
   
   
4. Wells RJ, Woods WG, Lampkin BC, et al.: Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group. J Clin Oncol 11 (3): 538-45, 1993.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008.  [PUBMED Abstract]
   
   
7. Oliansky DM, Rizzo JD, Aplan PD, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 13 (1): 1-25, 2007.  [PUBMED Abstract]
   
   
8. 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 (1): 56-62, 2001.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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 (22): 1428-34, 1996.  [PUBMED Abstract]
    
    
11. Feig SA, Lampkin B, Nesbit ME, et al.: Outcome of BMT during first complete remission of AML: a comparison of two sequential studies by the Children's Cancer Group. Bone Marrow Transplant 12 (1): 65-71, 1993.  [PUBMED Abstract]
    
    
12. Amadori S, Testi AM, Aricò M, et al.: Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 11 (6): 1046-54, 1993.  [PUBMED Abstract]
    
    
13. Bleakley M, Lau L, Shaw PJ, et al.: Bone marrow transplantation for paediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow Transplant 29 (10): 843-52, 2002.  [PUBMED Abstract]
    
    
14. Creutzig U, Reinhardt D: Current controversies: which patients with acute myeloid leukaemia should receive a bone marrow transplantation?--a European view. Br J Haematol 118 (2): 365-77, 2002.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. Alonzo TA, Wells RJ, Woods WG, et al.: Postremission therapy for children with acute myeloid leukemia: the children's cancer group experience in the transplant era. Leukemia 19 (6): 965-70, 2005.  [PUBMED Abstract]
    
    
17. Jourdan E, Boiron JM, Dastugue N, et al.: Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience. J Clin Oncol 23 (30): 7676-84, 2005.  [PUBMED Abstract]
    
    
18. Michel G, Rocha V, Chevret S, et al.: Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. Blood 102 (13): 4290-7, 2003.  [PUBMED Abstract]
    
    
19. Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.  [PUBMED Abstract]
    
    
20. Perel Y, Auvrignon A, Leblanc T, et al.: Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group. Leukemia 19 (12): 2082-9, 2005.  [PUBMED Abstract]
    
    
21. 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]
    
    

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