Treatment Options Under Clinical Evaluation
Current Clinical Trials

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 following diagnosis with most relapses occurring by 4 years from diagnosis.[1] The vast majority of relapses occur in the bone marrow, with central nervous system relapse being very uncommon.[1] 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).[2-4] 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%).[2-4]

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,[2] fludarabine plus idarubicin,[5,6] and L-asparaginase.[7] The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council AML 10 study for newly diagnosed children with AML (cytarabine plus 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.[4]

For children with recurrent acute promyelocytic leukemia (APL), the use of arsenic trioxide or regimens including all-trans retinoic acid should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission following treatment with this agent.[8-11] Data are limited on the use of arsenic trioxide in children, though published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[8,10,12] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias,[13] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[14] In a retrospective review of 11 patients with relapsed APL, allogeneic hematopoietic stem cell transplantation (HSCT) with a well-matched HLA-donor resulted in 5-year overall survival (OS) in 7 out of 11 patients.[15] If a reasonably well-matched allogeneic donor cannot be identified and a molecular (i.e., absence of t[15;17] transcripts) remission can be achieved, then autologous HSCT has been successful with OS of approximately 60% to 75% reported.[16,17]

The selection of further treatment following the achievement of a second remission depends on prior treatment as well as individual considerations. Consolidation chemotherapy followed by HSCT is the treatment of choice, though there are no controlled prospective data as to its contribution to the long-term cure of children with recurrent AML.[1] There is evidence of survival with a second stem cell transplant following a relapse after first transplant for select populations.[18] Clinical trials, including new chemotherapy and/or biologic agents and/or novel bone marrow transplant (autologous, matched or mismatched unrelated donor, cord blood) programs, should be considered.[16,17] Information about ongoing clinical trials is available from the NCI Web site.

In a study of newly diagnosed AML, 4.8% of patients entering remission had an isolated central nervous system (CNS) relapse. Age younger than 2 years, M5 leukemia, chromosome 11 abnormalities, and organomegaly were significant risk factors for CNS relapse. Treatment after relapse was variable, and no treatment proved to be significantly more effective in this setting. The 8-year OS for the entire cohort was 26% (±16%). The outcome of isolated CNS relapse is similar to bone marrow relapse and better treatment is required to improve survival.[19]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• AAML07P1 is a COG study that is evaluating the addition of the proteasome inhibitor bortezomib to AML relapse regimens (idarubicin/cytarabine or etoposide/cytarabine). Patients with prior treatment of below a threshold cumulative anthracycline dose (400 mg/m2) receive bortezomib with idarubicin and cytarabine, while patients who have received higher cumulative anthracycline doses receive bortezomib with etoposide and cytarabine.



• AAML06P1 is a pilot study to determine whether the FLT3 inhibitor lestaurtinib (CEP-701) can be safely combined with intensive reinduction chemotherapy for children with relapsed or refractory AML whose leukemia cells have an activating FLT3 mutation (either FLT3-ITD or FLT3 point mutation). Once a safe dose of lestaurtinib is identified, then the effectiveness of the regimen in inducing remission in children with relapsed or refractory FLT3-mutant AML will be determined.



• AAML0531 is a COG phase II study evaluating the combination of the nucleoside inhibitor and ribonucleotide reductase inhibitor clofarabine with high-dose cytarabine for children with relapsed or refractory AML or acute lymphoblastic leukemia.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood acute myeloid leukemia. 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. Webb DK: Management of relapsed acute myeloid leukaemia. Br J Haematol 106 (4): 851-9, 1999.  [PUBMED Abstract]
   
   
2. Wells RJ, Adams MT, Alonzo TA, et al.: Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. J Clin Oncol 21 (15): 2940-7, 2003.  [PUBMED Abstract]
   
   
3. Stahnke K, Boos J, Bender-Götze C, et al.: Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia. Leukemia 12 (10): 1534-8, 1998.  [PUBMED Abstract]
   
   
4. Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999.  [PUBMED Abstract]
   
   
5. Dinndorf PA, Avramis VI, Wiersma S, et al.: Phase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children's Cancer Group. J Clin Oncol 15 (8): 2780-5, 1997.  [PUBMED Abstract]
   
   
6. Fleischhack G, Hasan C, Graf N, et al.: IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. Br J Haematol 102 (3): 647-55, 1998.  [PUBMED Abstract]
   
   
7. Capizzi RL, Davis R, Powell B, et al.: Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study. J Clin Oncol 6 (3): 499-508, 1988.  [PUBMED Abstract]
   
   
8. Fox E, Razzouk BI, Widemann BC, et al.: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111 (2): 566-73, 2008.  [PUBMED Abstract]
   
   
9. Niu C, Yan H, Yu T, et al.: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94 (10): 3315-24, 1999.  [PUBMED Abstract]
   
   
10. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.  [PUBMED Abstract]
    
    
11. Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004.  [PUBMED Abstract]
    
    
12. Zhang P: The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents 13 (4): 195-200, 1999 Oct-Dec.  [PUBMED Abstract]
    
    
13. Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001.  [PUBMED Abstract]
    
    
14. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.  [PUBMED Abstract]
    
    
15. Bourquin JP, Thornley I, Neuberg D, et al.: Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant 34 (9): 795-8, 2004.  [PUBMED Abstract]
    
    
16. Meloni G, Diverio D, Vignetti M, et al.: Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90 (3): 1321-5, 1997.  [PUBMED Abstract]
    
    
17. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005.  [PUBMED Abstract]
    
    
18. Meshinchi S, Leisenring WM, Carpenter PA, et al.: Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 9 (11): 706-13, 2003.  [PUBMED Abstract]
    
    
19. Johnston DL, Alonzo TA, Gerbing RB, et al.: Risk factors and therapy for isolated central nervous system relapse of pediatric acute myeloid leukemia. J Clin Oncol 23 (36): 9172-8, 2005.  [PUBMED Abstract]
    
    

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