Childhood Acute Myeloid Leukemia Treatment (Professional) (cont.)
IN THIS ARTICLE
Recurrent Childhood AML and Other Myeloid Malignancies
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. The vast majority of relapses occur in the bone marrow, with central nervous system (CNS) relapse being very uncommon. 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).[2,3,4] 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%).[2,3,4]
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, fludarabine and idarubicin,[5,6,7], L-asparaginase, etoposide, and clofarabine.[9,10] The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council AML 10 study for newly diagnosed children with AML (cytarabine and 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.
In a report of 379 children with AML who relapsed after initial treatment on BFM protocols, a second complete remission (CR2) rate was 63% and overall survival was 23%.[Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving CR2, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)). The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration compared with 19% ± 6% for patients with shorter periods of first remission.
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 conventionally recommended, though there are no controlled prospective data regarding the contribution of additional courses of therapy once CR2 is obtained. Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[Level of evidence: 3iiA] The optimum type of preparative transplant regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied. Importantly, however, there are no data that suggest total-body irradiation (TBI) is superior compared with busulfan-based myeloablative regimens.[15,16]
There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6 months from first transplant), achievement of complete response prior to the second procedure, and use of a TBI-based regimen (after receiving a non-TBI regimen for the first procedure).
Clinical trials, including new chemotherapy and/or biologic agents and/or novel bone marrow transplant (autologous, matched or mismatched unrelated donor, cord blood) programs, are also considerations. Information about ongoing clinical trials is available from the NCI Web site
Isolated CNS Relapse
CNS3 disease has been reported in 11% to 16.5% of children with newly diagnosed AML and CNS2 disease in approximately 12.8%.[18,19] The cumulative incidence of CNS relapse has been reported to be greater for CNS2 versus CNS1 with an overall isolated CNS relapse incidence of 3.4% to 4.8%.[19,20] Age younger than 2 years, M5 leukemia, chromosome 11 abnormalities, and organomegaly were significant risk factors for CNS relapse.[19,20] The 8-year overall survival for a cohort of children experiencing CNS relapse was 26% ±16%. The outcome of isolated CNS relapse is similar to bone marrow relapse and better treatment is required to improve survival.
Recurrent Acute Promyelocytic Leukemia (APL)
Despite the improvement in outcomes for patients with newly diagnosed APL, approximately 10% to 20% of patients relapse.
An important issue in children is the prior exposure to anthracyclines, which can range from 400 mg/m2 to 750 mg/m2. Thus, regimens containing anthracyclines are often not optimal for children with APL who suffer relapse. For children with recurrent APL, the use of arsenic trioxide as a single agent 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.[22,23,24,25] 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.[22,24,26] Because arsenic trioxide causes QT interval prolongation that can lead to life-threatening arrhythmias, it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges. The use of anti-CD33/calicheamicin monoclonal antibody as a single agent resulted in 91% (9 of 11 patients) molecular remission after two doses and in 100% of patients (13 of 13) after three doses, thus demonstrating excellent activity of this agent in relapsed APL.
Retrospective pediatric studies have reported 5-year event-free survival (EFS) rates after either autologous or allogeneic transplantation approaches to be similar at approximately 70%.[30,31] When considering autologous transplantation, a study in adult patients demonstrated improved 7-year EFS (77% vs. 50%) when both the patient and the stem cell product had negative promyelocytic leukemia/retinoic acid receptor alpha fusion transcript by polymerase chain reaction (molecular remission) prior to transplant. Another study demonstrated that among seven patients undergoing autologous HSCT and whose cells were minimal residual disease (MRD)-positive, all relapsed in less than 9 months after transplantation; however, only one of eight patients whose autologous donor cells were MRD-negative relapsed. Another report demonstrated that the 5-year EFS for patients who underwent autologous HSCT in second molecular remission was 83.3% compared with 34.5% for patients who received only maintenance therapy. Such data support the use of autologous transplantation in patients in a MRD-negative CR2 who have poorly matched allogeneic donors.
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
eMedicineHealth Public Information from the National Cancer Institute
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