Recurrent Childhood AML and Other Myeloid Malignancies
The diagnosis of recurrent or relapsed acute myeloid leukemia (AML) according to Children's Oncology Group (COG) criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts and a diagnosis of AML according to World Health Organization (WHO) classification criteria.
Despite second remission induction in over one-half of children with 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.[2,3] Approximately 50% to 60% of relapses occur within the first year after 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).[3-5] 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%).[3-6] In addition, specific molecular alterations at the time of relapse have been reported to impact subsequent survival. For instance, the presence of either WT1 or FLT3-ITD mutations at first relapse were associated as independent risk factors for worse overall survival (OS) in patients achieving a second remission.
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,[8-10] L-asparaginase, etoposide, and clofarabine and etoposide. Regimens built upon clofarabine have also been used;[12-14][Level of evidence: 2Div] as have regimens of 2-chloroadenosine. The COG AAML0523 trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing hematopoietic stem cell transplantation (HSCT), was 46%. Minimal residual disease (MRD) before HSCT was a strong predictor of survival.[Level of evidence: 2Di] 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 COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall complete remission (CR) rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.
In a report of 379 children with AML who relapsed after initial treatment on the German Berlin-Frankfurt-Münster (BFM) group protocols, a second complete remission (CR2) rate was 63% and OS 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)). A subsequent study by the BFM group compared fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) with FLAG plus liposomal daunorubicin. Four-year OS was 38%, with no difference in survival for the total group; however, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core binding factor mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[Level of evidence: 1iiA] The Therapeutic Advances in Childhood Leukemia and Lymphoma 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 and 19% ± 6% for patients with shorter periods of first remission. A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who went to HSCT after achieving a CR2 (66%) than in patients not in remission (17%).
The selection of further treatment after the achievement of a second remission depends on previous 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 CR2, overt relapse, and primary induction failure, respectively.[Level of evidence: 3iiA] The optimal type of transplant preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied. A number of studies, including a large, prospective Center for International Blood and Marrow Transplant Research (CIBMTR) cohort study of children and adults with myeloid diseases, have shown similar or superior survival with busulfan-based regimens compared with total-body irradiation (TBI).[23-25]
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 before the second procedure, and use of a TBI-based regimen (after receiving a non-TBI regimen for the first procedure).[26,27] A large prospective cohort study that included children and adults with myeloid diseases showed comparable or superior outcome with busulfan-based regimens compared with TBI.
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.
Relapse in Children with Down Syndrome
A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. The Japanese Pediatric Leukemia/Lymphoma Study Group reported the outcomes of 29 Down syndrome patients with relapsed (n = 26) or refractory (n = 3) AML. As expected with Down syndrome, the children in this cohort were very young (median age, 2 years); relapses were almost all early (median 8.6 months, 80% <12 months from diagnosis); and 89% had M7 French-American-British classification. In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%.[Level of evidence: 3iiA] Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted with transplant compared with chemotherapy, but numbers were small. A CIBMTR study of children with Down syndrome and AML who underwent HSCT reported a similarly poor outcome, with a 3-year OS of 19%.[Level of evidence: 3iiA] The main cause of failure after transplant was relapse, which exceeded 60%; transplant-related mortality was approximately 20%. A Japanese registry study reported better survival after transplant of children with Down Syndrome using reduced intensity conditioning regimens compared with myeloablative approaches, but numbers were very small (n = 5), and the efficacy of reduced intensity approaches in Down children with AML requires further study.[Level of evidence 3iDi]
Isolated CNS Relapse
- Age younger than 2 years at initial diagnosis.
- M5 leukemia.
- 11q23 abnormalities.
- CNS involvement at initial diagnosis.
The outcome of isolated CNS relapse when treated as a systemic relapse is similar to that of bone marrow relapse. In one study, the 8-year OS for a cohort of children with an isolated CNS relapse was 26% ± 16%.
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 previous 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 after treatment with this agent.[34-37] Data are limited on the use of arsenic trioxide in children, although published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[34,36,38] 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 (gemtuzumab ozogamicin) 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. Gemtuzumab ozogamicin is currently not available in the United States, except for compassionate-use approval.
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%.[42,43] 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) before 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 was 83.3% for patients who underwent autologous HSCT in second molecular remission and was 34.5% for patients who received only maintenance therapy. Such data support the use of autologous transplantation in patients who are MRD-negative in second complete remission who have poorly matched allogeneic donors.
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.
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