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 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).[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%).[2-5]
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,[6-8] L-asparaginase, etoposide, and clofarabine and etoposide. Regimens built upon clofarabine have also been used;[10-12][Level of evidence: 2Div] as have regimens of 2-chloroadenosine. 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 the German Berlin-Frankfurt-Münster (BFM) group protocols, a second complete remission rate was 63% and overall survival (OS) was 23%.[Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, 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 hematopoietic stem cell transplantation (HSCT) after achieving a second complete remission (66%) than in patients not in remission (17%).
The selection of further treatment after 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 second complete remission 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 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. Of note, 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).[19-21]
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).[22,23] 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 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 after treatment with this agent.[30-33] 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.[30,32,34] 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%.[38,39] 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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- 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]
- 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]
- Tavil B, Aytac S, Balci YI, et al.: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) for the treatment of children with poor-prognosis acute leukemia: the Hacettepe experience. Pediatr Hematol Oncol 27 (7): 517-28, 2010. [PUBMED Abstract]
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- Jeha S, Razzouk B, Rytting M, et al.: Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Oncol 27 (26): 4392-7, 2009. [PUBMED Abstract]
- Shukla N, Kobos R, Renaud T, et al.: Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer 61 (3): 431-5, 2014. [PUBMED Abstract]
- Chaleff S, Hurwitz CA, Chang M, et al.: Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study. Br J Haematol 156 (5): 649-55, 2012. [PUBMED Abstract]
- Sander A, Zimmermann M, Dworzak M, et al.: Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia 24 (8): 1422-8, 2010. [PUBMED Abstract]
- Kaspers GJ, Zimmermann M, Reinhardt D, et al.: Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol 31 (5): 599-607, 2013. [PUBMED Abstract]
- Gorman MF, Ji L, Ko RH, et al.: Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatr Blood Cancer 55 (3): 421-9, 2010. [PUBMED Abstract]
- Bunin NJ, Davies SM, Aplenc R, et al.: Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy. J Clin Oncol 26 (26): 4326-32, 2008. [PUBMED Abstract]
- Locatelli F, Pende D, Maccario R, et al.: Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. Clin Immunol 133 (2): 171-8, 2009. [PUBMED Abstract]
- Woodard P, Carpenter PA, Davies SM, et al.: Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol Blood Marrow Transplant 17 (5): 723-8, 2011. [PUBMED Abstract]
- Uberti JP, Agovi MA, Tarima S, et al.: Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia. Bone Marrow Transplant 46 (1): 34-43, 2011. [PUBMED Abstract]
- Bredeson C, LeRademacher J, Kato K, et al.: Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood 122 (24): 3871-8, 2013. [PUBMED Abstract]
- 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]
- Nishikawa T, Inagaki J, Nagatoshi Y, et al.: The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes. Pediatr Transplant 16 (7): 722-8, 2012. [PUBMED Abstract]
- Taga T, Saito AM, Kudo K, et al.: Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 120 (9): 1810-5, 2012. [PUBMED Abstract]
- Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 19 (6): 893-7, 2013. [PUBMED Abstract]
- Muramatsu H, Sakaguchi H, Taga T, et al.: Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. Pediatr Blood Cancer 61 (5): 925-7, 2014. [PUBMED Abstract]
- 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]
- Abbott BL, Rubnitz JE, Tong X, et al.: Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience. Leukemia 17 (11): 2090-6, 2003. [PUBMED Abstract]
- Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009. [PUBMED Abstract]
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- 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]
- 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]
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- 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]
- 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]
- Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001. [PUBMED Abstract]
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