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%).[2-4]
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,[5-7], L-asparaginase, etoposide, and clofarabine.[9-11] 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)). 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 (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 and 19% ± 6% for patients with shorter periods of first remission.
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 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 to busulfan-based myeloablative regimens.[17,18]
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).[19,20]
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 of 26% was poor.[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%.Isolated CNS Relapse
- Age younger than 2 years at initial diagnosis.
- M5 leukemia.
- Chromosome 11 abnormalities.
- CNS involvement at initial diagnosis.
The outcome of isolated CNS relapse is similar to bone marrow relapse; in one study, the 8-year overall survival 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.[26-29] 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.[26,28,30] 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%.[34,35] 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 only received maintenance therapy. Such data support the use of autologous transplantation in patients in a MRD-negative CR2 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.References
- Webb DK: Management of relapsed acute myeloid leukaemia. Br J Haematol 106 (4): 851-9, 1999. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- Hijiya N, Gaynon P, Barry E, et al.: A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia 23 (12): 2259-64, 2009. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Lo-Coco F, Cimino G, Breccia M, et al.: Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104 (7): 1995-9, 2004. [PUBMED Abstract]
- Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009. [PUBMED Abstract]