Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia (AML) have poor survival. We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (<18 years) with highly-advanced and pre-treated AML [refractory de novo acute myeloid leukemia (n=10), de novo AML refractory to relapse (1st early: n=41; 1st late: n=10; 2nd or more: n=10), and secondary AML (n=5)]. At doses of 2.5-10 mg/m2, gemtuzumab ozogamicin was administered in 1-4 cycles as single agent (47%), combined with cytarabine (47%), or others (6%). Most common grade 3/4 adverse events were infections or febrile neutropenia (78% of severe adverse events), infusion-related immunological reactions (6%), and gastrointestinal symptoms (5%). Three patients experienced veno-occlusive disease (one fatal due to exacerbation of a pre-existing cardiomyopathy). Sixty-four percent received subsequent hematopoietic stem cell transplantation. Probability of 4-year overall survival was 18±5% in all, 27±7% in patients with and 0% in patients without hematopoietic stem cell transplantation (P<0.0001). Administration of gemtuzumab ozogamicin on a patient-specific, compassionate use basis was frequently considered in our study group and proved to be effective for bridging children with very advanced AML to hematopoietic stem cell transplantation. Uniform prospective studies for these patients are urgently needed.

Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Eppendorf University Hospital Hamburg Germany

Department of Pediatric Hematology and Oncology Hannover Medical School Germany

Department of Pediatric Hematology and Oncology University Hospital Essen Germany

Department of Pediatrics Jena University Hospital Germany

Division of Pediatric Hematology Oncology University Children's Hospital Zurich Switzerland

St Anna Children's Hospital and Children's Cancer Research Institute Department of Pediatrics Medical University of Vienna Austria

University Children's Hospital Münster Pediatric Hematology and Oncology Germany

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Zwaan CM, Kolb EA, Reinhardt D, et al. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia. J Clin Oncol. 2015;33(27):2949–2962. PubMed PMC

Kaspers G. How I treat paediatric relapsed acute myeloid leukaemia. Br J Haematol. 2014;166(5):636–645. PubMed

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. 2010;24(8):1422–1428. PubMed

Horton TM, Perentesis JP, Gamis AS, et al. A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2014;61(10):1754–1760. PubMed PMC

Nakayama H, Tabuchi K, Tawa A, et al. Outcome of children with relapsed acute myeloid leukemia following initial therapy under the AML99 protocol. Int J Hematol. 2014;100(2):171–179. PubMed

Cooper TM, Alonzo TA, Gerbing RB, et al. AAML0523: a report from the Children’s Oncology Group on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent acute myeloid leukemia. Cancer. 2014; 120(16):2482–2489. PubMed PMC

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. 2013;31(5):599–607. PubMed

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. 2010;55(3):421–429. PubMed

Webb DK. Management of relapsed acute myeloid leukaemia. Br J Haematol. 1999;106(4):851–859. PubMed

Rubnitz JE, Razzouk BI, Lensing S, Pounds S, Pui CH, Ribeiro RC. Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer. 2007;109(1):157–163. PubMed

Bose P, Vachhani P, Cortes JE. Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options Oncol. 2017;18(3):17. PubMed

Moore AS, Kearns PR, Knapper S, Pearson AD, Zwaan CM. Novel therapies for children with acute myeloid leukaemia. Leukemia. 2013;27(7):1451–1460. PubMed

Tasian SK, Pollard JA, Aplenc R. Molecular therapeutic approaches for pediatric acute myeloid leukemia. Front Oncol. 2014;4:55. PubMed PMC

Hinman LM, Hamann PR, Wallace R, Menendez AT, Durr FE, Upeslacis J. Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res. 1993;53(14):3336–3342. PubMed

Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood. 1999;93(11):3678–3684. PubMed

Maniecki MB, Hasle H, Bendix K, Moller HJ. Is hepatotoxicity in patients treated with gemtuzumabozogamicin due to specific targeting of hepatocytes? Leuk Res. 2011;35(6):e84–e86. PubMed

Zwaan CM, Reinhardt D, Corbacioglu S, et al. Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood. 2003;101(10):3868–3871. PubMed

Zwaan CM, Reinhardt D, Zimmerman M, et al. Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study. Br J Haematol. 2010;148(5):768–776. PubMed

Brethon B, Yakouben K, Oudot C, et al. Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia. Br J Haematol. 2008;143(4):541–547. PubMed

ClinicalTrials.gov. Expanded Access/Compassionate Use Protocol For Relapsed Or Refractory CD33 Positive AML Patients In The USA Without Access To Comparable Or Alternative Therapy (AML). 2017. [cited Jan 2018]; Available from: https://clinicaltrials.gov.

Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia. 2005;19(12):2030–2042. PubMed

Creutzig U, Zimmermann M, Lehrnbecher T, et al. Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol. 2006;24(27):4499–4506. PubMed

Creutzig U, Zimmermann M, Dworzak M, et al. Study AML-BFM 2004: Improved Survival In Childhood Acute Myeloid Leukemia without Increased Toxicity. Blood. 2010;116(21):181.

Creutzig U, Zimmermann M, Dworzak MN, et al. The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01. Haematologica. 2014;99(9):1472–1478. PubMed PMC

US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010. [cited August 2016]; Available from: http://ctep.cancer.gov.

Davila J, Slotkin E, Renaud T. Relapsed and refractory pediatric acute myeloid leukemia: current and emerging treatments. Paediatr Drugs. 2014;16(2):151–168. PubMed

Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood. 2005; 106(4):1183–1188. PubMed

Aplenc R, Alonzo TA, Gerbing RB, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2008;26(14):2390–3295. PubMed PMC

Brethon B, Auvrignon A, Galambrun C, et al. Efficacy and tolerability of gemtuzumab ozogamicin (anti-CD33 monoclonal antibody, CMA-676, Mylotarg) in children with relapsed/refractory myeloid leukemia. BMC Cancer. 2006;6:172. PubMed PMC

Roman E, Cooney E, Harrison L, et al. Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia. Clin Cancer Res. 2005;11(19):7164–7170. PubMed

Satwani P, Bhatia M, Garvin JH, Jr, et al. A Phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen. Biol Blood Marrow Transplant. 2012;18(2):324–329. PubMed

Parigger J, Zwaan CM, Reinhardt D, Kaspers GJ. Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia. Expert Rev Anticancer Ther. 2016;16(2):137–146. PubMed