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Gemtuzumab in pediatric acute myeloid leukemia
which are present in approximately 80-90% of childhood AML.14,15 Although CD33 has been considered as a specific marker for hematopoietic cells of the myeloid lineage for a long time, this surface marker is also found to be expressed in hepatocytes which may potentially cause some off-target effects.16
Treatment with GO in different settings has previously been shown to be of value in pediatric AML. The first international experience of treatment with GO as monotherapy for compassionate use for children with relapsed or refractory AML (n=15) in 2003 suggested the efficacy of this treatment with doses of 4-9 mg/m2 in up to 3 cycles.17 A later phase II study showed that treatment with two doses of 7.5 mg/m2 GO with 14-day intervals in children with advanced AML (refractory, first refractory relapse or ≥second relapse) led to significantly higher sur- vival in patients who received GO compared to patients who did not receive this treatment (3-year probability of overall survival: 27% vs. 0%, respectively; P=0.001).18 In addition to monotherapy, a good response rate was also achieved when GO was administered in combination with cytarabine in 17 children with relapsed or refractory AML [overall complete remission (CR) rate: 53%].19
Currently there are at least 9 active clinical trials world- wide investigating the effect of GO in AML (de novo, relapsed, or refractory). One of these trials only recruits children and 4 are recruiting children in addition to adults or elderly patients (Online Supplementary Table S1). Of interest, there is one active clinical trial which studies treatment with GO in compassionate use in refractory or relapsed AML (clinicaltrials.gov identifier: 02312037), which recruits children, adult, and elderly groups of patients.20
Considering the above-mentioned challenges in the treatment of relapsed and refractory pediatric AML, the infrequency of new treatment options, and in addition, the restricted accessibility of GO, we aimed to identify patients treated with GO as compassionate use in the AML-Berlin-Frankfurt-Münster (AML-BFM) study group and to evaluate the efficacy and safety in this heavily pre- treated group of patients.
Methods
Patients
Between January 1995 and March 2014, 2601 children with ini- tial diagnosis at the age of ≤18 years were documented within the AML-BFM study group. Patients or guardians provided written informed consent. The current analysis was performed in accor- dance with the Declaration of Helsinki and was approved by the local ethics committee. The AML-BFM Study Group centrally reviewed the diagnosis of initial disease or relapse via bone mar- row morphology and flow cytometry. All patients’ records were evaluated retrospectively for the use of GO. Medical reports of the patients treated with GO were reviewed retrospectively for eval- uation of treatment outcomes and adverse events (AE).
Treatment protocols
Before administration of GO, patients were treated based on randomized, phase III studies AML-BFM 93, 98, and 2004 running in 75 centers in Germany, Austria, Switzerland, and the Czech Republic. These treatment protocols have been previously described in detail.21-23 All studies were performed after the approval by national ethics committees and institutional review boards. The AML-BFM 93 recruited patients between January
1993 and June 1998, and was followed by AML-BFM 98 which was opened in July 1998 and closed in June 2003. Between July 2003 and April 2004, the AML-BFM 98 Interim Study continued treatment of recruited patients with the best arm of the AML-BFM 98 trial. The AML-BFM 04 study was opened in April 2004 and randomization continued until April 2010. After April 2010 and until February 2014, the AML-BFM 2004 Interim Study continued treatment of patients with the experimental arm of the AML-BFM 2004 trial. Second-line treatment of patients included the Relapse AML 2001/01 trial24 which recruited patients from November 2001 to April 2009 and the International Registry Relapsed AML 2009.7 Patients included in the current cohort had received intensive treat- ment and/or HSCT before administration of GO. Considering the first treatment after initial diagnosis as first attempt, and each fol- lowing treatment block or HSCT as further individual attempts, most of the patients (n=35, 46%) in the total cohort received GO as their 3rd treatment attempt (Online Supplementary Figure S1).
Treatment with GO
During the period of analysis, 217 patients with non-response (NR) and 654 patients with at least one event of relapse were doc- umented (Online Supplementary Figure S2). Within these patient records, 98 (from 39 different centers) were found with a positive history of GO treatment, 10 of which were included in the previ- ously mentioned phase II trial18 and who were, thus, excluded from the current study. The remaining 88 patients received GO on a compassionate use basis, after failure of their first- and/or sec- ond-line treatments and/or when the general condition of patients was so poor that further intensive chemotherapy was not possi- ble. Treatment with GO in these patients was recommended by the centralized study co-ordination office, and finally prescribed by the patients’ treating physicians at each local center. Patients or guardians provided written informed consent. GO was provided by International Pharmacy (San Francisco, CA, USA) through Clinigen (London, UK) and, for some patients, by Pfizer (New York, NY, USA) on a compassionate use program. From these 88 patients, 76 had sufficient data to evaluate the outcomes of GO use and were included in this study (Online Supplementary Figure S2). Three of the 76 patients have been previously reported.17 Grading of toxicity and adverse events was carried out using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, revised in June 14, 2010.25 Records concerning the safety evaluation of GO were not available for 5 patients (Online Supplementary Figure S2).
Definitions and statistical analysis
Bone marrow (BM) relapse was defined by presence of >5% of leukemic cells in the BM. Relapse events during the first 12 months from diagnosis of AML were considered as early relapse.3 Complete remission (CR) was defined with the presence of less than 5% blasts in morphological examination of BM in addition to satisfactory hematologic recovery (absolute neutrophil count > 1.0 x109/L, platelet count >80x109/L in the peripheral blood).21 Reaching CR without complete blood recovery was defined as incomplete CR (CRi).21 Response to GO was evaluated in patients who received HSCT after treatment with GO and was defined as CR plus CRi (CR/CRi). Persistence of ≥5% BM leukemic blasts was categorized as NR.
Overall survival (OS) after GO was defined as the time from the first dose until death by any cause or until the last follow up. Probability of OS was calculated according to Kaplan-Meier and compared by log-rank test. P<0.05 was considered significant. Data were analyzed using SAS (Statistical Analysis System Version 9.4; SAS Institute, Cary, NC, USA). Data acquisition was stopped on 1st June 2017.
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