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N. Niktoreh et al.
on a compassionate use basis in a cohort of children with refractory de novo AML and de novo or secondary AML refractory to relapse therapy. The use of GO in heavily pre-treated patients translated into a substantial rate of subsequent HSCT of 64% and a probability of 4-year OS of 27% in these patients. The safety profile in our cohort was tolerable, which may allow the use of GO in patients with a history of intensive therapies.
We have identified 88 and analyzed 76 children with relapsed/refractory AML who were treated with GO on a compassionate use basis. Compared to other studies which evaluated the outcomes of treatment with GO in patients with relapsed/refractory AML either on a com- passionate use basis (Zwaan et al., 15 patients;17 Brethon et al., 17 patients)19 or with other treatment strategies (29 patients with relapsed/refractory AML in an open-label, dose-escalation study;27 45 children with relapsed/refrac- tory AML included in the AAML00P2 randomized clinical trial;28 30 children with advanced relapsed/refractory AML in an investigator-initiated phase II study)18 the current cohort contains the largest number of patients.
With GO doses of 2.5-10 mg/m2, 64% of the patients included in our cohort subsequently received HSCT, and 51% of these patients reached complete remission with or without hematologic recovery before receiving HSCT. In 2005, Arceci et al. studied the effect of treatment with GO as a single agent with doses of 6-9 mg/m2 (2 doses, 2-week intervals) in 10 children with refractory AML and 19 with relapsed AML.27 They defined response to GO as achiev- ing CR (presence of ≤5% blasts in BM with full hemato- logic recovery: hemoglobin level ≥9 g/dL, absolute neu- trophil count ≥1.5x109/L, and platelet count ≥100x109/L) and showed a response rate of 30% and 26% in patients with refractory and relapsed AML, respectively, accompa- nied by acceptable safety profiles.27 In addition, in a study by Brethon et al., in 2006, outcome of monotherapy with GO on a compassionate basis (single dose: 3-9 mg/m2) in children with refractory (3 patients) and relapsed (9 patients) AML was investigated.29 The results of this study showed a CR (plus CR without hematologic recovery) rate of 25% in patients with subsequent HSCT.29 Of note, a subsequent study by the same group in 2008 showed that the response rate was higher (overall CR: 53%) when GO was administered in combination with cytarabine in children with relapsed or refractory AML.19 We could not confirm the benefit of this combination treatment in our cohort since combination of GO with cytarabine alone, or with cytarabine along with other agents or combination of GO with vincristine had no survival advantage com- pared to single agent therapy.
Myelosuppression accompanied by fever was the most
common GO-related AE in our patients (49 events in 58% of patients) (data not shown) that appeared to be independ- ent of GO dosage, combination/monotherapy, previous treatments, or disease status prior to GO. Rates of myelo- suppression by GO were previously reported at a range of 25-100% in different studies.19,28,29
In our cohort, the rate of VOD after treatment with GO was 4%. Frequency of VOD related to monotherapy or combination GO therapy in children has been previously reported with a wide range across different studies from no events29,30 to 10-24%.27,28,31 However, taken together, the results of previous studies show that the incidence of VOD is directly associated with the absolute single dose of GO, which is higher when it is administered as monotherapy.32 These findings are in accordance with the results of the current cohort. Considering the suggested increased risk of VOD in cases of monotherapy with GO, and the lack of a survival advantage between monothera- py and combination therapy in our current cohort, admin- istration of GO in combination with other agents, such as cytarabine, may be useful to prevent this complication.
It should be noted that the current analysis is limited by its retrospective study design and especially by the lack of a control group. These restrictions have hindered our efforts to identify the contribution of compassionate treat- ment with GO as a single factor to the outcomes of the current study.
In conclusion, we have shown in a large cohort of patients with relapsed/refractory de novo and secondary AML, with a history of very intensive treatments includ- ing chemotherapy and/or HSCT, that administration of GO on a compassionate use basis was frequently consid- ered. The study provides evidence that GO can enable a subsequent blast reduction that allowed HSCT in these patients and survival without imposing major adverse events. Since addition of GO showed the potential to improve treatment outcomes in the current cohort of patients with relapsed/refractory pediatric AML, the role of GO in these patient groups should ideally be proven in large prospective randomized clinical trials. Therefore, we have now included GO as front-line treatment of relapsed/refractory pediatric AML in our ongoing phase III multicenter clinical trial (EudraCT number: 2010-018980- 41, recruiting since August 2017).
Acknowledgments
We are grateful to all patients who recruited in the corresponding AML-BFM trials and physicians and study staff involved in patient care and studies maintenance. We thank Mr. Jans Enno Mueller for his valuable contribution to the study data-base. Supplementary information is available at Hematologica’s website.
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