Amsacrine, Etoposide and Methylprednisolone As Part of the Therapy Intensification in Children with Acute Lymphoblastic Leukemia: A Retrospective Analysis in the Trial Coall 08-09

Background

The combination of amsacrine, etoposide and methylprednisolone (AEP) is regarded as a salvage treatment option in pediatric acute lymphoblastic leukemia (ALL). A recent study already showed a significant response after the treatment with AEP in children with recurrent/refractory ALL without AEP-related mortality, an acceptable morbidity and moderate myelotoxicity. [1] The CoALL study group, that investigates the treatment of childhood ALL, has implemented this block as a part of a therapy intensification in the current CoALL 08-09 protocol, for patients with a high MRD load ( B-Precursor > 10^-³ at the end of induction (EOI), T-ALL >10^-³ after the first consolidation block) stratified to the High Risk intensified arm or for patients without remission at the EOI defined as late responder.

We examined the toxicity profile and the efficacy of this block in patients that have been treated within the current study.

Patients and Methods

So far 67 of 624 patients enrolled into the CoALL 08-09 trial, received the combination of amsacrine, etoposide and methylprednisolone as they have been treated according to the High Risk intensified arm (36 c-ALL, 8 pre-B-ALL, 3 pro-B-ALL, 8 T-ALL) or as they were specified as late responder (3 c-ALL, 1 pre-B-ALL, 1 pro-B-ALL, 7 T-ALL). The patients were characterized by a median age of 11 years and a median MRD value of 7x10^-3 (B-ALL)/ 1x10^-2 (T-ALL). All patients had received one cycle amsacrine 100mg/m²/day i.v. for 2 days, etoposide 500mg/m²/day i.v. for 2 days and methylprednisolone 1000mg/m²/day p.i. for 4 days at the end of the consolidation phase.

Results

Beside a profound myelosuppression 29 of the 67 enrolled patients exhibited toxicities after receiving AEP, mostly reflected by fever in neutropenia. In two cases septicemia was reported as a serious adverse event.

Only three fungal infections, two occurrences of mucositis, four cases of a diabetic metabolic state and two cases of cardiac arrhythmia were reported. There was no osteonecrosis and no steroid-related psychosis reported within this patient cohort. No treatment related death occurred. The median treatment interval was 28 days, 8 days longer than the so far reported median treatment interval.

A Kaplan-Meier analysis for event free (EFS) and the overall survival (OS), showed a trend in favor of the current cohort compared to patients of the predecessor trial and a comparable MRD load EOI (pOS: 87.7 SE 4.9 vs 76.3 SE 4.4; pEFS:78.8 SE 6.2 vs 61.1 SE 5.1 p= 0.1) . These patients were treated within the High Risk standard arm without the AEP treatment element.

Conclusion

Treatment intensification with AEP was well tolerated, without an excess of infectious complications in these heavily pretreated patients. AEP treatment intensification shows a trend towards an improved event-free survival.

[1] Horstmann, M. A., Hassenflug, W.-A., zur Stadt, U., Escherich, G., Janka, G., & Kabisch, H. (January 2006). Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Haematologica, S. 1701-3.