Introduction
Over the past 50 years the prognosis for children with ALL has improved markedly , but still refractory disease or relapse occurs in about 10 – 15 % of all patients.
Dose escalation of already used chemotherapeutic agents has been shown to be associated with a severe increase in short- and long-term toxicities and treatment-related mortality which abrogates the potential benefit for these patients . Upon initiation of the clinical trial CoALL08-09 in 2010, immunotherapy had not been approved precluding its integration into first-line protocols . For treatment intensification, we considered agents with proven biologic activity in refractory or multiply relapsed disease settings among which we identified the acridine derivative amsacrine (4’-(9-acridinylamino)-3-methoxyphenyl) methansulfon) . Amsacrine demonstrated promising efficacy in mostly adult patients with refractory acute myeloid leukemia (AML) when combined with etoposide or cytarabine. In addition, amsacrine in combination with etoposide and high-dose methylprednisolone was used as salvage therapy for relapsed and refractory ALL with moderate treatment-related morbidities Based on these results we introduced amsacrine, etoposide and high-dose methylprednisolone as a new add-on treatment element for primary high-risk ALL.
Patients presenting with a significant MRD load EOI or induction failure were eligible for the HR-I stratification and received a single AEP-block at the end of CoALL08-09 consolidation or as an individualized, MRD-guided off-protocol treatment subsequent to modified HR1 blocks (BFM-ALL 2000) to bridge to HSCT .
The anticipated number of patients in the HR-I group was too small to conduct a randomized evaluation of AEP compared to standard HR treatment. Hence, to determine the efficacy of the add-on AEP treatment element we performed a comparative analysis of a historical group of 42 HR patients from a previous trial (CoALL07-03) exhibiting a similar MRD level at EOI. These patients received the HR standard therapy without the AEP block.
To our knowledge, there has been no published clinical trial evaluating amsacrine as a component of first-line treatment of ALL at childhood. The primary objective of the trial CoALL-08-09 was to examine whether the introduction of potent second-line agents could reduce the risk of relapse in patients with HR-ALL without increasing treatment-related morbidity and mortality. The comparative non-randomized assessment of AEP in poor responding HR patients has been included as a post hoc study question.