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.