Treatment study for children and adolescents with Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia
(AML). APL is often clinically characterized by the presence of coagulation
abnormalities, including mostly hyperfibrinolysis, disseminated intravascular
coagulation (DIC), and unspecific proteolysis.
APL represents approximately 4-8% of pediatric AML.
Pediatric patients appear to present more commonly with hyperleukocytosis, as
compared to their adult counterparts. Approximately 35-40% of children with APL
fall within a HR group defined by a presenting WBC >=10 x 10 9/L, and predicts
for poorer outcome.This is due to both an increased risk of induction death,
particularly as a result of haemorrhage, and a significantly higher rate of
relapse.
Most of current treatment approaches are based on the combination of ATRA and
anthracycline-containing chemotherapy. The introduction of ATRA for the
treatment of adults and children, led to an increase of remission rates up to
98%, together with a reduction of morbidity and mortality, mostly associated
with early fatal coagulopathy. Despite the dramatic improvements achieved in
frontline therapy of APL with ATRA plus anthracycline-based regimens, relapses
still occur in approximately 20% of patients. Moreover, these regimens are
associated with significant toxicities due to severe myelosuppression
frequently associated with life-threatening infections and potentially serious
late effects, including development of secondary MDS/AML and
anthracycline-related myocardiopathy.
In a recent randomized clinical trial conducted in adults in SR APL (WBC at
diagnosis < 10 x 10 9/L, APL0406 trial), a combination of arsenic trioxide
(ATO) and ATRA has been shown to result into better survival and EFS rates with
significantly lower toxicity, compared to the standard ATRA + idarubicin (AIDA)
therapy. However, a treatment approach with frontline ATO has been tested in a
limited number of pediatric patients.
Inspired by both the results of ICC APL01 and the adult APL0406 trial we intend
to perform the first pediatric chemotherapy-free approach testing the
combination of ATRA/ATO +/- GO based on risk-stratification, expecting less
severe hematologic toxicity and treatment-related mortality, thus resulting in
an improved outcome for these children.

This study has been transitioned to CTIS with ID 2024-518669-83-00 check the CTIS register for the current data.

Primary objective:
To assess, in an international pediatric study, the efficacy, in terms of
event-free survival, of a combination of ATO and ATRA in newly diagnosed SR APL
children and adolescents and to explore the safety and efficacy of a
combination therapy comprising ATRA/ATO + GO in HR APL.

Secondary Objectives:
• To evaluate the short- and long-term toxicity profile of ATO in pediatric
patients, when combined with ATRA (SR APL) or ATRA plus GO (HR APL)
• To compare the clearance kinetics of minimal residual disease (MRD) with that
of the previous AIDA-like protocols, COG protocol and ICC APL Study 01
• To estimate the cumulative incidence of both molecular and hematological
relapse
• To calculate the probability of overall survival and the early death rate
• To prospectively evaluate the impact of FLT3-ITD on this patient population
• To compare the duration of hospitalization and quality of life with those of
the previous AIDA-like protocols and ICC APL study 01

The ICC APL Study 02 is an international, multi-center non-randomized study
delivering risk-stratified treatment based on the ICC APL 01 Study and
experiences from adults on the efficacy of the combination of ATRA plus ATO in
SR patients with APL.
The part of the study for HR patients was started after a safety run-in phase
enrolling 6 patients. The toxicity data from these 6 patients has been
evaluated, and no problems were identified.

The introduction of ATRA has been crucial for both antileukemic efficacy in APL
and for reducing the early death rate. More recently, ATO, first introduced for
treatment of patients with refractory/relapsed PML/RARα positive APL, has been
shown to be highly effective for achieving high cure rates in association with
reduced toxicity in adults with APL.
In a recent randomized clinical trial in adult patients affected by SR APL
showed that a combination of ATO and ATRA offers better survival rates with
significantly lower toxicity and better Quality of Life, as compared to the
standard ATRA + idarubicin (AIDA) therapy.

Side effects of GO are myelosuppression, allergic reactions and liver toxicity
including sinusoidal obstruction syndrome (SOS). GO has been shown to elicit a
significant antileukemic activity in AML, being especially active in APL, due
to the high expression of the CD33 antigen on APL cells.

We consider treatment according to ICC APL study02 the best available treatment
for pediatric APL patients. Therefore this treatment is the standard treatment
for these patients in the Netherlands. We expect to see less toxicity as a
result of this treatment.