Chemotherapy-free treatment for children and adolescents with newly diagnosed acute promyelocytic leukemia (APL): Results of the prospective ICC-APL-02 study. Free

Introduction: Treatment of acute promyelocytic leukemia (APL) has been revolutionized over the past two decades by the introduction of both all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to the use of chemotherapy-free protocols in standard-risk (SR) adult patients.

In October 2019, a multicenter European pediatric trial from the International Consortium for Childhood (ICC) APL delivering a non-chemotherapy-based treatment for children with newly diagnosed SR and High Risk (HR) APL was started [NCT04793919]. Here, we report the results of the second planned interim analysis of the ICC-APL-02 study.

Methods: ICC-APL-02 Study is an open-label prospective, non-randomized, multicenter trial for children and adolescents (up to the age of 18) with newly diagnosed APL delivering a risk-stratified treatment [according to the modified pediatric criteria (Testi, Blood 2018)] based on the use of ATRA and ATO, plus gemtuzumab ozogamicin (GO) only in HR patients.

During induction, ATO was given at the dose of 0.15 mg/kg/day iv and ATRA at 25 mg/m²/day orally. Treatment started on day 1 and was continued until achievement of hematological complete remission (CR), for at least 28 days and for a maximum of 60 days. In HR patients only, GO was administered on days +2 and +4 of induction treatment, at the dose of 3 mg/m² iv (maximum 5 mg/dose). During consolidation, ATO was given at the same dose employed during induction for 5 days/week, 4 weeks on and 4 weeks off, for 4 courses, while ATRA (25 mg/m²/day) was administered 2 weeks on and 2 weeks off for 7 courses. In the HR group only, triple intrathecal therapy was administered at the beginning of the 1^st and 3^rd consolidation.

The primary endpoint was to evaluate the efficacy in terms of event-free survival (EFS) of the treatment regimen. Early death, death in CR, resistant disease and hematological relapse were considered as events.

Results: The trial was opened in 52 centers across 5 countries (Italy, France, Czech Republic, Netherlands and Sweden). From 10/2019 to 06/2025, 110 patients were enrolled; 73 were SR (66.4%) and 37 HR (33.6%). Median white blood cell count at diagnosis for SR and HR patients was 2.5x10⁹/L (0.6-9.9) and 18.0x10⁹/L (10.55-151.00), respectively. Median age at diagnosis was 12 years (range 1-17); 45% of patients were females; 49% of patients were FLT3-ITD mutated. Median duration of induction was 37 days (range 28-59), with 36 patients (29 SR and 7 HR) interrupting the treatment for a median of 5 days (range 1-23), due to toxicity which resolved in all cases. During induction, 19 patients (17.3%) developed differentiation syndrome (DS) at a median time of 12 days (range 4-25) from treatment start, which resolved in all patients. Pseudotumor cerebri occurred in 14 patients (12.7%). Four patients experienced clinically-relevant prolongation of the QTc interval, which was successfully managed in all patients (in 3 with temporary ATO discontinuation). One patient developed myocarditis following GO which completely resolved without sequelae; no other drug-related side effect was registered.

One 16-year old, FLT3-ITD+ HR patient died of cerebral hemorrhage during induction (day +30). All patients achieved hematological CR at the end of induction. All but one evaluated patients achieved molecular CR after the third consolidation course. The only positive patient (HR) remained MRD+ also after the end of treatment; he obtained the molecular remission with 2 additional doses of GO and was then treated with autologous hematopoietic stem cell transplantation; he is now alive and disease-free. One SR patient experienced molecular relapse 1 year after completing the treatment protocol; he was re-treated with ATRA-ATO and he is now alive with negative MRD. With a median follow-up of 21 months (range 2-68.7), the 2-yr overall and EFS of the whole cohort are 99% (95% CI 93.4-99.9) (SR 100% vs HR 97.1%, p=n.s.) and 96.4% (95% CI 88.6-98.9) (SR 97.4% vs HR 94.2%, p=n.s.), respectively. Nineteen patients are still on treatment.

Conclusions: This is the first large prospective pediatric trial delivering a non-chemotherapy-based treatment for children with newly diagnosed SR and HR APL.We confirm that ATRA/ATO treatment is safe and highly effective in SR patients. More importantly, the combination of ATRA, ATO and GO in HR subjects showed an excellent safety profile and efficacy in pediatric patients with de novo APL.