Acute promyelocytic leukemia (APL) is among the most curable forms of pediatric acute myeloid leukemia, primarily due to the success of ATRA and arsenic trioxide (ATO)-based therapies. However, the contribution of cytarabine (Ara-C) to long-term outcomes remains debated. In this newly published study in Blood Science, researchers present the results of a prospective, randomized trial examining the long-term impact of adding Ara-C during consolidation therapy for children with APL.Study Design and Methods
The study enrolled 66 children aged 14 years or younger with newly diagnosed, genetically confirmed APL between 2010 and 2016. All patients received induction therapy with ATRA and ATO, followed by consolidation with idarubicin and ATO. Patients were then randomized into two groups: one received daunorubicin alone during consolidation (DNR group), while the other received daunorubicin plus cytarabine (DA group). Maintenance therapy consisted of oral ATRA, methotrexate, and 6-mercaptopurine for 1.5 years. All patients also received CNS prophylaxis with intrathecal Ara-C, methotrexate, and dexamethasone. The primary endpoint was event-free survival (EFS), with overall survival (OS) and relapse rates as secondary outcomes.
（Blood Science. 7(2):e00225, June 2025.）
Efficacy Outcomes and MRD Analysis
All patients achieved hematologic complete remission following induction. Measurable residual disease (MRD) testing confirmed that 89.2% of patients were PML-RARA negative after the first consolidation cycle, and 98.5% were negative after the second ATO treatment. Median time to hematologic CR was 31 days. At a median follow-up of 104 months, EFS was 100% in the DA group and 91.4% in the DNR group. Overall survival was 100% and 97.1% respectively. Though not statistically significant, the difference was clinically relevant: all three relapses, including one death, occurred in the DNR group, while no relapses were reported in the Ara-C arm.
Safety Profile and Tolerability
Treatment was generally well tolerated across both groups. However, the DA group experienced higher hematologic toxicity during consolidation, including more frequent neutropenia, greater need for transfusions, and a higher incidence of sepsis. Specifically, 84.2% of DA consolidation cycles resulted in WBC counts below 1.0 × 10⁹/L, compared to just 5.5% in the DNR group. Despite this, all adverse effects were reversible. No long-term toxicities, including neurotoxicity or interstitial lung damage, were observed in either group. There were no early deaths, and even patients presenting with intracranial hemorrhage survived. Supportive measures such as prophylactic antibiotics and liver-protective agents were effectively used.
High-Risk Subgroup Findings
The study examined outcomes in high-risk patients, defined by elevated WBC count at diagnosis. Of the 22 high-risk patients, only those in the DNR group experienced relapse. While the results did not reach statistical significance due to sample size, the trend suggested a protective effect of Ara-C in preventing relapse among high-risk children. The ability of Ara-C to penetrate the CNS may further contribute to its role in preventing extramedullary relapse, as no CNS relapses occurred in the entire cohort.
Mechanistic Context and Clinical Relevance
Preclinical studies have demonstrated that ATRA can enhance cellular sensitivity to Ara-C, and in vitro findings suggest a supra-additive cytotoxic effect when both agents are combined. Historical data also support the role of Ara-C in reducing relapse, particularly in high-risk adult APL. Importantly, Ara-C provides non-overlapping toxicity compared to anthracyclines, which are associated with cardiotoxicity and therapy-related secondary leukemia in children. The combination of ATRA, ATO, and Ara-C therefore presents a potentially safer and more effective long-term approach for pediatric patients, especially those with high leukocyte burden at diagnosis.
Conclusion
This long-term follow-up study reinforces the efficacy and tolerability of ATRA and ATO-based regimens in pediatric APL and provides early evidence that the addition of Ara-C during consolidation may improve long-term outcomes. Although the sample size limited statistical power, the complete absence of relapse in the Ara-C group and its manageable safety profile suggest a meaningful clinical benefit, particularly for high-risk patients. The authors advocate for Ara-C’s continued use during consolidation and encourage further multicenter research to validate these findings and guide treatment refinement.
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https://journals.lww.com/bls/fulltext/2025/06000/long_term_outcome_of_using_ara_c_or_not_in.10.aspx
