ATO Plus ATRA Shows EFS Benefit in Newly Diagnosed, High-risk APL

“We believe that these first results of a first-line therapy with ATRA/ATO with 2 initial doses of idarubicin results in superior EFS compared with conventional ATRA/chemotherapy in patients with high-risk APL,” lead study author Uwe Platzbecker, MD, said.

A combination strategy of arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) and idarubicin showed a significant improvement in event-free survival (EFS) compared with standard ATRA and anthracycline-based chemotherapy in patients with newly diagnosed, high-risk acute promyelocytic leukemia (APL), according to results of the phase 3 APOLLO trial (NCT02688140).¹

The findings, which were presented during the 2024 EHA Congress, showed that at 2 years, the EFS rates were 88% (95% CI, 80%-96%) with ATRA/ATO compared with 70% (95% CI, 59%-83%) with ATRA/chemotherapy (P = .02). Five-year EFS rates were 87% (95% CI, 79%-96%) and 55% (95% CI, 38%-78%), respectively (P = .0034).

“We believe that these first results of a first-line therapy with ATRA/ATO with 2 initial doses of idarubicin results in superior EFS compared with conventional ATRA/chemotherapy in patients with high-risk APL,” lead study author Uwe Platzbecker, MD, head of the medical clinic and policlinic of Hematology, Cell Therapy and Hemostaseology at the University Hospital Leipzig in Leipzig, Germany, said in an oral presentation during the meeting. “Further analysis of the APOLLO trial may support the implementation of this regimen as the new standard of care in patients with high-risk APL.”

ATRA plus ATO has been utilized as a frontline treatment strategy for patients with low- or intermediate-risk APL, based on results of the APOL0406 study.² However, the global gold standard for those with high-risk disease, defined as having a white blood cell (WBC) level at diagnosis of greater than 10 GPt/L, has been ATRA plus anthracycline-based chemotherapy, also known as the AIDA regimen. The ATRA/ATO combination has not been studied within the high-risk setting in the context of randomized trials, providing rationale for the APOLLO study, Platzbecker said.¹

In the international, multicenter, open-label, prospective APOLLO trial, investigators randomized patients to receive induction therapy with ATO and ATRA until complete response (CR), with 2 shots of intravenous idarubicin at 12 mg/m2, plus 4 cycles of consolidation therapy with ATO at a 4-weeks-on/4-weeks-off schedule and ATRA for a 14-days-on/14-days-off schedule (arm A), or induction therapy with idarubicin plus ATRA until CR followed by consolidation therapy with 15 days of anthracycline-based chemotherapy and idarubicin in cycle 1, 15 days of mitoxantrone in cycle 2, and another 15 days of anthracycline-based chemotherapy and idarubicin in cycle 3 before receiving maintenance 6-mercaptopurine plus methotrexate with ATRA for 2 years.

To be eligible for enrollment, patients had to have had newly diagnosed APL, be between 18 and 65 years, have a WBC of more than 10 GPt/L at diagnosis, an ECOG performance status of 0 to 3, a serum total bilirubin level of 3.0 mg/dL or lower (≤51 μmol/l), and serum creatinine level of 3.0 mg/dL or lower (≤260 μmol/l).

The primary end point was EFS. Investigators sought to improve EFS by 10% from 77% to 87% after 2 years, with a target enrollment of 280 patients and a HR of 0.53.

Patients were recruited from 143 sites in 6 European Union countries between 2016 and 2022, with 133 patients enrolled; Platzbecker noted that enrollment was delayed due to the COVID-19 pandemic and there was an early termination due to study drug expiration. A total of 131 patients

were evaluable for outcome analysis and 120 were evaluable for disease status after induction treatment.

Across both arms (n = 131), the median age was 46.0 years (range, 18-66; P = .910), more than half were male (51.9%; P = .650), the median WBC count was 35.7 x 10⁹/L (range, 10.1-489.0; P = .866), and the median ECOG performance status was 1 (range, 0-3; P = .381). The median follow-up was 31 months (range, 1.7-71.5).

Additional efficacy data showed that CR/CR with incomplete platelet recovery rates with induction therapy were slightly higher with ATRA/ATO, at 93% vs 90% with ATRA/chemotherapy, which was not statistically significant (P = .654).

Early death rates, considered to be in the first 30 days, were 7% and 10% with ATRA/ATO and ATRA/chemotherapy, respectively (P = .456). Causes of death included intracranial bleeding (ATRA/ATO, n = 3; ATRA/chemotherapy, n = 4), thrombosis (ATRA/ATO, n = 1; ATRA/chemotherapy, n = 1), sepsis (ATRA/chemotherapy, n = 2), and respiratory insufficiency due to hyperleukocytosis (ATRA/ATO, n = 1).

Molecular resistance rates were not statistically significant, reporting at 1.7% with ATRA/ATO and 5.5% with ATRA/chemotherapy (P = .268). Platzbecker added there were no achievements of molecular remission after the last consolidation course. The 2-year cumulative incidence of relapse was 1.6% (95% CI, 0.1%-7.5%) and 14.0% (95% CI, 6.2%-26.0%), respectively (P = .011), and 7 molecular relapses and 1 hematological relapse occurred within 2 years. These contributed to the significantly higher EFS rates with ATRA/ATO, Platzbecker said.

The 2-year overall survival (OS) rates were 93% (95% CI, 87%-99%) with ATRA/ATO and 87% (95% CI, 78%-96%) with ATRA/chemotherapy (P = .17). At 5 years, the OS rates were 93% (95% CI, 87%-99%) and 82% (95% CI, 71%-95%), respectively (P = .17). These data were not statistically significant, he added.

Regarding safety, hematologic toxicity was significantly lower in the experimental arm. Grades 1 to 4 thrombocytopenia within 15 days of treatment was 15% with ATRA/ATO vs 22% with ATRA/chemotherapy in the induction phase (P = .293), 0% vs 16%, respectively, in consolidation cycle 1 (P <.001), 0% vs 56% in cycle 2 (P <.001), and 0% vs 51% in cycle 3 (P <.001).

Grade 3/4 neutropenia within 15 days was 22% with ATRA/ATO and 46% with ATRA/chemotherapy in the induction setting (P = .005), 1% vs 19%, respectively, in consolidation cycle 1 (P <.001), 1% vs 52% in cycle 2 (P <.001), and 1% vs 24% in cycle 3 (P <.001).

Other reported toxicities between the 2 arms included grade 3/4 QTc prolongation at 4.4% with ATRA/ATO vs 0% with ATRA/chemotherapy, grade 3/4 hepatic toxicity (11.8% vs 14.3%, respectively; P = .8), and differentiation syndrome (1.5% vs 4.8%; P = .27).

Disclosures: Platzbecker cited honoraria/expenses from Celgene/Bristol Myers Squibb (BMS), Novartis, Jazz, and Abbvie; consulting/advisory board roles with Celgene/BMS; and funded research with Celgene/BMS, Novartis, Curtis, Jazz, Abbvie, and Teva.

References

1. Platzbecker U, Adès L, Montesinos P, et al. First results of the APOLLO trial: a randomized phase III study to compare ATO combined with ATRA versus standard AIDA regimen for patients with newly diagnosed, high-risk acute promyelocytic leukemia. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S102.
2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Eng J Med. 2013;369(2):111-121. doi:10.1056/NEJMoa1300874