Oral ATO/ATRA/Ascorbic Acid Regimen Delivers Durable Responses in APL


Harry Gill, MD, discusses the importance of offering patients with APL an entirely oral treatment regimen, key efficacy findings from this trial, and the tolerability of this regimen.

Harry Gill, MD

Harry Gill, MD

An all-oral regimen of oral arsenic trioxide (oral-ATO), all-trans retinoic acid (ATRA), and ascorbic acid represents an accessible, tolerable, and effective treatment option for patients with acute promyelocytic leukemia (APL), including pediatric patients, according to Harry Gill, MD.

In 2019, Gill and colleagues found that the addition of oral-ATO to induction ATRA and ascorbic acid followed by consolidation chemotherapy and 2 years of oral-ATO, ATRA, and ascorbic acid maintenance therapy led to a 100% complete response (CR) rate in the frontline setting in patients with newly diagnosed APL. At a median follow-up of 37 months (range, 13-82), no patients had relapsed.1

At the 2023 EHA Congress, Gill presented findings from a risk-adapted treatment strategy of an entirely oral ATO, ATRA, and ascorbic acid regimen in patients with newly diagnosed APL, who received no chemotherapy except in low- and high-risk cases.2 At a median follow-up of 27 months (interquartile range, 7-44), all treated patients achieved a CR . Additionally, the 3-year overall survival (OS) rate was 98.9%, and the 3-year relapse-free survival (RFS) rate was 97.1%.

“It’s important to have an oral formulation that’s available and accessible to patients, is convenient, and won’t disrupt patients’ quality of life,” Gill said in an interview with OncLive® during the EHA Congress.

In the interview, Gill discussed the importance of offering patients with APL an entirely oral treatment regimen, key efficacy findings from this trial, and the tolerability of this regimen.

Gill is a clinical associate professor of hematology in the Department of Medicine at the University of Hong Kong in China.

OncLive: What was the rationale for investigating oral ATO, ATRA, and ascorbic acid in patients with newly diagnosed APL?

Gill: [This is] an important study in our locality, as well as in Asia [as a whole, where there is] a lack of access to intravenous [IV] ATO because of cost and reimbursement issues. In this study, we recruited 105 patients over a 5-year period. Before the patients could be dosed, there were 7 early deaths. [The remaining] patients were treated with an entirely oral regimen of ATO, ATRA, and ascorbic acid.

Chemotherapy was only required if patients had a white blood cell [WBC] count of at least [109/L] at initial diagnosis. Those patients were given early concurrent chemotherapy with daunorubicin for 3 days. The subsequent consolidation and maintenance regimen was entirely oral and chemotherapy free, unlike the previous regimens for high-risk patients. The patients with a WBC count of less than 109/L were given a chemotherapy-free regimen from the beginning. If leukocytosis occurred, we gave a brief duration of hydroxyurea hydroxycarbamide for blood count control.

What were the eligibility criteria for this trial?

Our patients [were] aged from the pediatric population, so there was no age limitation. In 1 of the interim analyses, we already have 5 patients under the age of 18. The youngest patient was 3 years of age.

[This is] the advantage of the oral formulation. The oral formulation of pure ATO was invented and formulated in Hong Kong. Its solution is 1 mg/mL, so it’s suitable for pediatric dosing.

Patients tolerate it well. We looked out for pre-existing severe chronic comorbidities like chronic liver failure or underlying congenital long QT syndrome. These constituted some of the exclusion criteria. [Otherwise], patients tolerate [the regimen] well, and most patients diagnosed with APL were eligible for this treatment.

What were the efficacy findings from this trial?

All patients who were treated achieved a CR. [Regarding] molecular responses, after 4 to 8 weeks of treatment, we expected a 3-log reduction in the PML RARA fusion transcripts. After approximately 20 weeks of treatment, we expected complete molecular remission. Throughout the study period, and after the completion of treatment and throughout the follow-up period, we only had 1 relapse, and that relapse was because of a specific mutation in the PML B2 domain that conferred resistance to ATO. That patient died from refractory APL.

Otherwise, all patients responded, and they responded well. The median duration of follow-up was 27 months, and we’re seeing a [3-year] OS rate of 98.9% and an RFS rate of 97.1%. This study is still ongoing. We will be recruiting patients outside Hong Kong, in mainland China, as well as in other parts of Asia, such as Singapore, Malaysia, and Taiwan, at a later stage. [This is] a multicenter study in Asia.

What is the safety profile of this regimen?

There were no specific safety signals, and no treatment-related deaths. The most common non-hematologic toxicities were headache, which was all grade 1/2, as well as transaminitis, again, all grade 1/2. Headache occurred in 33% of patients, whereas [transaminitis] occurred in 55% to 50% of patients.

[All those adverse effects were] reversible with dosage reduction. None of the toxicities led to treatment discontinuations. There were no other safety signals, no cardiac signals, and no arrhythmias, [even] in the patients with long QT intervals.

How might this regimen fit into the treatment paradigm for patients with APL in the future?

The data show that [patients with] APL could be treated with an entirely oral regimen from induction, or early after CR is achieved [with a different frontline regimen]. These patients can be treated on an outpatient basis, [which is] in contrast to the [requirements of] current treatment regimens in high-risk patients that usually [consist of] chemotherapy. Patients [who receive chemotherapy] require prolonged hospital stays or repeated hospitalizations for consolidation chemotherapy. Even the low-risk populations outside Hong Kong are given IV ATO in repeated cycles, which also requires hospital attendance. Another implication is the cost and the accessibility of this agent to this needful population.

Disclosures: This research was funded by Jacobson Pharma Corporation.


  1. Gill H, Kumana CR, Yim R, et al. Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: a 5-year prospective study. Cancer. 2019;125(17):3001-3012. doi:10.1002/cncr.32180
  2. Gill H, Yim R, Chin L, et al. An entirely oral regimen of oral-ATO, ATRA and ascorbic acid in risk-adapted treatment of newly-diagnosed APL resulted in excellent clinical/molecular responses with durable remission. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S133.

Related Videos
Experts on FL
Expert on FL
Johannes Schetelig, MD, MSc, head, Stem Cell Transplantation Unit, University Hospital TU Dresden, head, DKMS Clinical Trials Unit,
Experts on myelodysplastic syndrome
Experts on myelodysplastic syndrome
Experts on GVHD
Experts on GVHD
Expert on FL
Experts on FL
Courtney DiNardo, MD, MSCE
Related Content