JHO: Phase 2 study of oral arsenic and tretinoin consolidation in the treatment of high-risk acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a leukemia with a dangerous onset of leukemia with a high recurrence rate and poor
overall survival with chemotherapy alone.
Now with the "dream combination" of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it has become a highly curable disease with a 5-year disease-free survival rate of more than
90%.

Previously, arsenic was administered intravenously, and Professor Huang Xiaojun's research group confirmed for the first time through prospective clinical trials that oral arsenic and intravenous arsenic have similar efficacy and safety, published in the Journal of Clinical Oncology in 2013
.
In 2014, Professor Huang Xiaojun's research group published an article in the New England Journal of Medicine in the form of a letter on oral arsenic combined with all-trans retinoic acid for the treatment of non-high-risk APL, and the molecular complete response rate was 65% at 3 months and 100% at 6 months, and no patients had molecular recurrence
at the last follow-up 。 In 2018, the phase III prospective, multicenter randomized controlled study results of "oral arsenic and tretinoin in the treatment of non-high-risk acute promyelocytic leukemia (APL)" led by Professor Huang Xiaojun were published in Lancet Oncology, and they randomized non-high-risk APL patients to oral arsenic and intravenous arsenic groups (both combined with all-trans tretinoin), and the results showed that the 2-year event-free survival rate was 97% in the oral group and 94% in the intravenous group, confirming the non-inferiority of the former.
To provide the highest level of evidence-based medical evidence
for a new era of non-high-risk APL treatment.

In 2018, the 2018 Chinese APL diagnosis and treatment guidelines recommended the preferred all-trans retinoic acid + arsenic agent induction therapy for APL, marking that China has officially entered the era
of APL without chemotherapy.
It is worth noting that the guidelines still recommend differentiation agents combined with chemotherapy drug induction, consolidation therapy such as anthracyclines combined with cytarabine, and alternate ATRA/arsenic maintenance therapy
for high-risk patients.

So what is the efficacy and safety of chemotherapy-free regimens with oral arsenic plus tretinoic acid in consolidation therapy for high-risk acute promyelocytic leukemia (WBC >10 × 109/L)? A preliminary study of oral arsenic combined with ATRA as first-line consolidation therapy without maintenance therapy was reported in BLOOD in 2018, and the results showed that the estimated 3-year overall survival (OS) and event-free survival rates of 20 high-risk APL patients were 100% and 89.
4%,
respectively.

Therefore, since May 2019, Prof.
Honghu Zhu, Prof.
Jie Jie Jin and Prof.
Suning Chen et al.
have designed a multi-center, single-arm, Phase 2 study to evaluate the efficacy and safety
of oral arsenic combined with ATRA as consolidation therapy in an outpatient setting for high-risk APL.
The findings were published today in the Journal of Hematology & Oncology
.

Research results

A total of 54 patients (ITT population) were enrolled in the study, 15 patients who did not complete the entire consolidation therapy were excluded, and 39 patients were included in the analysis (PP population); Among them, 28 cases were males and 26 were females, with a median age of 40 years
.
The median PML-RARA at enrollment was 0.
19% (0-99%)
.
Induction regimen: 13 (24%) received ATRA + ATO/RIF (no chemotherapy), 41 (76%) received ATRA+ ATO/RIF + chemotherapy; Chemotherapy drugs include anthracyclines, cytarabine, and homoharringlinoid
.
In induction therapy, 42 (77.
8%) and 12 (22.
2%) patients received RIF (compound yellow dai tablets) and ATO (arsenic trioxide).

With a median follow-up of 13.
8 months, the estimated 2-year disease-free survival (DFS) in ITT analysis was 93.
8% and the estimated 2-year OS was 100%; The estimated 2-year DFS in the PP analysis was 93.
1% and the 2-year OS was 100%.

All but three patients were receiving consolidation therapy, the remaining 51 patients achieved complete molecular response (CMR), nearly 90% of which reached CMR 4 months after initiation of induction therapy (Figure 1).

In total, only 2 patients relapsed, and the cumulative recurrence rate at 2 years was 6.
2%.

Forty-eight of the 52 participants who completed at least one cycle of consolidation therapy completed an adverse event assessment
.
As a result, no grade 4-5 adverse events occurred, and the most common non-hematopoietic system toxicity effects were headache (15%), arthralgia and myalgia (19%), dryness (19%), darkening of the skin (10%), and hair loss (10%), and no adverse events
such as infection, renal insufficiency, and cardiotoxicity occurred.
Most adverse events ranged from grade 1 to 2, with only three grade 3 adverse events
observed.
There were no patient deaths during the consolidation phase (table 1).

Taken together, this study found oral arsenic plus ATRA to be both safe and effective as consolidation therapy in adults with high-risk APL, and that all-oral and chemotherapy-free post-remission regimens without maintenance therapy would benefit
more patients with APL in the outpatient setting.

References

1.
Hong-Hu Zhu, Xiao-Jun Huang.
Oral arsenic and retinoic acid for non-high-risk acute promyelocytic leukemia.
N Engl J Med .
2014 Dec 4; 371(23):2239-41.
doi: 10.
1056/NEJMc1412035

2.
Ya-Fang Ma , Ying Lu , Qian Wu,et al.
Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.
J Hematol Oncol .
2022 Oct 18; 15(1):148.
doi: 10.
1186/s13045-022-01368-3.