Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia

TO THE EDITOR:

Acute promyelocytic leukemia (APL) has now become a highly curable disease using an all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)–based treatment. The practice-changing study APL0406 reported by Lo-Coco et al demonstrated that non–high-risk APL patients, defined by a presenting white blood cell (WBC) count ≤10 × 10⁹/L, can be cured using only ATRA and ATO without chemotherapy.^1,2  We also found similar results using a totally oral arsenic and ATRA chemotherapy-free outpatient protocol (outpatient model) for non–high-risk APL.³ 

For high-risk APL patients (WBC count >10 × 10⁹/L), attempts at minimizing chemotherapy have proven feasible using ATRA, ATO, and gemtuzumab ozogamicin (GO) or idarubicin with an overall survival (OS) of 65% to 87%.^4-6  Because of the lack of availability of GO outside of Europe, the necessity of ATO infusions being provided in hospital settings, and relatively inferior outcomes, a novel treatment of high-risk cases is warranted. Therefore, we attempt to extend our outpatient model to high-risk APL patients.

From April 2014 through September 2016, we conducted a single-center cohort study to evaluate the efficacy and safety of oral arsenic and ATRA for high-risk APL patients (protocol provided in the supplemental Material, available on the Blood Web site). Twenty patients received oral arsenic realgar-indigo naturalis equation (60 mg/kg daily in an oral divided dose) and ATRA (25 mg/m² daily in an oral divided dose) as induction therapy until achieving a hematologic complete remission (CR). For patients with a WBC count of (10-20) × 10⁹/L before treatment, only hydroxyurea (3.0 g daily in an oral divided dose) was used from the first day until a WBC <10 × 10⁹/L was achieved. For patients with a WBC count >20 × 10⁹/L before treatment, hydroxyurea (3.0 g daily in an oral divided dose) and cytarabine (200 mg daily in an IV dose) were used from the first day to diminish the burden of leukemia until a WBC <10 × 10⁹/L was achieved. The definition of differentiation syndrome and its moderate and severe forms were according to a previous report.⁷  No prophylactic drug for differentiation syndrome was administered during the induction therapy. At the earliest manifestations of suspected differentiation syndrome, prednisone (0.5 mg/kg daily) or dexamethasone (10 mg daily in an IV dose) was administered until the disappearance of signs and symptoms for a minimum of 3 days.

The consolidation therapy included realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m² daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary endpoint was the complete molecular response (CMR) postconsolidation, defined as the absence of detectable PML-RARA transcripts using ABL as an internal control by quantitative polymerase chain reaction. Secondary endpoints included CR, event-free survival (EFS), OS, safety, and medical costs. The median follow-up was 33 months (range 16-45 months) by January 2018.

All 20 patients achieved a CR after a median time of 30 days (range, 28-50 days) (supplemental Table 1). All 20 patients received hydroxyurea, including 16 patients who received cytarabine simultaneously (supplemental Table 1). The median time of cytarabine administration was 6 days (3-14 days). The CMR rate was 85% and 100% at 3 and 6 months (Figure 1A), respectively. Grade 3 to 4 liver adverse events and differentiation syndrome occurred in 0 and 7 patients during induction (Table 1). No hematological relapse occurred. Two patients had a molecular relapse at 12 and 15 months and achieved a CMR again and maintained a continuous CR until now after receiving the same protocol mentioned above without stem cell transplantation (supplemental Table 1). The 3-year estimated OS and EFS are 100% and 89.4% (95% confidence interval, 75.49% to 100%) (Figure 1B), respectively. The total hospital time was 25 days (4-37 days) per patient. All (100%, 20/20) of the patients completed the postremission therapy on an outpatient basis without hospitalization. The median of total medical costs was $7540 ($5490-$26 530). Patients resumed their usual lifestyle during postremission therapy and thereafter.

The last battle for a cure for all APL patients lies in the high-risk patients. Iland et al added ATO to an ATRA plus idarubicin regimen followed by consolidation with ATRA + ATO, which achieved a 5-year OS of 87%.⁶  Ravandi et al demonstrated the feasibility and long-term efficacy of a chemotherapy-free strategy of ATRA + ATO + GO in a 1-arm study,⁵  which was confirmed by a randomized trial AML17.⁴  The elimination of traditional cytotoxic chemotherapy clearly has potential advantages to minimize the risk of early death and long-term side effects. Owing to the use of oral arsenic, the potential for this outpatient treatment model is likely to become a reality in high-risk APL, similar to that in non–high-risk patients.³ 

In summary, our study, which employed a completely oral, chemotherapy-free outpatient postremission treatment of high-risk APL, proved to be effective, convenient, and cost saving. This approach exemplifies an ideal model for the treatment of high-risk APL. However, strict clinical and laboratory monitoring of these patients for long-term outcomes is warranted.