Acute Promyelocytic Leukemia (APL) is characterized by a chromosomal translocation containing the retinoic acid receptor alpha (RARα or RARA) gene and is distinguished from other forms of Acute Myeloid Leukemia (AML) by its responsiveness to anthracyclines, such as All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) therapy.1
On Monday 12th December, at the 59th American Society of Hematology (ASH) Annual Meeting, there was an oral abstract session titled “Acute Myeloid Leukemia: Clinical Studies: Novel Therapies for AML and APL”. This session was moderated by Mark G. Frattini, of the Columbia University Medical Center and Justin M. Watts, of the University of Miami Miller School of Medicine. At this session, there were two talks primarily on novel therapies for APL patients.
Hong-Hu Zhu from Peking University People’s Hospital, Beijing, China presented data at this oral abstract session from a multi-center, randomized, phase III non-inferiority study (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054), which is assessing the efficacy and safety of Realgar-Indigo Naturalis Formula (RIF), an oral arsenic, in combination with ATRA compared to intravenous ATO plus ATRA therapy in newly diagnosed non high-risk APL patients.2
Overall, 109 patients were enrolled and randomly assigned (2 : 1) to receive either oral RIF plus ATRA (n = 73) or ATO plus ATRA (n = 36) as induction therapy until complete hematologic remission. As post-remission therapy, RIF or ATO was given on a schedule of 4 weeks’ on and 4 weeks’ off, in addition, ATRA was administered on a schedule of 2 weeks’ on and 2 weeks’ off for 7 months. The primary endpoint of the study was Event Free Survival at two years. The secondary endpoints of the study were Complete Remission (CR), Overall Survival (OS) and safety.
The key findings in the intended treatment analysis in patients (n = 105) in the RIF-ATRA (n = 69) and ATRO-ATRA (n =36) arms at the data cut-off (August 2017) were as follows:
- CR in the RIF-ATRA and ATO-ATRA arms: 100% (69/69) vs 94.4% (34/36) respectively, P = 0.12
- 2-year EFS rate in the RIF-ATRA and ATO-ATRA arm: 97.1% vs 94.4%, P = 0.49
- EFS rate difference between the RIF-ATRA and ATO-ATRA arms was 2.7% (95% CI, 5.8–11.1)
- The lower limit of the 95% CI for EFS rate difference was greater than -10% non-inferiority margin, confirming non-inferiority; P = 0.0017
- OS was significantly longer in the RIF-ATRA arm compared to the ATO-ATRA arm: P = 0.046
- There was no significant difference in relapse between the RIF-ATRA and the ATO-ATRA arm: P = 0. 32
- Liver damage during induction in the RIF-ATRA vs ATO-ATRA arms: 58% vs 78%, P = 0.05
The presenter concluded by stating that RIF plus ATRA is not inferior to ATO plus ATRA as first-line treatment of patients with non high-risk APL. Hong-Hu Zhu further added that their results suggest that “oral, chemo-free outpatient model might be an alternative to current frontline treatment of APL.”
Previous results from a phase III randomized controlled trial which is evaluating the advantage of tamibarotene, synthetic retinoid, to ATRA in maintenance therapy for newly diagnosed APL have demonstrated that 4-year RFS did not significantly differ between patients treated with ATRA or tamibarotene. However, an improved efficacy of tamibarotene in high-risk patients was suggested, thus further investigation was required.4 The speaker presented the long-term outcomes of patients treated in this phase III randomized study.
Overall, 347 newly diagnosed APL patients (median age = 48 years) were enrolled in this study with cytogenetic and/or molecular evidence of t(15;17)/PML-RARA. For induction therapy, ATRA (45 mg/m2 daily) was administered to all patients until Complete Remission (CR) or for 60 Days. Of the 344 eligible patients, 318 (92.4%) patients achieved CR.
After completing three courses of consolidation therapy, 269 patients who achieved molecular remission were randomly assigned to two groups of maintenance therapy, and administered tamibarotene (6 mg/m2 daily, n = 134 [median age = 48 years]) divided into 2 doses for 14 days or ATRA (45 mg/m2, n = 134 [median age = 46 years]) divided into 3 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years. The primary endpoint of the study was hematological or molecular RFS during the maintenance and follow up period of 7 years.
- 7-year RFS in the tamibarotene and ATRA group; 92% vs 84%, P = 0.030
- 7-year RFS in high-risk patients (n = 52) with an initial leukocyte count ≥ 10,000/µl in the tamibarotene and ATRA group, respectively: 89% vs 63%, P = 0.034
- Twelve patients developed secondary hematopoetic disorders:
- Median time to onset: 3.2 years (range, 0.7–8.2)
- Fourteen patients developed secondary malignancies:
- Median time to onset: 6.0 years (range: 0.8–8.6)
- Grade 3 cardiac complications developed in five patients
- There was no difference in long-term complications between tamibarotene and ATRA groups
Overall, the presenter stated that the analysis at 7 years revealed that “maintenance therapy with tamibarotene was effective to decrease relapse compared with ATRA”. Moreover, tamibarotene was more effective than ATRA in high-risk patients with initial leukocyte count ≥ 10,000/μl. Additionally, due to the long-term complications observed in this study, the speaker noted that these complications should be “carefully evaluated in APL”, particularly in patients whose survival has been dramatically improved.
The speaker further concluded by stating that the results from this study “could lead to a new strategy for the treatment of high risk patients, which is one of the recent priority issues in the treatment of APL.”