Outcomes of APL patients treated with ATRA-ATO and gemtuzumab

Previous reports on three consecutive prospective trials (ID01-014, NCT01409161, & NCT00413166) with All Trans Retinoic Acid (ATRA) in combination with Arsenic Trioxide (ATO) either with or without gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody conjugated to the toxin calicheamicin, in Acute Promyelocytic Leukemia (APL) patients with high-risk (White Blood Count [WBC] higher than 10 x 10⁹/L) disease and low-risk disease who develop leucocytosis (WBC > 10 x 10⁹/L) during initial therapy has revealed that ATRA-ATO with or without GO is an effective regimen.¹ There is a paucity of studies demonstrating the durability of these prospective studies.

Yasmin Abaza from The University of Texas MD Anderson Cancer Center (MDACC) Houston, Texas, and colleagues carried out a long-term follow-up study on these three consecutive prospective trials in APL patients. The results of the study were published in Blood.²

187 newly diagnosed APL patients (low-risk, n = 133; high-risk, n = 54; median age = 50 years) and treated at the MDACC between July 2002–May 2015 were enrolled. Patients received ATRA-ATO (ATRA = 45 mg/m² daily and ATO = 0.15 mg/kg daily) combination with a dose of GO (9 mg/m² on day 1) or idarubicin (when GO is unavailable) added to high-risk patients or low-risk patients who experience leucocytosis during induction. Median follow-up of surviving patients was 47.6 months.

The key results of the study were:

• Complete Remission (CR) after induction course: 96% of patients (n = 176)
• Relapses reported in 4% of patients (n = 7, 5 high-risk, 2 low-risk), with relapse occurred 7.9–79.5 months after achieving CR
• 5-year Event Free Survival (EFS), Overall Survival (OS), and Disease Free Survival (DFS) were 85% (P < 0.001), 96% (P = 0.484), and 88% (P < 0.001), respectively
• 5-year EFS, OS, and DFS in low-risk and high-risk patients; 87%, 99%, and 89% vs 81%, 89%, and 86%, respectively
• Death occurred during induction due to disease-related complications (n = 7), relapsed/refractory APL (n = 2), and unrelated causes (n = 17)
• Most frequent grade 3–4 Adverse Events (AEs) include infections (n = 44), QT prolongation (n = 14), and hemorrhage (n = 10)

In summary, combination of ATRA-ATO with or without GO is safe and effective in newly diagnosed APL patients with durable responses.

The authors noted that their study is limited by its “single-group non-randomized nature”. They concluded their study by stating that “the combination of ATRA, ATO, with or without GO, should be considered as the new standard of care for all newly diagnosed patients with APL”.

Uwe Platzbecker from The University Hospital Carl Gustav Carus, Dresden, commented on the findings of this study.³ Of note, he highlighted that relapses in APL patients occurred during the first year of treatment and further suggested that “patients should be followed by MRD surveillance for a period of at least 2 years”. He also emphasized that the findings of this study provided the basis of prospective trials that led to the approval of ATRA-ATO combination by the European Medicines Agency (EMA) for first line therapy in lower-risk APL patients. He concluded by stating that “ATRA and ATO have now progressed beyond an occasional date to a true civil union for lower-risk APL patients”.

Abstract

The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.