A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535)

Abstract

High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

Conflict of interest statement

Conflict-of-interest disclosure: J.E.L. has a consulting or advisory role with Jazz Pharmaceuticals, Agios, AbbVie, Pfizer, and Daiichi-Sankyo and receives research funding from Prescient. M.S.T. receives research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, and Biosight and has a consulting or advisory role with AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta-Fly Pharma, Oncolyze, and Jazz Pharmaceuticals. M.O. has a consultant or advisory role with Celgene, Glycomimetics, and Merck. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment schema. CR, complete response; 6-MP, 6-mercaptopurine.

Figure 2.

Study flow diagram. Note that 1 patient who achieved CR did not complete induction therapy because of insurance issues. *Two patients who were ineligible for step 1 also registered for steps 2 and 3; they are not shown here after induction therapy. AE, adverse event; C, cycle; CNS, central nervous system; MD, treating physician; RT, reverse transcription; tx, treatment.

Figure 3.

Survival analyses. (A) EFS. (B) OS. (C) RFS. (D) EFS in patients with CR.