New Findings in Acute Promyelocytic Leukemia


Key Points

  • There may be benefit of tamibarotene vs ATRA maintenance in high-risk acute promyelocytic leukemia.
  • Arsenic trioxide–related cardiac events are rare despite frequent QTc prolongation.
  • ATRA/arsenic trioxide is associated with some health-related quality-of-life benefits vs ATRA/chemotherapy.

Three studies reported in the Journal of Clinical Oncology provide information on maintenance treatment with the synthetic retinoid tamibarotene in acute promyelocytic leukemia, potential implications of QT interval prolongation related to arsenic trioxide (Trisenox), and potential health-related quality-of-life benefits with all-trans retinoic acid (ATRA) plus arsenic trioxide vs ATRA/chemotherapy in low- or intermediate-risk acute promyelocytic leukemia.

Tamibarotene vs ATRA Maintenance

In a Japanese phase III trial in 344 patients, Shinagawa et al found no significant difference in relapse-free survival with the synthetic retinoid tamibarotene vs ATRA as maintenance therapy in patients with newly diagnosed acute promyelocytic leukemia in molecular remission after consolidation therapy. Both agents were given for 14 days every 3 months for up to 2 years. Tamibarotene is more potent in vitro than ATRA and has a lower affinity for the cellular retinoic acid binding protein, which has been found to be overexpressed in cases of ATRA resistance.

Relapse-free survival at 4 years was 91% in the tamibarotene group vs 84% in the ATRA group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.26–1.13). Analysis restricted to 52 high-risk patients showed benefit of tamibarotene (87% vs 58%, HR = 0.26, 95% CI = 0.07–0.95). In patients without high-risk disease, the HR was 0.82 (95% CI = 0.32–2.01); the test for interaction between treatment effect and these subgroups approached significance (P = .075). Both treatments were reported to be well tolerated.

The investigators concluded: “[N]o difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.”

QT Prolongation With Arsenic Trioxide

Arsenic trioxide is a standard of care in relapsed/refractory acute promyelocytic leukemia, but is associated with a high frequency of QT segment prolongation that may limit effective treatment. In an analysis by Roboz et al of 113 patients with non–acute promyelocytic leukemia acute myeloid leukemia and myelodysplastic syndrome treated with arsenic trioxide in a previous trial, Roboz et al found no cardiac events despite a high frequency of QTc prolongation and also noted marked differences in rates of prolongation according to different rate correction formulas.

Overall, 26% of patients had rate-uncorrected QT values > 470 ms and 12% had values > 500 ms. On the widely used Bazett rate correction formula, 90% had QTc > 470 ms, including 65% with QTc > 500 ms. However, on alternative correction formulas, only 24% to 32% had QTc > 500 ms.

Prior to a protocol amendment in the trial that allowed rate-uncorrected QT measurements, instead of Bazett correction QTc < 500 ms, for continuation of therapy, dosing was held due to prolonged QTc 52 times in 16 patients. The QTc interval always returned to normal and no patient discontinued therapy. After the protocol change, there were 167 instances of prolonged Bazett correction QTc prolongation, but only 29 instances of holding treatment due to prolonged rate-uncorrected QT. Among all patients, there were no clinically significant arrhythmias during routine electrocardiography, no symptomatic dizziness or syncope, and no cardiac deaths.

The investigators concluded: “QT interval prolongation is common with [arsenic trioxide] treatment, but clinically significant arrhythmias are rare and can be avoided with appropriate precautions. Use of the Bazett correction may result in unnecessary interruptions in [arsenic trioxide] therapy, and alternative rate correction formulas should be considered for routine electrocardiographic monitoring.”

Health-Related Quality of Life With ATRA/Arsenic Trioxide vs ATRA/Chemotherapy

A European phase III trial reported in 2013 showed noninferiority of first-line ATRA plus arsenic trioxide vs ATRA plus chemotherapy in event-free survival among 162 patients with low- or intermediate-risk acute promyelocytic leukemia. As reported by Efficace et al, there were health-related quality-of-life benefits associated with the ATRA-plus–arsenic trioxide regimen. Analysis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, showed that fatigue was the only scale with a significant overall difference between treatment groups (P = .0220), favoring the ATRA/arsenic trioxide group overall and after induction therapy (P = .034), but not after the third consolidation course (P = .660).

After induction, the ATRA/arsenic trioxide group also had small but clinically relevant improvements in severity of nausea/vomiting, appetite loss, and constipation and in the functional measures of physical and cognitive functioning compared with ATRA/chemotherapy. The only difference between groups after third consolidation was a small but clinically relevant improvement in diarrhea in the ATRA/arsenic group vs the ATRA/chemotherapy group.

The investigators concluded: “Overall, current [health-related quality-of-life] findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk [acute promyelocytic leukemia].”

Masamitsu Yanada, MD, PhD, of Fujita Health University School of Medicine, is the corresponding author for the tamibarotene vs ATRA maintenance study. The study was supported in part by grants from the Ministry of Health, Labor, and Welfare of Japan and the National Cancer Center Research and Development Fund.

Gail J. Roboz, MD, of Weill Medical College of Cornell University, is the corresponding author for the study examining QT prolongation with arsenic trioxide.

Fabio Efficace, PhD, of GIMEMA, is the corresponding author for the study on health-related quality-of-life benefits with ATRA/arsenic trioxide. The study was supported in by the Associazione Italiana contro le Leucemie-linfomi e mieloma and Associazione Italiana per la Ricerca sul Cancro, the Federal Ministry of Education and Research, and in part by Lundbeck.

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