Long-Term Follow-Up Shows Arsenic Trioxide Plus All-Trans Retinoic Acid Extends Survival for Acute Promyelocytic Leukemia

Results from a 12-year follow-up study of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) confirm that the ATRA/ATO combination leads to longer survival, with acceptable toxicity, in patients with newly diagnosed acute promyelocytic leukemia (APL).

Previous trials examined ATRA/ATO with or without chemotherapy in this patient population, but, according to first author Hongming Zhu, MD, from the Shanghai Institute of Hematology, and colleagues, this is the first study to report on the adverse effects (AEs), long-term toxicity, and secondary carcinogenesis of ATO.

Dr. Zhu and co-authors assessed AEs and survival, as well as total arsenic (TA) retention, in 265 patients with newly diagnosed APL. Patients were enrolled between January 2001 and June 2012; all were treated with ATRA/ATO with or without chemotherapy. A total of 112 patients participated in the final assessment; their outcomes were compared with 112 age- and gender-matched healthy controls.

Of the 265 patients enrolled, 178 received chemotherapy during the induction period. Eighteen patients (6.8%) died during induction due to intracranial hemorrhage (n=12), disseminated intravascular coagulation (n=3), differentiation syndrome (n=1), and cerebral infarction (n=1). Two additional patients failed to reach complete remission (CR), both of whom remained positive for the disease-defining molecular translocation of PML-RARA.

Overall, 245 patients (92.5%) achieved CR, though four patients relapsed and died during the consolidation and maintenance phases of the study. By September 30, 2015, another 17 patients had relapsed, four occurring five years after treatment initiation.

After a median follow-up of 83 months (range = 0-173 months), the estimated survival rates were:

  • 80.9% for 12-year event-free survival (EFS)
  • 87.4% for median overall survival (OS)
  • 89.1% for median disease-free survival (DFS)

The survival benefit with ATRA/ATO was particularly significant for patients with low- to intermediate-risk APL (defined as a white blood cell [WBC] count ≤10×109/L; TABLE). “ATO appears to have a limited contribution to the high-risk group, indicating that the current regimen may not be sufficient to completely eliminate APL-initiating cells,” the authors noted.

In the 112 APL patients who were selected for the comparison with healthy controls, Dr. Zhu and colleagues found that “though ATO is considered a potential toxicant and carcinogen … the common signs of chronic arseniasis, such as cardiovascular events, chronic renal insufficiency, diabetes, or neurologic dysfunction, were not observed.” One patient developed breast cancer three years after the cessation of ATO treatment, though this is not a typical type of secondary cancer caused by ATO, according to the authors.

However, grade 1 liver dysfunction occurred in 15.2 percent of patients (n=17) and hepatic steatosis occurred in 42.9 percent (n=48), though none of these patients had previous hepatitis. No liver fibrosis was detected during follow-up. “The involvement of chemotherapy, the significantly higher dose of ATO in our regimen, and other conditions including dietary habits might also contribute to hepatic disorders,” the authors wrote.

Eight patients developed skin lesions, including hyperpigmentation, hypopigmentation, or hyperkeratosis/hyperplasia. Development of these lesions occurred during maintenance therapy or within six months after treatment and were reversed within two to 18 months, leading the authors to note that “skin lesions might be associated with ATO, but were reversible.”
ATRA/ATO treatment did not appear to have a significant negative effect on patients’ quality of life, the authors added. Mean scores on quality-of-life-scale, functional scale, and symptom scale were 79.2, 92.7, and 6.9 (all out of 100), respectively, and the chief complaints were related to mild-to-moderate weakness (55.4%), degenerated memory (41.1%), and financial difficulties (33%).

TA retention, measured via plasma mass spectrometry of blood, urine, hair, and nail samples, was significantly elevated during ATO infusion, but returned to normal levels within six months after cessation of treatment – to levels similar to those of healthy controls (6.43 vs. 8.99 ng/g in plasma; p<0.001 and 45.28 vs. 57.55 ng/mL in urine; p=0.004). TA levels in hair and nail samples revealed a delayed increase in TA levels, which decreased to normal and stable levels after six months. Again, these levels were comparable to those in the control group (195 vs. 198 ng/g in hair and 294.65 vs. 338 ng/g in nails; p>0.05 for both).

“APL patients treated with ATRA/ATO combination therapy demonstrated encouraging long-term survival, particularly in the low-to-intermediate risk group, with good quality of life,” the authors concluded. “ATO was generally safe for APL patients, with no major chronic AEs, secondary carcinoma, or arsenic retention.”

However, the study results showed a higher incidence of hepatic disorders in patients, though the mechanisms of this effect are yet to be elucidated. The authors noted that laboratory studies should be performed to evaluate the role of ATO in hepatic disorders so that the dose can be modified if necessary.


Reference

Zhu H, Hu J, Chen L, et al. The 12-year follow-up of survival, chronic adverse effects and retention of arsenic in patients with acute promyelocytic leukemia. Blood. 2016. [Epub ahead of print]

TABLE. Comparison of Survival Rates Between Patients with Low- to Intermediate-Risk and High-Risk APL
Low- to intermediate-risk group High-risk group P Value
Event-free survival 85.2% 67% 0.002
Overall survival 90.4% 77.5% 0.008
Disease-free survival 92.6% 76.8% 0.001

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