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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 ), longterm 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 diseasedefining 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 followup of 83 months ( range = 0-173 months ), the estimated survival rates were :
• 80.9 % for 12-year eventfree survival ( EFS )
• 87.4 % for median overall survival ( OS )
• 89.1 % for median diseasefree survival ( DFS )
TABLE 1 . 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
The survival benefit with ATRA / ATO was particularly significant for patients with low- to intermediaterisk APL ( defined as a white blood cell [ WBC ] count ≤10x10 9 / L ; TABLE 1 ). “ 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-lifescale , 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-tomoderate 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 followup of survival , chronic adverse effects and retention of arsenic in patients with acute promyelocytic leukemia . Blood . 2016 . [ Epub ahead of print ]
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