The toxicity profile in the initial series reported by us was mild, in the majority.16
Significantly, there were no infusion related toxicities, alopecia or evidence of exacerbation of coagulopathy. Post induction, almost all patients for the rest of the duration of treatment had ECOG performance scores of 0 or 1. The non hematological toxicities, as reported earlier,16
in the majority were mild, frequently reverted on continuing ATO and in the rest were reversible on discontinuing the drug for an interval of 1 – 2 weeks.16
As reported previously 5 (6.9%) cases developed a differentiation syndrome which resolved in 4 and was fatal in one. There were no sudden deaths attributable to a cardiac event in this series of patients and on long term follow up there were no cases with clinical cardiac dysfunction. There were no documented second malignancies documented in this cohort.15
Post remission induction, this regimen, was administered on an out patient basis. With the exception of some early reports of increased hepatic and cardiac toxicity32–35
the majority of subsequent reports using ATO in newly diagnosed cases is similar to our experience.18,19,29–31
There have been periodical major concerns raised about the administration of ATO. Very early there was a concern about cardiac arrhythmia related sudden deaths in patients with APL who were treated with ATO. Almost all these deaths happened in induction in previously heavily treated patients.32–34
There have been no such deaths reported when ATO was used for treating a number of other malignancies, albeit stable patients. Similarly, it does not appear when administered to patients with APL who are in remission (none reported in the literature). The role of QTc interval prolongation and limitations of the corrected QTc interval value generated with tachycardia due to any cause such as infection have been reviewed previously and it increasingly recognized and accepted that QTc prolongation is an electrocardiographic phenomenon with little clinical significance in the majority of patients.36
This does not mean we should not monitor it or ignore it, though response should be judicious and clinically appropriate. It has been reported that in more than 2900 cases treated by US-FDA approved ATO there have been no arrhythmia related deaths.36
We do not believe that there is anything sacrosanct or superior about the US-FDA approved ATO but rather that it in reality it was never a significant clinical problem beyond a few case reports where the arrythmia’s were probably related to other etiologies or at least in part contributed by them.
Next was the suggestion of acute hepatic failure and death from hepatoxocity occurred with ATO.37
There have been no other major reports since this initial publication about 12 years ago. This has definitely not been our experience with more than 250 patients treated to date at our center (newly diagnosed and relapsed).
There has always been a concern of second malignancies with the use of ATO. This is based on in-vitro experiments suggesting oxidative DNA damage38
and clinical observations from cases with long term environmental exposure. This theoretical concern is in contrast to clinical data available. In early reports of investigators from China it was noted that there was no increase in second malignancies in patients followed up for 10 years.11
A similar observation was made in 1982, in a cohort of 479 patients who had been treated with Fowlers solution [potassium arsenite] for duration varying from 2 weeks to 12 years during the period 1945 – 1969. The median cumulative dose in this cohort was 448 mg. It was noted that in this cohort of patients there was a marginal increase in fatal and non-fatal skin cancers but no increase in the incidence of internal malignancies.39
A recent report that was meant to highlight the low probability of ATO having induced cancers in patients (3 cases) receiving oral ATO40
was interpreted in a more recent review article as ‘highlights the concern of second malignancies’ in patients treated with ATO.41
To the best of our knowledge there are no other (if one insists on considering the previous report as second cancer to ATO therapy) reported cases of second cancers after administration of ATO at currently defined therapeutic doses. It would be reasonable at this point, though with limited long term follow up data, to state that second cancers following ATO are less than that reported following therapy of acute myeloid leukemia with currently accepted standard of care regimens.
There have been concerns raised about embryo toxicity based on animal models and some data from cases with environmental exposure.42
This again is not based on data in humans exposed to currently accepted therapeutic doses of ATO, this data for obvious ethical reasons is unlikely to be ever generated. However in our series, seven of the patients (4 women and 3 men) have had 8 normal babies,15
though all happened after completion of therapy. In this relatively young cohort there were no reports of abortions, fetal abnormalities or still births in any couple. While we did not actively evaluate fertility there were no reports of couples requesting evaluation for sterility.15
Hair and nail samples from 5 patients of this cohort who had completed therapy at least two years earlier was compared with that of 5 patients who had just completed therapy (not from this cohort) and 5 healthy controls. There was no significant difference in the ATO retention in hair and nail samples of controls and patients who had completed therapy at least two years earlier.15
The median levels, even among the patients who had just completed therapy was below the lower limit of the normal range described for normal controls by the Agency for Toxic Substances and Disease Registry (ATSDR based in Atlanta, Georgia, USA (http://www.atsdr.cdc.gov/