The FDA has approved Trisenox (arsenic trioxide) for the treatment
of patients with acute promyelocytic leukemia (APL) who have not
responded to, or have relapsed following the use of all trans-retinoic
acid and anthracycline-based chemotherapy, which is considered first line
Development of Trisenox was rapid. The drug was approved for
marketing only 3 years after the study of the drug was first started in
APL is a cancer of the white blood cells. It is characterized by a
rapid accumulation of abnormal white blood cells in the bone marrow and
blood resulting in anemia, susceptibility to infections, bleeding, and
hemorrhage. Patients who have a relapse or who have APL that doesn't
respond to first line therapy are currently retreated with all trans-retinoic acid and anthracycline-based chemotherapy or both. Response to
therapy is good if a long time has elapsed since initial treatment but
usually not if relapse is rapid or if there is no initial response.
Trisenox offers a new alternative.
Trisenox was approved as an orphan drug, a drug intended for the
treatment of rare diseases or conditions. An estimated 1500 new cases of
APL are diagnosed each year, of which an estimated 400 patients will not
respond to, or will relapse from, first line therapy.
Arsenic-containing preparations have been in medical use for more
than 2000 years. Arsenic-based therapy was used in the United States and
Europe more than 100 years ago for leukemia therapy as well as for
treatment of infections, but these treatments were subsequently replaced
by modern chemotherapy and antibiotics. More recently, interest in
arsenic-based therapy was revived by reports of the anti-leukemic
activity of some traditional Chinese preparations. Chinese scientists
subsequently found that the active ingredient was arsenic trioxide.
The safety and effectiveness of Trisenox were evaluated in the
treatment of relapsed or refractory APL in a multicenter clinical study
involving 40 patients who received arsenic trioxide infusions. Twenty-
eight of the 40 patients (70%) had a remission of their leukemia and met
the study-defined criteria for "response". The median time to
remission was 51 days. Arsenic trioxide converts the immature cancerous
white blood cells into normal white blood cells, an effect similar to
that of all trans-retinoic acid. A consequence of this can be a sudden
increase in the white blood cell count. In some cases the increase in
white blood cells is accompanied by signs of inflammation and fluid
accumulation, particularly in the lining of the heart and lungs. This is
termed the "APL differentiation syndrome" and can be fatal. The usual
treatment is to temporarily stop the leukemia therapy and treat with high
dose steroids. In the study submitted to support the approval of
Trisenox, the APL differentiation syndrome appeared in 8 of the 40
patients (20%), but in no cases was there a need to interrupt therapy
with arsenic trioxide.
Trisenox can cause an important change in the electrocardiogram, an increase in what is termed the Q-
T interval. An increase in the Q-T interval can in some cases lead to irregular heart rhythms that can be fatal.
Significant increases of the Q-T interval appeared in 16 of the 40 patients (40%). In those patients, no serious
abnormal rhythm developed (one patient had a brief episode) but the risk of the effect required that the ECG
and patients be closely monitored. Other adverse effects of Trisenox are abdominal discomfort, nausea,
vomiting, headache, fatigue, skin changes, and fluid accumulation. Most of the adverse effects were
considered mild and resolved after therapy was completed.
In March 1998 arsenic trioxide was granted orphan designation for
the treatment of patients with APL. Cell Therapeutics, Inc., will market