ROCKVILLE, MdCell Therapeutics, Inc.s Trisenox (arsenic
trioxide) injection has won marketing approval from the Food and Drug
Administration only 3 years after its pivotal phase II trial began.
The agency approved the drug for treating patients with acute
promyelocytic leukemia (APL) who do not respond to or have relapsed
following first-line treatment with all-trans-retinoic acid (ATRA)
and anthracycline chemotherapy.
The FDA found the safety and efficacy data presented by the company
from the phase II study persuasive enough that it did not submit the
new drug application to its Oncologic Drugs Advisory Committee (ODAC)
Trisenox was approved as an orphan drug, a category for therapeutics
intended to treat rare diseases. About 1,500 new APL cases are
diagnosed annually, and an estimated 400 patients do not respond to
or relapse from first-line therapy.
For patients with APL whose disease has recurred following
initial treatment, the use of salvage therapy is highly toxic and
rarely curative, said Carolyn Paradise, MD, vice president of
clinical development for Cell Therapeutics. Results of the
clinical trials using Trisenox demonstrated that a significant number
of those patients who suffered multiple relapses were able to achieve
a complete remission.
Twenty-eight (70%) of the 40 patients treated at nine US cancer
centers in the phase II trial had complete remissions, according to
Cell Therapeutics. The median time to remission was 51 days. Of the
patients achieving a complete remission, 86% also had clearing of the
chromosomal abnormality associated with APL.
At a median follow-up of 16 months, 68% of the patients who achieved
complete remission were alive and 58% were disease-free.
We are impressed at both the high rate of complete remissions
and the relapse-free survival in this high-risk population,
said lead investigator Steven Soignet, MD, of Memorial
Sloan-Kettering Cancer Centers Developmental Chemotherapy Service.
Arsenic-based drugs were used to treat leukemia in the United States
and Europe more than 100 years ago, but they went out of fashion with
the development of more modern chemotherapy.
Renewed interest in the drugs followed reports that some traditional
Chinese treatments showed antileukemic activity and that Chinese
scientists had identified the active ingredient in these therapies as
APL Differentiation Syndrome
According to the FDA, Trisenox converts the immature white cells of
APL into normal cellsan effect, similar to that of all-trans-retinoic
acid, which can result in a sudden surge in the white cell count.
Sometimes this increase in cells is accompanied by APL
differentiation syndrome, which consists of inflammation and a build
up of fluid, particularly in the lining of the heart and lungs. This
adverse effect can prove fatal.
Normally, oncologists treat the syndrome by stopping therapy
temporarily and giving high-dose steroids. In the pivotal phase II
study, 8 (20%) of the 40 patients developed APL differentiation
syndrome, but none of them needed to have their Trisenox therapy
The drug can also increase the QT interval on a patients
electrocardiogram, which, in some cases, can lead to potentially
fatal arrhythmias. In the study supporting Trisenox approval, 16
(40%) of the patients developed significant in-creases in the QT
interval. However, none of the 16 suffered serious ar-rhythmias,
although one patient did experience a brief episode of irregular heartbeats.
Other common side effects included nausea, vomiting, diarrhea,
abdominal pain, cough, rash, headaches, and dizziness. Mucositis and
hair loss were uncommon. Most adverse events were considered mild and
ended after completion of the therapy.
Trisenox therapy consists of induction and consolidation cycles, both
of which use a dosage of 0.15 mg/kg. In the induction cycle, the drug
is infused intravenously daily for 1 to 2 hours until the bone marrow
is clear of leukemic cells, with a limit of 60 days of treatment. In
the phase II trial, most patients were treated for 44 days or less,
although some went the full 60-day course.
About 3 weeks after tests show the bone marrow is free of abnormal
cells, consolidation treatment is begun. This consists of 25
treatments given on weekdays over 5 weeks.