Worst Hematologic Malignancy Treated Without Chemotherapy

Zosia Chustecka

December 09, 2012

"Groundbreaking research" presented today at a plenary session of the American Society of Hematology (ASH) 54th Annual Meeting shows that acute promyelocytic leukemia (APL) can be treated without chemotherapy. Instead, it was treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), compounds that have long been used in traditional Chinese medicine.

Dr. Francesco Lo-Coco

The study, known as APL0406, was presented by Francesco Lo-Coco, MD, professor of hematology at the University of Tor Vergata in Rome, Italy, who said the results provide evidence for "the demolition of a dogma." They show that it is possible to transform malignant cancer cells (with ATRA) instead of killing them (with chemotherapy) and that "cancer is not an irreversible condition," he said here at a press briefing.

Cancer is not an irreversible condition. Dr. Francesco Lo-Coco

"This is an exciting development, because it is a shift in the way we think of treating potentially fatal diseases," commented ASH president Armaud Keating, MD, professor of medicine and director of hematology at the University of Toronto, Canada.

"I found this study amazing," commented ASH secretary Charles Abrams, MD, professor of medicine and associate chief of the hematology/oncology division at the University of Pennsylvania, in Philadelphia. Both were speaking at a premeeting press briefing for selected journalists.

APL used to be a devastating disease, with a 100% mortality and patients dying within weeks, if not days. "This used to be the worst among the worst" of hematologic malignancies, Dr Abrams commented; "now we see for the first time that it can be treated by nonchemotherapy."

Current treatment for APL is a combination of ATRA and chemotherapy, and this "gold standard" therapy achieves 80% cure rates, Dr. Keating explained. When patients relapse, the treatment of choice is arsenic trioxide (ATO), he added.

However, the new study shows that in newly diagnosed APL patients, the noncytotoxic combination of ATRA and ATO can achieve results that are similar to those seen with ATRA plus chemotherapy, and this is "really quite impressive," Dr. Keating commented.

Similar Outcomes Without Chemotherapy

The APL0406 study was a phase 3 trial conducted in 40 centers in Italy and 27 centers in Germany; it involved 162 patients with newly diagnosed APL that was genetically confirmed and not high risk.

Patients who were randomly assigned to receive noncytotoxic treatment (n = 79) received ATO 0.15/kg plus ATRA 45 mg/m2 daily until complete response, and then ATO for 5 days per week, 4 weeks on and 4 weeks off, for a total of 4 courses, and ATRA, 2 weeks on and 2 weeks off, for a total of 7 courses.

Patients in the control arm (n = 80) received standard ATRA plus idarubicin induction, followed by 3 cycles of anthracycline-based plus ATRA consolidation, followed by ATRA and low-dose chemotherapy (including methotrexate and 6-mercaptopurine) for maintenance.

The results show that the outcomes were very similar in the 2 treatment arms. After a median follow-up of 31 months, the 2-year event-free survival was 97% in the ATRA plus ATO treatment arm vs 86.7% in the ATRA plus chemotherapy arm. Overall survival was 98.7% vs 91.1%, respectively.

There were 1 death and 2 relapses in the ATRA plus ATO treatment arm, and 3 deaths and 5 relapses in the ATRA plus chemotherapy arm, Dr. Lo-Coco reported.

There were more adverse events in the ATRA plus chemotherapy treatment arm: fever episodes, prolonged neutropenia, and thrombocytopenia were significantly more frequent, Dr. Lo-Coco reported. However, in the ATRA plus ATO arm, there was a higher incidence of QT prolongation (leading to discontinuation of ATO in 1 patient) as well as more hepatotoxicity and leukocytosis (which was managed by hydroxyurea). However, these side effects were manageable, Dr. Lo-Coco commented, and he emphasized that there was less hematologic toxicity.

ATRA plus ATO is "at least not inferior" to ATRA plus chemotherapy in terms of 2-year event-free survival for patients with low- and intermediate-risk APL, Dr. Lo-Coco concluded. In view of the lower toxicity of the noncytotoxic regimen, he proposed that it should become a new standard of care.

Dr. Lo-Coco had disclosed no relevant financial relationships.

American Society of Hematology (ASH) 54th Annual Meeting. Abstract 6.