Resistance to the anti-malaria drug artemisinin has now been detected in Myanmar and Vietnam, the WHO said, five years after it warned that the drug was no longer effective in treating the disease on the Cambodia-Thailand border.
"The emergence of artemisinin resistance could undo the enormous progress made towards malaria control and elimination --- and potentially pose a serious global health threat," regional director Shin Young-Soo said in a statement.
"Key development partners strongly support our efforts. However, we still face a funding gap of at least $450 million over the next three years."
Malaria, which is caused by a parasite infecting mosquitos that feed on humans, kills 660,000 people each year, according to WHO figures.
Artemisinin-based therapies are the first-line treatment for cases of malaria caused by Plasmodium falciparum, the deadliest strain of the disease.
The drug is credited for the remarkable success in reducing the number of malaria deaths globally in recent years.
"If resistance to artemisinin emerges elsewhere, the consequences for global health could be grave," Shin said.
He said the drug-resistant strain was now found in four of the six states that make up Asia's Greater Mekong region, which also includes Laos and China's Yunnan province.
Resistance to the drug may have been caused by the parasite's long exposure to artemisinin therapies, as well as "substandard or counterfeit" drugs in circulation, the WHO said.
Resistance to other formerly effective malaria drugs had also originated along the Cambodia-Thailand border, before spreading west to South Asia, then Africa where most malaria deaths occur, it added.
Malaria also remains a problem in Malaysia, Papua New Guinea, the Philippines, the Solomon Islands, South Korea and Vanuatu.
The warning came as senior health officials from East Asia and the Western Pacific met in Manila this week to coordinate support for international efforts to contain malaria and other diseases.
Shin said the Swiss-based Global Fund to Fight AIDS, Tuberculosis and Malaria had pledged US$100 million to the campaign to prevent the spread of drug-resistant malaria, which was also backed by Australia and the Bill and Melinda Gates Foundation.