Pyrimethamine Targets Key Driver of Chronic Lymphocytic Leukemia

DECEMBER 30, 2021

Dana-Farber scientists have found that a generic anti-microbial drug can block a key molecular driver of chronic lymphocytic leukemia (CLL) cells, and when tested in a small clinical trial of advanced CLL patients who had relapsed, the drug slowed disease progression in half of them.

The drug, pyrimethamine, achieved stable disease in eight of the 16 patients in the trial, with one patient remaining on the drug for a year and two others for four and six months before the leukemia progressed. The patients had all received multiple treatments that were no longer working.

“This is particularly unusual and encouraging for a single-agent, non-toxic drug,” says David Frank, MD, PhD, senior author of a report on the trial in the American Journal of Hematology. First author is Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber.

He says the drug, which has been used to treat parasitic infections in AIDS patients and as a preventive for malaria, is well tolerated, and that patients could probably receive higher doses than those used in this small clinical trial, and for longer periods of time, perhaps achieving greater responses. Frank says that the drug caused leukemia cells to self-destruct through apoptosis, and that pyrimethamine also appears to make cancer cells more visible to the immune system, suggesting that it could be combined with immunotherapy drugs in future trials. “They might have a synergistic effect,” he says.

吡米达胺针对慢性淋巴细胞白血病的关键驱动性突变  (12月30日, 2021;  珍妮弗-布朗)

达纳-法伯血液学恶性肿瘤部CLL中心的主任珍妮弗-布朗发现，一种普通的抗寄生虫药物pyrimethamine(吡米达胺)可以阻断慢性淋巴细胞白血病（CLL）细胞的一个关键驱动性突变，在对复发的晚期CLL患者进行的小型临床试验中，pyrimethamine(吡米达胺)减缓了其中一半患者的疾病进展。这些患者都曾接受过多种治疗但都白血病进展。试验中的16名患者中有8名患者的病情稳定，其中一名患者坚持用药一年，另外两名患者在白血病进展前坚持了4个月和6个月。对于一种单用无"毒"的药物来说，这发现特别不寻常且令人鼓舞。抗寄生虫药物pyrimethamine(吡米达胺)已被用于治疗艾滋病患者的寄生虫感染，并作为疟疾的预防措施，它的耐受性很好，患者可能可以接受比这个小型临床试验中更高的剂量，而且用药时间更长，也许能取得更大的反应。抗寄生虫药物pyrimethamine(吡米达胺)使白血病细胞通过凋亡而自毁，而且似乎还能使癌细胞暴露出，这表明它可以在未来的试验中与免疫治疗药物相结合,  它们可能会产生协同效应。