Real-world assessment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome.

Ivosidenib and enasidenib are targeted agents that inhibit mutant isocitrate dehydrogenase (IDH) enzymes, restoring normal cellular differentiation in affected acute myeloid leukemia patients. Both agents carry a risk of differentiation syndrome (DS), a potentially life-threatening complication. In this multicenter, retrospective study we sought to determine the real-world incidence and characterize DS in patients with a myeloid malignancy treated with an IDH inhibitor. Of 49 total patients, 15 patients (31%) had a documented diagnosis of DS and 8 patients (16%) met the criteria of DS by Montesinos, et al. The most common signs and symptoms of DS were dyspnea/hypoxia (56%), unexplained fever (56%), bone pain/arthralgia (44%), edema/weight gain (39%), and pleural/pericardial effusions (33%). Our study reports a higher real-world incidence of DS in patients treated with IDH inhibitors for myeloid malignancies than previously reported.

Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1.

The Sonic hedgehog (Shh) signaling pathway plays a critical role in normal cerebellar development and has been implicated in medulloblastomas, common malignant childhood tumors of the cerebellum. To test whether Shh mis-expression is sufficient for medulloblastoma formation, we used ultrasound biomicroscopy-guided in utero injection of a Shh-expressing retrovirus into the cerebellum of 13.5-day mouse embryos to show that direct activation of the Shh pathway can lead to tumor formation. Significantly, medulloblastomas were observed in 76% of the mice infected with Shh-expressing retrovirus. Furthermore, contrary to recent suggestions that the Shh transcriptional target Gli1 plays a critical role in Shh-induced tumorigenesis, we found that medulloblastomas form in Gli1 null mutant mice. We have developed an efficient mouse model of medulloblastoma and shown that Gli1 is not required for tumorigenesis when Shh signaling is activated upstream in the pathway.