Currently, there is no established consensus on whether P2RY8::CRLF2 positivity or high CRLF2 expression alone could be a poor prognostic factor that warrants a change in treatment strategy. To the best of our knowledge, no prior case report has described an ALL patient with P2RY8::CRLF2 fusion, high CRLF2 expression, and HHD with a detailed clinical course. This evidence concerns the gene CRLF2 and acute lymphoblastic leukemia.