MYD88 L265P and CXCR4 mutations

What is measured: the MYD88 L265P point mutation and, alongside it, CXCR4 nonsense or frameshift mutations (S338X the commonest) and CD79B mutations. How: allele-specific PCR or next-generation sequencing on bone marrow in Waldenström's, on tumour tissue in lymphoma, and on cerebrospinal fluid or vitreous cell-free DNA in CNS and ocular lymphoma, where it helps make a diagnosis without a brain biopsy. Frequencies: Waldenström's 90 to 95 percent, IgM MGUS 50 to 80 percent, marginal zone lymphoma under 10 percent (so a wild-type result favours marginal zone over Waldenström's), primary CNS lymphoma 60 to 80 percent with CD79B, and the MCD or cluster 5 subgroup of activated B-cell DLBCL; CXCR4 mutations are subclonal and present in 30 to 40 percent of Waldenström's. What a result changes: in Waldenström's, MYD88-mutated disease responds best to ibrutinib, zanubrutinib and acalabrutinib (ASPEN compared zanubrutinib and ibrutinib), CXCR4-mutated disease responds more slowly and less deeply with more IgM flare, favouring zanubrutinib or bendamustine-rituximab and proteasome-inhibitor regimens, and MYD88 wild-type disease does poorly on BTK inhibitors, steering to chemo-immunotherapy; in CNS lymphoma it supports BTK inhibitor trials, and in MCD DLBCL ibrutinib added to R-CHOP helped younger patients in a PHOENIX subgroup. Where it matters: Waldenström's, primary CNS lymphoma, marginal zone lymphoma and DLBCL.