MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is an immunoglobulin M-associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88^L265P. Owing to low prevalence of the wild-type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10-fold increased risk of mortality in this subgroup compared to patients with MYD88^L265P mutation. We studied a large cohort of patients with MYD88^L265P and MYD88^WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88^L265P mutation status, as determined by allele-specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88^L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88^WT genotype, 44 had active disease. The estimated median follow-up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4-16.5) for MYD88^L265P versus 13.9 years (95% CI: 6.4-29.3) for the MYD88^WT (P = 0.86). The time-to-next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time-to-progression to active disease was 2.8 years (95% CI: 2.2-3.8) in the MYD88^L265P cohort and 1.9 years (95% CI: 0.7-3.1) in the MYD88^WT cohort (P = 0.21). The frequency of transformation to high-grade lymphoma, or the development of therapy-elated myelodysplastic syndrome was higher in the MYD88^WT cohort (16% versus 4% in the MYD88^L265P, P = 0.009). In conclusion, MYD88^L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease-defining feature in WM. Our findings warrant external validation, preferably through prospective studies.