POD24 is a Novel Determinant of Prognosis in Patients with Waldenström Macroglobulinemia Open Access

• CXCR4 mutations portend inferior outcome for patients with WM treated with frontline BR, whereas MYD88L265P does not impact survival.

• POD24 serves as an early surrogate endpoint by reliably identifying patients with unfavorable subsequent survival.

Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in chemoimmunotherapy-treated patients remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early endpoint, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each, p=0.4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median, 3.3 versus 8.8 years; HR 2.8, p=0.0036) and OS (HR 2.6, p=0.036) compared to CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS: 71% versus 86%; HR 3.1, p=0.005) and higher mortality (SMR 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR 1.1). In conclusion, BR is effective, irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Non-POD24 patients represent a cohort with distinctly favorable outcome.