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

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.

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Journal
Blood Advances
Published
2026-01-07
DOI
https://doi.org/10.1182/bloodadvances.2025017751
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Angela A. Dispenzieri, Dirk R. Larson, Jithma P. Abeykoon, Raphael Fonseca et al.
Blood Advances
Chronic Lymphocytic Leukemia Research
article

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

Angela A. Dispenzieri, Dirk R. Larson, Jithma P. Abeykoon, Raphael Fonseca, Shaji Kunnathu Kumar, Prashant Kapoor, JJ Castillo, Sikander Ailawadhi, Colin Colby, Pierre Morel, Shayna Sarosiek, Saurabh Zanwar, M Dimopoulos, Steven P. Treon, Damien Roos‐Weil, Oliver Tomkins, Encarl Uppal, Anne Quinquenel, Shirley D'Sa, Lydia Verónica Jiménez Montes, Efstathios Kastritis, Jonas Paludo, Morie A Gertz, Pascalle Cornillet-Lefebvre, Patrizia Mondello, Olabisi Ogunbiyi, Stephen M. Ansell, Eric Durot, S Vincent Rajkumar
article en

Abstract

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.

Blood Advances
University College Hospital (GB), Mayo Clinic (US), University College London Hospitals NHS Foundation Trust (GB), National and Kapodistrian University of Athens (GR), Jacksonville College (US), WinnMed (US), Sorbonne Université (FR), Centre Hospitalier Universitaire Amiens-Picardie (FR), Centre Hospitalier Universitaire de Reims (FR), Dana-Farber Cancer Institute (US), Pitié-Salpêtrière Hospital (FR), Hôpital Robert-Debré (FR), Mayo Clinic Hospital (US), Mayo Clinic in Florida (US), University College London (GB), Université de Reims Champagne-Ardenne (FR)
Amgen, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Sanofi, Celgene, Regeneron Pharmaceuticals, BeiGene, National Institutes of Health, Pharmacyclics, National Cancer Institute
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