Clonal Hematopoiesis Is Associated with Increased Risk of Progression of Asymptomatic Waldenström Macroglobulinemia

Introduction

Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström Macroglobulinemia (WM) and its association with clinical outcomes.

Methods

We retrospectively reviewed clinical data of 602 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM), and WM who had clinical next-generation sequencing (NGS) performed on bone marrow aspirates or peripheral blood obtained between October 2014 and February 2020 at the Dana-Farber Cancer Institute. An Illumina Truseq amplicon-based NGS assay of 95 genes recurrently mutated in myeloid and lymphoid neoplasms was utilized. Each specimen yielded ~2 million reads and ~1500X average coverage, with 90% of amplicons having >200X coverage. Pathogenic driver variants were identified based on mutation type, position, and frequency in published reports and public databases. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA).

Results

The cohort included 147 patients with MGUS or asymptomatic WM and 453 patients with symptomatic WM, with a median age of 66 years (range = 40-89) and 68 years (range = 33-93), respectively, at the time of first NGS assay. The prevalence of CH-DTA was 14% in symptomatic WM patients and did not differ significantly in MGUS (13%) or SWM (14%). Among precursor patients, there was an increased risk of progression to symptomatic WM for those with CH-DTA [7/20 patients with vs. 11/116 without CH-DTA progressed over a median of 54 months (P = 0.002)]. In symptomatic WM patients, CH-DTA was positively associated with older age (P < 0.001) at the time of NGS, with a median age of 72 vs. 67 years for patients with versus those without CH-DTA. CH-DTA was not associated with inferior overall survival (OS) with a relatively short median follow-up from diagnosis and NGS assay. OS was 6.7 years (95% CI = 6.1-7.6) for patients with CH-DTA and 2.5 years for patients without DH-DTA (95% CI = 2.2-2.8). The most common cause of death was disease progression, with no significant difference between those with or without CH-DTA. Patients with CH-DTA had an increased risk of cardiovascular disease (30% vs. 18%, P = 0.036).

Conclusions

We demonstrate that CH is common in WM patients and is associated with an increased risk of progression from precursor states but not with inferior survival. Further work is needed to determine how the presence of CH might promote progression to WM and whether it can be incorporated into future risk stratification models. Importantly, our data do not support changes in clinical management or alterations in therapy for patients with WM and coexistent CH and reinforce the need to interpret NGS results within their specific clinical context.