Clinical Characteristics and Outcomes of Patients with MYD88 Positive Waldenström Macroglobulinemia: A Single Center Retrospective Analysis

Background: Waldenström macroglobulinemia (WM) is diagnosed clinicopathologically by identifying clonal lymphoplasmacytic proliferation in the bone marrow and excess secretion of monoclonal IgM protein. Driver mutations in the MYD88 and CXCR4 genes are detected in more than 90% and 30-35% of WM patients (pts), respectively. Chemoimmunotherapy (CIT) remains a preferred choice in first line setting for many symptomatic WM pts due to its tolerability and fixed duration. Continuous Bruton tyrosine kinase inhibitors (BTKi) are alternatives for pts ineligible for CIT. MYD88 and CXCR4 mutations both inform sensitivity and resistance to BTKi. We present a retrospective analysis of clinical characteristics and outcomes in a large cohort of pts with MYD88 positive (MYD88+) and MYD88 negative (MYD88-) WM.

Methods: We included pts diagnosed with WM at Moffitt Cancer Center between January 2000 and June 2023. Patients with second hematological malignancy, transformation to large cell lymphoma and metastatic solid cancers were excluded. The primary objective was to determine the median overall survival (mOS) of pts stratified by MYD88 status. Secondary objectives included evaluating clinical presentation and time to next line of treatment (TTNT) in MYD88+ patients, and mOS in CXCR4+ and CXCR4- pts.

Results: 338 pts were included in the study. Patient characteristics at diagnosis were median age of 68.6 yrs, male 63.3% and predominantly white race, 97.5%. 89.7% pts were positive for MYD88 mutation among 272 pts (missing n-66) and 23.8% were positive for CXCR4 among 130 pts (missing n- 208). 43.5 % patients with MYD88+ were symptomatic at presentation compared to 67.9% who were MYD88-. Median hemoglobin, platelet count, B2-microglobulin and IgM levels were 11.4 g/dl, 212000/ml, 2.90 and 2202 in MYD88+ and 11.1 g/dl, 257000, 3.20 and 2945 in MYD88- pts respectively. Median bone marrow lymphoplasmacytic infiltration at the time of diagnosis was 45% in MYD88+ pts, compared to 40% MYD88- pts.

With a median follow-up of 50 mo, 16.9% (n=57) of pts had died. Of the total 336 pts, 76.8% required treatment, with a median of 2 lines (range 1-15). Among 240 MYD88+ pts, the most common first-line regimen was CIT (Bendamustine/Rituximab, Cyclophosphamide/Rituximab/Prednisone, Fludarabine/Rituximab) in 45.7% pts. Other first line regimens included Immunotherapy (Rituximab, ofatumumab) in 28.3 %, proteasome inhibitors-based regimen in 7.61%, BTK inhibitors in 16.3 %, and others (clinical trials, chemotherapy alone) in 2.17% pts. This was similar in MYD88- negative pts, where 52.4% received CIT and 14.3% received BTKi as first line regimen. Additionally, 33.2 % of pts received BTK inhibitors, regardless of MYD88 status, including later lines of treatment.

OS among MYD88+ patients were 234.1 months compared to 224.8 months in MYD88- (p=0.22). Similarly, 8-years OS was 81% (range 74%- 88%) among MYD88+ and 63% (range 41% - 98%) in MYD88- patients. At the 4-year follow-up, among MYD88+ pts who received first-line CIT, OS was 89% (ranging from 81% to 98%). In comparison, among those who received BTKi, OS was 77% (ranging from 60% to 98%). After first line treatment, mTTNT in MYD88+ pts were 90 mo and 30 mo in MYD88- group. Regarding CXCR4 status, 8-year OS was 90% in CXCR4 pts compared to 83% in CXCR4- patients, with p value of 0.76, regardless of whether they required treatment.

Conclusion: In this cohort of WM pts, clinicopathological presentation and treatment outcomes were comparable in MYD88+ and MYD88- pts. MYD88- pts showed a trend toward higher risk at diagnosis, shorter periods without treatment after first-line therapy, and reduced overall survival. However, statistical significance cannot be determined because of the differing sample sizes between the two groups. OS for MYD88+ pts who received first line BTKi was also lower compared to those who received CIT.

*ST and DK are co-first authors