Clinical Outcomes in Consecutive Newly Diagnosed Patients with Waldenstrom's Macroglobulinemia Treated with Different Regimens in the Real-World Setting

Introduction Waldenstrom macroglobulinemia (WM) remains an incurable indolent B-cell lymphoma, however, the introduction of novel chemo-immunotherapy and targeted treatments have increased management options during the last decades. Pts with WM are mostly elderly and often frail due to age-associated comorbidities and the benefit from the introduction of new therapies may not be evident in the real-world practice. The aim of this analysis was to compare disease response and patient outcomes among pts with newly diagnosed WM (NDWM) who were treated with different first line regimens in the real-world setting. Methods We analyzed data of 711 consecutive patients (pts) with NDWM, diagnosed and treated in the Department of Clinical Therapeutics, Athens over the last 30 years. A survival analysis and competing risks analysis was conducted to assess differences in treatment efficacy and patient outcomes among first-line regimens categorized as follows: Bortezomib-Dexamethasone-Rituximab with or without Cyclophosphamide (BDR/BDR-C), Dexamethasone-Rituximab-Cyclophosphamide (DRC), Bruton's tyrosine kinase inhibitors (BTKi) and Other. Results Out of the 711 NDWM pts, 63 (8.9%) were treated with BDR (n=35) / BDR-C (n=28), 263 (37.0%) with DRC, 57 (8.0%) with BTKi and 328 (46.1%) with other older regimens including chlorambucil-based combinations (n=159), chemoimmunotherapy regimens such as RCHOP/RCOP (n=58) and rituximab monotherapy (n=50). The median age was 69 years (IQR 62 - 93), 41% were females, with no differences between groups (p=0.301 and p=0.136 respectively). The main reason to start therapy across treatment groups was anemia (54.3%). MYD88L265P, available in 184 pts, was detected in 80.4% (no difference between treatment groups), whereas a CXCR4 mutation was detected in 18.0%. The median follow-up was 5.12 years for BDR/BDR-C, 5.72 years for DRC, 1.48 years for BTKis and 6.63 years for the other regimens. The major response rate (at least partial response or better) was 55 % for BDR/BDR-C, 58.3% for DRC, 72.0% for BTKi and 51.2% for other regimens. Median progression-free survival (PFS) was 3.77 years (95% CI: 1.49-8.09) for BDR/BDR-C, 4.29 years (95% CI: 3.75 - 5.75) for DRC and 4.45 (95% CI: 3.83 - 5.41) for other treatments while it has not been reached for BTKi (95% CI: 6.13 - NA), although it seems to be prolonged compared to all other groups. Disease transformation was documented in 3.2%, 3.5%, 4.3% and 4.3% of the cases, respectively (p=0.061). Moreover, 74 out of the 711 pts (10.4%) developed a second primary malignancy (SPM) - 3 (4.8%) on BDR/BDR-C, 28 (10.6%) on DRC, 1 (1.8%) on BTKis and 38 (11.6%) on other treatments. Overall, there were 339 (47.7%) deaths; 24 (38.1%) in the BDR/BDR-C group, 99 (37.6%) in the DRC group, 9 (15.8%) in the BTKi group and 207 (63.1%) in the group treated with other therapies. The estimated median overall survival (OS) was 11.22 years (95% CI: 6.9 - NA) for BDR/BDR-C treated pts, 12.41 years (95% CI: 9.39 - NA) for those on DRC, 9.24 years (95% CI: 8.25 - 10.1) for those on other regimens while it has not been reached for those on BTKis. The 5-year cumulative incidence (CI) for death due to a WM-related cause, with unrelated death as a competing event was: 18.5% for BDR/BDR-C pts, 17.4% for DRC, 4.2% for BTKi and 29.4% for pts on other treatments; with differences between groups being statistically significant (p<0.001). Consistent and statistically significant were the results at 10-years (26.3% vs 24.9% vs NA vs 48.9% respectively, p<0.001). Five and 10-year cumulative incidences (CI) for death due to causes unrelated to WM as competing events were similar between groups (5-years: 15.1% vs 21.8% vs 16.8% vs 15.0% and 10-yrs: 30.3% vs 31.9% vs NA vs NA vs 22.1% respectively, p=0.124). Conclusions Modern therapies seem to improve WM-specific survival. The lack of overt OS benefit, may be due to the use of modern effective salvage therapies, the advanced age of a significant proportion of WM pts which is related to non-WM related mortality and the shorter follow up of the BTKi cohort. Our data suggest that the evaluation of the benefit of new treatments should not be restricted only to traditional endpoints such as PFS, OS and response rates, but should evaluate other patient-oriented metrics including QOL and toxicity burden, especially when continuous is compared to fixed duration treatments.