Application and Outcomes of Bendamustine- or Bortezomib-Based Therapy for Waldenstrom's Macroglobulinemia

Abstract

Background: Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a rare lymphoproliferative disorder typically affecting older patients and characterized by unique complications of IgM paraproteinemia. Treatment of this disease largely relies on phase 2 clinical trials or extrapolation of data from pooled studies in indolent B-cell lymphomas. We have previously shown a rapid uptake of novel, expensive therapies (bendamustine and bortezomib) for WM/LPL in the US, despite uncertain advantage over classical cyclophosphamide-based chemoimmunotherapy (Olszewski et al., Oncologist, 2016). We now examined patterns of use of these novel agents, associated survival, and cost outcomes, in population-based data. Methods: Using Medicare claims linked to the Surveillance, Epidemiology, and End Results registry, we identified WM/LPL patients aged ≥65 years who initiated first-line rituximab-based therapy in 2008-2014, and had complete Medicare claims available. We classified regimens into: rituximab alone, rituximab in combination with classical cytotoxic agents (cyclophosphamide, fludarabine, etc.) or with novel agents: bendamustine or bortezomib. We evaluated patient characteristics associated with the use of classical immunochemotherapy, bendamustine, or bortezomib, in a multinomial logistic model, reporting relative risk ratio (RRR) with 95% confidence intervals (CI). We then compared overall survival (OS) after therapy in a proportional hazard model adjusting for age, sex, race, comorbidity index, presence of kidney disease, poor performance status, and indicators of WM severity: anemia, neuropathy, need for plasmapheresis, transfusions, or hospitalization prior to therapy. Mean total Medicare spending within 1 year from starting therapy was compared in a log-gamma model, inflation-adjusted to 2013 dollar value. Results: Among 681 patients, 58% received upfront rituximab alone (N=392), 22% rituximab in combination with classical chemotherapy (N=151), 11% with bortezomib (N=76), and 9% with bendamustine (N=62). The proportion receiving bendamustine or bortezomib significantly increased between 2008 and 2014, displacing classical immunochemotherapy, but not rituximab monotherapy (Fig. A). In the multivariable model, patients treated with bortezomib were significantly more likely to be black than white (RRR, 7.49; 95%CI, 1.62-34.7; P=.010), more likely to be diagnosed as WM rather than LPL (RRR 2.38; 95%CI, 1.25-4.53; P=.008), and more likely to have chronic kidney disease (RRR, 3.18; 95%CI, 1.12-9.02; P=.029) or plasmapheresis before treatment (RRR, 2.99; 95%CI, 1.01-8.85; P=.048). Conversely, no black patients received bendamustine, which was also significantly less often administered to women (RRR, 0.46; 95%CI, 0.23-0.92; P=.027), patients with a prior hospitalization (RRR, 0.37; 95%CI, 0.17-0.78; P=.009), or with WM diagnosis code (RRR, 0.55; 95%CI, 0.29-1.04; P=.07). After adjustment for baseline patients characteristics we observed no significant difference in OS between immunochemotherapy combinations with classical agents and with bendamustine (hazard ratio, HR, 0.84; 95%CI, 0.46-1.53; P=.57) or bortezomib (HR, 1.07; 95CI, 0.68-1.69; P=.77; Fig. B). Mean total Medicare spending during the first year of therapy was over $20,000 higher for patients treated with bortezomib (P=.015) or bendamustine (P=.011) compared with the classical immunochemotherapy (Fig. C). Conclusions: Although about half of older patients with WM/LPL in the US continue to be treated with rituximab alone, bendamustine and bortezomib have largely replaced classical cytotoxic agents for those who receive combination immunochemotherapy. Clinicians favor bortezomib for patients with paraprotein-associated complications, and bendamustine for LPL-like presentations, even though differential benefits of these drugs are not supported by prospective evidence. Treatment decisions may thus result from extrapolation of data on myeloma or other lymphomas. Considering no apparent survival difference and higher costs of treatment with the novel agents, their value compared with classical regimens (like dexamethasone-cyclophosphamide-rituximab [Kastritis et al., Blood, 2015]) should be reconsidered in the US practice, and more precisely defined with further clinical research. Download : Download high-res image (145KB) Download : Download full-size image Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding.