First‐line treatment of Waldenström's macroglobulinemia in Italy: A multicenter real‐life study on 547 patients to evaluate the long‐term efficacy and tolerability of different chemoimmunotherapy strategies
Authors: Francesco Autore, A. Tedeschi, G. Benevolo, V. Mattiello, E. Galli, N. Danesin, R. Rizzi, J. Olivieri, E. Cencini, B. Puccini, I. Ferrarini, D. Marino, M. Bullo, B. Rossini, M. Motta, I. Innocenti, A. Fresa, L. Stirparo, D. Petrilli, R. Pasquale, P. Musto, G. Scapinello, A. Noto, V. Peri, G. Zamprogna, S. Hohaus, A. M. Frustaci, F. Piazza, S. Ferrero, L. Laurenti
Journal: American Journal of Hematology (2024)

Treatment is indicated in Waldenström macroglobulinemia (WM) when clinical manifestations arise due to the IgM paraprotein or lymphoplasmacytic infiltrate.1 The main classes of drugs used for WM treatment include monoclonal antibodies, chemotherapeutic agents, proteasome inhibitors, and Bruton Tyrosine Kinase inhibitors (BTKi). The most frequently used chemotherapeutic agent is bendamustine, which is largely administered for its efficacy and relatively favorable toxicity profile with low rates of non-hematological adverse events.2 Bendamustine plus rituximab (BR) is considered to be especially useful in fit patients in need of rapid disease control.3 Rituximab has been evaluated in combination not only with bendamustine (BR), but also with dexamethasone and cyclophosphamide (DRC).4 A retrospective comparison between BR and DRC was performed at Mayo Clinic, reporting a significantly greater two-year progression free survival (PFS) for BR (88% vs. 61%, respectively) but without a significant difference in overall response rate (ORR) at 18 months (93% vs. 96%, respectively).4 In contrast, both a superior ORR (98% vs. 85%, respectively) and major response rate (96% vs. 60%, respectively) were reported for BR in the study of Abeykoon et al.5 To further evaluate the efficacy and safety of the different chemoimmunotherapy regimens used for the treatment of WM patients, we conducted a retrospective multicenter study involving 14 different Italian centers of the Fondazione Italiana Linfomi (FIL). The study group included unselected, consecutive WM patients who received frontline treatment with a chemoimmunotherapy regimen between January 2008 and December 2022. Primary outcome measures included ORR, PFS, and OS, as defined by the International Workshop on Waldenström's macroglobulinemia.6 Primary outcomes were also assessed based on the total received bendamustine dose, which was categorized using the percentage of the relative dose intensity (RDI). The RDI was calculated for each patient as the percentage of drug actually administered compared to that estimated at the beginning of treatment. The starting dose was 90 mg/m2/day, administered on days 1 and 2 of each of the six planned cycles. The statistical analyses were conducted on four different treatment groups which included BR, DRC, and two other groups that were named "other R-chemo" and "chemo alone." The "other R-chemo" group included patients treated with a Rituximab-containing regimen other than BR, such as Chl-R (chlorambucil-rituximab), FCR (fludarabine-cyclophosphamide-rituximab), or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), whereas the "chemo alone" group included patients treated with chemotherapeutic agents such as chlorambucil or cyclophosphamide as single agents. Categorical variables were analyzed with the Chi-square or Fisher's exact tests, while numerical variables underwent assessment with the Wilcoxon–Mann–Whitney test or Kruskal–Wallis ANOVA test. Survival analysis was conducted with the Kaplan–Meier method. The statistical analyses were performed using the NCSS 2020 Statistical Software by NCSS, LLC, Kaysville, Utah, USA (ncss.com/software/ncss). We enrolled 547 WM patients, among which 245 received BR, 116 DRC, 86 other R-chemo, and 52 chemo alone; 48 patients treated with Rituximab monotherapy only for IgM-associated symptoms were excluded from the analysis. Baseline characteristics of the four analyzed groups of patients are shown in Table S1. The BR and DRC populations differed with respect to age at treatment initiation (68 vs. 72 years old, respectively, p = .018), comorbidities (higher CIRS and more frequent presence of respiratory disease in DRC, p < .001 and p = .025, respectively), and IPSSWM score and beta2microglobulin levels (higher values in BR, p < .001). ORR was 93.3% for BR, 79.2% for DRC, 75% for other R-chemo, and 44% for chemo alone (Table S2). The difference in terms of ORR was statistically significant when comparing BR to DRC (HR 3.71 (1.88–7.31), p < .001) and BR to other R-chemo (OR 4.75 (2.34–9.64), p < .001). When analyzing PFS curves, we noted a 4-year PFS of 80% for BR, 68% for other R-chemo, 60% for DRC, and 25% for chemo alone (Figure 1). The difference was significant between BR and DRC (p < .001) but not between BR and other R-chemo (p = .143) or between DRC and other R-chemo (p = .362). OS curves did not differ between the first three main treatment groups (4-year OS was 86% for BR, 89% for DRC, and 93% for other R-chemo), whereas a reduced 4-year OS was observed for patients treated with chemo alone (58%; Figure 1B). Multivariate analysis identified age >75 years (RR 1.83), anemia with Hb <10 g/dL (RR 1.63), and choice of treatment (DRC rather than BR; RR 1.86) as significant variables impacting PFS (Table S3). Regarding tolerability, a significantly higher rate of hematological toxicities was observed in BR (55%) compared to DRC (38%) and other R-chemo (31%) treated patients, resulting in significantly more frequent dose reductions in the BR (14.3%) than in the DRC (6.0%) or other R-chemo group (4.9%) [HR 0.38 (0.16–0.89), p = .026] (Table S4). BR patients were also analyzed according to the different dose of bendamustine administered. A first comparison was performed between 129 patients treated with the recommended starting dose of 90 mg/m2 and 59 patients treated with a starting dose of 70 mg/m2; both groups of patients received no dose reduction during treatment. Patients receiving the lower dose were older (median age 70 vs. 64 years, p = .005), whereas the other baseline characteristics were similar between the two subgroups (Table S5). No significant difference was observed with respect to 4-year PFS, which was 84% for the 90 mg/m2 and 85% for the 70 mg/m2 subgroup (Figure 1C). A second comparison was performed between 206 patients treated with an RDI of ≥70% and 34 patients treated with an RDI of <70%. In this case there was a significant difference, with a 4-year PFS of 83% in the first subgroup and 64% in the second subgroup (p = .035, Figure 1D). Finally, we compared the outcome of patients treated with a >30% or ≤30% bendamustine RDI reduction with the outcome of the DRC treated patients. BR-treated patients with a RDI reduction >30% showed the same outcome as DRC-treated patients in terms of PFS (Figure 1E). Univariate analysis identified the following variables associated with bendamustine RDI reduction of >30%: age (both >65 years and >75 years), presence of a grade 2 neuropathy according to CTCAE, creatinine clearance (CrCl) <70 mmol/L, and ECOG>1. In multivariate analysis, when using age >65 or ≤65 years as a variable, only neuropathy and CrCl were found to be significant, whereas when using age >75 or ≤75 years as a variable, neuropathy and age were significant (Table S6). To our knowledge, this is one of the largest retrospective real-life studies on treatment-naive WM patients. The comparison between 245 BR patients and 116 DRC patients, even if retrospective, is unique because of the size of the subgroups, allowing us to obtain robust results on efficacy and tolerability for the main chemoimmunotherapy regimens. The obtained data show a significantly higher 4-year PFS for BR compared to DRC, confirming the results of Paludo et al.4 over a longer median follow-up of 54 months. We also investigated the optimal starting bendamustine dose and show that a reduction from the recommended 90 mg/m2 to 70 mg/m2 is equivalent in terms of PFS. It is worth noting, however, that patients receiving the lower dose were generally older, which could have resulted in better compliance and fewer treatment discontinuation because of toxicities and side effects. In contrast, we show that RDI reduction of >30% resulted in reduced PFS that was comparable to that of DRC. A significant impact of bendamustine dose on PFS was also reported by Arulogun et al.3 although in that study a total bendamustine dose of < or ≥1000 mg/m2 was predictive of PFS. In conclusion, we report that the BR regimen remains a highly effective treatment option for untreated WM patients even in the era of BTKis. This regimen showed a high ORR and exhibited excellent PFS even when the initial bendamustine dose was reduced to 70 mg/m2 and dose intensity was decreased up to 30% from the initial dose. Only in case of a relative dose intensity reduction of >30%, the PFS of BR-treated patients was comparable to those treated with DRC. Age over 75 years and CrCl lower than 70 mmol/L were the main risk factors for this significant dose reduction. Patients with these characteristics are likely to benefit less from the BR regimen and should be considered for alternative treatments. FA, AT, SF, and LL performed research; GB, VM, ND, RR, JO, EC, BP, IF, DM, MB, BR, MM, II, LS, DP, RP, PM, GS, AN, VP, GZ, SH, AMF, FP collected data; EG and AF performed data analysis; FA, EG, AF, and LL wrote the manuscript; AT, GB, and SF supervised the study. All authors reviewed the manuscript. The authors would like to thank the Fondazione Italiana Linfomi (FIL) for contribution of patients data. The authors also acknowledge Prof. Dimitar Efremov (Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy) for the revision of the manuscript. Minister of Health (MoH)-Ricerca Corrente 2024. The authors declare that they have no competing interests. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Data S1. Supporting tables. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.