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Abstract INTRODUCTION Central nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM. METHODS This international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR). RESULTS Baseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94). Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47). CONCLUSION CNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Abstract The outcome of patients (pts) with WM, a rare B-cell malignancy, varies widely. The international community has convened a panel to develop a prognostically meaningful staging system for survival after treatment initiation. Toward establishing IPSS, we performed multivariate analyses with bootstrap validation in a series of 587 pts (median age 67, range: 28 to 95, M/F ratio: 1.7) diagnosed between September 1979 and December 2001. Diagnostic and treatment criteria fulfilled recommendations of the 2nd international WM workshop. Front-line treatment was initiated at diagnosis in 69% and 4 mo to 164 mo later in the remaining pts. Criteria for initiation of therapy included cytopenia, constitutional symptoms, organomegaly, hyperviscosity, IgM-related disorders, which pertained to 51%, 44%, 35%, 31% and 13%, respectively. Treatment regimens comprised alkylating agents, fludarabine and rituximab in 369, 195 and 23 subjects, respectively. Baseline parameters included age>65 yr in 57%, Hb≤11.5 g/dL in 65%, platelet count ≤100 x109/L in 9%, granulocyte count ≤1.5 x109/L in 9%, B2M >3 mg/L in 56%, albumin ≤3.5 g/dL in 36% and monoclonal protein >7.0 g/dL in 7%. With a median follow-up of 64 mo (range, 6 mo–182 mo), the median survival after treatment initiation was 87 mo (95%CI 79–103) regardless of the type of therapy applied (p=0.3). Using results of univariate survival analyses, recursive partitioning and martingale residuals analyses, 7 adverse characteristics for inclusion in multivariate analyses were identified during an expert meeting: age >65 yr, platelet count ≤ 100x109/L, B2M >3 mg/L, M-protein >7.0 g/dL, granulocytes ≤1.5 x109/L, Hb ≤11.5 g/dL and albumin ≤3.5 g/dL. The Cox proportional hazard model with stepwise selection selected the first 6 covariates. Bootstrap resampling (500 replicates) validated the selection of the first 4 covariates in at least 80% of the replicates. Selection of at least one of the last 2 covariates in more than 80% of the replicates indicated a correlation between these 2 covariates, and validated the inclusion of Hb only. Using the combination of age, Hb, platelet count, B2M and M-protein, low risk was defined by the presence of ≤1 adverse characteristic except age, high risk by the presence of >2 adverse characteristics; the remaining patients with 2 adverse characteristics or age >65yr had intermediate risk, comprising 27%, 38% and 35% of patients with 5-yr survival rates of 87%, 68% and 36% (p<0.0001), independent of treatment and age. IPSS split each subgroup identified by previous scoring systems (Morel, Merlini, Dhodapkar). Conversely, log-rank test was significant only when the latter prognostic system was assessed in low IPSS-risk pts. Thus the combination of age, B2M, M-protein and blood counts provides simple prognostic model for survival in WM, hopefully serving as an objective basis for initiation of therapy and comparison of treatment results.

Abstract Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström’s Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM.

Abstract Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

Abstract Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109/L, β2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.