Varettoni, Marzia

Abstract Introduction: The prognosis of patients (pts) with histological transformation (HT) of Waldenström macroglobulinemia (WM) remains dismal with standard chemoimmunotherapy. CD19-targeted chimeric antigen receptor T-cell therapies (CAR-T) can lead to durable responses in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and are approved in the second or third line settings. Pts with HT-WM were largely excluded from CAR-T trials. We previously reported high response rates in a series of 23 pts. The aim of the present study was to evaluate a larger cohort of pts with R/R HT-WM treated with CAR-T with a longer follow-up. Methods: We performed a multicenter retrospective study of pts with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with CAR-T in the French DESCAR-T registry (NCT04328298), 4 centers from ECWM and 4 US centers. This study includes updated data from previously published cases (Durot et al, Blood, 2024). Responses were assessed according to the Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Progression-free survival (PFS) and overall survival (OS) were calculated from the date of CAR-T infusion and estimated using the Kaplan-Meier method. Results: 50 pts were included (39 from DESCAR-T centers, 7 from US centers and 4 from ECWM centers). Median age was 60 (range: 32-72) and 68 (range: 42-82) years at WM diagnosis and CAR-T infusion, respectively. MYD88L265P and CXCR4 mutations were present in 79% (23/29) and 15% (2/13) of patients with available data, respectively. The median time from WM to HT diagnosis was 5.3 years (range: 0-32). Median prior lines of therapy was 1 (range: 0-9) for WM and 2 for HT (range: 0-4). Twenty (40%) pts previously received a BTK inhibitor for WM or HT, 12 (24%) underwent prior autologous SCT and 1 pt allogeneic SCT. 40% of pts presented primary refractory disease and 44% were refractory to last treatment before CAR-T. 40 pts (80%) received bridging therapy, of whom 17 (44%) responded (7 complete responses (CR)). 35 (70%), 10 (20%), and 5 (10%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), respectively. The best overall response rate (ORR) was 94%, with 44 (88%) pts reaching CR. With a median follow-up of 25.7 months (range: 1-69) from CAR-T infusion, the median PFS was 1.2 years (95% CI: 0.5-4.5) and median OS was 4.2 years (95% CI: 1.2-not reached). Median duration of response was 1.5 years (95% CI: 0.4-4.4), with a median of 4 years (95% CI: 1.5-NR) for pts still in CR at 6 months after CAR-T. 22 pts experienced relapse/progression after CAR-T, 19 related to LBCL and 3 to WM. Median survival after relapse was 7.9 months (95% CI: 3.8-25.3). At LBCL relapse after CAR-T, salvage therapy consisted of CD20xCD3 bispecific antibodies for 9 pts, lenalidomide +/- anti-CD20 or anti-CD19 antibody for 6 pts, and BTKi for 3 pts. Among 19 pts who died, 14 (74%) were due to progressive disease and 5 (26%) from infections. 37 (76%) pts experienced CRS, including 2 (4%) grade 3 events, and 22 (45%) had ICANS, with 2 (4%) ≥ grade 3 events. 17 (35%) pts presented infections, including 12 ≥ grade 3. 21 (43%) pts developed ≥ grade 3 prolonged cytopenias (ie, not resolved within 30 days post infusion). CNS involvement due to LBCL was present in 11 pts (22%) at the time of CAR-T. 6 of them had ICANS, with 1 grade 4. The best ORR was 91% (best CR 91%). Only 1 patient did not obtain a response, with stable disease at 1 month and progression at 3 months. The median PFS was 1.2 year (95% CI: 0.2-NR) and median OS was NR (95% CI: 0.5-NR). On univariate analysis, only elevated LDH was correlated with worse PFS (HR 2.5, p=0.04) and OS (HR 3.3, p=0.04). Other variables, including number of prior lines of therapy, MYD88 mutation status, primary refractory disease, refractory to last treatment, CNS involvement before CAR-T, response after bridging therapy and type of CAR-T received, were not associated with inferior PFS or OS. Conclusion: This cohort represents the largest series of pts with transformed WM treated with anti-CD19 CAR-T. We confirm the high efficacy previously reported with an acceptable safety profile, including for pts with CNS involvement due to LBCL at CAR-T infusion.

ABSTRACT As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.

8049 Background: The treatment paradigm of Waldenström macroglobulinemia (WM) continues to evolve as new therapies expand our options for this indolent and incurable disease. While more profound responses are generally associated with longer treatment-free intervals, the impact of depth of response from fixed duration therapy in WM patients' survival needs further evaluation. In this international, multicenter cohort study, we report the prognostic impact of depth of response in WM. Methods: 319 WM patients treated with frontline fixed duration therapy [Dexamethasone/Rituximab/Cyclophosphamide (DRC), Bendamustine/Rituximab (BR), or Bortezomib/Dexamethasone/Rituximab (BDR)] were included. Response at the completion of therapy (6 months) was used in a landmark analysis for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) (defined as time from 6 months post treatment response to event or censor). Response was defined by modified IWWM-6 criteria. Associations between clinical variables and outcomes were evaluated using Cox proportional-hazard models. Results: The median age at the time of treatment initiation was 64 years (range: 29-94), 59% were men, and risk category by International Prognostic Scoring System (IPSS)-WM was low (n=67, 23%), intermediate (n=83, 29%), and high-risk (n=141, 48%). Evaluable responses at 6 months from frontline therapy [DRC (n=105; 41%), BR (n=83; 32%), BDR (n=68; 27%)] were available in 256 patients and included in the landmark analysis. Median follow-up was 63 months (95% CI: 59-70). The rate of major response (PR or better) at 6 months was 74% for the entire cohort. Five-year PFS rates from completion of therapy for patients who attained major response vs. those who did not were 71% and 43%, respectively (p<0.001). Five-year TTNT rates for patients who attained major response vs. not were 84% and 54%, respectively (p<0.001). Five-year OS rates for patients who attained major response vs. not were 92% and 77%, respectively (p<0.001). In multivariable analyses including other WM prognostic factors evaluated at initiation of frontline therapy, attaining a major response at 6 months was associated with superior PFS (HR 0.33, p<0.001), TTNT (HR 0.23, p<0.001), and OS (HR 0.31, p=0.001–Table). Conclusions: Achieving a major response at 6 months after frontline chemoimmunotherapy emerges as a significant prognostic factor for PFS, TTNT and OS in patients with WM.[Table: see text]

Abstract Background: The oral BTK inhibitor ibrutinib is the only approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Bing-Neel syndrome (BNS) is a rare complication of WM that results from infiltration of malignant lymphoplasmacytic cells into the central nervous system (CNS) causing neurological deficits. Treatment options in patients with BNS are limited to agents with CNS penetration. Ibrutinib can penetrate into the CNS, but data on its efficacy in BNS is lacking outside case reports. Methods: We performed a multicenter retrospective study evaluating the efficacy of ibrutinib in patients with BNS. The diagnosis of BNS was established in patients with a clinicopathological diagnosis of WM by radiological and/or cytological evidence of CNS involvement by WM, and response was assessed based on recently published criteria. Ibrutinib was given orally at doses of 420-560 mg PO once daily until disease progression or intolerable toxicity. Response was assessed using criteria from the 8th International Workshop for WM (Minnema et al. Haematologica 2017). Events were defined as death from any cause, progression of disease and stopping ibrutinib from any reason. Time to events was estimated using the Kaplan-Meier method. Results: We present data on 24 patients with BNS treated with ibrutinib. The median age at diagnosis of WM was 60 years (range 38-76 years) and 14 patients (58%) were men. The median lines of therapy for WM prior to BNS diagnosis was 1 (range 0-7 lines), and 9 patients (38%) were untreated for WM at the time of BNS diagnosis. Previous WM therapies included anti-CD20 antibodies (n=15), alkylators (n=13), nucleoside analogues (n=8), proteasome inhibitors (n=3), immunomodulators (n=2), and autologous transplant (n=1). The median age at BNS diagnosis was 65 years (range 38-80). The median time from WM to BNS diagnosis was 4 years (range 0-27 years). In 2 patients, the diagnosis of BNS was made concurrently with WM diagnosis. The median number of BNS lines prior to ibrutinib was 1 (range 0-5 lines). Previous BNS therapies included intrathecal chemotherapy (n=9), high-dose methotrexate (n=6), bendamustine (n=3) and radiation therapy (n=3). In 7 patients (29%), ibrutinib was the first line of treatment for BNS. The most common symptoms at BNS presentation were cognitive deficits (n=10), sensory deficits (n=8), ataxia/falls (n=8), motor deficits (n=6), headache (n=5) and seizures (n=5). MRI findings included leptomeningeal enhancement (n=16) and brain masses (n=5). Cerebrospinal fluid (CSF) flow cytometry confirmed the presence of clonal CD19+ in 19 patients (79%). Biopsies were performed in 5 patients (21%) and confirmed presence of WM cells. 4 patients had normal MRI but had abnormal CSF cytology and/or flow cytometry. Tissue was not obtained in 1 patient in whom MRI showed leptomeningeal enhancement. Interestingly, 2 patients were diagnosed with lymphoplasmacytic lymphoma secreting IgG paraprotein. The median serum IgM (n=20) prior to ibrutinib initiation was 1,294 mg/dl (range 125-5,938 mg/dl), and the median hemoglobin level was 11.9 g/dl (7.7-15.2 g/dl). Ten patients (42%) received ibrutinib 560 mg PO once daily, and 14 (58%) received ibrutinib 420 mg PO once daily. At best response, median serum IgM and hemoglobin levels were 340 mg/dl (82-3,330 mg/dl) and 14.6 g/dl (range 9.2-16.0 g/dl). Based on consensus BNS response criteria, complete response was attained in 2 patients (8%), partial response in 14 (58%) and clinical improvement in 3 patients (13%). With a median follow-up time of 13 months (95% CI 8-21 months), 5 patients have stopped ibrutinib, 3 due to BNS progression, 1 due to grade 3 muscle cramps and 1 due to arrhythmia, and 3 patients have died, 2 from infection and 1 from BNS progression. The median event-free survival (EFS) from ibrutinib initiation was not yet reached. The 1-year and 2-year EFS rates were 71% (95% CI 46-86%) and 52% (23-75%), respectively. Conclusion: Ibrutinib is a safe and effective treatment option for patients with BNS. Disclosures Palomba: Pharmacyclics: Consultancy; Celgene: Consultancy. Talaulikar:Amgen: Consultancy, Honoraria; Takeda: Research Funding; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Buske:Janssen: Honoraria, Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ansell:Affimed: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding. Treon:Johnson & Johnson: Consultancy; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Castillo:Millennium: Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

SummaryThe diagnosis of Waldenström macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi‐institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history‐taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing‐Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.