Diagnosis Of Waldenstrom's Macroglobulinemia Research Articles

Diagnosis and treatment understanding of Waldenström macroglobulinemia in China: a cross-sectional study

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.

Ethnic Diversity in Presentation of Waldenström Macroglobulinaemia and IgM Mgcs in the United Kingdom- a Real-World Data Analysis

Introduction: Waldenström Macroglobulinaemia (WM) is a low-grade B-cell lymphoma characterised by lymphoplasmacytic marrow infiltration with a circulating IgM protein with an incidence of approximately 0.55 cases per 100,000 in the United Kingdom (UK). WM may be asymptomatic, symptomatic and/or associated with IgM-related entities (monoclonal gammopathies) of clinical significance (MGCS). A central aim of the WMUK Charity and Clinical Forum is to systematically upload demographic, clinical data and treatment outcomes from a significant proportion of the UK's WM population. Such data provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Clinical correlates with ethnicity are important but sparsely characterised. This analysis focusses on baseline demographics and outcomes across different ethnic groups in the UK. Methods: We retrospectively reviewed data from the Rory Morrison WMUK Registry, collating descriptive data of WM, non-IgM lymphoplasmacytic lymphoma and IgM MGCS from 24 centres across the UK, diagnosed between June 1978 and June 2023. Research ethics approval was obtained. Baseline characteristics were compared using χ 2 or Fisher's exact tests (categorical variables) or Wilcoxon Mann-Whitney/Kruskal-Wallis tests (continuous variables). Differences were considered significant at p-values &amp;lt;0.05. Statistical analyses were performed using STATA v17.0 (StataCorp, Texas, USA). Results: 1073 patients with documented self-reported ethnicity and a diagnosis of WM (n=985), non-IgM LPL (n=32) or IgM MGCS (n=88) were included. Those with asymptomatic IgM MGUS were excluded. Of 982 with a diagnosis of WM, 12% (114/985) had concurrent MGCS. Across the entire cohort, IgM MGCS comprised peripheral neuropathy including anti-MAG neuropathy (n=114), cold agglutinin disease/syndrome (n=43), AL amyloidosis (n=20), mixed autoimmune haemolytic anaemia (n=13), cryoglobulinaemia (n=8), Schnitzler syndrome (n=8) and C1 esterase deficiency (n=2). Non-IgM LPL had similar baseline characteristics to WM although a trend towards a lower presenting M-protein (7g/l vs 18g/l, p=0.07). Ethnicity was categorised in accordance with the UK National Census (ethnicity-facts-figures.service.gov.uk). The majority was white (90%; 968/1073: English/Welsh/Scottish/Irish) including 35 patients identified as ‘other’ white. The remaining 105 (10%) were from the following ethnic groups (collectively ‘ethnic minorities’, EM): 54 Asian (22 Indian, 4 Pakistani, 1 Bangladeshi, 7 Chinese, 20 other), 19 Black (5 African, 11 Caribbean, 3 other), 6 Mixed/multiple, 26 Other ethnic group. EM presented at a younger age compared to the white cohort (60 vs 65 years, p&amp;lt;0.001) with a lower presenting M-protein at WM diagnosis (11g/l vs 18g/l, p=0.028). A similar proportion of patients had IgM MGCS in white vs EM cohorts (11% vs 8%, p=0.69). In those with IgM MGCS alone, presenting M-protein was similar across both ethnic categories (5g/l vs 3g/l, p=0.36). MYD88 L265P mutation was assessed in 387 WM patients (36%), of which MYD88 L265P was identified in 88% (322/364) and CXCR4 mutation tested in 91 patients and mutated in 29% (26/91). MYD88-mutated WM was observed less frequently in the EM versus white cohorts (79% vs 90%, p=0.05). A similar proportion presented with symptomatic WM across ethnic groups (56% vs 53%, p=0.56). In those with WM diagnosed since 2010 (n=956), median follow up was 8 years (95% CI 7-8), median overall survival was not reached. International Prognostic Scoring System for WM (IPSSWM) was predictive of overall survival. Overall survival estimates did not differ when comparing ethnic groups. Conclusions: Analysis of the national registry for WM shows that ethnic minorities comprise 10% of WM/IgM MGCS, present with WM at a younger age, a lower M-protein and with a higher proportion of MYD88-wild type cases which may suggest different disease biology. There was no difference in overall survival in our cohort. Limitations include the retrospective analysis of real-world data and incomplete documentation of baseline data. Further analysis of molecular signatures across ethnicities, treatment and outcome is warranted and ongoing.

Single-Center Experience of Carfilzomib-Based Combinations for Patients with Lymphoplasmacytic Lymphoma

Single-Center Experience of Carfilzomib-based Combinations for patients with Lymphoplasmacytic Lymphomas Background Use of bortezomib in Waldenstrom macroglobulinemia (WM) produces a response rate of 60-70% in treatment naïve or relapsed WM(Dimopoulos et al., 2005)(Chen et al., 2006). However, it is associated with an increased risk of peripheral neuropathy (PN). This is important considering that WM can be associated frequently with PN. Carfilzomib(K) is a second-generation proteasome inhibitor that is associated with a lower PN risk and offers a PN-sparing approach for treatment for patients(pts) with WM. In the CARD trial, K-based combinations produced a high ORR with a tolerable safety profile(Treon et al., 2014). We report our single-center experience with the use of K-based combinations in pts with treatment naïve or relapsed lymphoplasmacytic lymphoma (LPL). Patients and Methods We conducted a single-center retrospective study on an IRB-approved protocol for all pts who were treated with K-based combinations at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Efficacy outcomes included overall response rates (ORR), progression free survival (PFS), overall survival (OS). Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). PFS was defined as time from initiation of treatment to progression of disease or death whichever occurred first. OS was defined as time from initiation of treatment to death. The consensus criteria from the 6 th International Workshop on WM were utilized for response assessment. Results We identified 36 patients with a diagnosis of WM and 1 patient with IgA-kappa LPL who were treated with K-based combinations between June 2015 and July 2022. 4 patients (10.8%) had a concomitant diagnosis of systemic light chain amyloidosis (AL). 67.6% pts were male, the median age at treatment initiation was 67.5 yrs. Majority of the pts were treatment naïve (86.4%, N=32). Data for MYD88 mutation was available in 30 pts, 93.3% (n=28) were found to have MYD88 mutation on next generation sequencing (NGS) performed on bone marrow aspirate samples. As per the RPISSWM risk stratification, 30% (9) pts were found to have poor risk, 33.3% (10) had intermediate risk and 36.7% (11) had good risk. Median bone marrow involvement by WM was 30%. The majority of the pts (91.9%, n=34) received KCD-R (Carfilzomib, cyclophosphamide, dexamethasone and rituximab) as their treatment regimen, while the remaining patients received KD-R(carfilzomib, dexamethasone and rituximab). Pts received a median of 6 cycles of treatment. ORR was found to be 97.3% (n=36) with 48.6%(n=18) pts achieving a very good partial response or better (&amp;gt;=VGPR). Median PFS was found to be 51.08 months and median OS was not reached (NR). Two patients needed treatment discontinuation following 1 cycle or less, due to toxicity (dyspnea, one of which was non-cardiogenic) associated with carfilzomib and were changed to an alternative regimen (Bortezomib, cyclophosphamide, dexamethasone and rituximab). Further data for toxicities are being gathered and will be presented at the meeting. Baseline characteristics and outcomes data are summarized in Table 1. Conclusions K-based combinations produce a high ORR with durable responses in patients with symptomatic LPL. Treatment discontinuation rate due to toxicity was low with only two patients needing change of therapy in our cohort. Our data supports the use of K-based combinations in pts with treatment naïve or relapsed LPL.

CD19-Targeting CAR T-Cell Therapy in Transformed Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Descar-T and US Collaborative Study

Introduction: Patients with histological transformation (HT) of Waldenström macroglobulinemia (WM) who relapse or are refractory (R/R) have a poor prognosis with standard chemoimmunotherapy, notably patients who are unable to undergo high dose chemotherapy (HCT) and autologous stem cell transplantation (ASCT) or who relapse after HCT/ASCT. CD19-targeted chimeric antigen receptor (CAR) T-cell therapies can lead to durable responses in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and thus may represent a promising therapeutic option in R/R transformed WM (tWM); however, data from pivotal trials is lacking. This study aimed to evaluate the efficacy and safety of anti-CD19 CAR T-cells in real-word patients with R/R tWM. Methods: We retrospectively identified patients with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in the French DESCAR-T registry (NCT04328298) and 2 US centers. The primary endpoint was best complete response rate (CRR). Secondary outcomes were best overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Responses were assessed according to the Lugano 2014 criteria at 1 month, 3 months and 6 months. Subsequent assessments were per institutional pratice. 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). Results: Between June 2017 and May 2023, 22 patients (18 from DECAR-T centers and 4 from US centers) with R/R tWM were treated with anti-CD19 CAR T-cells (13 axi-cel and 9 tisa-cel). Median age at WM diagnosis was 58 years (range 35-72). MYD88 L265P and CXCR4 mutations were present in 85% (11/13) and 29% (2/7) of patients with available data, respectively. Patients received a median of 1 prior line of treatment (range, 0-4) for WM and 2 prior lines (range, 1-4) for HT. Eight patients had received prior ASCT (2 for WM and 6 for HT) and 1 patient allogeneic SCT. The median time from WM to HT diagnosis was 4.5 years (range, 0-32) and 26 months (range, 3-90) from HT diagnosis to CAR T infusion. Of note, CNS involvement was present in 3 patients at DLBCL relapse before CAR T-cell therapy. At time of infusion, the median age was 66 years (range, 41-82) and 8 patients (36%) were older than 70 years. Median Eastern Cooperative Oncology Group (ECOG) was 1 (range, 0-2). Bridging therapy was administered to 16 patients (73%). Following bridging therapy, 6 patients had progressive disease (PD), 4 stable disease (SD) and 6 were responders (2 complete responses (CR) and 4 partial responses (PR)). After CAR T-cell infusion, best CRR was 82% and best ORR was 95%. The ORR/CRR was 95%/77% at 1 month, 76%/71% at 3 months and 68%/68% at 6 months. Seventeen patients (78%) experienced CRS, including 2 grade 3 (all after axi-cel), and 9 ICANS occurred (41%), including 1 grade 3 and 1 grade 4 (all after axi-cel). Eight patients (36%) presented infections, including 3 grade 3 and 1 grade 4. Neutropenia was reported in 78% (grade 3-4 = 68%), thrombocytopenia in 86% (grade 3-4 = 45%) and anemia in 86% (grade 3-4 = 32%) of patients. After a median follow-up of 17 months (range, 1-47), the 1-year PFS and OS were 70% and 84% respectively (figure). Five deaths were reported, 4 due to progressive disease and 1 from SARS-CoV-2 infection. Conclusion: This study shows a high efficacy of anti-CD19 CAR T-cell therapy in R/R tWM with no unexpected toxicity. Longer follow-up is needed to confirm the long-term efficacy of CAR T-cells in tWM.

Prospective Evaluation of Minimal Residual Disease in Waldenström Macroglobulinemia across Different Tissues and Treatments: Results of the “BIO-WM” Trial of the Fondazione Italiana Linfomi (FIL)

Introduction. MYD88 L265P is the hallmark mutation in Waldenström Macroglobulinemia (WM) and is becoming increasingly important in the management of IgM-gammopathies, due to its role as prognostic and predictive biomarker. Recently, MYD88 L265P detection by allele-specific quantitative PCR was proposed as reliable minimal residual disease (MRD) marker in bone marrow (BM) samples (Varettoni, Hematol Oncol 2022). Novel, more sensitive, techniques as droplet digital PCR (ddPCR) might extend the feasibility of MRD detection in WM also in non-invasive tissues, as peripheral blood (PB) or plasmatic cell-free (cf) DNA. This was a secondary endpoint of the multicenter, observational “BIOWM” (NCT03521596) trial, sponsored by the Fondazione Italiana Linfomi (FIL) and the International WM Foundation/Leukemia and Lymphoma Society. From 2018 to 2020 this trial enrolled 300 consecutive patients with primary diagnosis of WM or IgM-MGUS and a systematic biobanking was performed. Here are presented the first results of the MRD study on the patient subset who received frontline treatment, with the aim of driving correlations with clinical response, type of therapy received and outcome prediction. Methods. Paired BM, PB and plasma samples were collected for each patient at baseline (T0) and follow-up and MYD88 L265P detection was performed by ddPCR in all specimens (Drandi, Haematologica 2018). As of today, 59/300 patients (58 WM and 1 IgM-MGUS) received frontline treatment and MRD levels after therapy (T2) were detected by ddPCR: actually, T0-T2 paired samples were available in 49 (BM), 56 (PB) and 48 (cfDNA) cases, respectively. Moreover, MRD was evaluated also by 8-color multiparametric flow cytometry (MFC) in 23 BM and 24 PB samples with a minimum of 10 million cells acquired. Results. Median age of the 59 treated patients was 68 years (24-85), 32% were female, median IgM value was 2420 mg/dL (101-8840), median Hb 10.5 g/dL (8 -17) and IPSS-WM was high in 35% and intermediate in 46%. MYD88 L265P mutation rate was 94% (46/49) in BM, 80% (45/56) in PB and 90% (43/48) in cfDNA samples, respectively. Treatment was started because of anemia in 32% cases, lymphadenopathy or splenomegaly in 34%, hyperviscosity in 20%, other reasons in 13%, and the only MGUS patient required treatment for anti-myelin-associated glycoprotein polyneuropathy. Thirty-one out of 59 patients received bendamustine-rituximab (BR), 23/59 dexamethasone, rituximab and cyclophosphamide (DRC) or DRC-like regimen and 5/59 a single agent therapy (namely, 3 rituximab, 1 cyclophosphamide, 1 ibrutinib). Overall response rate was 90% (87% for BR and 96% for DRC), with 19% CR, 29% VGPR and 35% PR in BR and 4% CR, 0% VGPR and 91% PR in DRC, respectively. Overall, MRD negativity after treatment was 30% (14/46) in BM, 89% (40/45) in PB and 54% (23/43) in cfDNA, respectively. Moreover, among patients still MRD positive after treatment, median MYD88 L265Ptumor burden shrinkage was about 2 Logs in BM (5.5E-03 vs 2.1E-01) and around 1 Log in cfDNA (5.9E-03 vs 3.7E-02) and in PB samples (3.6E-03 vs 2.5E-02), respectively (Figure 1). Interestingly, the MRD shrinkage in BM was deeper among patients receiving BR (48% MRD negative with a median MYD88 L265P decrease of more than 2 Logs among patients still MRD positive) vs patients receiving DRC (10% MRD negative with a median decrease of 1 Log), Figure 2. Similar trends in favor of BR in inducing MRD negativity were reported in PB (96% vs 88%) and cfDNA (70% vs 35%), respectively. MRD results by MFC were overall in line with ddPCR results: namely 27% of patients reached MRD negativity in BM and 69% in PB. The median follow-up for the whole series was 41 months, resulting in a 3-years PFS of 71% and 3-years OS of 89%, respectively. Interestingly, despite the current limited follow-up for such an indolent disease, MRD positivity by ddPCR in PB predicted a dismal clinical outcome if compared with MRD negative patients (3-years PFS 40% vs 73%, p=0.038). Conclusions. To the best of our knowledge, this is the first report of prospective MRD evaluation in a WM clinical trial. Our preliminary results suggest that MYD88 L265P monitoringby ddPCR is a suitable target for MRD analysis, in the contest of common immunochemotherapeutic schedules. Moreover, different levels of disease persistence were described across BM, PB and cfDNA, with MRD monitoring in non-invasive tissues showing promising predictive value for outcome discrimination.

Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia

Background: Waldenström Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous outcomes. The recently developed, Revised International Prognostic Scoring System for WM (rIPSS-WM) did not examine the prognostic impact of MYD88L265P, a somatic alteration present in most patients with WM. Moreover, rIPSS-WM could only be partially validated in an external cohort. Here, we report the performance of rIPSS-WM and propose a refined prognostic model with external validation. Methods: We reviewed medical records of treatment-naïve patients with active WM consecutively seen at Mayo Clinic, Rochester (MCR) between 01/01/1996 and 12/31/2017. We applied the rIPSS-WM model in patients with data available for all required parameters, including age, serum beta-2 microglobulin (β2M), serum lactate dehydrogenase (LDH) and serum albumin at diagnosis to assess the prognostic utility of this model. We then identified the dichotomized clinical and laboratory parameters prognostic for overall survival (OS) by univariate analyses (UVA) in our cohort. The significant parameters were analyzed to independently predict OS in a multivariable analysis (MVA) and to create a prognostic model, which was subsequently validated in an independent multi-institutional cohort. Results: We identified 889 patients with active WM at MCR, with a median follow-up of 8.2 [95% confidence interval (CI): 7.5-9] years. The estimated median OS for this cohort was 10.6 (95%CI: 9.7-11.4) years. Patients with available data in this cohort for the validation of rIPSS-WM (n=241) were risk stratified into very low (n=46), low (n=64), intermediate (n=58), high (n=46) and very-high risk groups (n=27) per rIPSS-WM, with the respective 5-year OS rates of 96%, 76%, 72%, 77% and 32%, demonstrating overlapping survival curves for the low, intermediate and the high-risk groups. Because rIPSS-WM could not be validated, we used the data from the MCR cohort and identified age at diagnosis of active WM, LDH &amp;gt;upper limit of normal (ULN), β2M &amp;gt;3µg/mL and albumin &amp;lt;3.5g/dL as statistically significant prognostic markers for OS on UVA. Notably, the presence of MYD88 L265P did not impact OS [median 11.4 years (95%CI: 10.1-not reached (NR) for MYD88 L265P genotype (n=231) versus 10 years (95% CI: 8.1-NR) for MYD88 WT genotype (n=65); p=0.33]. On MVA, LDH &amp;gt;ULN (HR 2.34), serum albumin &amp;lt;3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and &amp;gt;75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin &amp;lt;3.5 g/dL and age group 66-75 years and similarly, 2 points each for age &amp;gt;75 years and serum LDH &amp;gt;ULN per their impact on OS. Patients with the composite scores of 0, 1 and 2 were categorized as low risk, low- intermediate risk and intermediate risk, respectively. Due to similar OS for the scores of 3 to 5, these were combined to form the high-risk group of our proposed model: Modified Staging System for WM (MSS-WM). The median OS was 14.6 years [95%CI: 9.1 years-NR] for low-risk (score 0, n=71, 21%), 11.2 years (95% CI: 9.1-15.2 years) for low-intermediate risk (score 1, n=110, 32%), 8.1 years (95% CI: 6.4-12.2) for intermediate risk (score 2, n=81, 24%) and 5.5 years (95 % CI: 3.9-11 years) for the high-risk group (score ≥3, n=79, 23%); p&amp;lt;0.0001. In this derivation cohort, the 5-year OS rate was 93%, 82%, 69% and 55% and 10-year OS rate was 60%, 53%, 45% and 30% for the low, low-intermediate, intermediate, and high-risk cohort, respectively ( Figure 1A). We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p&amp;lt;0.0001). We then used data from an independent series of 335 treatment-naïve symptomatic patients from academic institutions (n=5) across the US and Europe for external validation of the MSS-WM model. The median follow-up for the validation cohort was 6.3 years (95% CI: 5.5-7.2 years). The 5-year OS was 93%, 90%, 75% and 57% and the estimated 10-year OS was 91%, 80%, 64% and 35% for the low risk (n= 86, 26%), low-intermediate (n=107, 32%), intermediate (n=86, 26%) and high-risk (n=59, 18%) cohorts, respectively (p&amp;lt;0.0001, Figure 1B). Conclusions: Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.

Multicenter Prospective Phase II Study of Rituximab Combined, Bortezomib, Lenalidomide, Dexamethasone Followed By Lenalidomide Maintenance (R-VRD) in Patients with Waldenstrom's Macroglobulinemia (KMM1803)

Backgroud: Waldenström macroglobulinemia (WM) is an indolent B-cell malignancy characterized by the presence of immunoglobulin M (IgM) monoclonal gammopathy and lymphoplasmacytic bone marrow infiltration. Recently, the superior efficacy of BTK inhibitors and other novel agents has been established. However, BTK inhibitors has been shown limited efficacy in patients with CXCR4 mutation and MYD88 wild type. Therefore, the importance of chemotherapy which do not contain BTK inhibitors still remain. This study was conducted to estimate the efficacy and safety of the combination of rituximab, bortezomib, lenalidomide and dexamethasone in patients with WM in South Korea. Methods : Between Aug. 2018 and Aug. 2022, a total of 39 patients were included in this study at 12 academic institutes in South Korea. The primary end-point of the study was the median progression-free survival (PFS), and the secondary end-points were the overall survival (OS), overall response rate (ORR), minimal residual disease (MRD) achievement and toxicities. Eligible patients were confirmed clinicopathological diagnosis of WM who has Measurable and symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia (IMWWM) for requiring treatment. Pateints who received rituximab treatment within the last 12 months before the first dose of study drug were excluded. Patients received the 28-day cycle of Rituximab (375 mg/m 2 IV on day 1), Bortezomib (1.3 mg/m 2 SC on day 1, 8, 15), Lenalidomide (15 mg per oral day 1-21) and dexamethasone (20 mg iv or oral day 1-4). Enrolled patients were received induction therapy with rituximab and bortezomib, lenalidomide and dexamethasone every 4 weeks for 6 cycles and then lenalidomide (10 mg on day 1-21) maintenance for 2 years. All patients were checked MYD88 and CXCR4 mutation at the baseline work up of this study and MRD achievement was checked by MYD88 PCR every 6 months for 3 years. Results : The median (range) age was 65.2 years. Lymphadenopathy were noted around 50%. In this study, MYD88 mutation was noted 74.3% and CXCR4 mutation was noted 20%, respectively. The response rates were following: CR in 4 (13.3%), VGPR in 3 (10.0 %) PR in14 (46.7 %), MR in 3 (10.0%) and &amp;lt; MR in 6 (20.0 %). Overall response rates (≥PR (partial response)) rate was 70.0 % and more than MR were 80%. 2yrs PFS and OS were 56% and 93%, respectively. We are now checking MRD by MYD88 PCR for ongoing patients. The detailed response rates and survival outcomes will be reported soon according to MYD88 and CXCR4 mutation status. And comparison of survival difference according to MRD negativity will be also announced after finishing data collection of MRD. Conclusions: R-VRD regiment could be helpful for MYD88 mutation negative or CXCR4 mutation positive patients. BTK inhibitors show superior response and survival outcomes for patients with MYD88 mutation positive and CXCR4 mutation negative. So, we are supposed that R-VRD could be optional treatment for patients who are not suitable for BTK inhibitors.

Waldenström Macroglobulinemia diagnosis, risk assessment and treatment in Portugal – results from a Delphi-like Panel

Clinical features of Waldenström Macroglobulinemia (WM) are variable, often leading to heterogeneous decisions regarding patients’ diagnosis, risk stratification, and treatment. This study assessed the agreement rates on WM diagnosis, risk stratification, and active treatment strategies to capture how this heterogeneity may influence national practices among hematologists. A two-round Delphi-like Panel with 22 national hematologists experienced in WM was conducted online, where 33 statements were classified using a 4-point Likert scale. For each statement, the consensus level was set at 70% for “fully agree/disagree”; the majority level was defined as &amp;gt;70% in agreement or disagreement. After two rounds, no statements were categorized as consensus, and 15 out of 33 failed to obtain a qualified majority. Globally, the experts could not reach a qualified majority in approximately half of the sentences from each category (diagnosis, risk assessment, and therapeutic decision), indicating that contradictory opinions are transversal to all the topics involving WM. A lack of consensus in diagnosing and managing WM among Portuguese hematologists became evident. These results illustrate heterogeneity in clinical practices, and future research initiatives should be considered to improve and reinforce accepted guidelines for diagnosing, assessing, and treating WM patients.

Incidence of skin cancer among patients with Waldenström macroglobulinemia: Analysis of the SEER database (2000-2019).

e18893 Background: The association between non-Hodgkin lymphoma, including chronic lymphocytic leukemia, and aggressive skin cancers is well established. We studied the incidence of melanoma and non-melanoma skin cancers (NM) skin malignancies (SM) among patients with Waldenstrom macroglobulinemia (WM). Methods: We used the SEER 17 registry to identify adult [Age &gt; 20] patients(pts) with an index diagnosis (dx) of WM between 2000- 2019. We included ICD-O-3 codes 9671/3 (Lymphoplasmacytic lymphoma) and 9761/ (Waldenstrom macroglobulinemia) to identify index dx. Only first of the two codes was used if both were mentioned for same pt. We excluded patients with diagnosis made from death certificate or autopsy. We used ICD-O-3/WHO 2008 codes assigned to melanoma of skin and other NM SM to identify subsequent diagnosis ( &gt; 2months after index diagnosis) of SM excluding basal cell and squamous cell cancers. SM were categorized using ICD-O-3 codes for histology. Follow up period was till December 2019. Data variables and standardized incidence ratio [SIR] for SM were obtained with multiple primary SIR analyses using SEER Stat v 8.4.0.1 software. Kaplan Meier method was used to estimate overall survival (OS) using R 4.2.2. Results: We identified 8099 patients with WM of which 68 patients (0.84%) had a subsequent dx of SM. WM and SM were diagnosed at median (IQR) ages of 69 (60-77) and 74 (67-81), with a median gap of 52 (30-95) months. Majority of WM survivors with SM were males (51 or 75%), white (100%) and older than 60 years of age (72%) at WM diagnosis. Almost half of the patients who developed SM underwent chemotherapy for WM (n = 35, 45%). The overall risk of developing SM was significantly higher in WM patients as compared to the general population [SIR (95%CI) = 1.34 (1.01-1.74) (p &lt; 0.05) for melanoma and 2.85 (1.52-4.87) (p &lt; 0.05) for NM]. Eleven different types of histology for SM were noted, with malignant melanoma, NOS (n = 30, 44%) and Merkel cell carcinoma (n = 7, 10%) being the most common melanoma and NM subtype (Table). The median survival after SM dx was 68 (55-NA) months. Conclusions: Patient with WM had higher risk of SM (melanoma and NM skin cancers, excluding basal cell and squamous cell cancers) compared to the general population. This study highlights the need for screening and counseling for skin cancers in WM patients in routine clinical practice. [Table: see text]

Waldenström macroglobulinemia diagnosed by bronchoalveolar lavage.

An 88-year-old woman with no significant medical history was admitted to the emergency room with persistent dyspnea and cough. Chest computed tomography (CT) showed diffuse ground-glass opacities in both the lungs (Fig. 1A). Collagen disease and infection were ruled out, and lymphoproliferative disease was suspected based on high level of WBC 15 200/μL (lymphocyte 63.7%), soluble interleukin 2 receptor 3070 (151–474) IU/mL and LDH 421 (115–245) U/L. Fluorodeoxyglucose (FDG) did not accumulate in the lymph nodes throughout the body, and its accumulation as ground-glass shadows (Fig. 1B) led us to suspect a lung lesion; therefore, we performed a bronchoscopy. The patient experienced severe hypoxemia during bronchoalveolar lavage, and the biopsy was cancelled. Cell block of bronchoalveolar lavage fluid showed CD20-positive atypical lymphocytes and plasma cells, which were κ chain-positive, IgM-positive, IgG-, IgA- and λ chain-negative (Fig. 2). Blood protein fractionation showed M-protein, with increased IgM at 679 (46–260) mg/dL, and decreased IgG at 425 (870–1700) mg/dL and IgA at 8 (110–410) mg/dL. Based on these findings, the patient was diagnosed with Waldenström macroglobulinemia (WM). The patient was treated with steroids, and fever and dyspnea symptoms were relieved. The haematologist performed a bone marrow biopsy (Fig. 3), and confirmed the diagnosis of WM based on the findings of the bone marrow biopsy and flow cytometry of peripheral blood, which showed small B cells with a κ > > λ bias, negative CD5 and CD23, and IgM-κ and Bence Jones protein-κ detected by immunofixation, after which the patient received rituximab. On chest CT 120 days after starting rituximab, the ground-glass opacities in the both lungs disappeared (Fig. 4), and there has been no relapse for more than a year to date.

Ibrutinib response in a patient with refractory mixed essential cryoglobulinemia.

A 74-year-old male presented with fatigue, parasthesiae, Raynaud's phenomena, visual disturbances, and recurrent lower extremity rash (left). Investigations revealed an elevated serum cryoglobulin, rheumatoid factor >1320 IU/ml (ref. <15 IU/mL), undetectable C4, and C3 of 25 mg/dL (ref. 87–200 mg/dL). A small amount of IgM kappa monoclonal protein (M spike of 2.5%) and polyclonal IgG were identified by immunofixation. A diagnosis of mixed (Type II) cryoglobulinemia was made. Testing for Hepatitis B and C was negative. Positron emission/computed tomography (PET-CT) showed no evidence of lymphoma. Although the bone marrow appearance raised suspicion for Waldenstrom macroglobulinemia (WM), testing for MYD88 L265P mutation, which is commonly associated with this disorder, was negative. Of note, scattered CD20-positive B-cells comprised only ∼5% of bone marrow cellularity. The patient's rash gradually evolved into large ulcers over bilateral medial malleoli. Despite treatment with immunosuppression, rituximab, and plasmapheresis, they expanded to 9.3 × 8.9 × 0.3 cm on the left and 8.6 × 5.6 × 0.4 cm on the right (middle), requiring extensive use of opioids and significantly interfering with patient's mobility. A second bone marrow biopsy was again suggestive of WM. However, the frequency of abnormal B-cells was even lower (1.7%), likely reflecting prior therapy. Therefore, B-cells were purified by flow sorting using antibodies against CD19, CD20, and CD38 prior to molecular testing. Critically, this approach revealed the presence of MYD88 L265P mutation, supporting the diagnosis of WM and justifying therapy with Ibrutinib, a Bruton kinase inhibitor which is highly effective in this disease. Starting Ibrutinib 420 mg daily was a clear turning point in the patient's clinical course. After just a few days, he reported a drastic improvement in fatigue and leg ulcer pain. Within the following 2 months, he became pain-free and no longer required narcotics. By the end of the 9 months of therapy, the ulcers were completely healed (right) and quantitative IgM went down from 1058 to 325 mg/dL after the first 3 months. Nearly 2 years since starting the treatment, the patient is asymptomatic except for mild parasthesiae. He continues on Ibrutinib at a lower dose (280 mg daily). Cryoglobulinemia (CG) is a rare multisystem disorder which is caused by immunoglobulins with a capacity to aggregate at lower temperatures (cryoglobulins). Notably, even a small amount of cryoglobulin in the serum is sufficient to cause disease. Hence, a low-burden lymphoproliferative disorder that serves as the source of monoclonal cryoglobulin may be difficult to diagnose, precluding the use of targeted therapies. In agreement with a single prior report [1], our case shows that Ibrutinib can be remarkably effective in refractory CG due to WM. Unexpectedly, we found that despite a near-complete resolution of symptoms with Ibrutinib, the patient's cryoglobulins/IgM paraprotein persisted. In addition, the rheumatoid factor was still elevated, and C4 complement remained undetectable. This suggests that the therapeutic benefit of Ibrutinib may be explained not only by anti-tumor effect but also anti-inflammatory properties, as demonstrated by its efficacy in COVID [2], graft-versus-host disease [3], and autoimmune conditions [4]. Finally, our case shows that enriching for B-cells prior to molecular analysis may aid the diagnosis of occult lymphoproliferative disorder in other patients, for example those with IgM monoclonal gammopathy of clinical significance, who may also benefit from a trial of targeted therapy. H. Jamali wrote the manuscript. D. Wu performed cell sorting and molecular analysis. L. Soma performed morphological assessment of the bone marrow. M. Linenberger contributed to clinical management of the patient (plasma exchange). M. Wener provided rheumatology expertise and co-managed the patient with LS. L. Silberstein provided haematology expertise, co-managed the patient with MW, and wrote the manuscript. The authors have nothing to report. The authors received no specific funding for this work. None of the authors received financial compensation from an external source in return for writing or publishing this paper. The patient consented to the use of their clinical data and photographs for this correspondence.

Zanubrutinib in patients with treatment-naïve or relapsed/refractory Waldenström macroglobulinemia: An expanded-access study of 50 patients in the United States.

Zanubrutinib in patients with treatment-naïve or relapsed/refractory Waldenström macroglobulinemia: An expanded-access study of 50 patients in the United States.

Waldenstrom Macroglobulinemia and the Clinical Implications of Acquired Von Willebrand Syndrome

Introduction Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma that can manifest with impairment of hemostasis and platelet dysfunction. Very rarely, patients (pts) with WM can develop acquired von Willebrand syndrome (AVWS), a bleeding disorder generally associated with another systemic process. There is limited literature demonstrating the association of these conditions, and the clinical manifestations and symptomatology associated with treatment remain poorly explored. Our study aimed to assess the prevalence of this condition at our institution and determine the associated clinical manifestations and outcomes. Methodology Consecutive pts with a diagnosis of WM evaluated at Mayo Clinic, MN, FL and AZ who underwent von Willebrand factor (VWF) testing from 01/2002 to 01/2022 were included. Laboratory confirmation was obtained in the Special Coagulation Laboratory at Mayo Clinic, and those with a confirmed diagnosis of WM and AVWS were included in our final cohort. Bleeding symptoms, WM- and AVWS-related treatment, and associated laboratory data were abstracted. Results Of 2210 pts with a diagnosis of WM, 73 (3%) received testing for VWF, and 11 (15% of those tested and 0.5% of all pts) were diagnosed with AVWS. The median follow-up for these 11 pts was 34.0 months (95% CI, 30.1 - 163.6). Baseline testing at time of initial AVWS diagnosis [median (range, normal)] revealed: platelet count 170 (49-281, 135-317), VWF-activity (latex immunoassay) 25% (12-31, 55-200), ristocetin co-factor activity 21% (12-31, 55-200), VWF-antigen 32 (13-44, 55-200), and Factor VIII activity 40% (16-64, 55-200). Multimer analysis available in 6 patients revealed a normal distribution pattern. The most common underlying reason for testing was bleeding symptoms, observed in 9 (82%) pts. Other reasons for testing included pre-surgical (n=1) and routine screening (n=1). Eight (73%) pts were diagnosed with AVWS prior to frontline treatment initiation for WM. Concurrent diagnosis of AVWS and WM was made in 5 (45%) pts, 3 (27%) pts were diagnosed with AVWS before the progression of smoldering WM to WM and WM-directed therapy initiation, 2 (18%) pts were diagnosed during progressive WM after frontline therapy, and 1 (9%) pt was diagnosed during frontline therapy. In the 5 pts with concurrent diagnosis, WM was diagnosed a median of 35 days (range, 4-83) after the diagnosis of AVWS. All pts received WM-directed treatment. Recurrent epistaxis was the most observed bleeding symptom and was seen in 6 (55%) pts. Other observed symptoms included spontaneous hematoma (n=2), gastrointestinal (GI) bleeding (n=2), retinal hemorrhage (n=2), and subarachnoid hemorrhage (n=1). Seven (64%) pts had a major bleeding event leading to hospitalization due to spontaneous hematoma (n=2), GI bleeding (n=2), epistaxis (n=2) and subarachnoid hemorrhage (n=1). Two (18%) pts required surgical embolization due to severe epistaxis. Pharmacologic hemostatic treatments were administered in 6 (55%) pts, including Factor VIII/VWF complex (n=4, 36%), administered due to GI bleed, hematoma, epistaxis, and pre-surgical prophylaxis. Desmopressin was administered to 4 (36%) pts for hematoma, GI bleed, and epistaxis. Three (27%) pts received intravenous immunoglobulin (IVIG) for GI bleed, hematoma and pre-surgical prophylaxis, and 1 (9%) pt received prednisone for hematoma. These therapies led to at least temporary bleeding symptom improvement (<3 months) in all 6 pts. Of the 9 pts who had bleeding symptoms, 6 (67%) had improvement in their symptoms after WM-directed therapy. Three pts who were refractory to WM-directed therapy had no improvement in bleeding symptoms while on WM therapy (Table). Conclusions We found that <1% of pts had an identified diagnosis of AVWS secondary to WM, highlighting the rarity of this diagnosis and its potential under-recognition. The bleeding risk associated with AVWS in combination with WM, a malignancy inherently associated with bleeding, likely underlies the high rates of life-threatening bleeding events. The high morbidity associated, leading to events such as CNS bleeding and retinal hemorrhage, signals that one needs to evaluate pts with WM who are presenting with symptomatic bleeding for AVWS. Additionally, given a fraction of pts had worsening bleeding events after therapy initiation, agents with lower bleeding risk should be considered in pts with this diagnosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancy in Waldenström Macroglobulinemia: Insights from a Population-Based Analysis

INTRODUCTION: Waldenström Macroglobulinemia (WM), is a hyper-viscosity syndrome characterized by unrestricted proliferation of lymphoplasmacytic precursors in the bone marrow and monoclonal IgM gammopathy. The development of secondary primary malignancy (SPMs) in WM is a multifactorial phenomenon; the indolent nature of the disease, associated immune dysregulation, environmental factors and therapeutic measures, are responsible for high incidence of SPM in WM. This study was conducted to analyse the site-specific incidence of SPM in WM using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. METHODS: A retrospective study was conducted using the SEER-18 dataset. WM patients who were diagnosed between 2000 and 2018, according to the ICD-O-3 = 9761/3 were included. Patients diagnosed on autopsy or through death certificates, and patients with incomplete follow-up data were excluded. SPM was defined as other malignancy appearing at least 1 year after WM diagnosis. Latency was defined as interval between WM and SPM diagnosis. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated using SEER*Stat software (version 8.3.9). P-values and 95% confidence intervals (CI) were generated assuming Poisson distribution of observed incidence of SPM. RESULTS: A total of 4112 WM patients were identified. SPM was reported in 699 (17.0%) patients. The overall risk of developing SPM was significantly higher in WM patients as compared to the general population (SIR= 1.53, 95% CI=1.42-1.65, p <0.05) with an AER of 102.69 per 10,000 population. The risk of developing second primary solid tumors was significantly greater compared to the general population (SIR = 1.12, 95% CI= 1.02-1.23, p >0.05), but significantly increased risks were reported for secondary tumours of the lung and bronchus (SIR = 1.44), skin melanoma (SIR = 1.88), mouth (SIR 3.28), brain (SIR 2.73) and non-melanotic skin tumors (SIR = 4.09). The overall risk of developing secondary hematological malignancies was significantly increased (SIR = 4.95, 95% CI 4.31-5.66, p <0.05). Significantly increased risks were reported for nodal non-Hodgkin lymphoma (NHL) (SIR = 6.62), extranodal NHL (SIR = 11.3), acute lymphocytic leukemia (ALL) (SIR 8.04), acute non-lymphocytic leukemia (ANLL) (SIR = 4.2) and acute myeloid leukemia (AML) (SIR 4.22). Increased risk of SPMs was noted for patients with age 50-74 years (SIR= 1.65, 95%CI=1.44-1.89, p value <0.05) or > 75 years (SIR= 1.3, 95% CI= 1.13-1.49, p value <0.05), but not for patients younger than 50 years. Patients aged 50-74 years had a significantly increased risk of developing SPMs of lungs and bronchus (SIR 2.23), skin (SIR 3.09), vulva (SIR 8.5), thyroid (SIR 3.59), nodal NHL (SIR 6.06), extranodal NHL (SIR 11.87), ANLL (SIR 5.77) and AML (SIR 6.37). Patients aged >75 years had a significantly increased risk of developing SPMs of cecum (SIR 2.50), colon (SIR 1.62), soft tissues (SIR 5.25), nodal NHL (SIR 2.38), extranodal NHL (SIR 7.51), ANLL (SIR 3.69) and AML (SIR 3.63). Risk of SPM was significantly increased in both males (SIR 1.39) and females (SIR 1.59). On subsite evaluation, males had a significantly greater risk of SPMs involving lung and bronchus (SIR 1.71), soft tissues (SIR 4.52), skin (SIR 1.88), nodal NHL (SIR 3.85), extra-nodal NHL (SIR 6.9), ANLL (SIR 5.4) and AML (SIR 5.55). Females reported a significantly increased risk of SPM involving cecum (SIR 3.88), skin (SIR 2.87), vagina (SIR 11.51) nodal NHL (SIR 3.86) and extranodal NHL (SIR 13.57). The risk of SPM was significantly greater in Caucasians (SIR 1.46) but not African Americans or other races. The risk of SPM was significantly greater in patients at all latencies. The risk of SPM of cecum (SIR 2.76) and non-melanotic skin cancer (SIR 5.52) was significantly greater in patients with latency of 12-59 months, but not at subsequent latencies. The risk of melanotic skin cancer (SIR 2.61) was significantly greater in patients with latency of 60-119 months but not other latencies. The risk of thyroid cancer (SIR 6.43) was significantly increased for patients with latency 120+ months only. CONCLUSION: This study showed that 17% of WM patients developed SPM. WM patients were at a 53% greater risk of developing SPM compared to the general population. Caucasians and patients aged greater than 50 years were at particularly high risk of developing SPM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Follow-up of Bendamustine Plus Rituximab Regimen in 69 Treatment Naïve (TN) Patients with Waldenström Macroglobulinemia, a Study on Behalf of the French Innovative Leukemia Organization (FILO)

Background Waldenström macroglobulinemia (WM) is a rare hematological malignancy characterized by the accumulation of IgM-secreting clonal lymphoma cells with a lymphoplasmacytic morphological differentiation. Recently, BTK inhibition has emerged as a promising therapeutic strategy in WM (Buske, JCO 2022; Tam, Blood 2020). However, in real life, a large part of patients(pts) continue to be treated by chemoimmunotherapy (Buske, Lancet Hematol2018) including bendamustine (B)-rituximab (R) in salvage (Tedeschi , Leukemia Lymphoma 2015) or first line MW (Treon, ASH2016). We have previously reported a series of 69 WM pts treated by BR (Laribi, BJH 2018) and demonstrated that this regimen is efficient. However, the follow-up was relatively short and some questions remained unresolved in terms of long-range response and second cancer occurrence. Here we report results of this series with a longer follow-up. Methods Sixty-nine symptomatic previously untreated pts with WM diagnostic criteria according to the second WM Workshop recommendations were enrolled in this retrospective multi-center study between January 2013 and December 2017 in 13 French centers. MYD88L265P and CXCR4 mutations were searched using qPCR and or next generation sequencing. Del(17p) and/or TP53 mutation were investigated in 34 pts. All pts received a BR regimen consisting of 375 mg/m2 of R on day 1 and 90 mg/m2 of B on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Cumulative incidence of secondary malignancies and high-grade lymphomas were computed, considering death free of malignancies as a competing event. Event-free survival (EFS), time to next treatment (TNT), progression-free survival (PFS) and overall survival (OS) were plotted using the log rank test and Kaplan-Meier graphical comparison. Results Pts median age was 69 years old (yo; range 45-88) at WM diagnosis and 71 yo (range 46-88) at therapy initiation. MYD88 and CXCR4 mutations were present in 45/51 (88%) and 11/44 (25%) of pts, respectively. A complex karyotype was disclosed in 6/44 (14%) pts, and 1/34 (3%) had TP53 alteration. According to the IPSSMW score, 14 (22%) pts were low risk, 32(46%) intermediate, and 32 (46%) high risk. Using consensus response criteria, the overall response rate was 97% (very good partial response [VGPR] with negative immunofixation 19%, VGPR 37%, PR40%, MR 1%) and the major response rate was 96%. Cumulative incidence of VGPR or better was 47.8%, 53.6%, 55%, and 56% at 6, 12, 18, and 24 months, respectively. After a median observation time of 68.5 months (range 23.13-106) post BR, the median OS was not reached (83-NR) , and the median PFS was 82 months (75-NR). Median OS for pts with mutated or WT MYD88 was NR and 72.8 months, respectively (p=0.046). Median OS for pts with mutated or WT CXCR4 was 70.2 months and NR, respectively (p=0.64). Median OS related to disease or treatment was not reached, while median OS related to other causes was 106 months. Sixteen (23.2%) pts relapsed. Fourteen received second line therapy and 2 supportive care. Eight patients received ibrutinib, and 6 chemo-immunotherapy. TNT was 31.55 months (range 2.66-82.43). Median PFS after a second line of treatment (PFS2) was 45 (9.13-NR) or 21 months (range 9.13-NR), for pts receiving ibrutinib or not. Eleven pts developed a second cancer: 9 solid tumors (2 pancreatic, 2 gastric, 1colic, 1 pulmonary, 1 breast, 1 cutaneous), and 2 treatment-related myeloid neoplasms (TRMN). Median EFS, defined as occurrence of death, relapse or second cancer was 82 months (61-NR). The cumulative incidence of second cancer was 2.90%, 5.80%, 10.49%, and 17.6% at 12, 24, 48, and 96 months, respectively (figure 1). Univariate analyses on OS disclosed statistically significant differences for age at diagnosis (p=0.001), age at first therapy (p <0.001), IgM>70g/L (p: 0.018), complex karyotype (p=0.037), and high risk IPSSMW (p<0.01). In multivariate analysis, only IPSSMW remained statistically significant (p<0.001) (table1). Univariate analyses on PFS only singled out age at diagnosis (p=0.03) or at first therapy (p=0.049) as statistically significant. Mutated MYD88 or CXCR4 did not impact OS nor PFS. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

How Age, Comorbidities and Concomitant Medications Influence Ibrutinib Management and Survival in Waldenstrom Macroglobulinemia

Introduction: Although Waldenstrom Macroglobulinemia (WM) typically affects the elderly, no studies so far have specifically addressed the impact of age, comorbidities, ECOG-PS and concomitant medications on treatment outcomes. Data on WM receiving ibrutinib outside of clinical trials are sparse, showing 18-20% and 8-35% of pts requiring permanent dose reduction (PDR) and toxicity-related definitive treatment discontinuation (Tox-DTD). Furthermore, the impact of polypharmacy and drug interference while on ibrutinib is still unexplored. The aim of this study is to evaluate which fitness parameters are significant for treatment outcome and management in patients with WM receiving ibrutinib in clinical practice. Methods: This is a multicenter retrospective study analyzing the impact of age (≥75y), CIRS (>6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG-PS (>1), polypharmacy (>3 concomitant medications), type of concomitant medications, CrCl (<30; <50 ml/min), baseline nephropathy, cardiopathy, hypertension, neuropathy, neutropenia and disease characteristics on tox-DTD; PDR; PFS, EFS (event: tox-DTD, PDR, progression, death) and OS. Medical conditions that were deemed to be complications of WM and WM diagnosis itself, were not included in CIRS score calculation. Results: From Aug 2016 to Apr 2022, 206 pts were included in the analysis. Pts' characteristics are reported in table 1. After a median follow up of 26.6 mo (range 0.5-70.5 mo), 139 pts (67.5%) are still on ibrutinib. Treatment temporary interruption occurred in 60 pts (29.6%) for a median of 18 consecutive days. Overall, 67 pts discontinued ibrutinib due to: PD in 30 (14.6%); toxicity in 23 (11.2%, Tox-DTD); other reasons in 14 (6.8%). Median time to Tox-DTD was 7.5 mo with recurrent atrial fibrillation (AF) in 10/23 pts being the most common recorded toxicity. Fifty-three pts (25.7%) required ibrutinib dose reduction at least once, followed by PDR in 40 (19.4%) of them. AF and diarrhea were the most common reasons for PDR both occurring in 7 pts. Median time to PDR was 7.1 mo. Pts with very-high revised-IPSSWM and CrCl<50 showed higher risk of Tox-DTD, that was confirmed also at multivariate analysis (p .002 and p .025, respectively). While ECOG-PS>1, CIRS>6 and cardiocomorbidity significantly influenced PDR at univariate analysis, only ECOG-PS maintained its independent role (p <.001). Number and type of concomitant medications had no impact on ibrutinib management. Median PFS, EFS and OS for the whole population were not reached and resulted 73.3%, 54.1% and 85.3% at 2 years, respectively. Age, ECOG-PS, CrCl>50 and nephropathy negatively predicted all survival outcomes at univariate analysis. The presence of major comorbidities, but not CIRS>6 impacted on OS. At Cox proportional regression hazard model, only ECOG-PS>1 confirmed its role on PFS, EFS and OS (p <.001), while CrCl<50 was significant for EFS (p .007) and OS (p .003). Among baseline disease characteristics CXCR4 mutation was the only factor independently associated with progression (p .023). Results from univariate analysis are summarized in Table 2. PFS was significantly impacted by PDR (p<.0001), also showing a trend in pts temporarily interrupting ibrutinib (p .053). Conclusions: To our knowledge this is the first series analyzing the role of age, comorbidities and concomitant medications in patients with WM receiving ibrutinib. Poor ECOG-PS and compromised renal function emerged as significant prognostic baseline parameters on both treatment management and survival. High comorbidity burden (CIRS>6) but not presence of major comorbidity shows to associate with schedule modifications. Age per se did not result as a risk factor for toxicity-related discontinuations or dose reductions, nevertheless pts with very-high revised-IPSSWM, that includes age in its score calculation, were at higher risk of Tox-DTD. Importantly, as per our data neither polypharmacy, nor type of concomitant medication interfere with ibrutinib management. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S1971 Waldenstrom Macroglobulinemia: A Malignant Mimicker of IBD

Introduction: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma in the bone marrow with IgM gammopathy in the blood. Annually ∼1400 cases are diagnosed in the US, with typical presentation of B symptoms, fatigue, neuropathy, and mucosal bleeding. Only 3% of patients present with colonic symptoms. We describe a case of WM with rectal involvement presenting as bloody diarrhea, mimicking inflammatory bowel disease (IBD). Case Description/Methods: A 56-year-old man with depression, anxiety, and fibromyalgia presented with 6 months of diarrhea with mucous and rectal bleeding. He underwent upper endoscopy and colonoscopy with Helicobacter pylori gastritis, proctitis, and inflammatory polyps. He symptoms worsened despite rectal mesalamine, including weight loss and night sweats. Budesonide oral and foam resolved the bleeding but diarrhea continued despite rifaximin. Around this time, he was thought to have irritable bowel syndrome. Two years later, he had recurrence of daily bowel movements with mucous and rectal bleeding, plus fecal incontinence, tenesmus, and rectal and abdominal pain. He also noticed myalgias, arthralgias, parasthesias, fatigue, and chills. Rheumatology suggested fibromyalgia as the culprit, in part due to elevated ESR. After his GI symptoms renewed suspicion for IBD, repeat colonoscopy showed a 3 cm rectal mass with ulcer and stenosis at the recto-sigmoid colon. Biopsies showed eosinophilic proteinaceous material positive for PAS-D, negative for fibrosis and amyloid and concerning for malignancy. EUS confirmed inflammatory polyps and rectal thickness ( Figure 1). Hematology performed immunofixation with faint monoclonal IgM-lambda, and bone marrow biopsy confirmed lymphoplasmacytic lymphoma concerning for WM. Discussion: WM rarely involves the GI tract, with fewer colonic and rectal presentations than small bowel. The IgM deposition can cause severe malabsorption, steatorrhea, obstructive symptoms, or GI bleeding. Especially in cases of bloody stools and localized colonic thickening, WM can be mistaken for IBD. In our case, factors more suggestive of WM included degree of colonic thickening and pathologic PAS-D positivity. Particularly, raised lesions should prompt investigation for malignant processes, despite surrounding inflammatory changes. Diagnosis of WM usually involves multiple specialists and procedures such as bone marrow biopsy. WM treatment includes bruton tyrosine kinase inhibitors or bendamustine with rituximab, the latter of which improved our patient’s GI symptoms.Figure 1.: Image 1. Colonoscopy and lower endoscopic ultrasound (EUS) visualized circumferential wall thickening and stenosis in rectum, with polyps and stenosis in sigmoid colon. a. During colonoscopy, a benign-appearing, intrinsic moderate stenosis measuring 4 cm in length was found in the recto-sigmoid colon, due to circumferentially congested edematous polypoid mucosa with overlying exudate. b. Several 10 to 16 mm sessile polyps were seen with inflammatory appearance in the sigmoid colon. c-d. During EUS, circumferential wall thickening was found in the rectum at the superficial and deep mucosa. There was no evidence of an infiltrative subepithelial mass. The muscularis propria layer was normal throughout.

Bing-Neel Syndrome, a Rare Presentation of Waldenström Macroglobulinemia-A Multicenter Report by the Polish Lymphoma Research Group.

Bing-Neel syndrome (BNS) is a rare presentation of Waldenström macroglobulinemia (WM). BNS is a consequence of the central nervous system (CNS) involvement by lymphoplasmacytic lymphoma (LPL) and, rarely, the peripheral nervous system. The data on BNS are extremely scarce. Therefore, we performed a multicenter retrospective analysis of BNS patients diagnosed and treated in centers aligned with the Polish Lymphoma Research Group. The analysis covers the years 2014–2021. Eleven patients were included, 55% females and the median age at BNS diagnosis was 61 years. The median time from WM to BNS was 3.5 years; 27% of patients did have a diagnosis of WM and BNS made simultaneously or within 30 days from each other. Isolated parenchymal involvement was the least frequent (20%). Patients were treated with different regimens, mostly able to cross the blood-brain barrier, including 18% treated with ibrutinib first line. The cumulative objective response to treatment was 73%. With the median follow-up of 20 months (95% CI, 2–32), the 36-month estimates were: overall survival (OS) 47%, progression-free survival (PFS) 33%, and cumulative incidence of BNS-associated death 41%. The performance status according to ECOG was significant for PFS (HR = 7.79) and the hemoglobin concentration below 11 g/dL was correlated with PFS. To conclude, BNS is a very rare manifestation of WM. It is associated with a poor outcome with most patients succumbing to BNS.

A Focus on Waldenström Macroglobulinemia and AL Amyloidosis.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma that is characterized by the overproduction of an IgM monoclonal protein. It may cause adenopathy, hepatomegaly, splenomegaly, as well as other disease-related complications such as cold agglutinin anemia, cryoglobulinemia, hyperviscosity, and neuropathy. While light chain amyloidosis in patients with WM only occurs in about 10% of patients, it is important that advanced practitioners are able to recognize concurrent AL amyloidosis, which will affect the patient's treatment trajectory. Diagnosis of WM with AL amyloidosis is based on bone marrow biopsy and a fat pad biopsy. If AL amyloidosis is suspected, the bone marrow and fat pad biopsy should undergo Congo red staining. If it is negative, and there is a strong suspicion of AL amyloidosis, then an organ biopsy can be considered. Treatment of WM uses rituximab-based therapy in combination with a variety of other agents, including proteasome inhibitors, alkylating agents, and BTK inhibitors. Treatment of light chain amyloidosis uses bortezomib as the backbone of therapy and can be administered with cyclophosphamide, dexamethasone, and now daratumumab, which was recently approved. Waldenström macroglobulinemia and light chain amyloidosis are both rare diseases and can lead to a variety of disease-related complications. Fortunately, many options exist for both diseases. This article will highlight a case of WM with amyloidosis and a case of a patient with relapsing WM with considerations for advanced practitioners managing this patient population.

ORAL WALDENSTROM MACROGLOBULINEMIA

<h3>Objective</h3> Waldenstrom macroglobulinemia (WM) is a rare B-cell lymphoproliferative disorder that is characterized by bone marrow infiltration with lymphoplasmacytic cells and immunoglobulin M monoclonal gammopathy. The extramedullary infiltration of WM is uncommon but predicts a worse prognosis. To date, there has been only 1 reported case of biopsy-proven oral manifestation of WM. <h3>Case Summary</h3> A 72-year-old man with a medical history significant for hypertension and WM, which was in good clinical and laboratory control on ibrutinib, a Bruton tyrosine kinase inhibitor, for the past 4 years, was referred by his dentist for evaluation of an asymptomatic palatal mass. The patient was known to have medication-related osteonecrosis of the jaw stage 1 of left mandible. This was secondary to Zometa prescribed to address skeletal involvement of WM. Intraoral examination demonstrated a firm, nontender, 3 × 3 cm sessile mass with surface ulcerations involving the right hard and soft palate. A panoramic radiograph did not reveal any right maxillary sinus pathology, any central lesion, or any periapical radiolucency associated with the right maxillary teeth. A biopsy of the lesion was obtained. The pathology report indicated diffuse infiltration of small to intermediate-sized lymphoplasmacytic cells within the lamina propria that were positive for B-cell markers CD19, CD20, and CD22 (on immunoperoxidase studies) with kappa light chain restriction (with in situ hybridization) confirming the diagnosis of WM. This extramedullary manifestation of WM held great importance because it indicated disease progression in the context of his current management with ibrutinib. He underwent a bone marrow biopsy that demonstrated a previously undetected Bruton tyrosine kinase mutation. He was enrolled in a Phase 1 trial of dasatinib, a tyrosine kinase inhibitor. There was almost complete resolution of the palatal mass after 6-month systemic treatment with dasatinib. However, despite noted improvement in oral WM, the patient died 7 months later. <h3>Conclusions</h3> Although rare, oral health care providers should be cognizant of potential oral manifestation of WM and should communicate the findings to the oncology team because it can be of vital importance in the overall treatment plan. As in this case, the diagnosis of oral WM signified the progression of underlying malignancy.