Academic literature on the topic 'Wm 203.5'

Abstract Abstract 776 Background: Waldenstrom's macroglobulinemia (WM) and related-disorders (Marginal Zone Lymphoma: MZL, and non immunoglobulin IgM lymphoplasmacytic lymphoma: LPL) are rare diseases Very few randomized trials were reported in this setting. Most commonly patients with WM are initially treated with an alkylating agent, such as chlorambucil (CBL) or with a nucleoside analogue such as fludarabine (F) or 2CdA, alone or in association with monoclonal antibody. Methods: WM1 study was a prospective international randomized open-label study that included patients with previously untreated WM MZL and LPL. At registration, patients were stratified as having WM, SLVL, or LPL, and were randomized in the two arms. The aim of the study was to compare the efficacy of oral CBL at a dose of 8 mg/m2 for 10 days every 28 days to a maximum of 12 cycles with oral F at a dose of 40 mg/m2 orally for 5 days every 28 days to a maximum of 6 cycles. 418 patients were enrolled into the study from 07/01 to12/09. 414 patients were included and 405 received at least one course of chemotherapy. There were 339 WM, 37 MZL and 38 LPL with a median age of 68 years (40-89). 207 patients were randomized in the F arm and 207 patients in the CBL arm. At inclusion, the median of haemoglobin (g/l), platelets (Giga/l), albumin (g/l) and beta 2 microglobulin (mg/l) were 9.9, 218, 37.1 and 3.47 respectively. Results: In intention to treat basis, the overall response rate (CR+PR) was 47.8 % in the F arm versus 38.6% in the CBL arm (p=0.06). With a median follow-up time of 35.9 months, the median of progression free survival time (PFS) and disease free survival (DFS) were statistically longer in the F arm: PFS 36.3m vs 27.1 m ( p=0.01) and DFS 38.3m vs 19. 9m (p= 0.0006). In WM group, factors influencing negatively PFS were CBL arm, albumin< 35g/l, platelets<100 G/l and age> 70 years. Main toxicity was haematological with 17/203 (8.3%) vs 18/203 (9%) of grade III- IV thrombocytopenia and 50/203 (24.6%) vs 39/202 (19.3%) of grade III-IV anemia in F and CBL arms respectively. Overall survival rate at 5 years was 61.4% [52.9;71.3] in CBL arm and 70.3% [62.7-78.8] in F arm (p=0.04) (Fig 1). Cumulative Incidence of second malignancies (solid tumors and haematological malignancies except Richter syndrome (RS)) was statistically higher in the chlorambucil arm (25 versus 8, p= 0.004) (Fig 2). The number of RS was 8 in F arm and 9 in CBL arm. Conclusion: F by oral route is a safe and effective ambulatory treatment in WM and close related disorders patients, even in the elderly and more effective than CBL with a duration of response over 3 years. An unexpected finding was a statistically higher number of second malignancies in the C arm and we cannot rule out an oncogenic role of CBL in this setting. Of note, we stress that it is the first time that a front- line treatment has a significant impact on overall survival in WM patients. Disclosures: Leblond: mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tournilhac:Amgen: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

Backgroud: Waldenström macroglobulinemia (WM) is an uncommon indolent B cell non-Hodgkin lymphoma, which has heterogeneous clinical presentations and indications for treatment. Mostly the choice of first-line therapy is based on the individual patient's characteristic and indications for treatment. In China, previous studies on WM are mostly from single-center with small sample size, limiting the information available on treatment and outcome patterns. To address this knowledge gap, we present data from an analysis based on a nationwide multicenter registry with 17-years follow-up. Our study focuses on the clinical presentation, first-line therapies, as well as outcome and prognosis of WM in China. Methods: Patients diagnosed with WM between January 2003 and December 2019 at 35 academic hospitals in China, which have been entered in the database of the China Waldenström macroglobulinemia Registration (CWMG), were included in this retrospective study. Data including baseline clinical features, symptoms requiring treatment, treatment and survival were collected. The overall survival (OS) was defined as the duration from the diagnosis of WM to the date of death or last follow-up. Results: Overall 1141 patients were enrolled, 829 patients were male (72.7%), with a male-to-female ratio of 2.7:1. The median age at diagnosis was 64 years (range, 29-89 years), which 472 patients (41.4%) were older than 65 years, and 126 patients (11.0%) were older than 75 years. The patients' family histories included 6 WM and 4 other lymphoproliferative disorders. Symptoms leading to treatment initiation including anemia in 828 patients (72.6%), organomegaly in 441 patients (38.7%), thrombocytopenia in 302 (26.5%), neutropenia in 246 (21.6%), constitutional symptoms in 203 (17.8%), Bing-Neel syndrome in 13 (1.1%), IgM-related symptoms in including secondary amyloidosis in 32 (2.8%), secondary autoimmune hemolysis in 25 (2.2%), peripheral neuropathy in 23 (2.0%), secondary cold agglutinin disease in 21 (1.8%), secondary cryoglobulinemia in 11 (1.0%). At the time of diagnosis, 1125 patients had full information for IPSS-WM risk stratification. Among them, 194 patients (17.2%) were classified as low risk, 436 patients (38.8%) were intermediate risk, and 495 patients (44.0%) were high risk. Overall, 734 patients had documented treatment information. 75 patients (10.2%) received monotherapy, 264 (36.0%) received chemoimmunotherapy, and 395 (53.8%) receive other combination regimens (Figure 1). The most frequently used monotherapy was chlorambucil (3.1%), followed by ibrutinib (2.9%) and rituximab (2.5%). Rituximab, cyclophosphamide and dexamethasone or prednisone (DRC or RCP) were the most frequently used chemoimmunotherapy (10.8%). Followed by rituximab plus cyclophosphasmide, vincristine/vincristine and prednisone/prednisolone (R-COP) (6.8%), R-COP plus doxorubicin/epirubicin (R-CHOP) (6.1%), rituximab plus fludarabine, cyclophosphamide (R-FC) (4.5%), rituximab plus bortezomib based regimen (3.5%). Other combination regimens including bortezomib based regimen (18.6%), FC (10.6%), CHOP (9.3%), immunomodulatory drug based regimen (5.7%), chlorambucil plus prednisone (4.4%). After a median of 23 months (range 1-201 months) follow-up, 123 patients died. The estimated 5-year OS was 74.9%. Median OS were similar among patients who received monotherapy, chemoimmunotherapy or other combination regimens. To evaluate the prognostic factors of OS using multivariate Cox regression model, age &gt; 65 years old (P=0.011, HR 0.622, 95% CI 0.431-0.898), platelet &lt; 100×109/L (P=0.006, HR 0.570, 95% CI 0.381-0.853), serum albumin &lt;3.5 g/dl (P=0.020, HR 0.582, 95% CI 0.369-0.918), β-2 microglobulin concentration ≥4 mg/L (P=0.019, HR 0.630, 95% CI 0.429-0.926), LDH≥250 IU/L (P=0.016, HR 0.538, 95% CI 0.326-0.890) and secondary amyloidosis (P&lt;0.001, HR 0.277, 95% CI 0.137-0.562) at baseline had significantly shorter OS . Conclusion: Frontline treatment choices of WM are wide heterogeneity due to various clinical presentations and the rarity of the disease. Old age, low platelet, low albumin, high β-2 microglobulin, high LDH and secondary amyloidosis indicate worse prognosis in WM. These findings may provide guidance for management of WM and better prognostic stratification of risk-adapted treatment strategies. Figure 1 Disclosures No relevant conflicts of interest to declare.

The present study was aimed to observe and record the avifaunal diversity of Gautala Autramghat Wildlife Sanctuary and its adjacent areas, Maharashtra, India. This study was carried out during October 2021 to July 2022. 210 bird species belonging to 55 families and 17 orders were recorded during the study period. Out of these, 136 species were found Resident (R), 68 species Winter Migrant (WM), 4 species Breeding Migrant (BM) and 2 species were found Passage Migrant (PM). As per the IUCN population status 5 species were found Near Threatened (NT), 1 Critically Endangered (CR), 1 Vulnerable (VU) and 203 species were found Least Concern (LC). Order Passeriformes was found dominant with 25 families and 93 bird species followed by Ciconiformes with 3 families and 19 bird species and Charadriformes with 5 families and 18 bird species. This study will be useful for conservation and protection of avian fauna of the Gautala Autramghat Wildlife Sanctuary.

Abstract Introduction: Waldenstrom's macroglobulinemia (WM) is a rare disease with a worldwide incidence of approximately 3-4 per million persons per year. The definition of WM includes presence of lymphoplasmacytic lymphoma (LPL) in bone marrow and IgM monoclonal immunoglobulin at any concentration (MI) in serum. LPL with nodal disease is mostly included in most epidemiological studies. In Sweden the age adjusted incidence for WM and LPL is high; 10.6 per million persons per year. The aim of this study is to describe the WM population in Sweden from a prospective nationwide population-based registry and to compare outcome in relation to prognostic factors and first line treatment. Methods and study population: Between January 1, 2000 and December 31, 2014, in total 1511 patients with WM/LPL were registered in the Swedish Lymphoma Registry (SLR). The diagnosis was verified from medical records in 1135 patients and were classified as following; WM 978 (86.2 %), LPL 124 (10.9 %), other diagnosis 15 (1.3 %), and unclassified 18 (1.6 %). Results: For the WM population (n = 978) the median age at diagnosis was 73 years (range: 29 to 94) with a male/female ratio of 1.5 and with no difference in age between males and females. Only 26 patients (2.7 %) were diagnosed below 50 years of age and 718 (73.4 %) patients were older than 65 years. The median size of the IgM monoclonal immunoglobulin (MI) in 960/978 patients at diagnosis was 19 g/l, and only 33 (3.4 %) patients had an IgM MI >70 g/l. The most common IgM MI was of kappa type; 642/794 (81 %). Twenty-six (3 %) patients had biclonal immunoglobulins. The median overall survival (OS) for all WM patients was 96 months with a 3-years and 5-year OS of 78 % and 66 %, respectively. The OS has improved over the time. Significant prognostic factors for OS in newly diagnosed patients (symptomatic and asymptomatic) in univariate analysis were; age (p < 0.001), WHO performance status (PS) 1-4 (p < 0.001), B-symptoms (p < 0.001), elevated LDH (p < 0.001), haemoglobin ≤ 115 (p < 0.001), albumin ≤ 35 (p < 0.001), Beta-2-microglobuline (B2M) > 3 (p < 0.001), platelets ≤ 100 (p < 0.001), and lymphocytosis ≥ 5x109/l (p < 0.001), but not the size of the IgM MI (p = 0.36), IgM MI > 70 (p = 0.66), the light chain (kappa/lamda) (p = 0.32) or hypogammaglobulinemia. In multivariate analysis age (p > 0.001), elevated LDH (p = 0.01), PS 1-4 (p < 0.001), and haemoglobin ≤115 (p < 0.001) remained significant (B2M, platelets and lymphocytosis were excluded due to many missing values). Female sex emerged as a positive prognostic factor (p = 0.003). In Sweden is "watch and wait" (w&w) the recommended strategy in asymptomatic patients and w&w patients had a superior median OS compared to symptomatic patients, 101 and 77 months respectively. Approximately one fourth of the patients were symptomatic at diagnosis and data on first line treatment 0 - 3 months after diagnosis are available for 203 patients. Univariate and multivariate analyses on prognostic factors were performed separately for the patients with systemic therapies initiated 0 - 3 months after diagnosis (n = 203). Age (p < 0.001), PS 1-4 (p < 0.001), and haemoglobin ≤ 115 (p > 0.001) were significant prognostic factors in multivariate analysis. The size of the IgM MI (p = 0.87) or IgM MI > 70 (p = 0.58) was not significant prognostic factors. Rituximab was introduced in WM therapy in the years 2007/2008 and when including treatment with rituximab (single or in combination with chemotherapies) and treatment with chemotherapies in the multivariate analysis emerged rituximab (p = 0.005), female sex (p = 0.002) as positive prognostic factors and LDH (p = 0.002), albumin ≤ 35 (p = 0.045) as negative prognostic factors. Conclusion: The incidence of WM is higher in Sweden compared to the worldwide incidence. In this large unselected nation-wide WM population with trough medical records confirmed diagnosis, earlier known prognostic risk factors were confirmed, except the size of the IgM MI. Treatment with rituximab was independently associated with improved OS in multivariate analysis. The OS had improved over the time, the reason for that is unclear but one explanation could be the introduction of rituximab to the treatment. Disclosures Kimby: Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings.

Abstract Abstract 4566 Cytogenetic abnormalities are present in virtually all cases of Waldenström's macroglobulinemia (WM). Among them, deletion of the long arm of chromosome 6 (6q-) is the most frequently reported in the literature, but the potential impact on disease evolution has not been completely elucidated. In this study we have analyzed the prevalence of this aberration in 203 patients with B-cell lymphoproliferative disorders (B-LPD) producing a monoclonal IgM component. Detection was evaluated by In Situ Fluorescence Hybridization in CD19+ separated cells and results were correlated with disease characteristics. The frequency of 6q21 deletion varied according to the type of B-LPD: 1/42 (2%) in IgM-MGUS, 5/69 (7%) in asymptomatic WM (aWM), 25/83 (30%) in symptomatic WM (sWM) and 0/9 in other IgM B-LPD. Within MGUS and aWM, patients with deletion of 6q displayed a high frequency of adverse prognostic features and required treatment earlier than patients with normal 6q (37 mo vs. +120 mo, p<0.05) although they finally displayed a similar overall survival. Within the sWM, those patients with del(6q) displayed parameters of high tumor burden, such as high levels of b2M and monoclonal paraprotein and more frequent anemia and hypoalbuminemia. Interestingly, there was a correlation between the presence of 6q deletion and the ISS prognostic index (frequency of 6q- among patients stratified in stages 1, 2 and 3 was 24%, 42% and 67% respectively). However, overall survival analysis did not show any difference between patients with and without 6q-, independently if the overall survival was considered globally or free of specific disease mortality. In summary, in IgM monoclonal gammopathies, 6q deletion is associated with more symptomatic forms, higher probability of treatment requirement and high tumor load, although the presence of this abnormality does not represent necessarily an adverse prognosis for OS. Disclosures: Ocio: PharmaMar: Patents & Royalties, Research Funding. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.

Background Waldenström's Macroglobulinemia (WM) is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow (BM). Smoldering WM (sWM) is the asymptomatic/indolent form with a high risk of progressing to symptomatic WM requiring treatment whereas IgM monoclonal gammopathy of undetermined significance (IgM MGUS) is an early precursor stage of WM. Despite recurrent and activating mutations, including MYD88, CXCR4, ARID1A, KMT2D, and CD79B have been identified, the genetic basis for WM and the risk of progression of IgM MGUS to WM remain to be fully elucidated. Methods Based on the mutational profiling of WM and our previous wide transcriptome analyses on BM CD19+ and CD138+ cells of patients with WM and IgM MGUS, we decided to investigate the mutation status of these patients as follows: WM (n=10), sWM (n=7), and IgM MGUS (n=5), by performing high throughput targeted AmpliSeq next generation sequencing on 117 target genes potentially involved in B-cell lymphomagenesis and in the risk of progression of IgM MGUS to WM (Trojani A. et al. Cancers, 2021). Results We identified genetic aberrations in multiple genes, including previously described classic mutations in MYD88 (L260P alias L265P) found in 82.3% (14/17) of WM/sWM patients and in 60% (3/5) of IgM MGUS subjects. The CXCR4 mutation (S338Ter) was detected in 23.5% of CD19+ cells of WM patients, whereas it was absent in IgM MGUS subjects. Interestingly, we also identified new mutated genes, including WNK2 somatic mutations affecting 47% of WM patients, for which a recurrent allelic variant (V1635Ter) was observed, and BCL9 with a recurrent frameshift variant (P516Lfs) identified in 29.4% of WM patients exclusively in the CD19 cell fraction. The BCL9 (P516Lfs) variant was also detected in the B cells of one IgM MGUS patient. Moreover, sequencing evaluation revealed recurrently frameshift or missense mutations involving NFKB2 (L473Afs), PTPN13 (P1546Tfs), CARD11 (S622del), KMT2C (I823T), and ATM in WM and IgM MGUS patients (Figure 1). Of interest, KMT2C (also known as MLL3) exhibited a somatic hypermutated phenotype in both CD19+ and CD138+ cells of WM and IgM MGUS samples. The KMT2C mutations were not mutually exclusive with those involving KMT2D in our cohort of patients. Conclusion The present genomic analysis revealed new insights into the mutational landscape of Waldenström Macroglobulinemia, providing evidence of the recurrence of some variants in subjects with IgM MGUS as well. Notably, we uncovered new genetic mutations with somatic variants recurrently observed (n≥3) in KMT2C, WNK2, BCL9, PTPN13, CARD11 and NFKB2 genes. These recurring somatic events provide a genomic basis for future research and a better understanding of the WM pathogenesis as well as the risk of transformation of IgM MGUS to WM.

Variation of surface sensible heat flux over the west coast in the premises of National Center for Antarctic and Ocean Research (NCAOR), Vasco-da-Gama (15° 21' N, 73° 51' E), Goa during Offshore trough (phase-I) and Warm pool campaigns (phase-II) of ARMEX is studied. Sensible heat flux as measured by sonic anemometer at 5 m above surface is -50 to 150 Wm-2 during 13-28 July, 2002 (phase I) and -5 to 350 Wm-2 during 21-24 April, 2003 (phase II). Coastal atmospheric surface layer at Goa during night time is found to be near neutral (nearly zero heat flux) in April 2003 whereas stable (negative heat flux) in July 2002. All components of solar radiation measured by Eppley radiometers at 2 m above surface are used to compute net radiation which is 900 Wm-2 at noon in April 2003. Net solar radiation is nearly equal to incoming short wave radiation during daytime as net long wave radiation (100 Wm-2) compensates the loss due to reflection of short wave radiation (-100 Wm-2) by the ground. High winds in the surface layer are observed during late night hours with calm winds around sunrise and after sunset giving rise to two minima in the diurnal curve. Influence of sea-breeze on the surface layer over land is discussed.

7556 Background: Responses to sildenafil citrate (Viagra), a phosphodiesterase-5 inhibitor used to treat erectile dysfunction, have been observed in patients with Waldenstrom’s Macroglobulinemia (WM). Moreover, sildenafil citrate induces apoptosis of WM lymphoplasmacytic cells (Clin Lymphoma 5:205, 2004). We therefore conducted a prospective phase II study of sildenafil citrate in patients with slowly progressing WM who did not meet consensus eligibility for active therapy (Semin Oncol 2003; 30:116). Intended therapy was as follows: Week 1 25 mg po qD Week 2 50 mg po qD Week 3 75 mg po qD Week 4, then Months 2–24 100mg po qD or Maximum Tolerated Dose Methods: Thirty patients were enrolled, 18 of whom were previously untreated. All patients demonstrated progressing disease prior to enrollment. Median age was 66 (range 43–85 yrs), baseline BM involvement was 30% (range 5–90%), serum IgM was 3,640 (range 790–6,720 mg/dL), hematocrit was 37.1% (range 32.7–58.5%), and B2M was 2.3 (range 1.5–8.9 mg/dL). Patients were evaluable for response after 3 months of therapy. Results: At a median of 3 months, serum IgM levels declined in 19/30 (63%) patients from a median of 3,640 (range 790–6,720 mg/dL) to 2,965 (range 1,170–6,110 mg/dL). 5/30 patients (17%) demonstrated at least a minor response (≥25% IgM decrease). Two patients were taken off study for non-response to therapy. Toxicities were mild and included headaches, sinus congestion, facial flushing, dyspepsia, and generally resolved on their own with prolonged sildenafil citrate usage. Only two patients required dose modification to 25 mg and 75 mg po qD, respectively. Corollary studies to determine putative mechanisms of action for sildenafil citrate in WM were also performed and will be updated at the meeting. Conclusions: This prospective clinical trial provides preliminary evidence for activity of sildenafil citrate in patients with advancing WM. With minimal toxicity, sildenafil citrate appears to have suppressed disease progression in more than half of patients and has resulted in objective responses, thus warranting further investigation in WM and possibly other B-cell disorders. No significant financial relationships to disclose.

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 &gt;upper limit of normal (ULN), β2M &gt;3µg/mL and albumin &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 &gt;ULN (HR 2.34), serum albumin &lt;3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and &gt;75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin &lt;3.5 g/dL and age group 66-75 years and similarly, 2 points each for age &gt;75 years and serum LDH &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&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&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&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.

Background: We previously identified three subtypes of Waldenstrom's Macroglobulinemia (WM): B-cell like (BCL), Plasma cell like (PCL), and an intermediate group enriched for early/smoldering WM from which the other two subtypes evolved (Hunter et al, ASH 2022). Diffusion pseudo-time (DPT) analysis suggested all WM samples could be placed on a shared evolutionary path independent of subtype, and when samples were separated into Early and Late DPT values, it mirrored disease progression. The role of epigenetic dysregulation that underlies subtype classification and disease evolution remains poorly understood in WM. Methods: We therefore performed chromatin availability analysis using ATACSeq and bisulfite sequencing of WM patients. ATAC-Seq libraries were constructed from 37 CD19+ BM cells from treatment-naive WM patients along with 6 paired CD19+CD27- and CD19+CD27+ selected healthy donor (HD) peripheral blood (PB) controls and 3 HD CD138+ plasma cell (PC) samples. Enhanced reduced representational bisulfite sequencing (ERRBS) was also performed on 65 MYD88 mutated and 13 MYD88 wild type (WT) WM patients using CD19-selected BM lymphoplasmacytic cells. For 11 WM MYD88 mutated patients, CD138+ cells were also selected. In addition ERRBS was also performed on paired CD19+ and CD138+ selected samples from 5 IgM multiple myeloma (MM) patients, 6 paired CD19+CD27- and CD19+CD27+ selected healthy donor (HD) peripheral blood cells; 8 HD CD138+ selected PC; as well as MYD88 mutated BCWM.1, BCWM.2, MWCL-1, RPCI-WM1, OCI-Ly3, TMD-8, HBL-1 and SU-DHL2 cells; MYD88 wild-type OCI-Ly7, OCI-Ly19, Ramos B-cells. To infer 5-hydroxymethylcytosine (5HMC) levels, oxidative bisulfite sequencing was also performed for 73 samples including the HD, MM, WT and WM CD19/138 pairs. All ATAC-Seq and 37 of the WM ERRBS samples were part of our multi-omic study that included 253 treatment naïve patients who underwent whole exome and RNASeq sequencing. Results: A UMAP projection of the CpG ERRBS data clustered WM patients into two distinct groups ( Figure 1). One group clustered directly with HD Memory B-cells (MB) and was greatly enriched for CXCR4 mutated WM patients. The other WM group clustered with IgM MM patients and was largely CXCR4 WT. The findings are consistent with the BCL and PCL WM subtypes, which were confirmed by a perfect assignment correlation with our larger multi-omic data set wherein these subtypes were defined. Notably, BCWM.1, BCWM.2 and MWCL-1 WM cell lines clustered with the WM samples. The 5HMC data displayed no clear clustering of the patient samples but clearly separated all HD samples from those of WM and IgM MM samples, consistent with a role for 5HMC dysregulation in oncogenesis. Differential methylation analysis showed differences by MYD88 and CXCR4 mutation status, deletions in Chr6q, familial history for WM, WM subtype, and stratification by early and late DPT values. Notably, the only comparison that did not yield any differences was WM CD19+ to WM CD138+, suggesting that this may not be a meaningful epigenetic distinction in WM. Similar comparisons were performed on the ATAC peaks. Differential chromatin accessibility was noted near many of the corresponding differentially expressed genes. ATAC peak coverage significantly correlated with the expression of top genes. This was particularly true for WM subtype and DPT comparisons ( Table 1). DNA sequences from differentially accessible peaks between BCL and PCL subtypes were also evaluated for relative TF motif enrichment in open vs. closed chromatin revealing PAX5, FUBP1, and ZNF121 enrichment in BCL subtypes using PCL subtype peaks as a background control. TFs REL, SP1, SPIB, BC11A and JUN were enriched PCL subtype compared with BCL subtype. Correlation between DPT associated genes revealed two clear groups, one associated with stem cell and pre-B-cell genes (Group 1) and the other with inflammatory, myeloid, and T-cell genes (Group 2). Motif analysis of differential peaks correlating with genes in each group demonstrated comparative enrichment for MYC, MXI1, and E2F2 in group 1 while RUNX1, NFKB1, and ATF1 were in enriched in group 2. Conclusions: This is the first independent validation of our previously reported multi-omic driven WM subtype classification. The studies underscore that epigenetic differences underlie the biology of WM subclassification and support a strong role for epigenetic changes driving WM evolution.