Journal articles: 'Wm 203.5'

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Leblond, Veronique, Julie Lejeune, Olivier Tournilhac, Pierre Morel, marie Sarah Dilhuydy, Caroline Dartigeas, Marion Malphette, et al. "International Phase III Study of Chlorambucil Versus Fludarabine As Initial Therapy for Waldenstrom's Macroglobulinemia and Related Disorders: Results in 414 Patients on Behalf of FCG CLL/ WM, GOELAMS, GELA, NCRI, ALLG." Blood 118, no. 21 (November 18, 2011): 776. http://dx.doi.org/10.1182/blood.v118.21.776.776.

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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.

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Cao, Xin-xin, Shuhua Yi, Zhongxing Jiang, Jingsong He, Wei Yang, Juan Du, Chunyan Sun, et al. "Waldenström's Macroglobulinaemia in the Modern Era: Real World Outcomes and Prognostication across 35 Chinese Academic Hospitals." Blood 136, Supplement 1 (November 5, 2020): 5–6. http://dx.doi.org/10.1182/blood-2020-134785.

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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 > 65 years old (P=0.011, HR 0.622, 95% CI 0.431-0.898), platelet < 100×109/L (P=0.006, HR 0.570, 95% CI 0.381-0.853), serum albumin <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<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.

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Abhay D., Shelke. "Avifaunal Diversity of Gautala Autramghat Wildlife Sanctuary and its Adjacent Areas, Maharashtra, India." International Journal of Zoological Investigations 08, no. 02 (2022): 321–36. http://dx.doi.org/10.33745/ijzi.2022.v08i02.041.

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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.

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Brandefors, Lena, Beatrice Melin, Jack Lindh, Lundqvist Kristina, and Eva Kimby. "Waldenstrom's Macroglobulinemia and Overall Survival in Relation to Prognostic Factors and First Line Treatment: An Observational Study from Swedish Lymphoma Registry." Blood 128, no. 22 (December 2, 2016): 1805. http://dx.doi.org/10.1182/blood.v128.22.1805.1805.

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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.

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García-Sanz, Ramón, Roberto JP Magalhaes, Enrique M. Ocio, Pilar Giraldo, Natalia de las Heras, Carmen Aguilera, Jose Mariano Hernández, et al. "6q Deletion Helps in the Discrimination Between Symptomatic Waldenström's Macroglobulinemia and Asymptomatic Forms of IgM Monoclonal Gammopathies." Blood 120, no. 21 (November 16, 2012): 4566. http://dx.doi.org/10.1182/blood.v120.21.4566.4566.

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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.

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Trojani, Alessandra, Alessandro Beghini, Luca Emanuele Emanuele Bossi, Marta Rachele Stefanucci, Cassandra Palumbo, Antonino Greco, Annamaria Frustaci, Barbara Di Camillo, Marco Montillo, and Roberto Cairoli. "Mutational Landscape of Bone Marrow CD19 and CD138 Cells in Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS)." Blood 142, Supplement 1 (November 28, 2023): 3406. http://dx.doi.org/10.1182/blood-2023-180580.

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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.

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MURTHY, B. S., and S. SIVARAMAKRISHNAN. "Surface fluxes over Goa during Indian monsoon." MAUSAM 56, no. 1 (January 19, 2022): 251–56. http://dx.doi.org/10.54302/mausam.v56i1.900.

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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.

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Patterson, C. J., J. Soumerai, Z. Hunter, X. Leleu, I. Ghobrial, and S. P. Treon. "Sildenafil citrate suppresses disease progression in patients with Waldenstrom’s macroglobulinemia." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7556. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7556.

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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.

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Zanwar, Saurabh, Jennifer Le-Rademacher, Eric Durot, Shirley D'Sa, Jithma Prasad Abeykoon, Patrizia Mondello, Shaji Kunnathu Kumar, et al. "Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 3030. http://dx.doi.org/10.1182/blood-2023-179940.

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

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Hunter, Zachary R., Nickolas Tsakmaklis, Kris Richardson, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Shirong Liu, et al. "Changes in Methylation and Chromatin Accessibility Underlie Subtype Classification and Disease Evolution in Waldenström's Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 755. http://dx.doi.org/10.1182/blood-2023-190825.

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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.

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Wang, Zhen, Yan-Jun Du, Yan-Jun Ding, Zheng Li, and Zhi-Min Peng. "Monitoring of ambient carbon monoxide concentrations based on wavelength modulation direct absorption spectroscopy." Acta Physica Sinica 71, no. 4 (2022): 044205. http://dx.doi.org/10.7498/aps.71.20211772.

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Wavelength modulation-direct absorption spectroscopy (WM-DAS) has the advantages of both direct absorption spectroscopy (DAS) measurable absorptivity function and wavelength modulation spectrum (WMS) with high signal-to-noise ratio (SNR). In this paper, the WM-DAS spectrum is used to measure the absorptivity of 4300.7 cm–1 line of CO molecule and the detection limit is as low as 4 × 10–7 (200 s) at 0.5 m optical path, room temperature and low pressure. Then, through combining the WM-DAS spectrum with a 120 m long optical path Herriott cell, at room temperature and atmospheric pressure, the standard deviation of the fitting residual error of the absorptivity function is reduced down to ~5.1 × 10–5 (1 s). Finally, different concentrations of CO are continuously monitored by long-path WM-DAS measurement system, and compared with the results obtained from the cavity ring-down spectroscopy (CRDS). The experimental results show that the measurement results from the long-path WM-DAS and CRDS method are the same. The detection limit of CO concentration in long-path WM-DAS system is as low as 0.9 ppb (200 s), and the WM-DAS system is simple and the measurement speed is much faster than CRDS. At the same time, the long-path WM-DAS system is used to continuously monitor the atmospheric trace CO concentration and trend for one month, and the measured results are highly consistent with those from the China Environmental Monitoring Station.

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Sinaga, Eko Martin, and Albinus Silalahi. "KEBERHASILAN BELAJAR SISWA SMA PADA MATERI AJAR LAJU REAKSI MELALUI PEMBELAJARAN BERBASIS MASALAH MENGGUNAKAN WEBLOG." Jurnal Inovasi Pembelajaran Kimia 2, no. 1 (April 30, 2020): 26. http://dx.doi.org/10.24114/jipk.v2i1.17831.

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This study aims to show: (1) the difference between the student learning outcomes taught by the PBL model using weblog media (PBL-WM) and taught by the same learning model but not using the media (PBL); (2) the correlation between student learning motivation and PBL-WM improvement; (3) differences in student learning motivation based on PBL-WM and PBL. The sample studied was class XI student of SMA Negeri 1 Percut Sei Tuan in the academic year 2019/2020 on the reaction rate teaching in 2013 curriculum. The instrument that used by test (learning outcome) and non-test (motivation). The results showed the average increase in PBL-WM was 74.7; while the average increase in PBL was 62,658. The average student motivation based on PBL-WM was 85.92; while the average student motivation based on PBL was 78.45. The statistical analysis results of SPSS 22.0 at α=5% can be stated that (1) PBL-WM was higher than PBL; (2) there was a significant correlation between student learning motivation and increase in PBL-WM , with a correlation coefficient of 0.925 and the contribution of learning motivation to increase PBL-WM of 85.5% while 14.5% was influenced by other factors; (3) student motivation based on PBL-WM was higher than PBL.

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Paludo, Jonas, Nishanth Vallumsetla, Stephen Ansell, Abhisek Swaika, Tania Jain, Sikander Ailawadhi, Craig B. Reeder, et al. "Survival Trends in Young Patients with Waldenstrom Macroglobulinemia: Over 5 Decades of Experience." Blood 128, no. 22 (December 2, 2016): 1810. http://dx.doi.org/10.1182/blood.v128.22.1810.1810.

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Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

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Chohan, Karan, Jonas Paludo, Surendra Dasari, Patrizia Mondello, Joseph P. Novak, Jithma Prasad Abeykoon, Kerstin Wenzl, et al. "Genome-Wide DNA Methylation Analysis Reveals Epigenetic Influence on Intracellular and Cytokine Signaling Pathways in Waldenström Macroglobulinemia Compared to IgM-MGUS." Blood 142, Supplement 1 (November 28, 2023): 1622. http://dx.doi.org/10.1182/blood-2023-182874.

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Introduction: Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma that may be preceded by an asymptomatic IgM-monoclonal gammopathy of undetermined significance (MGUS). The mechanisms underlying the progression from IgM-MGUS to WM remain to be fully elucidated; however, the stepwise accumulation of genomic abnormalities has been suggested as a potential driver. Currently, the role of epigenetic regulation of DNA remains underexplored in this disease spectrum. Aberrant DNA methylation is a hallmark of oncogenesis that plays an important role in hematologic malignancies. The aim of this study was to assess differential DNA methylation in WM compared to IgM-MGUS and identify hyper- and hypomethylated pathways that may alter key cellular functions. Methods: This study included 15 patients with WM and 6 with IgM-MGUS. Bone marrow samples were prospectively collected and CD19+ and/or CD138+ B cells were positively selected. Subsequently, genome-wide DNA methylation analysis was performed. CpG methylation ratios were segmented into 200-bp regions and differentially methylated regions (DMRs) comparing WM to IgM-MGUS were identified. DMRs with a Q-value <0.05 and absolute methylation difference of ≥20% were considered significant and utilized for analysis. DMRs were annotated according to genomic regions of interest (promotors, 3'UTR, 5'UTR, introns, exons, CpG islands, CpG shores). Next, genes with significant promotor hyper- or hypomethylation were assessed using the Ingenuity Pathway Analysis. Pathways with a corrected p-value<0.05 were considered statistically significant and a Z-value was calculated based on the degree of differential methylation. Results: Genome-wide DNA methylation analysis revealed a significant number of DMRs (n= 15691, hyper: 8248; hypo: 7443) in WM compared to IgM-MGUS. Assessing genomic regions, promotors (hyper: 1379; hypo: 2403), introns (hyper: 1548; hypo: 2292), CpG shores (hyper: 587; hypo: 849) and 3'UTR (hyper: 66; hypo: 193) regions were observed to have a significantly greater number of hypomethylated DMRs (all comparisons, p<0.001) in WM compared to IgM-MGUS (Figure A). While exons (hyper: 1686; hypo: 1378), CpG islands (hyper: 2128; hypo: 82), and 5'UTR (hyper: 854; hypo: 246) regions had a significantly greater number of hypermethylated DMRs (all comparisons, p<0.001) (Figure A). Next, promotor methylation-based pathway analysis revealed differential methylation of multiple cellular pathways important in WM pathogenesis (Figure B). These included pathways involved in intracellular signaling and the regulation of cellular proliferation, such as the STAT3 and CXCR4 pathways which were hypomethylated, and the PTEN signaling pathway which was hypermethylated. Of interest, we have previously demonstrated the transcription factor, STAT3, to have an increased expression in WM and to be implicated in IgM secretion (Elsawa, 2011). Next, multiple cytokine signaling pathways were observed to be hypomethylated in WM compared to IgM-MGUS including members of the interleukin (IL) family (IL-1, IL-8, IL-15, IL-23), VEGF, and TGF-β. Of relevance, previous studies have demonstrated the elevation of IL-8, IL-15, and increased expression of angiogenic cytokines, including VEGF, in patients with WM (Lewicki, 2010; Anagnostopoulos, 2007). Furthermore, our group has also shown miRNA-based epigenetic regulation of IL-8 and IL-15 in WM compared to IgM-MGUS (Chohan, 2023). Lastly, several pathways critical in the regulation of the cell structure and the extracellular matrix (ECM) were found to be hypomethylated including the FGF, actin cytoskeleton, PAK, and FAK signaling pathways. Of note, the FGF/FGFR axis has been demonstrated to be dysregulated in WM, and its targeting has been shown to halt WM cell growth (Sacco, 2021). Conclusions: This study demonstrates differential DNA methylation of key genomic regions in WM compared to IgM-MGUS. Promotor methylation-based analysis reveals hypomethylation of several important cellular pathways involved in cytokine signaling, cell structure/ECM, and intracellular signaling. These results underscore the influence of epigenetics in the IgM-gammopathy disease spectrum and suggest the potential role of aberrant DNA methylation underlying the malignant progression from IgM-MGUS to WM.

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Han, Weiguo, Stephan Josef Matissek, David Jackson, Brandon Sklavanitis, and Sherine F. Elsawa. "Targeting the tumor microenvironment with the monoclonal antibody Tocilizumab, reduces IgM secretion in Waldenström macroglobulinemia." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 194.35. http://dx.doi.org/10.4049/jimmunol.202.supp.194.35.

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Abstract The tumor microenvironment (TME) plays an important role in cancer and has been shown to play a role in resistance to therapy and is therefore important in cancer cell biology. In Waldenström macroglobulinemia (WM), a B cell malignancy characterized by the overproduction of a monoclonal IgM protein, the TME secrets cytokines that promote malignant phenotype. In previous work, we have shown that TME-IL-6 promotes WM cell growth and IgM secretion in WM. Tocilizumab/Actemra is an anti-IL-6R antibody, which can competitively block IL-6 binding to the IL-6R. Here we investigated the efficacy of Tocilizumab in a preclinical mouse model of WM that considers the role of the TME in disease biology. Hairless SCID mice were injected subcutaneously with BCWM.1 or RPCI-WM1 and bone marrow stromal cells (HS-5) at a ratio of 5:1. Groups of mice with treated with Tocilizumab or control antibody three times/week for 5 weeks and the effect on tumor burden and disease biology were evaluated. Although Tocilizumab had no effect on mice survival, there was a reduction in tumor growth rate in mice injected with RPCI-WM1 cells + stromal cells and treated with Tocilizumab (p=0.0394). In mice injected with BCWM.1 + stromal cells, there was a significant reduction in human IgM secretion in mice sera with Tocilizumab treatment (p=0.0099). There was no significant change in mice weight suggesting Tocilizumab induced no toxicities to the mice. Taken together, our data suggests that administration of Tocilizumab to tumor bearing mice, results in a significant reduction in tumor volume and IgM secretion. Therefore, the evaluation of the role of Tocilizumab in WM patients may provide therapeutic efficacy by reducing IgM production and slowing the rate of tumor growth.

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Ghobrial, Irene M., Mona Melhem, Ujjal Singha, Diane George, Michael Timm, Lanie Francis, Yazan Alsayed, et al. "Role of the Chemokine Receptor CXCR4 in Waldenstrom Macroglobulinemia." Blood 106, no. 11 (November 16, 2005): 993. http://dx.doi.org/10.1182/blood.v106.11.993.993.

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Abstract Waldenstrom Macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow, and often in the lymph nodes. The mechanisms by which cells migrate/home to the bone marrow are poorly understood. The chemokine receptor CXCR4 and its ligand SDF-1 have been implicated in the migration and homing of lymphocytes. The objective of this study was to begin to identify the role of CXCR4 in WM. Paraffin embedded tissues were obtained after informed consent from 10 bone marrow samples of asymptomatic WM/monoclonal gammopathy of undetermined significance (MGUS) (n=5) and symptomatic WM (n=5). Four normal bone marrow samples were obtained for control. CXCR4 expression was determined using anti-CXCR4 antibody (Affinity Bioreagents, Golden, CO) 1:200 dilution for 16hrs, and a scale of 0–3+ was used to determine relative expression in the lymphocytes. Anti-CD20 antibody was used to determine the presence of lymphocytes in the samples. To determine whether the receptor is functional, migration was performed with the WM cell line (WSU-WM, kind gift from Dr. Al-Khatib, Wayne State University) and using a transwell migration assay (Costar, Corning, NY) with serial dilutions of SDF-1 (10-100nM). Comparison between the asymptomatic and symptomatic WM groups was performed by c2 test, and Mann-Whitney test, as appropriate. The baseline patient characteristics are displayed in table 1. CXCR4 expression was present on the surface of scattered lymphocytes in the normal bone marrow (median expression 1+). The expression of CXCR4 was increased in the asymptomatic/MGUS cases of WM (median expression 2+). In contrast, CXCR4 expression was downregulated in 4/5 cases of symptomatic WM specifically all the ones with extensive involvement of the bone marrow with lymphoplasmacytic cells (median expression 0). SDF-1 induced a bell- shaped response of migration in the WM cells with the maximal migration occurring at 1-10nM SDF-1. SDF-1 1-10nM induced 340% increase in migration as compared to untreated cells. However, high doses of SDF-1 100nM did not induce any migration as compared to untreated cells indicating inhibition of migration in response to high doses of SDF-1. In summary, we demonstrate that the CXCR4 receptor is functional and induces migration indicating that it plays a role in the migration of WM cells to the bone marrow. In addition, we demonstrate that CXCR4 expression is downregulated in WM with high infiltration of cells in the bone marrow as compared to those with minimal infiltration. These results may be due to the high level of SDF-1 in the bone marrow that induce downregulation of CXCR4. High levels of SDF-1 may downregulate the receptor and inhibit migration in order to confine the cells within the bone marrow. Supported in part by an ASH scholar award and the RFW. Patient characteristics Asymptomatic WM/MGUS, (range), (N=5) Symptomatic WM, (range) (N=5) Median age at diagnosis 67.6 (55.8–78) 71.5 (61–77) Median IgM level (mg/dL) 997 (904–1490) 5410 (2000–7820) Median Hb (gm/dL) 12.6 (11.1–15.1) 10.8 (9.3–11.6) Organomegaly (liver or spleen) N 20% Lymphadenopathy N 40% Median involvement of tumor cells in the BM in % 5% 30(10–60)

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Pulte, Dianne, Janick Weberpals, Lina Jansen, Alexander Katalinic, Alice Nennecke, Holleczek Bernd, Ressing Meike, Luttmann Sabine, and Hermann Brenner. "Survival of Patients with Rare Plasma Cell or Lymphoplasmacytoid Malignancies in Germany and the United States in the Early 21st Century." Blood 128, no. 22 (December 2, 2016): 4767. http://dx.doi.org/10.1182/blood.v128.22.4767.4767.

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Abstract Background: Population level survival has improved for myeloma in the early 21st century, but it is unknown whether a similar improvement has occurred in other plasma cell or lymphoplasmacytoid conditions. Methods: Data were extracted from 12 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results database in the United States (US). Cases of Waldenström macroglobulinemia (WM), lymphoplasmacytic lymphoma (LPL), and plasmacytoma diagnosed in 1998-2012 were included. Myeloma survival was analyzed for comparison. Plasma cell leukemia was not included due to case numbers being too small to produce reliable estimates. Period analysis was used to determine 5-year relative survival for patients with the above malignancies in 2003-12. Trends in survival in the early 21st century were analyzed using modeled period analysis, comparing survival for 2003-07 to 2008-12. Results: In Germany, 5-year age adjusted relative survival in 2003-12 was 72.1% overall and 56.5% for patients with plasmacytoma, 74.9% for LPL not otherwise specified and 80.8% for WM. In the US, survival was higher overall at 75.1%, with survival for individual entities of 81.9% for WM, 77.2% for LPL, and 62.3% for plasmacytoma. Five year relative survival estimates for myeloma in 2003-12 were 45.2% and 43.1% in Germany and the US, respectively. Trend analysis for the years 2003-07 and 2008-12 revealed an increase in survival overall in Germany and the US, with survival for all malignancies going from 69.2% to 74.2% in Germany and 73.3% to 76.8% in the US (see table). A small, borderline significant increase in survival was observed for WM in Germany, with survival going from 74.8% to 84.3% (p=0.05) and a significant increase was observed for LPL, going from 71.7% to 77.4% (p=0.01). A pattern of small increases in survival was observed for plasmacytoma in Germany and each individual malignancy in the US. A strong and significant increase was observed in both countries for myeloma, with 5-year survival going from 41.4% to 47.9% in Germany and 38.8% to 47.0% in the US (p<0.0001 for both). Conclusions: Five year survival for patients with plasma cell and plasmacytoid conditions other than myeloma varies depending on the morphology. Some evidence of increased survival was observed in rare plasma cell and plasmacytoid malignancies, but small case numbers make determination of statistical significance difficult and magnitude of the differences are less than for myeloma in most cases, with the exceptions of WM in Germany. Increased research focusing specifically on rare plasma cell malignancies and implementation of findings into cancer care may improve survival further. Table Trends in 5-year relative survival for 2003-07 to 2008-12 for rare plasma cell and plasmacytoid malignancies, with comparison to myeloma. Table. Trends in 5-year relative survival for 2003-07 to 2008-12 for rare plasma cell and plasmacytoid malignancies, with comparison to myeloma. Disclosures Pulte: EBSCO: Other: Review of content for Dynamed medical reference product; Selexys Pharmaceuticals: Research Funding; ApoPharma: Research Funding.

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Vij, Ravi, Michael Savona, David S. Siegel, Jonathan L. Kaufman, Ashraf Badros, Irene M. Ghobrial, Agne Paner, et al. "Clinical Profile of Single-Agent Oprozomib in Patients (Pts) with Multiple Myeloma (MM): Updated Results from a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study." Blood 124, no. 21 (December 6, 2014): 34. http://dx.doi.org/10.1182/blood.v124.21.34.34.

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Abstract Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings of OPZ in pts with hematologic malignancies (HM) have been reported previously (Savona, ASH 2012, 203; Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with MM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives (phase 1b portion) are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective (phase 2 portion) is to determine the best overall response rate (ORR; ≥PR). In the phase 1b portion, OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments up to 330 mg/d. In the phase 2 portion, pts are receiving OPZ (240 mg/d) on the 5/14 schedule (initial phase 2 schedule opened to enrollment). For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 68 pts with MM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with MM are presented in Table 1. Median treatment duration (phase 1b) was 21.3 weeks (range, 0.3–62.1; 2/7 schedule) and 10.1 weeks (range, 0.3–81.1; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 5.4 weeks (range, 0.7–26.7). In all patients with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. Of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule, all 3 DLTs (including hypotension [300 mg/d, n=1], grade 3 diarrhea and grade 4 thrombocytopenia [330 mg/d, n=1 each]) were observed in pts with MM. Of 4 DLTs on the 5/14 schedule, 2 DLTs (grade 3 renal failure [180 mg/d, n=1] and grade 3 tumor lysis syndrome [270 mg/d, n=1]) were observed in pts with MM. The most common adverse events (AEs) in patients with MM are shown in Table 2. Grade 4 AEs included 8 pts (11.8%) with thrombocytopenia, 4 pts (5.9%) with anemia, and 1 pt each (1.5%) with sepsis, leukopenia, decreased platelet count, hyperkalemia, and acute renal failure. Two pts died from upper gastrointestinal bleeding (5/14 schedule, 240 mg/d). One pt (5%) on the 2/7 schedule (phase 1b), 3 pts (15%) on the 5/14 schedule (phase 1b), and 8 pts (30%) on the 5/14 schedule (phase 2) discontinued treatment due to an AE; 6 pts (29%) on the 2/7 schedule (phase 1b), 7 pts (35%) on the 5/14 schedule (phase 1b), and 11 pts (41%) on the 5/14 schedule (phase 2) had their dosage reduced at least once due to an AE. Thirty-four pts in the phase 1b portion were eligible for response. In the phase 1b portion, the ORR in 15 pts on the 2/7 schedule (all were carfilzomib [CFZ]-naïve) was 33.3%; the clinical benefit rate (CBR) was 46.7% (3 very good partial response [VGPR], 2 partial response [PR], and 2 minimal response [MR]). Among 19 pts on the 5/14 schedule (phase 1b portion; all were CFZ-naïve), the ORR was 36.8%; the CBR was 42.1% (1 complete response, 2 VGPR, 4 PR, and 1 MR). In the 5/14 schedule (phase 1b), the ORR among bortezomib [BTZ]-refractory pts (n=7) was 14.3%. On the phase 2 portion (5/14 schedule), the ORR among CFZ-refractory pts (n=11) and CFZ-sensitive pts (n=12) was 27.3% (3 PR) and 33.3% (2 VGPR and 2 PR), respectively; the ORR among BTZ-refractory pts (n=12) was 25.0%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all patients with HM. The most common grade 3 AEs were diarrhea, nausea, and vomiting; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity. Enrollment of pts with MM is continuing on the phase 2 study in both treatment schedules. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Vij: Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria. Off Label Use: Carfilzomib as treatment in multiple myeloma and solid tumors. Savona:Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other. Paner:Celgene Corporation: Honoraria. Jagannath:Millenium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho: Membership on an entity's Board of Directors or advisory committees; im: Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Optum Health Worldwide: Membership on an entity's Board of Directors or advisory committees; PER group: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Advisory Board Other, Consultancy, Honoraria; Celgene: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Janssen: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Millennium: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Novartis: Advisory Board Other, Honoraria; Onyx: Advisory Board, Speaking Other, Consultancy, Honoraria; Skyline Dx: Advisory Board Other, Honoraria. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment.

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Liu, Shirong, Amanda Kofides, Xia Liu, Alexa G. Canning, Nickolas Tsakmaklis, Maria Luisa Guerrera, Christopher J. Patterson, et al. "Pacritinib Blocks Key Pro-Survival Signaling Related to Mutated MYD88, Produces High Levels of Apoptosis and Overcomes Mutated BTK Cys481 Related BTK-Inhibitor Resistance." Blood 142, Supplement 1 (November 28, 2023): 3300. http://dx.doi.org/10.1182/blood-2023-190463.

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Background: Somatic mutations in MYD88 are prevalent in many B-cell malignancies, including Waldenström Macroglobulinemia (WM; 95-97%), primary CNS lymphoma (70-80%), ABC DLBCL (40%), marginal zone lymphoma (5-10%) and CLL (5-15%). Mutated MYD88 drives oncogenic pro-survival signaling through multiple signaling cascades that include HCK-directed BTK, ERK and SYK, as well as IRAK1/IRAK4 activation. HCK is an SRC family member that mutated MYD88 transcriptionally upregulates, and its activation is triggered by IL-6/IL-6R/gp130/JAK2 signaling. BTK inhibitors are active in MYD88 mutated B-cell malignancies, but fail to produce complete responses, and show varying durations of response that are disease dependent and impacted by depth of response. Acquired resistance to BTK inhibitors is commonly related to a BTK Cys481 mutation. Pacritinib is a kinase inhibitor, FDA-approved for myelofibrosis, that is well tolerated and targets pro-signaling cascades that are relevant to mutated MYD88 signaling, including IRAK1, JAK2, and SRC, a homologue of HCK ( Fig. 1). Pacritinib may therefore represent a more effective option in blocking mutated MYD88 pro-survival signaling versus BTK-inhibitors. Methods: We performed comparative studies to evaluate the activity of pacritinib and the covalent BTK-inhibitors ibrutinib and zanubrutinib on mutated MYD88 relevant pro-survival signaling, as well as proliferation and survival in MYD88 mutated cell lines and primary MYD88-mutated WM cells. Further to these studies, we assessed the activity of pacritinib in well-characterized mutant (BTK Cys481Ser) expressing covalent BTK-inhibitor resistant WM and ABC DLBCL lymphoma cell models. Results: Pacritinib produced higher levels of apoptosis in MYD88-mutated WM (BCWM.1) and ABC DLBCL (TMD-8), and primary (CD19 +) MYD88-mutated WM cells relative to the BTK inhibitors ibrutinib or zanubrutinib.The apoptotic activity of pacritinib showed dose dependence with high levels of apoptosis at 0.5 µM, which is well within its pharmacologically achievable levels. Importantly, pacritinib, in addition to its known effects on JAK2 and IRAK1 activation, also showed robust inhibition of p-HCK (Y411) and its downstream signaling partner p-BTK (Y223) in MYD88 mutated BCWM.1 and TMD-8 cells. By combination index and normalized isobologram analyses, pacritinib showed synergistic interactions with covalent BTK inhibitors, and more so with the BCL-2 inhibitor venetoclax in MYD88 mutated cell lines and primary WM cells. Lastly, pacritinib alone and combined with venetoclax induced high levels of apoptosis in BTK Cys481Ser expressing covalent BTK-inhibitor resistant MYD88 mutated WM and ABC DLBCL lymphoma cells. Conclusions: Pacritinib more broadly extinguishes mutated MYD88 pro-survival signaling cascades ( Fig 1.) and demonstrates high levels of apoptotic activityin mutated MYD88 WM and ABC DLBCL cells versus selective covalent BTK-inhibitors. Pacritinib also synergizes with covalent BTK- and BCL2 inhibitors and can overcome covalent BTK-inhibitor resistance related to mutated BTK Cys481. Our studies provide a framework for investigating pacritinib in MYD88 mutated lymphomas. A clinical trial of pacritinib in relapsed/refractory WM is being initiated.

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Peterson, Rachel K., Yan Chen, Kevin Oeffinger, Yutaka Yasui, Wendy Leisenring, Gregory T. Armstrong, Leslie L. Robison, et al. "5 The Impact of Sex and Associations With Treatment Exposures on Neurocognitive Impairment in Pediatric Cancer Survivors: A report from the Childhood Cancer Survivor Study." Journal of the International Neuropsychological Society 29, s1 (November 2023): 315–16. http://dx.doi.org/10.1017/s1355617723004368.

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Objective:Sexual dimorphism in human brain structure and behavior is influenced by exposure to sex hormones during critical developmental periods. In children, cancer and cancer treatments may alter hormone activity and brain development, impacting neurocognitive functions.Participants and Methods:Five-year survivors of childhood cancer (N=15,560) diagnosed at <21 years from 1970 to 1999, and 3,206 siblings from the Childhood Cancer Survivor Study completed the Neurocognitive Questionnaire (NCQ), a measure of self-reported task efficiency (TE), emotion regulation (ER), Organization, and working memory (WM). We compared rates of cognitive impairment (i.e., NCQ scores >90th percentile) in survivors and same-sex siblings, and sex differences in risk factors for cognitive impairment (i.e., treatment exposures, chronic health conditions (CHCs), cancer diagnosis, age at diagnosis) using modified Poisson regressions.Results:Survivors were more likely to report cognitive impairment than same-sex siblings (Males: TE OR=2.3, p<.001; ER OR=1.7, p=.008; Organization OR=1.5, p=.04; WM OR=2.3, p<.001. Females: TE OR=2.6, p<.001; ER OR=1.9, p<.001; Organization OR=1.5, p=.02; WM OR=2.6, p<.001). Within survivors, females were more likely than males to report impairment in TE (OR=1.2, p=.001), ER (OR=1.5, p<.001), and WM (OR=1.2, p<.001). There were no sex differences in symptom severity in siblings (all ps>.05). Risk factors for cognitive impairment in survivors included cranial radiation dose (TE <20Gy OR=1.5, p=.008, ≥20Gy OR=2.5, p<.001; ER OR=1.5, p<.001; Organization <20 Gy OR=1.4, p<.001; < WM 20 Gy OR=1.8, p<.001, ≥20Gy OR=2.7, p<.001), presence of moderate to severe CHCs (TE 1 CHC OR=1.9, p<.001, >1 CHC OR=3.6, p<.001; ER 1 CHC OR=1.7, p<.001, >1 CHC OR=2.2, p<.001; Organization 1 CHC OR=1.5, p=.001, >1 CHC OR=2.5, p<.001; WM 1 CHC OR=1.8, p<.001, >1 CHC OR=4.1, p<.001). There were sex differences in cognitive impairment risk factors in survivors. In females, cranial radiation dose (<20 Gy TE OR=1.6, p=.02; ≥20Gy TE OR=1.4, p=.01), leukemia diagnosis (TE OR=1.4, p=.02), or diagnosis age between 3-5 years (WM OR=1.4, p=.02) conferred higher risk for cognitive impairment compared to males with the same history. Females diagnosed with Hodgkin’s lymphoma (Organization OR=0.61, p=.05) or non-Hodgkin’s lymphoma (Organization OR=0.55, p=.03) were at lower risk for cognitive impairment compared to males.Conclusions:We found sex-specific differences in rates of, and risk factors for, neurocognitive impairment, suggesting a sex vulnerability. Future studies examining interactions between sex hormones and treatment exposures during brain development will enable tailoring treatments follow-up interventions to ensure that quality of life is maximized.

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Khwaja, Jahanzaib, Nicole Japzon, Maria Gabriel, Charles Lilley, Charalampia Kyriakou, Ali Rismani, and Shirley D'Sa. "Ethnic Diversity in Presentation of Waldenström Macroglobulinaemia and IgM Mgcs in the United Kingdom- a Real-World Data Analysis." Blood 142, Supplement 1 (November 28, 2023): 1668. http://dx.doi.org/10.1182/blood-2023-186561.

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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 <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<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.

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Kyriakou, Charalampia, Carmen Canals, David Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese, Karin Kolbe, et al. "High-Dose Therapy and Autologous Stem-Cell Transplantation in Waldenström Macroglobulinemia: The Lymphoma Working Party of the European Group for Blood and Marrow Transplantation." Journal of Clinical Oncology 28, no. 13 (May 1, 2010): 2227–32. http://dx.doi.org/10.1200/jco.2009.24.4905.

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Purpose The role of autologous stem-cell transplantation (ASCT) in Waldenström macroglobulinemia (WM) is not defined. The aim of this study was to analyze the results of ASCT in patients with WM and to determine the prognostic factors that have a significant impact on outcome. Patients and Methods We analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005. Median time from diagnosis to ASCT was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatment failure with at least three lines of therapy, and 93% had sensitive disease at the time of ASCT. Conditioning regimen was total-body irradiation–based in 45 patients. Median follow-up for surviving patients was 4.2 years (range, 0.5 to 14.8 years). Results Nonrelapse mortality was 3.8% at 1 year. Ten patients developed a secondary malignancy, with a cumulative incidence of 8.4% at 5 years. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) and overall survival were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemorefractoriness at ASCT. The achievement of a negative immunofixation after ASCT had a positive impact on PFS after ASCT. When used as consolidation at first response, ASCT provided a PFS of 44% at 5 years. Conclusion ASCT is a feasible procedure in young patients with advanced WM. ASCT should not be offered to patients with chemoresistant disease and to those who received more than three lines of therapy.

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Hunter, Zachary R., Maria Luisa Guerrera, Ruben D. Carrasco, Nickolas Tsakmaklis, Kris Richardson, Amanda Kofides, Xia Liu, et al. "Atypical Stem Cell, Pre-B-Cell, T-Cell and Myeloid Gene Expression Characterizes Early Waldenstrom's Macroglobulinemia Clones Which Diminishes with Advancing Disease and Has Therapeutic Implications." Blood 142, Supplement 1 (November 28, 2023): 756. http://dx.doi.org/10.1182/blood-2023-190685.

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Background: In previous studies using multi-omic data for 253 treatment-naive patients with Waldenstrom's Macroglobulinemia (WM), we identified three subtypes of WM: B-cell like (BCL), Plasma cell like (PCL), and an intermediate clone enriched for early/smoldering WM from which the other two evolved (Hunter et al, ASH 2022). The BCL and PCL subtypes show distinct mutation and transcriptional signatures, as well as clinical characteristics. Diffusion pseudo-time (DPT) analysis suggests all patient tumors, regardless of subtype have a shared evolutionary path and can be divided into Early and Late DPT determined stages that mirror disease progression. Additional analysis of DPT suggests it represents a continuous process akin to clonal evolution. We therefore sought to further characterize the DPT signal in MYD88 mutated WM. Methods: RNASeq was performed on CD19-selected bone marrow (BM) samples from 249 of the 253 treatment-naive WM patients who were MYD88 mutated, as well as 13 paired CD19+CD27- and CD19+CD27+ selected healthy donor (HD) peripheral blood samples. Whole exome sequencing of CD19-selected BM cells along with CD19-depleted peripheral blood mononuclear controls was also performed for 215 of the WM samples. To assess BM histology, slides from 66 BM paraffin blocks from these WM patients were analyzed. Results: WM patients had median age of 66 (range 31-95 years), BM involvement of 50% (5-95%) and serum IgM level of 3,162 (104-10,321 mg/dL). The median follow-up for the study cohort was 8.8 (range 0.2 - 33.8 years). Patients were stratified into 5 cohorts by DPT values. Analysis of BM involvement by DPT cohorts revealed a stepwise increase with the median involvement rising from 20% in the lowest to 80% in the highest cohort (p<0.0001). Increasing DPT predicted for shorter time from biopsy to first therapy (p=0.0003) but was not predictive of time from diagnosis to first therapy consistent with DPT alignment by stage of WM development. RNASeq analysis revealed high expression of genes atypical of mature B-cells that diminished with increasing DPT ( Figure 1). Among these were the myeloid chemo-attractants CXCL1, CXCL8 and CXCL12 which fell from a median of 4.4, 67.2 and 41.1 to 0.1, 3.6 and 0.8 transcripts per million (TpM) in the lowest and highest DPT cohorts, respectively (p<0.0001). Accordingly, all the top 20 gene ontology (GO) terms associated with DPT were related to activation, degranulation, and migration of myeloid cells and leukocytes. Pathological review of the 66 BM slides ranked by DPT, showed increased early myeloid cells and eosinophils clustering near small lymphoid aggregates, and as DPT increased, increased lymphocytes and mast cells with decreased myeloid cell involvement was observed. By RNASeq, pre-B-cell genes including MYB, the VDJ recombination genes RAG1, RAG2 and DNTT as well as the surrogate light chain genes IGLL1 and VPREB1 fell from 22.5, 10, 13.5, 61.1, 144 and 38.3 to 2.2, 1, 1.1, 9.1, 12.2 and 4.3 TpM, respectively (p<0.0001). T-cell and myeloid genes including CD4, CD8A, FCGR3A (CD16), CD14 and CD33 also decreased with increased DPT from 67.6, 7.1, 80.5, 200, and 23.2 to 2.4, 0.9, 1.7, 3.6 and 0.7 TpM, respectively (p<0.0005). A subclonal stem cell signature was also detected, including CD34 and KIT (CD117), which fell from 1.67 and 0.64 to 0.15 and 0.06 TpM, respectively (0<0.0001). CD34, KIT, preBCR, CD4, CD8A, FCGR3A, CEACAM8 (CD66b), and CD33 expression was confirmed by CD19+ light chain restricted flow cytometry in WM but not in HD samples. In addition, the MB and plasma blast genes PRDM1 and XBP1 were elevated in all samples regardless of DPT, consistent with a putative memory B-cell origin. Progression free survival (PFS) in response to proteasome inhibitors revealed strong stratification by subtype (p=0.001), as well as inferior PFS with BTK-inhibitors in low DPT patients (p= 0.044; Figure 2), suggesting less BTK dependence in the early DPT clones. Consistent with this finding, gene set enrichment identified increased BCR signaling with increased DPT. Conclusions: This analysis suggests that stem cell program reactivation and atypical marker expression characterize early WM clones that are ultimately replaced by clones exhibiting more typical B-cell markers with disease progression. The findings may be relevant to treatment selection and provide a framework for investigating subtype and early/late evolutionary staging in the treatment approach to WM.

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Bowman, K. W., D. T. Shindell, H. M. Worden, J. F. Lamarque, P. J. Young, D. S. Stevenson, Z. Qu, et al. "Evaluation of ACCMIP outgoing longwave radiation from tropospheric ozone using TES satellite observations." Atmospheric Chemistry and Physics 13, no. 8 (April 18, 2013): 4057–72. http://dx.doi.org/10.5194/acp-13-4057-2013.

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Abstract. We use simultaneous observations of tropospheric ozone and outgoing longwave radiation (OLR) sensitivity to tropospheric ozone from the Tropospheric Emission Spectrometer (TES) to evaluate model tropospheric ozone and its effect on OLR simulated by a suite of chemistry-climate models that participated in the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP). The ensemble mean of ACCMIP models show a persistent but modest tropospheric ozone low bias (5–20 ppb) in the Southern Hemisphere (SH) and modest high bias (5–10 ppb) in the Northern Hemisphere (NH) relative to TES ozone for 2005–2010. These ozone biases have a significant impact on the OLR. Using TES instantaneous radiative kernels (IRK), we show that the ACCMIP ensemble mean tropospheric ozone low bias leads up to 120 mW m−2 OLR high bias locally but zonally compensating errors reduce the global OLR high bias to 39 ± 41 m Wm−2 relative to TES data. We show that there is a correlation (R2 = 0.59) between the magnitude of the ACCMIP OLR bias and the deviation of the ACCMIP preindustrial to present day (1750–2010) ozone radiative forcing (RF) from the ensemble ozone RF mean. However, this correlation is driven primarily by models whose absolute OLR bias from tropospheric ozone exceeds 100 m Wm−2. Removing these models leads to a mean ozone radiative forcing of 394 ± 42 m Wm−2. The mean is about the same and the standard deviation is about 30% lower than an ensemble ozone RF of 384 ± 60 m Wm−2 derived from 14 of the 16 ACCMIP models reported in a companion ACCMIP study. These results point towards a profitable direction of combining satellite observations and chemistry-climate model simulations to reduce uncertainty in ozone radiative forcing.

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Richardson, Kris, Nickolas Tsakmaklis, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Shirong Liu, Catherine A. Flynn, et al. "Novel Isoforms Identified By Isoseq Analysis Drive Expression Differences in Key Genes That Delineate the Subtypes of Waldenstrom's Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 1946. http://dx.doi.org/10.1182/blood-2023-190631.

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Background: Alternative isoforms can alter regulatory motifs, binding partners, localization, and function of gene or even inhibit its function. While isoform regulation in humans is generally well described, there are still many tissue specific isoforms that remain to be fully documented. Moreover, mutations and broad dysregulation of transcriptional and RNA processing machinery is common in cancer resulting in additional novel isoforms. Analysis of 249 MYD88 mutated patients from our multi-omic data set of 253 treatment-naive patients with Waldenstrom's Macroglobulinemia (WM) identified three subtypes of WM: B-cell like (BCL), Plasma cell like (PCL), and an intermediate clone enriched for early/smoldering WM from which the other two evolved. (Hunter et al, ASH 2022) The BCL and PCL subtypes have distinct clinical as well as mutational and transcriptional characteristics. To investigate isoform usage, including novel disease related isoforms, we utilized PacBio single molecule real-time (SMRT) sequencing which can produce reads up to 10Kb allowing for end-to-end single transcript sequences for most genes. Methods: PacBio Isoseq analysis was performed on RNA isolated from CD19+ bone marrow (BM) samples from 11 WM patients; CD19+CD27+ memory B-cells (MB) from two healthy donors; and CD138+ plasma cell (PC) from two healthy donors. SMRT analysis data was aligned and processed using minimap2 with Cupcake. Observed isoforms were filtered, categorized, and annotated using Squanti. High confidence novel isoforms were then added into hg38 Gencode annotation which was used to realign our existing high depth Illumina 150bp paired end RNASeq data set of 249 untreated MYD88 mutated WM patients using STAR and Salmon. DTU analysis and functional annotation was performed using the isoformSwitchAnalyzeR package from Bioconductor in R. Results: The 11 patients in PacBio novel isoform discovery cohort had a median age of 63 (range 48-78 years) at time of sample acquisition; serum IgM of 2,150 (598-5,830 mg/dL); and BM involvement of 75% (range 20-95%). Six (55%) were female; 4 (36%) had a familial history of WM; 4 (36%) had a familial history of other B-cell malignancies; and 3 (27%) were sporadic. MYD88 and CXCR4 mutations were present in 10/11 (91%) and 6/11 (55%) patients, respectively. In the MYD88 mutated RNASeq cohort, 102/249 (41%) were female, the median age at biopsy was 66 (range: 31-95 years), BM involvement was 50% (5-95%), and the median serum IgM was 3,162 (104-10,321 mg/dL). PacBio analysis added 194,997 novel isoforms to the gencode annotation which ranged in function from minor alterations in untranslated regions (UTRs) to the introduction of novel coding sequences. Of the 3,134 genes differentially expressed between BCL and PCL, 1,175 (37.5%) and 1,149 (36.6%) had greater that 50% of their expression assigned to novel isoforms for BCL and PCL, respectively (p=NS), which highlights the impact of the improved annotation. The top result from the DTU analysis was DUSP22, a negative regulator of MAPK and ERK1/2 signaling ( Figure 1). DUSP22 was overexpressed in early/smoldering WM and PCL, with overexpression driven by a novel internal start with a partial intron inclusion. These novel isoforms express only half of DUSP22's functional domain but also contain novel 5' signal peptide sequences targeting the transcript to the endoplasmic reticulum for translation. Another top result was FCRLB, an FC receptor that can promote survival in B-lymphocytes. In HD and BCL, the minimal expression corresponded to a canonical non-coding isoform, while in PCL and early/smoldering WM most of the expression resulted from novel coding isoforms that contained the core protein coding regions of the gene. Other genes with significant DTU included HDAC4, HDAC9, and ARID5B all of which are critical modulators of chromatin accessibility. Functional validation of novel isoforms and DTU analysis of additional genomic, and clinical factors is ongoing. Conclusions: Novel transcripts identified by PacBio IsoSeq analysis drive expression of key genes including the important MAPK/ERK regulator DUSP22, and FC receptor FCRLB that promotes survival of B-lymphocytes. Other genes of interest included modulators of chromatic accessibility. Our findings demonstrate important new insights into isoform usage associated with WM subtype in WM and provide novel insights into the underlying biology of the disease.

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Saito, Akio, Atsushi Isoda, Akihiko Yokohama, Hiroshi Handa, Norifumi Tsukamoto, Yutaka Tsukune, Makoto Sasaki, et al. "Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan." Blood 126, no. 23 (December 3, 2015): 5028. http://dx.doi.org/10.1182/blood.v126.23.5028.5028.

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Abstract Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.

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Wang, Zhixing, Wayne Fritschle, Richard Bennington, Bettina Burnworth, Angela Bennington, Collette Wentzel, Stephanie Verkamp, et al. "MYD88 L265P Mutation Detection: Analysis of Flow Cytometry Sorted Plasma and Lymphoid Cell Clones Improves Sensitivity and Specificity for WM/LPL Diagnosis." Blood 124, no. 21 (December 6, 2014): 1645. http://dx.doi.org/10.1182/blood.v124.21.1645.1645.

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Abstract Background: Waldenström's macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL) are lymphoproliferative disorders with bone marrow infiltration by clonal lymphoplasmacytic cells (Treon et al., 2003, 2005). The somatic point mutation L265P in the myeloid differentiation primary response gene 88 (MYD88) has been reported in more than 90% of WM patients (Treon et al., 2012). Therefore MYD88 mutation analysis has been implemented in clinical practice to support the diagnosis of LPL/WM. After the implementation of MYD88 L265P assays with increased detection sensitivity, a substantial portion of patients with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS) was also reported MYD88 L265P positive. Splenic marginal zone lymphoma (SMZL), B-cell chronic lymphoproliferative disorders (B-CLPD) and diffused large B-cell lymphoma (DLBCL) have been found positive with much lower incidence rates (Varettoni et al., 2013; Xu et al., 2013). Hence the remaining need to differentiate WM/LPL from other lymphoproliferative disorders with co-occurring plasma cells with high confidence. Patients and Methods: In this study, flow cytometric cell sorting was utilized to isolate clonal plasma and B lymphoid cell fractions as previously described (Zehentner et al., 2011). 69 patient specimen fractions with a clinical history of WM /LPL, multiple myeloma, CLL and lymphoma were analyzed for MYD88 L265P mutation using Sanger sequencing. Furthermore, the Biomed-2 primer sets for the immunoglobulin heavy (IgH) and/or the immunoglobulin kappa light chain region (IgK) were used to compare B cell clonality profiles in the lymphoid versus plasma cell compartments. Results: MYD88 L265P mutation was detected in all specimens with confirmed Waldenström's macroglobulinemia (17/17, 100%). Of these 16/17 (94%) revealed MYD88 L265P as well as identical monoclonality profile by gene rearrangement analysis in both the plasma and the B lymphoid cell collections. In 47% (8/17), the mutation was only detected in the plasma and B cell fractions, but not in the whole bone marrow specimens. 21 patient specimens with a known clinical history of LPL and co-occurring clonal plasma cells were tested. 9 of 21 (43%) were categorized with identical B cell clonality profile when comparing plasma and B lymphoid cells; whereas 12 (57%) had unrelated clonality profiles. 7 of the 9 (78%) specimens in the identical clonality group tested positive for MYD88 L265P in both the plasma and B lymphoid clone. None of the unrelated clonality group specimens carried the mutation in both cell fractions; for 7/12 (58%) MYD88 L265P was found in either the plasma (2) or the B-cell fraction (5) whereas 5/12 (42%) tested negative. 11 bone marrow aspirate specimen with known presence of lymphoma (including splenic marginal zone (SMZL), mantle cell and marginal zone) were analyzed. 10/11 (90%) tested negative for MYD88 L265P, with the exception of one SMZL specimen. Furthermore, 12 known myeloma, 5 CLL and 3 healthy donor specimens were analyzed, all tested negative. Conclusions: In this study, we developed and tested a novel approach to assess MYD88 L265P mutation status in order to assist WM/LPL diagnosis. Flow cytometric cell sorting for clonal plasma and B cell populations was combined with molecular analysis. Subsequently, MYD88 L265P mutation as well as B-cell clonality profile was compared in both cell fractions. Our study postulates a significant improvement in sensitivity and most importantly specificity when applying MYD88 L265P mutation status in combination with cell sorting for WM/LPL diagnostic decisions. 47% WM patients (8/17) and 44% LPL patients (4/9) were positive for the MYD88 mutation exclusively in both flow cytometry sorted cell fractions but not in whole bone marrow specimens. 94% (16/17) WM as well as 78% (7/9) LPL specimens with identical plasma and B-cell clonality profile revealed the presence of the MYD88 L265P mutation in both the plasma cell and the B lymphoid cell clones. Whereas LPL specimens with unrelated clonality profile of the plasma and lymphoid cell fractions as well as other control specimens (lymphoma, myeloma, CLL and healthy) either tested negative or positive only in one of the sorted cell fractions. We therefore conclude that confirming the presence of MYD88 L265P in both B-lymphoid and plasma cell fraction is an important prerequisite to distinguish LPL/WM from related disorders with high confidence. Disclosures Wang: HematoLogics Inc.: Employment. Fritschle:HematoLogics Inc.: Employment. Bennington:HematoLogics Inc.: Employment. Burnworth:HematoLogics Inc.: Employment. Bennington:HematoLogics Inc.: Employment. Wentzel:HematoLogics Inc.: Employment. Verkamp:HematoLogics Inc.: Employment. Nguyen:HematoLogics Inc.: Employment. Ghirardelli:HematoLogics Inc.: Employment. Broderson:HematoLogics Inc.: Employment. Wells:HematoLogics Inc.: Employment, Equity Ownership. Loken:HematoLogics Inc.: Employment, Equity Ownership. Zehentner:HematoLogics Inc.: Employment, Equity Ownership.

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Varettoni, Marzia, Angela Ferrari, Alessandra Tedeschi, Virginia Valeria Ferretti, Rita Rizzi, Marina Motta, Francesco Piazza, et al. "Waldenström Macroglobulinemia in Young Patients Treated in the Modern Era: A Multi-Institutional Italian Study." Blood 134, Supplement_1 (November 13, 2019): 1539. http://dx.doi.org/10.1182/blood-2019-125835.

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Background. Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma typical of the elderly population, with a median age at diagnosis of 65-70 years and median overall survival of approximately 10 years. Age is the most important prognostic factor in WM, and unrelated mortality significantly impacts survival in elderly patients. The past two decades have witnessed important treatment advances in WM, with the introduction of anti-CD20 monoclonal antibodies in the early 2000s and of ibrutinib in more recent years. Less than 10% of WM patients are diagnosed at young age, and few studies have addressed their characteristics and outcome in the era of immunotherapy and targeted therapies. Here we report the presenting features, treatment and outcome of WM patients younger than 55 years diagnosed in 12 Hematologic Centers across Italy between 2000 and 2018. Patients and Methods. Diagnostic criteria were those established during the second International Workshop on WM (Owen et al, 2003) and were retrospectively applied to patients diagnosed before 2003. The overall survival (OS) observed in the study cohort was compared with the expected survival of the general Italian population matched by sex, age and calendar year. The expected survival estimates were derived from Italian life tables (Istituto Nazionale di Statistica, ISTAT). Results. The median age of patients included in the study was 50 years (interquartile range, IQR: 46-52). Their clinical characteristics at diagnosis are reported in Table 1. With a median follow-up of 5.6 years (IQR 3.1-9.1), 76 of 129 patients (59%) have been treated, at diagnosis (n=31, 41%) or after initial observation (n=45, 59%). The median treatment-free survival was 39 months. According to ISS-WM prognostic score, 58% were classified as low risk, 30% as intermediate risk and 12% as high risk. Frontline therapy included Rituximab in 71/76 patients (93%). Rituximab was associated with chemotherapy in 62 patients (82%), whereas 9 patients (12%) received a chemo-free induction. Five patients (7%) received chemotherapy only as first-line therapy (Table 2). The overall response rate (ORR) to induction therapy was 85%, including 39% CR+VGPR. Two patients received Rituximab maintenance for 2 years. The median progression-free survival (PFS) after first-line therapy was 76 months. Four of 76 patients (5%) received an autologous stem cell transplantation at relapse/progression. Overall, 14/76 patients (18%) received ibrutinib as first (n=2) or as subsequent line of therapy (n=12). During follow-up, 4/76 patients (5%) developed a solid cancer (bladder n=2, breast n=1, prostate n=1) and 2 a second hematologic cancer (chronic myelomonocytic leukemia n=1, secondary MDS n=1). Using a competing-risk model, accounting for death from any cause as the competing event, the cumulative incidence of second cancers was 2% at 5 years and 5.8% at 10 years. Three patients have died, 2 due to WM and 1 due to acute myeloid leukemia. The 5-and 10-year OS from diagnosis were 99% and 96% respectively. In a time-dependent survival analysis, considering therapy as a time-dependent covariate, the OS of treated and untreated WM patients was not significantly different (P = 0.162) (Figure 1). Among treated patients, the OS was significantly shorter in high-risk patients as compared with low- and intermediate-risk patients (5-year OS 85.7% versus 100%, P=0.018) (Figure 2). The OS of young WM patients was not significantly reduced as compared with age-, sex- and calendar year- matched general population (P > 0.05) (Figure 3). Conclusions. The presenting features of young WM patients resemble those typically described in the elderly WM population. Among treated patients, more than half are low-risk according to ISS-WM, confirming age as the most important prognostic factor. More than 90% of patients received Rituximab as part of the upfront treatment, mainly in combination with chemotherapy. Ibrutinib seems to be preferred over autologous stem cell transplantation in the relapsed/refractory setting. The outcome of young WM patients treated in Italy in the contemporary era was excellent in terms of both PFS and OS, with a life expectancy not significantly reduced as compared with the general population. Figure 1 Disclosures Varettoni: Gilead: Other: travel expenses; Janssen: Consultancy; Roche: Consultancy; ABBVIE: Other: travel expenses. Tedeschi:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Benevolo:Novartis Pharmaceuticals: Consultancy. Del Fabro:Janssen: Consultancy. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Arcaini:Gilead Sciences: Research Funding; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy.

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Siegel, David S., Jonathan L. Kaufman, Noopur S. Raje, Joseph R. Mikhael, Prashant Kapoor, Steven P. Treon, Jorge J. Castillo, Linda L. Neuman, Ju RueyJiuan Lee, and Irene Ghobrial. "Updated Results from a Multicenter, Open-Label, Dose-Escalation Phase 1b/2 Study of Single-Agent Oprozomib in Patients with Waldenström Macroglobulinemia (WM)." Blood 124, no. 21 (December 6, 2014): 1715. http://dx.doi.org/10.1182/blood.v124.21.1715.1715.

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Abstract Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that has shown promising antitumor activity in patients (pts) with hematologic malignancies (HM), including WM (Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with WM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, multicenter, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives of the phase 1b portion of the study are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective of the phase 2 portion of the study is to determine the best overall response rate (ORR; ≥minimal response [MR]). In the phase 1b portion, single-agent OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments. In the phase 2 study, pts have received 240 mg/d on the 5/14 schedule, which was the initial phase 2 schedule opened to enrollment. For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 36 pts with WM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with WM are presented in Table 1. For WM patients in the phase 1b portion, median treatment duration was 17.1 weeks (range, 3.1–51.4; 2/7 schedule) and 51.7 weeks (range, 3.9–74.9; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 8.1 weeks (range, 0.7–22.0). In all pts with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. None of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule occurred in patients with WM. Two of the 4 DLTs observed on the 5/14 schedule occurred in pts with WM (grade 4 tumor lysis syndrome [240 mg/d, n=1] and grade 3 vomiting [270 mg/d, n=1]). The most common adverse events (AEs) in pts with WM are shown in Table 2. Grade 4 AEs were thrombocytopenia (n=1; phase 1b; 2/7 schedule) and influenza and tumor lysis syndrome (n=1 each; phase 1b; 5/14 schedule). No on-study deaths occurred in pts with WM. In the phase 1b portion, two pts (25%) in the 2/7 schedule and 1 pt (9%) in the 5/14 schedule discontinued treatment due to an AE; 6 pts (35%) discontinued treatment due to an AE in the phase 2 portion. In the phase 1b portion, 3 pts (38%) (2/7 schedule) and 6 pts (55%) (5/14 schedule) had their dosage reduced at least once due to an AE; 10 pts (59%) in the phase 2 portion had their dosage reduced at least once due to an AE. In the phase 1b portion, all 19 pts were eligible for response and were carfilzomib (CFZ)-naïve. The ORR in 8 pts enrolled on the 2/7 schedule was 38% (3 pts had a partial response [PR]). Among 11 pts enrolled on the 5/14 schedule, the ORR was 73% (1 complete response, 1 very good partial response, 5 PRs, and 1 MR); the ORR for BTZ-refractory pts (n=4) was 75%. All 17 pts enrolled on the phase 2 portion were response-eligible. The ORR in the phase 2 portion was 59% (there were 5 PRs and 5 MRs). The ORR among CFZ-naïve pts (n=16) in the phase 2 portion was 56; the ORR among BTZ-refractory pts (n=3) was 67%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all pts with HM. In pts with WM who received single-agent OPZ, the most common grade 3 AEs were neutropenia and diarrhea; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity in pts with WM. Enrollment of patients on the 2/7 schedule is continuing; the target enrollment for the phase 2 portion of the study is 66 patients. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Disclosures Siegel: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Off Label Use: Monoclonal antibody/toxin fusion protein. For treatment of multiple myeloma. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Raje:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Ely Lilly: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Treon:Onyx: Consultancy, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other.

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SOLIA, EIRINI, IOANNIS NTANASIS-STATHOPOULOS, EFSTATHIOS KASTRITIS, EVANGELOS TERPOS, MELETIOS A. DIMOPOULOS, and MARIA GAVRIATOPOULOU. "Long-term Survival in a Patient With Transformation of Waldenström’s Macroglobulinemia into DLBCL." Cancer Diagnosis & Prognosis 4, no. 1 (January 2, 2024): 77–80. http://dx.doi.org/10.21873/cdp.10289.

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Background/Aim: Waldenström’s macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Case Report: Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein–Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. Conclusion: The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

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Kyriakou, Charalampia, C. Canals, A. Sureda, G. Taghipour, C. Gisselbrecht, P. Mazza, E. Montserrat, et al. "The Role of Autologous Stem Cell Transplantation (ASCT) in Patients with Advanced Waldenström’s Macroglobulinemia." Blood 110, no. 11 (November 16, 2007): 941. http://dx.doi.org/10.1182/blood.v110.11.941.941.

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Abstract Waldenström’s macroglobulinaemia (WM) is a relatively rare disorder that primarily affects elderly patients. Conventional therapies for symptomatic WM result in response rates of up to 70%. However, complete responses are rare and the disease remains incurable. Due to the indolent nature of the disease and the older age of patients the role of autologous stem cell transplantation (ASCT) in the treatment of patients with WM has not been analyzed in large series. In this retrospective multicenter study we report the outcome of 201 WM patients (132 male, 69 female), who underwent ASCT between 1992 and 2005. The median age at transplant was 53 years (22–73) and the median time from diagnosis to transplant was 18 months (3–239). Forty patients (20%) were in 1st maximum response (MR1), 24 (12%) in ≥MR2, 83 (41%) in PR1, 27 (13%) in ≥PR2 and 27(14%) were primary refractory to treatment. Conditioning regimens were BEAM (44%), TBI/Cyclophosphamide or Melphalan (28%), Melphalan (14%), BuCy (2%) and others (12%). The source of stem cells was PB in 188, BM in 10, and both in 3 patients. All patients but 3 had successful engraftment. With a median follow-up of 26 months (5–163), 112 (56%) patients are alive and free of disease, 73 (36%) patients have relapsed after a median of 14 months (1–110) post ASCT. Fifty-two patients died, 36(18%) from disease progression and 16(8%) from treatment toxicity. Non- relapse mortality was 6% at 1 year. The actuarial OS was 86% at 1 year, 75% at 3 years, and 61% at 5 years. The probability of relapse was 20% at 1 year, 38% at 3 years and 55% at 5 years with an estimated PFS of 74%, 54% and 33% at 1, 3, and 5 years respectively. Multivariate analysis revealed that, chemosensitive disease at the time of ASCT was the most important factor for NRM (p<0.001), relapse rate (p<0.01), PFS (p<0.001) and OS (p<0.001). In conclusion, this study suggests that ASCT is a safe procedure in patients with WM and that a significant proportion of heavily pre-treated patients with this disorder can respond to the procedure and achieve prolonged PFS.

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Trojani, Alessandra, Barbara Di Camillo, Luca Emanuele Bossi, Antonino Greco, Livia Leuzzi, Alessandra Tedeschi, Anna Maria Frustaci, et al. "Common Gene Expression Signature of B-Cells of Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathies of Undetermined Significance (IgM MGUS) Compared to Healthy Subjects." Blood 138, Supplement 1 (November 5, 2021): 4317. http://dx.doi.org/10.1182/blood-2021-147712.

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Abstract We performed a comparative gene expression profiling (GEP) study on B-cells and plasma cells of Waldenström Macroglobulinemia (WM), IgM monoclonal gammopathies of undetermined significance (IgMMGUS), and normal individuals (CTRLs) to identify GEP changes as reliable predictors of progression of IgMMGUS to WM. We analyzed bone marrow B-cells and plasma cells from 36 WM patients, 13 IgMMGUS subjects, and 7 CTRLs by Affymetrix microarray, respectively (Table 1). GEP experiments were performed on the CD19+ and CD138+ cells using GeneChip-HGU133 Plus 2.0. Data were preprocessed and normalized by Robust Multi-Array Average and ComBat. Selection of the different expressed genes was performed separately for CD19+ and CD138+ cells, using Significance Analysis of Microarrays (SAM) on the 3 groups and a false discovery rate threshold of 5%, followed, for significance comparisons, by a pair-wise SAM test corrected for multiple testing. We focused on the comparison of the CD19+ cells of WM vs. IgMMGUS vs. CTRLs which highlighted 2038 unique genes whereas the same comparison of the CD138+ cells determined 29 unique genes (Trojani et.al. Cancers 2021). Among the 2038 DEGs, 115 genes were grouped in KEGG pathways involved in Wnt-signaling, BCR-signaling, calcium signaling, hematopoietic cell antigens, cell adhesion, adherens junctions, coagulation cascade, platelet activation, cytokine receptor, and signaling pathways responsible for cell cycle, apoptosis, and survival. Interestingly, most of the 115 DEGs in B-cells were different expressed in WM vs. IgMMGUS and CTRLs. Only 9/115 DEGs were significantly different expressed in WM vs. CTRLs and in IgMMGUS vs. CTRLs, but no significant expression changes were noted between WM and IgMMGUS (Table 2). To further inspect the similarities and the differences among WM and IgMMGUS, we computed the Euclidean pair-wise distance between subjects and, using this distance as weight, constructed a minimum spanning tree (MST) (Figure 1). Considerably, four probesets identified ADRB2 (transmembrane Beta adrenergic receptor) which was up regulated in WM and IgMMGUS compared to CTRLs. The over expression of ADRB2 was also demonstrated in Mantle Cell Lymphoma cell lines and in Diffuse large B-cell lymphoma (DLBCL) lymphocytes compared to normal B-cells (doi10.1016/j.cellsig.2017.08.002), and in most malignancies (doi10.1007/s11033-021-06250-y) . As far as we know, ADAM23 (ADAM Metallopeptidase Domain23) has not been found in WM, whereas we suggest its possible role in WM patients with Sjogren's syndrome (SS). ADAM23 plays a role in the peripheral neuropathy by controlling the activity of potassium channels in SS (doi10.1007/s10067-016-3499-z). Some authors found that sensory/motor neuropathies were associated with MGUS patients (doi10.1017/s0317167100011483). We strongly believe that the down regulation of ADAM23 in WM and IgMMGUS has a good chance to be associated with clinical neuropathy in WM and IgMMGUS. RASGRP3 (RAS Guanyl Releasing Protein3) and PIK3AP1 (Phosphoinositide 3 Kinase Adaptor Protein1) play crucial roles in BCR signaling pathway: PIK3AP1 activates the PI3K-Akt signaling while RASGRP3 stimulates MAPK signaling pathway. The deregulation of LEF1 (Lymphoid Enhancer Binding Factor1) and genes of Wnt-pathway were previously demonstrated in B-cell disorders and multiple myeloma (doi10.1007/s00277-017-3207-3, doi10.1016/j.pathol.2019.09.009). According to these studies, we showed the under expression of LEF1 in WM and IgMMGUS compared to CTRLs. We identified the down regulation of EZH2 (Enhancer Of Zeste2 Polycomb Repressive Complex2Subunit) in WM and IgMMGUS compared to CTRLs. EZH2 is involved in Follicular lymphoma and DLBCL (doi10.1080/2162402X.2017.1321184). CDHR3 (Cadherin Related Family Member3), CHEK1 (Checkpoint Kinase1), and HIST1H1B (Histone-H1.5) were over expressed in CTRLs compared to IgMMGUS and WM. In conclusion, the common gene-set in WM and IgMMGUS could suggest two-hit hypothesis. First, the gene-set could play a role in the risk of progression of IgMMGUS to WM. Until now, all the IgMMGUS subjects have not been transformed in WM or other NHL, but they have been monitored every 6 months, and their possible transformation to lymphoma could highlight new insights. The second hypothesis suggests their involvement in the biological processes of leukemogenesis in WM and IgMMGUS which will be further investigated. Figure 1 Figure 1. Disclosures Tedeschi: AbbVie: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

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Liu, Shirong, Xia Liu, Kara M. Soroko, Alexa G. Canning, Amanda Kofides, Choudhury Fabliha Binte Yusuf, Johany Penailillo, et al. "Establishment of the Bcwm.2 Cell Line As a BTK-Inhibitor Resistant, BCL2 Inhibitor Sensitive in Vitro and In Vivo Study Model for Waldenström's Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 6613. http://dx.doi.org/10.1182/blood-2023-190147.

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Background: Waldenström's macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by bone marrow (BM) infiltration with lymphoplasmacytic lymphoma and monoclonal immunoglobulin M (IgM) production. Mutations in MYD88 are present in 95-97% of WM patients. Deletions involving chromosome 6q (del6q) are found in up to 50% of WM patients, and include genes that regulate MYD88, BCL2 and apoptotic signaling. Cell lines can play a pivotal role as disease models, contributing to a comprehensive understanding of WM biology and advancing therapeutic strategies. The availability of cell lines for the study of WM remains limited, and none demonstrate del6q. Patient and Methods: We developed and characterized a novel cell line (BCWM.2) from long-term cultures of CD19 + selected BM lymphoplasmacytic cells from a symptomatic, treatment naive WM patient who then received ibrutinib monotherapy on a clinical trial. The patient attained a major response to treatment, and after 2 years progressed. The patient underwent serial bone marrow biopsies, and extensive genomic and transcriptome analysis of his tumor during the study, and the corresponding cell line established at baseline. An in vivo xenograft mouse model of BCWM.2 was also established in NOD SCID mice, and the origin of the xenografted tumor was confirmed by genomic sequencing and immunohistochemistry. Results: BCWM.2 cells exhibited morphologic and immunophenotypic characteristics resembling lymphoplasmacytic cells and demonstrated robust propagation when co-cultured with HS-5 stromal cells in IMDM medium supplemented with 20% FBS. Flow cytometric analysis revealed that BCWM.2 exhibited an immunophenotype consistent with the source WM patient. Whole genome sequencing demonstrated that both BCWM.2 cells and original patient WM cells carried somatic activating mutation in MYD88 (S243N) and shared trisomy in chromosomes 3 and 12, heterozygous deletion of 6q, and amplification of 6p. Notably, a novel mutation in the SRC family member LYN (I297N; T>A), a component of BCR, was identified in BCWM.2 but not the original patient tumor. The I297N mutation found in the regulatory hinge region is predicted to cause activation of LYN. At time of progression on ibrutinib, the dominant clone that emerged in the patient's tumor also carried the I297N mutation. Additionally, mutated genes in BCWM.2 included histone deacetylase HDAC5, tumor suppressor RUNX3, B-cell transcriptional activator SPI1, and AKAP9 (A-Kinase Anchoring Protein 9). Transcriptome analysis showed shared expression patterns between BCWM.2 and patient tumor samples, including diminished gene expression of chromosome 6q. Drug response testing revealed that BCWM.2 cells did not respond to the BTK-inhibitors ibrutinib, zanubrutinib or pirtobrutinib but were sensitive to the BCL2 inhibitor venetoclax. Furthermore, BCWM.2 cells readily engrafted in NOD-SCID mice by direct subcutaneous injection of 2 x 10^6 cells/mouse. Tumor growth (~500 mm^3) was observed in the mice four weeks post-inoculation. Importantly, follow-up evaluations demonstrated serial increases in human IgM levels in the mouse sera post-engraftment. Moreover, BCWM.2 engraftment was confirmed by immunohistochemistry with tumors exhibiting intermediate lymphoid cell morphology with plasmacytoid differentiation, CD20 and MUM1 expression, clonality for lambda light chain and IgM heavy chain, 60% KI67 staining. Whole exome sequencing of engrafted tumors further confirmed the presence of the MYD88 S243N and LYN I297N mutations detected in the cell line and the patient at the time of ibrutinib progression. Conclusions: BCWM.2 represents a novel, BTK-inhibitor resistant, BCL2 inhibitor sensitive WM cell line that demonstrates MYD88 (S243N) and LYN (I297N) somatic activating mutations, and deletions of 6q. BCWM.2 thereby provides an important new disease appropriate cell model for the in vitro and in vivo study of WM, including the development of targeted therapies for this disease.

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Ruan, G., J. Abeykoon, S. Zanwar, M. Gertz, S. Ansell, C. Reeder, S. Ailawadhi, et al. "PF484 MARKERS ASSOCIATED WITH SHORT SURVIVAL IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA." HemaSphere 3, S1 (June 2019): 194. http://dx.doi.org/10.1002/j.2572-9241.2019.tb00083.x.

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Background:Waldenström Macroglobulinemia (WM) is a rare, indolent B‐cell lymphoplasmacytic malignancy. Patient outcomes are highly heterogeneous, with a proportion of patients surviving less than 5 years (short survivors) and another proportion that survive longer than 10 years. The laboratory parameters in the currently used International Prognostic Scoring System for WM (IPSSWM) include hemoglobin, serum IgM, platelet count, and serum β2‐microglobulin.Aims:We aim to identify unique patient characteristics and prognostic features associated with short survival in WM.Methods:The medical records of patients with active WM that were diagnosed at Mayo Clinic Rochester, Arizona, and Florida between January 1st, 1996 and December 31st, 2013 were reviewed. The patients with smoldering WM were excluded. Cohorts of patients who either survived ≤ 5 years (Short Survival Group) or those with an overall survival (OS) ≥ 10 years (Long Survival Group) from the diagnosis of active disease were compared. Survivors with a follow‐up of ≤ 5 years were not included in the analyses. Two‐sided Wilcoxon rank sum test and Chi square/Fisher's exact test were used to compare the continuous and categorical variables, respectively. The variables that were statistically significant on univariate analysis (P < 0.05) were included in a multivariate logisitic regression analysis.Results:Of 893 consecutively seen WM patients (median follow‐up of 9 years [95% CI 8.4–9.7]), we identified 387 patients who could be categorized into either the Short Survival Group (n = 171 patients, 44%) or the Long Survival Group (n = 216, 56%). The Short Survival Group had a median OS of 2.4 years (2.1–2.8) and median age at diagnosis of 73 years (42–93), while the Long Survival Group (n = 216, 56%) had a median OS of 18.9 years (16‐NR) and median age at diagnosis of 62 years (31–85). The baseline characteristics and significant findings between the two groups are listed in the Table. Parameters significant on univariate analysis included age >65 years, albumin < 3.5 g/dL, β2‐microglobulin >3 μg/ml, and LDH > upper limit of normal (ULN). On multivariate analysis, albumin <3.5 g/dL and LDH > ULN were independently associated with short survival. Among the Long Survivors, 60 (28%) patients survived 15 years or more.Summary/Conclusion:Lactate dehydrogenase above the ULN and serum albumin <3.5 g/dL are independent biomarkers of short survival in WM. The MYD88 L265P status and the size of serum IgM are not prognostic in WM. Our data suggest the need for simplification of the current staging system with the use of widely available markers: serum albumin and lactate dehydrogenase.image

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Arrighi, Alois, Elena del Corro, Daniel Navarro Urrios, Marius V. Costache, Juan F. Sierra, Kenji Watanabe, Takashi Taniguchi, et al. "Heat dissipation in few-layer MoS₂ and MoS₂/hBN heterostructure." 2D Materials 9, no. 1 (October 25, 2021): 015005. http://dx.doi.org/10.1088/2053-1583/ac2e51.

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Abstract State-of-the-art fabrication and characterisation techniques have been employed to measure the thermal conductivity of suspended, single-crystalline MoS2 and MoS2/hBN heterostructures. Two-laser Raman scattering thermometry was used combined with real time measurements of the absorbed laser power. Measurements on MoS2 layers with thicknesses of 5 and 14 nm exhibit thermal conductivity in the range between 12 Wm−1 K−1 and 24 Wm−1 K−1. Additionally, after determining the thermal conductivity of the latter MoS2 sample, an hBN flake was transferred onto it and the effective thermal conductivity of the heterostructure was subsequently measured. Remarkably, despite that the thickness of the hBN layer was less than a hal of the thickness of the MoS2 layer, the heterostructure showed an almost eight-fold increase in the thermal conductivity, being able to dissipate more than ten times the laser power without any visible sign of damage. These results are consistent with a high thermal interface conductance G between MoS2 and hBN and an efficient in-plane heat spreading driven by hBN. Indeed, we estimate G ∼ 70 MW m−2 K−1 for hBN layer thermal conductivity of 450 Wm−1 K−1 which is significantly higher than previously reported values. Our work therefore demonstrates that the insertion of hBN layers in potential MoS2-based devices holds the promise for efficient thermal management.

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Xu, Lian, Nicholas Tsakmaklis, Guang Yang, Jiaji G. Chen, Xia Liu, Jie Chen, Maria Demos, et al. "Molecular Basis of Ibrutinib Resistance in Waldenstrom's Macroglobulinemia." Blood 128, no. 22 (December 2, 2016): 756. http://dx.doi.org/10.1182/blood.v128.22.756.756.

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Abstract Ibrutinib is a small molecule that is approved by the U.S. FDA for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's Macroglobulinemia (WM). In WM, mutated MYD88 supports the growth and survival of malignant lymphoplasmacytic cells (LPC) through BTK, while CXCR4WHIM mutations promote ibrutinib resistance (Yang et al, Blood 2013; Cao et al, Leukemia 2013). Ibrutinib irreversibly binds to Cys481 on BTK, and blocks its kinase activity. Despite high response rates and durable remissions in WM (Treon et al, NEJM 2015; Dimopoulos et al, ASH 2015), disease progression can occur in WM patients on active ibrutinib therapy. To investigate the molecular basis of ibrutinib resistance in WM, we first focused on BTK mutations at Cys481 that have been associated with ibrutinib resistance in CLL and MCL using Sanger sequencing and nested AS-PCR. To capture the known variants at BTK Cys481, three AS-PCR assays for Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C were developed with a sensitivity of detecting 0.1% of mutant alleles. Using these assays, we evaluated 8 WM patients who progressed on ibrutinib. Among these 8 patients, 5 had BTK Cys481 mutations: 3 were positive for Cys481SerG>C, and2 were positive for all the three (Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C) mutations. Cloning/sequencing analysis confirmed co-occurrence of multiple Cys481 mutations within individual WM patients and the presence of mutations at different alleles. Furthermore, targeted deep sequencing (>300X coverage) confirmed all BTK Cys481 mutations, and identified an additional mutation at Cys481 (Cys481TyrG>A) in both patients who were positive for Cys481SerG>C, Cys481SerT>A and Cys481ArgT>C. The estimated allele frequencies by targeted deep sequencing for individual BTK mutations ranged from 1-34%. In contrast, no BTK Cys481 mutations were identified in 100 ibrutinib naive WM patients using the nested AS-PCR assays. Among the 8 WM patients included in this study, all had activating MYD88 mutations, and 4 had CXCR4WHIM mutations. All 4 patients with CXCR4WHIM mutations had BTK Cys481 mutations. We next utilized targeted deep sequencing to expand the mutation analysis to the entire coding regions of the BTK, as well as select genes relevant to BCR and MYD88 signaling. A missense mutation in CARD11 (L878F) was identified in one patient who lacked any BTK Cys481 mutations, while a missense mutation in PLCG2 (Y495H) was found in another patient with a Cys481SerG>C mutation. The findings provide the first reported insights into the molecular mechanisms associated with ibrutinib resistance in WM, and highlight the emergence of multiple BTK mutated clones within individual patients who progress on ibrutinib. Disclosures Castillo: Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria; Millennium: Research Funding; Otsuka: Consultancy; Janssen: Honoraria. Palomba:Pharmacyclics: Consultancy. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Treon:Janssen: Consultancy; Pharmacyclics: Consultancy, Research Funding.

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Castillo, Jorge J., Joshua Gustine, Kirsten Meid, Toni Dubeau, Irene M. Ghobrial, and Steven P. Treon. "Lower Doses of Bendamustine Are Not Associated with Lower Response Rates in Previously Untreated Patients with Waldenström Macroglobulinemia." Blood 128, no. 22 (December 2, 2016): 2969. http://dx.doi.org/10.1182/blood.v128.22.2969.2969.

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Abstract Introduction: Waldenstrom macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the accumulation of malignant lymphoplasmacytic cells in the bone marrow and other organs. Bendamustine-rituximab has shown in a randomized clinical trial to be highly effective on treating patients with WM (Rummel Lancet Oncol 2013). In that study, bendamustine was administered at a dose of 90 mg/m2 IV for 6 cycles (total dose: 1080 mg/m2). Recent studies have suggested that lower doses of bendamustine might be associated with similar efficacy. However, this has not been previously evaluated in WM. Methods: In this retrospective study, we searched our database looking for previously untreated patients with WM who have received primary therapy with bendamustine and rituximab between 2008 and 2015. All patients met clinicopathological criteria for WM (Owen Smein Oncol 2003), and had at least one indication for initiation of therapy (Kyle Semin Oncol 2003). Pertinent clinical data were gathered. With regards to treatment, we calculated the total dose of bendamustine in mg/m2 received during induction therapy. Response was assessed based on current criteria (Owen Br J Haematol 2012). Logistic regression models were used to evaluate the relation between bendamustine dose with response, respectively. Results: A total of 48 patients who received frontline bendamustine-based therapy were included in this analysis. The median age at diagnosis of WM was 66 years (range 43-91), and the median age at initiation of therapy was 69 years (range 44-95). The median time from diagnosis to therapy was 9 months (range 0-178 months). 57% of patients were male, median hemoglobin level was 10.4 g/dl (range 4-15.3), and median serum IgM level was 3,645 mg/dl (range 356-9610). The median bone marrow involvement was 50% (range 0-90%), 43% had lymphadenopathy and 30% had splenomegaly. Based on the IPSSWM, 25% of patient were low risk, 30% intermediate risk and 45% were high risk. The reasons for initiation of therapy were anemia (57%), symptomatic extramedullary disease (22%), hyperviscosity (22%), neuropathy (11%), constitutional symptoms (9%) and thrombocytopenia (4%). At best response, the ORR was 95% (19% CR, 28% VGPR, 43% PR, 5% MR and 5% NR). The rate of major response (CR+VGPR+PR) was 90%, and the rate of deep response (CR+VGPR) was 47%. Based on total bendamustine dose, patients were divided in 3 groups: 90 mg/m2 days 1 and 2 for 6 cycles (1080 group; n=20), 90 mg/m2 on days 1 and 2 for 4 cycles (720 group; n=18), and 70 mg/m2 on days 1 and 2 for 4 cycles (560 group; n=10). There was no difference in age, hemoglobin levels, platelet counts, serum IgM levels, beta-2-microglobulin levels or IPSSWM scores between the 3 groups (Chi-square p>0.05 for all comparisons). The rates of major response were 95% in the 1080 group, 89% in the 720 group, and 90% in the 560 group (Chi-square p=0.78); and the rates of deep response were 55% in the 1080 group, 44% in the 720 group, and 50% in the 560 group (Chi-square p=0.81). Logistic regression analysis showed no relation between total bendamustine dose and attainment of major or deep response (p>0.05 in both models). Separate stratified analyses of patients who received (n=26) or did not receive (n=22) maintenance rituximab showed no relation between total bendamustine dose and depth of response (p>0.05 in all models). Conclusion: Our study suggests that receiving lower total bendamustine dose, administered concurrently with rituximab, does not affect negatively the attainment of major or deep response to therapy in previously untreated patients with WM. Disclosures Castillo: Biogen: Consultancy; Otsuka: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria; Millennium: Research Funding; Janssen: Honoraria. Ghobrial:Novartis: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria.

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Khwaja, Jahanzaib, Aisha S. Patel, Suzanne O. Arulogun, Ali Rismani, Simon Salter, Charalampia Kyriakou, Josephine M. I. Vos, and Shirley D'Sa. "IgM Paraprotein-Associated Type 1 Cryoglobulinaemia: Clinical Characteristics and Outcomes." Blood 138, Supplement 1 (November 5, 2021): 4503. http://dx.doi.org/10.1182/blood-2021-151662.

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Abstract Introduction Type 1 cryoglobulinaemia (CG) is characterised by monoclonal immunoglobulins which precipitate at temperatures below 37°C and redissolve on warming. They may be associated with lymphoproliferative disorders including Waldenström's macroglobulinemia (WM), other non-Hodgkin lymphoma (NHL), chronic lymphocytic leukaemia (CLL) or monoclonal gammopathy of undetermined significance (MGUS). Due to their rarity and heterogeneous clinical manifestations, incidence and outcomes are not well characterised and they are likely underdiagnosed. We retrospectively reviewed our cohort of patients (pts) with IgM paraprotein-associated type 1 CG. Methods Data from consecutive pts during 2013 and 2021, aged >18 years were extracted from clinical databases at two specialist centres [UCLH, United Kingdom (UK) and AMC, Netherlands]. Results A total of 62 pts (38 male, 24 female) were identified (Table 1); 59 from UK and 4 from Netherlands: 49 (79%) had WM, 7 (11%) IgM MGUS and 6 (10%) NHL (5 other lymphoma, 1 CLL). Median age at CG diagnosis was 66 (range 39-90) years; 32 (52%) were >65 years. MYD88 was mutated in 23/25 (92%) evaluable cases of WM. All cases were negative for hepatitis C. CG was detected after the monoclonal disorder in 46 (74%), with a median time to CG diagnosis of 8 (range 0-1390) months, concurrently in 11 (18%) pts and at a median of 1 month (range 0-4) in 5 (8%) pts prior to the monoclonal disorder. These patients were diagnosed due to CG symptoms. Eight pts (of which 50% had WM) also had active cold agglutinin disease (CAD). CG symptoms were present at time of testing in 25 (40%) pts; the others were diagnosed as a part of asymptomatic screening. CG symptoms were more common in those with MGUS / NHL compared to WM, most frequently in MGUS compared to WM (33% v 71%, p=0.05). Skin manifestations including acrocyanosis, purpura, ulcer and necrosis were noted in 14 (23%); 11 (18%) had peripheral neuropathy (6 sensory, 5 mixed) and 8 (13%) hyperviscosity. Median plasma viscosity was >7 (range 4.7 - >7) mPa of 5/8 pts measured with hyperviscosity and a median paraprotein of 29 (range 5-63) g/l. One patient with WM had cryoglobulinaemic glomerulopathy demonstrated by renal biopsy. In all, 53 (85%) pts received treatment, 10 (16%) for the CG and 43 for the monoclonal disorder, including plasma exchange (11/53). Thirty had Rituximab-based therapy (Table 1), and one received Ibrutinib. All achieved complete resolution of symptoms and 3/6 (50%) treated for CG had complete biochemical response with cryoglobulins undetectable after treatment. Two (20%) required further lines of therapy >4 years later. Overall at a follow up of 21 (range 0-94) months, median survival was not reached. Nine (14%) pts died, with 1 (2%) CG-related death due to relapse disease. Estimated 5-year overall survival (OS) was 67% (95% CI 40-84%) (figure 1). Conclusions In our cohort of 62 pts with type I IgM paraprotein-associated CG, the majority had WM compared to other NHL and MGUS, likely reflecting the clinical bias of the centres and our policy of screening for CG at first visit. A greater proportion of cases (40%) were symptomatic than previous reports (16%; Néel et al, 2014); when present, symptoms were dominated by skin manifestations, neuropathy and hyperviscosity. Patients tested for CG with IgM MGUS were more likely to be symptomatic compared to WM. CAD co-existed in a proportion. Those with CG symptoms treated had good clinical responses; treatment subgroups were too small to draw conclusions as to relative efficacy, but Rituximab-based therapy appeared effective in most cases. CG-related mortality was low with an estimated 5-year OS 67%. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

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Rasmussen, Kelli M., Vikas Patil, Hsu-Chih Chien, Deborah Kay Morreall, Catherine Li, Zachary R. Burningham, Brian C. Sauer, and Ahmad S. Halwani. "Real-World Practice Patterns in a Nationwide Cohort of Veterans with Waldenström's Macroglobulinemia." Blood 134, Supplement_1 (November 13, 2019): 5270. http://dx.doi.org/10.1182/blood-2019-127738.

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Background Waldenström's macroglobulinemia (WM) is a rare indolent cancer. Because of its low incidence, the treatment practices for WM primarily rely on data from phase 2 trials, which often have no consensus as to how to best treat this uncommon disease. The heterogeneity of treatments available can be observed in clinical practice guidelines, which recommend traditional chemotherapies, second-generation proteasome inhibitors, multiagent immunotherapies, and the novel Bruton's tyrosine kinase inhibitor, ibrutinib (IBR). Yet, despite clinical evidence and treatment guidelines recommending multiagent chemoimmunotherapy in first-line (1L) patients with WM, a majority of patients still receive monotherapy, namely chlorambucil in Europe and monotherapy rituximab (R) in the United States. To date, there have been no reports on the real-world treatment practices in 1L of WM since the introduction of IBR. The primary objective of this study is to understand the 1L treatment practices for WM in a nationwide cohort of Veterans treated in the largest integrated healthcare system in the United States, the Veterans Health Administration (VA). Methods Using the VA Cancer Registry System and electronic healthcare records, we identified Veterans diagnosed with WM between January 1, 2006, to December 31, 2018. Treatment regimens were classified in accordance with the National Comprehensive Cancer Network (NCCN) guidelines for WM (versions 1.2006, 2.2013, and 2.2019). Eligible patients were followed until loss to follow-up, death or the end of the study observation period (June 30, 2019). The 1L of treatment was examined; with the start date for 1L being the index date. Patients with a cancer diagnosis other than WM and patients who did not receive 1L treatment were excluded from the study. Results We identified 340 patients who were diagnosed with WM and received a 1L treatment regimen between 2006-2019 in the VA. Median age at diagnosis was 68 years (range: 37-92); 334 (98%) of patients were male. Demographics are further described in Table 1. At diagnosis, the median serum IgM was 3083 mg/dl (range: 10-11500), the median hemoglobin was 11 g/dl (range: 5-17), and the platelet count was 204 k/dl (range: 5-732). A noticeable shift in the adoption of treatments can be observed when comparing treatment practices in patients treated between 2006-2009, 2010-2014, and those treated between 2015-2019. From 2006-2009 the majority of 1L patients received monotherapy with R (23, 37%) or chlorambucil (14, 22%). Between 2010-2014, the majority of patients received monotherapy R (43, 34%), with increasing adoption of bendamustine + R (8, 6%) and bortezomib (27, 21%). Between 2015-2019, IBR became the leading 1L treatment (38, 25%), followed by bendamustine + R (33, 22%), monotherapy R (33, 22%), and bortezomib + R (28, 19%). The estimated survival rate of WM patients treated with 1L was 79% at three-years, 68% at 5-years, and 55% at 7-years. Conclusions Our study is one of the first to examine the real-world treatment practices of WM patients treated with 1L after the approval of novel agent IBR. Our results highlight the heterogeneity of treatment options available for WM patients. We also describe the evolution of treatment choices in 1L over the last decade: from chlorambucil and rituximab monotherapy, to ibrutinib, bendamustine, and bortezomib. Retrospective and/or observational studies examining treatments and outcomes in WM patients should take these shifts in treatment practices into consideration. Given the persistent utilization of monotherapy R as a treatment in 1L, despite the superior efficacy of other treatment options such as ibrutinib, bendamustine and bortezomib regimens, our results indicate the need for continued efforts to educate clinicians about the appropriate treatment options available for this rare disease. Acknowledgments: The study was sponsored by Pharmacyclics Disclosures Sauer: University of Utah and SLC VA Medical Center: Employment. Halwani:Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Amgen: Research Funding; Kyowa Hakko Kirin: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Miragen: Research Funding.

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Seymour, John F., Chan Yoon Cheah, Ricardo Parrondo, Meghan C. Thompson, Don A. Stevens, Masa Lasica, Michael L. Wang, et al. "First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)." Blood 142, Supplement 1 (November 28, 2023): 4401. http://dx.doi.org/10.1182/blood-2023-180109.

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Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

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Hatzianastassiou, N., A. Fotiadi, Ch Matsoukas, K. Pavlakis, E. Drakakis, D. Hatzidimitriou, and I. Vardavas. "Long-term global distribution of earth’s shortwave radiation budget at the top of atmosphere." Atmospheric Chemistry and Physics Discussions 4, no. 3 (May 14, 2004): 2671–726. http://dx.doi.org/10.5194/acpd-4-2671-2004.

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Abstract. The mean monthly shortwave (SW) radiation budget at the top of atmosphere (TOA) was computed on 2.5° longitude-latitude resolution for the 14-year period from 1984 to 1997, using a radiative transfer model with long-term climatological data from the International Satellite Cloud Climatology Project (ISCCP-D2) supplemented by data from the National Centers for Environmental Prediction - National Center for Atmospheric Research (NCEP-NCAR) Global Reanalysis project, and other global data bases such as TIROS Operational Vertical Sounder (TOVS) and Global Aerosol Data Set (GADS). The model radiative fluxes at TOA were validated against Earth Radiation Budget Experiment (ERBE) S4 scanner satellite data (1985–1989). The model is able to predict the seasonal and geographical variation of SW TOA fluxes. On a mean annual and global basis, the model is in very good agreement with ERBE, overestimating the outgoing SW radiation at TOA (OSR) by 0.93 Wm−2 (or by 0.92%), within the ERBE uncertainties. At pixel level, the OSR differences between model and ERBE are mostly within ±10 Wm−2, with ±5 Wm−2 over extended regions, while there exist some geographic areas with differences of up to 40 Wm−2, associated with uncertainties in cloud properties and surface albedo. The 14-year average model results give a planetary albedo equal to 29.6% and a TOA OSR flux of 101.2 Wm-2. A significant linearly decreasing trend in OSR and planetary albedo was found, equal to 2.3 Wm−2 and 0.6% over the 14-year period (from January 1984 to December 1997), indicating an increasing solar planetary warming. This planetary SW radiative heating occurs in the tropical and sub-tropical areas (20° S–20° N), with clouds being the most likely cause. The computed global mean OSR anomaly ranges within ±4 Wm−2, with signals from El Niño and La Niña events or Pinatubo eruption, whereas significant negative OSR anomalies, starting from year 1992, are also detected.

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Hatzianastassiou, N., A. Fotiadi, Ch Matsoukas, K. Pavlakis, E. Drakakis, D. Hatzidimitriou, and I. Vardavas. "Long-term global distribution of earth's shortwave radiation budget at the top of atmosphere." Atmospheric Chemistry and Physics 4, no. 5 (August 3, 2004): 1217–35. http://dx.doi.org/10.5194/acp-4-1217-2004.

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Abstract. The mean monthly shortwave (SW) radiation budget at the top of atmosphere (TOA) was computed on 2.5° longitude-latitude resolution for the 14-year period from 1984 to 1997, using a radiative transfer model with long-term climatological data from the International Satellite Cloud Climatology Project (ISCCP-D2) supplemented by data from the National Centers for Environmental Prediction – National Center for Atmospheric Research (NCEP-NCAR) Global Reanalysis project, and other global data bases such as TIROS Operational Vertical Sounder (TOVS) and Global Aerosol Data Set (GADS). The model radiative fluxes at TOA were validated against Earth Radiation Budget Experiment (ERBE) S4 scanner satellite data (1985–1989). The model is able to predict the seasonal and geographical variation of SW TOA fluxes. On a mean annual and global basis, the model is in very good agreement with ERBE, overestimating the outgoing SW radiation at TOA (OSR) by 0.93 Wm-2 (or by 0.92%), within the ERBE uncertainties. At pixel level, the OSR differences between model and ERBE are mostly within ±10 Wm-2, with ±5 Wm-2 over extended regions, while there exist some geographic areas with differences of up to 40 Wm-2, associated with uncertainties in cloud properties and surface albedo. The 14-year average model results give a planetary albedo equal to 29.6% and a TOA OSR flux of 101.2 Wm-2. A significant linearly decreasing trend in OSR and planetary albedo was found, equal to 2.3 Wm-2 and 0.6% (in absolute values), respectively, over the 14-year period (from January 1984 to December 1997), indicating an increasing solar planetary warming. This planetary SW radiative heating occurs in the tropical and sub-tropical areas (20° S–20° N), with clouds being the most likely cause. The computed global mean OSR anomaly ranges within ±4 Wm-2, with signals from El Niño and La Niña events or Pinatubo eruption, whereas significant negative OSR anomalies, starting from year 1992, are also detected.

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Ollila, Antero. "Radiative Forcing and Climate Sensitivity of Carbon Dioxide (CO2) Fine-tuned with CERES Data." Current Journal of Applied Science and Technology 42, no. 46 (December 5, 2023): 111–33. http://dx.doi.org/10.9734/cjast/2023/v42i464300.

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An updated effective radiative forcing (ERF) value for constructing a simplified logarithmic forcing equation, and a transient climate response (TCR) value, are presented for CO2, CH4, and N2O. The results are based on line-by-line (LBL) calculations utilizing the HITRAN database and the CERES radiation flux data for fine-tuning. The ERF value derived when doubling the CO2 concentration from 280 ppm (2xCO2) is 2.65 Wm-2 which is in line with the instantaneous radiative forcing (IRF) values of climate models referred to by the IPCC. The difference between the ERF values comes from the stratospheric cooling effect. It is a question about an essential paradigm change of the IPCC approach. In the former 2xCO2 value of 3.7 Wm-2, its portion was about 5 %, and in the present value, it is about 30 %. According to this study, the same effect is 10 %. The updated TCR value is 0.7 ±0.15 °C.

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Durot, Eric, Cecile Tomowiak, Anne-Sophie Michallet, Jehan Dupuis, Stephane Lepretre, Elise Toussaint, Sophie Godet, et al. "Retrospective Analysis of 56 Cases of Transformed Waldenström Macroglobulinemia. a Study on Behalf of the French Innovative Leukemia Organization (FILO)." Blood 128, no. 22 (December 2, 2016): 2982. http://dx.doi.org/10.1182/blood.v128.22.2982.2982.

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Abstract Introduction : Histologic transformation (HT) to an aggressive non-Hodgkin lymphoma is a well-described event in the natural history of patients with indolent lymphomas, mainly follicular lymphomas and chronic lymphocytic leukemia/small lymphocytic lymphoma. HT has been reported also in lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) but only case reports or small patients series are available. Material and methods : We retrospectively searched the databases of 14 French and Belgian centers for patients with sequential or simultaneous diagnosis of LPL/WM and diffuse large B-cell lymphoma (DLBCL). Fifty-six patients (39 men and 17 women) were analyzed of whom 8 had simultaneous diagnosis of LPL/WM and DLBCL. At the time of diagnosis of LPL/WM, the median age was 65 years (range, 33-85 years). Thirty-one percent of patients presented lymphadenopathy and 27% splenomegaly. The median level of serum monoclonal IgM was 17.7 g/L (range, 2.3-66.7 g/L). The IPSSWM was available for 32 patients : 12 (38%) were low, 13 (40%) were intermediate and 7 (22%) were high-risk. At time of HT, 3 patients were previously untreated for WM. The median number of therapies for WM was 2 (range, 0-5), including chlorambucil (60%) and fludarabine-based regimens (48%). Only half of the patients were exposed to rituximab. The median time from LPL/WM diagnosis to HT for patients with sequential diagnosis (n = 48) was 59 months (range, 4-300 months). At time of transformation, 32 patients (57%) presented altered ECOG performance status (≥ 2) and B symptoms were found in about half of the patients. Tumor mass higher than 5 cm and extranodal involvement were found in 54% and 95% of patients respectively. The median serum IgM level was 6.7 g/L (range, 0-40 g/L). Serum lactate deshydrogenase levels were elevated in 72% of cases. Histology was mainly represented by DLBCL, with only 2 cases described as B-cell lymphoma, intermediate between DLBCL and Burkitt lymphoma. In situ hybridization for EBER was negative in 17 of 18 informative cases. The median number of lines of therapy given for HT was 1 (range, 0-5). First-line treatment for HT consisted of CHOP-like regimen +/- rituximab in 47 patients (85%). Five patients (9%) received DHAP association and 3 (5%) GEMOX due to cerebral involvement and/or previous CHOP-exposure. Rituximab was part of the first-line treatment for HT in 49 patients (89%). Six patients underwent autologous stem cell transplantation (SCT) and 3 allogeneic SCT. The overall response rate after first-line treatment for HT was 55% (complete response, 45%) and the median progression-free survival and overall survival after HT were 18 and 25 months respectively. The majority of deaths were attributed to disease progression (75%) or infections (18%). Conclusion : HT appears to be a critical event in the clinical course of patients with LPL/WM, associated with poor outcome. Risk factors for developing DLBCL and molecular pathogenesis of transformation in patients with LPL/WM remain to be studied. Disclosures Dupuis: janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Leblond:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Yu, Ying, Yuting Yan, Jun Wang, Wenjie Xiong, Yao Yao, Yanshan Huang, Rui Lyu, et al. "The Incidence, Clinical Application and Prognostic Significance of MYD88 and CXCR4 Mutation in Chinese Patients with Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 6089. http://dx.doi.org/10.1182/blood-2023-188786.

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Introduction Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare B-cell lymphoma with prevalent somatic mutations, including MYD88 and CXCR4. However, their mutation rates in Chinese LPL/WM and the comparison of different detection methods remain unclear. Moreover, the clinical implications of MYD88 and CXCR4 mutations in the immunochemotherapy and targeted therapy eras need exploration. Methods This study included 458 LPL/WM patients (418 WM, 40 non-IgM LPL) from December 2014 to June 2023. Four methods, such as Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and droplet digital polymerase chain reaction (ddPCR), were used to detect MYD88L265P and CXCR4 mutations. Demographic data, clinical characteristics, tumor burden, cytogenetic abnormalities, treatment regimens, and survival data were collected. Results A total of 458 patients were assessed for MYD88 L265P mutation, of whom 266 were tested by Sanger sequencing, 300 by NGS, 370 for AS-PCR, 251 for ddPCR. The MYD88 L265P mutation was found in 398/458 (86.9%) of the patients. AS-PCR and ddPCR showed the highest sensitivity (97.2% and 96.5%, respectively), outperforming Sanger sequencing and NGS, which had higher false-negative rates in low tumor load patients. A high false-negative rate for MYD88 by Sanger sequencing and NGS was observed in patients with tumor burden less than 10% (40.0% and 21.9% respectively). There was no significant difference in the MYD88 mutation rate detected by ddPCR and ASPCR among patients with different tumor burden groups (P=0.402, P=0.252). MYD88 mutation was detected in a high incidence of 86.7% and 85.5% in less than 1% infiltrated WM tumor cells specimens by ddPCR and ASPCR. Thus, ddPCR and ASPCR assay were effective and accurate enough for un-sorted low infiltrated WM specimens. CXCR4 mutation testing was performed in 428 patients of LPL/WM, comprising 311 with Sanger sequencing, 300 with NGS, and 371 with AS-PCR. Overall, 31.8% (136/428) patients were identified as having the CXCR4 mutation. NGS exhibited the highest sensitivity (79.2%) among the three detection means. Among the 458 patients of LPL/WM, 60 (13.1%) were classified as MYD88 wild-type patients. MYD88 wild-type patients had a significantly lower hemoglobin levels (median 83g/L vs. 92g/L, P=0.044), lower proportion of males (56.7% vs. 72.5%, P=0.012) and a significantly higher proportion elevated β2-macroglobulin (81.5% vs. 68.5%, P=0.027), and lactic dehydrogenase (32.2% vs. 11.1%, P<0.001). However, there were no significant differences in either PFS or OS between MYD88 L265P wild-type and MYD88 L265P mutation group (PFS: median 35.7 months vs. 52.9 months, P=0.40; OS: 5-year rate 72.0% vs. 81.8%, P=0.62). MYD88 wild-type patients had worse PFS and post-BTKi failure-free survival under immunochemotherapy (median 34.3 months vs. 58.4 months, P=0.03), and BTKi regimens (median: 26.2 months vs. 45.2 months, P=0.02), respectively. Patients with CXCR4 mutation tended to be older (median 64 vs. 60, P=0.001), had lower hemoglobin levels (median 83g/L vs. 94g/L, P=0.008), and higher baseline BM involvement (by FCM, median 12.6% vs. 6.2%, P<0.001) compared with CXCR4 wild-type patients. The proportion of patients with thrombocytopenia (43.7% vs. 20.6%, P<0.001), serum IgM level more than 40g/L (47.4% vs. 34.6%, P=0.019) was significantly higher, the proportion of patients with low risk profile of IPSSWM (17.2% vs. 30.5%, P=0.007) was significantly lower in mutation group. Notably, CXCR4 mutation group had significantly worse survival compared with the wild-type group (PFS: median 40.5 months vs. 62.5 months, P=0.024; OS: median 103.8 months vs. not reached, P=0.022). Meanwhile, patients with CXCR4 mutation experienced inferior post-BTKi failure-free survival (median 30.4 months vs. 57.6 months, P=.04) and post-BTKi overall survival (3-year rate 71.9% vs. 84.9%, P=0.03) in BTKi therapy groups. Conclusions This study sheds light on MYD88 and CXCR4 mutations in Chinese WM/LPL based on a large cohort. AS-PCR and ddPCR were highly sensitive for MYD88 mutation detection, especially in low infiltrated WM. NGS was the most sensitive method for detecting CXCR4 mutation. MYD88 mutation had prognostic significance in BTKi-based therapy, while CXCR4 mutation indicated higher tumor burden and inferior survival in BTKi-based therapy.

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Tsakmaklis, Nickolas, Zachary R. Hunter, Xia Liu, Amanda Kofides, Shirong Liu, Alexa G. Canning, Kris Richardson, et al. "Quantitative MYD88 L265P Analysis Represents a Powerful Tool for Assessing Disease Response and Evaluating Clinical Trial Performance in Waldenstrom's Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 211. http://dx.doi.org/10.1182/blood-2023-190520.

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Serum IgM measurements represent the current standard for assessing changes in disease burden in Waldenström's Macroglobulinemia (WM). Many agents used to treat WM can significantly affect serum IgM levels without impacting the underlying burden of clonal lymphoplasmacytic cells thereby producing discordant findings. Such agents can raise (CD20-directed monoclonal antibodies, IMiDs), or lower (BTK-, proteasome-, MTOR- inhibitors) serum IgM levels, and impact categorical response assessment. Somatic mutations in MYD88 are found in 95-97% of WM patients, and support tumor growth through activation of multiple pro-survival pathways that include HCK/BTK, SYK and ERK. Nearly all MYD88 mutations in WM are of the L265P variant. Previous studies by us and others have shown that serial quantitative measurements of both bone marrow (BM) and peripheral blood (PB) MYD88 L265P (c.978 T>C) by allele-specific PCR can be used to assess changes in underlying BM disease burden (Blood 121:2051-2058; Leukemia 28:1698-1704). However, the utility of using quantitative allele-specific MYD88 L265P (qMYD88 L265P) analysis has not been studied in prospective clinical trials. As such, we performed a comprehensive study of qMYD88 L265P response assessment utilizing BM and PB CD19-selected tissue across 5 prospective clinical studies in WM: Ixazomib, Dexamethasone and Rituximab (IDR; NCT02400437) Ibrutinib monotherapy (IBR; NCT02604511); Venetoclax monotherapy (VEN; NCT02677324); Ibrutinib plus Ulocuplomab (IBR/ULO; NCT03225716); and Ibrutinib plus Venetoclax (IBR/VEN; NCT04273139). Changes in MYD88 L265P ΔCt were assessed as reported above with ΔCt = Mutant Ct - Wild-type Ct, and higher ΔCt values indicating a lower mutant allele burden, with each ΔCt unit reduction representing a 50% decrease in mutant MYD88 L265P burden. Changes in MYD88 L265P ΔCt were compared to changes in underlying BM disease burden and categorical response assessment using the current (IWWM-11) response criteria (Semin Hematol. 60:97-106). Across all five trials, BM (r=0.52; p<0.001) and PB (r=0.43; p<0.001) MYD88 L265P ΔCt changes from baseline were highly correlated at best response with corresponding changes in underlying BM disease burden determined by repeat BM biopsies. As shown in Fig. 1, comparing changes from baseline in BM MYD88 L265P ΔCt assessments across studies showed marked differences, with greatest reductions observed in patients treated with IBR/VEN, IDR, and VEN alone, than for those treated with IBR alone or IBR/ULO. Similar findings were also observed for corresponding PB MYD88 L265P ΔCt assessments from baseline, with changes in PB MYD88 L265P ΔCt strongly correlating with those of BM MYD88 L265P ΔCt findings across all 5 clinical trials (r=0.67; p<0.001), thereby signifying the ability to use PB MYD88 L265P ΔCt assessments to evaluate treatment responses. We next compared findings from BM and PB MYD88 L265P ΔCt to changes from baseline in serum IgM levels across all 5 trials. At best response, major categorical responses denoted by >50% reduction in serum IgM using IWWM-11 criteria showed commensurate decreases in BM and PB MYD88 L265P ΔCt from baseline in patients receiving IBR/VEN, IDR and VEN alone ( Fig. 2). In contrast, minimal changes in BM and PB MYD88 L265P ΔCt from baseline were observed at best response for most major responders on IBR or IBR/ULO, including individuals who achieved very good partial responses denoted by >90% decrease in IgM by IWWM-11 criteria. In this first prospective evaluation of BM and PB qMYD88 L265P response assessment, we show that both BM and PB L265P qMYD88 analysis can provide more accurate assessment of treatment related changes in disease burden over the current standard of IgM response assessment alone, and can be used to more robustly evaluate clinical trial performance byidentifying treatments or regimens that produce more meaningful tumor reductions in WM patients.

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Konishi, Yoshinobu, Romanos Sklavenitis-Pistofidis, Daniel L. Mallory, Ting Wu, Michelle P. Aranha, Junko Tsuji, Nicholas J. Haradhvala, et al. "Single-Cell RNA Sequencing Reveals Hypo-Responsiveness of T and NK Cells to Interferon Stimulation As an Immune Hallmark in Asymptomatic Waldenstrom's Macroglobulinemia." Blood 142, Supplement 1 (November 28, 2023): 2026. http://dx.doi.org/10.1182/blood-2023-186470.

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Introduction Waldenstrom macroglobulinemia (WM) is a rare, indolent non-Hodgkin lymphoplasmacytic lymphoma of the bone marrow (BM), characterized by monoclonal IgM protein production. WM is preceded by IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and smoldering WM (SWM), which are clinically detectable but asymptomatic precursor phases (collectively referred to as asymptomatic WM; AWM). Recent work has revealed significant changes in the immune microenvironment of patients with overt WM, however, less is known about immune dysregulation in patients with early-stage disease. Methods We performed 5' single-cell RNA sequencing (scRNAseq) on BM immune cells from patients with AWM (n=28), healthy donors (HD, n=23), and patients with smoldering multiple myeloma (SMM) (n=27). We also performed an in vitro stimulation experiment using universal Type I interferon (IFN) and subsequent scRNAseq on bone marrow mononuclear cells (BMMCs) and peripheral blood mononuclear cells (PBMCs) from AWM (n=3) and HD (n=3). Results Overall, we annotated 210,019 immune cells, excluding normal B cells. Despite their early stage, AWM patients showed significantly altered BM immune cell composition, including increased proportions of CD56dim NK cells, CD8+ effector memory cells, and CD16 + Monocytes and decreased proportions of pro-inflammatory CD14 + monocytes and activated and interferon (IFN)-stimulated T and NK cells (q<0.2). Low-risk AWM presented similar changes in immune cell composition as intermediate- and high-risk AWM, implying that compositional alterations may be established early in the disease course. Notably, however, the proportion of Tregs was significantly increased in patients with SWM compared to IgM MGUS (p=0.04), suggesting that Tregs may play a role in disease progression. Next, we compared BM immune cell composition between patients with AWM and SMM. In both tumor types, patients showed significantly higher proportions of CD56dim NK cells and CD16 + monocytes compared to healthy donors. However, strikingly, a significant decrease in activated and IFN-stimulated T and NK cells was only observed in AWM, suggesting it may be a hallmark of disease. Comparison of BMMCs and PBMCs from patients with AWM following in vitro culture revealed that the lack of IFN-stimulated cells was systemic-in both BMMCs and PBMCs-although the effect was significantly more pronounced in BMMCs than PBMCs. Interestingly, while in vitro stimulation with Type I IFN resulted in the generation of IFN-stimulated T and NK cells in both HD and AWM, the levels of IFN stimulation did not entirely normalize, reproducing the gradient observed in the control samples without in vitro stimulation: AWM BM < AWM PB < HD BM. To test whether the observed defect was due to a lack of IFN in AWM, we next compared the gene expression profile of monocytes from AWM and HD, which revealed significantly higher activity of the IFN signature in monocytes from AWM compared to HD (p < 10 -5). This suggests that IFN levels in patients are at least not reduced. Collectively, these results indicate that T and NK cells from AWM are hypo-responsive to IFN stimulation, despite the presence of normal or possibly increased IFN in the BM microenvironment. Conclusion Our results indicate that despite the absence of symptoms, patients with AWM already have immune dysregulation in the BM, including the absence of IFN-stimulated T and NK cells, which may provide a rationale for therapeutic intervention. Previous studies have demonstrated clinical responses to therapeutic IFN administration, suggesting that novel formulations with improved therapeutic windows may have a role in treating patients with WM in the future.

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Hunter, Zachary, Evdoxia Hatjiharissi, Jenny Sun, Yang Cao, Hsiuyi Tseng, Megan Lewicki, Lian Xu, et al. "Gene Expression Profiling Distinguishes Waldenstrom's Macroglobulinemia Patients Presenting with Familial Disease, Advanced IPSS Prognostic Score, and Previous Treatment with Rituximab." Blood 114, no. 22 (November 20, 2009): 3930. http://dx.doi.org/10.1182/blood.v114.22.3930.3930.

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Abstract Abstract 3930 Poster Board III-866 Background The use of gene expression profiling (GEP) was used to dissect the molecular profile of Waldenstrom's macroglobulinemia. Bone marrow CD19+ cells from 22 WM patients and 8 healthy donor (HD) were used in these studies, with application of analytics geared toward non-normally distributed data. Patient characteristics were as follows: median age 64 years; bone marrow disease involvement 35%; serum IgM 3,295 mg/dl; beta-2 microglobulin (B2M) 2.7 mg/L; WM ISS Prognostic Score 2. Four patients (18%) previously received rituximab, and 4 (18%) patients had a family history of WM and/or related B-cell disorders. Materials and Methods GEP was performed using the Affymetrix U133 plus 2 platform on CD19+ selected, CD138 depleted bone marrow cells. Array quality checks, normalization, and unsupervised hierarchical clustering were conducted using dChip (Li and Wong 2001 PNAS). These results were then used for further analysis via custom perl scripts that used 10,000 resampled groups to calculate bootstrap percentile based 95% confidence intervals (CI) for both mean and median values. Comparisons between groups were evaluated using approximate permutation testing. To help identify potential biomarkers, absence/presence calls from DCHIP based on the perfect match vs. mismatch comparisons were tabulated for each group and the contingency table resulting from group comparisons were analyzed using a Fisher's exact test. A gene was considered significant if 50% of its probes displayed at least a 2-fold change, mutual exclusion of means/median values and respective 95% CI, and p < 0.01 for both mean and median comparisons. This data was then compared with dChip clustering results and analyzed using Ingenuity Pathway Analysis (Ingenuity Systems). Results Significantly down regulated genes included DLL1 (-13.5 fold, expressed 0% WM vs. 88% HD, P<0.0001), LILRB5 (-13.9 fold expressed in 5% WM vs. 62% HD, P=0.003), MXD1 (-10.3 fold), FOSL2 (-8.8 fold), CXCL12 (-8.0 fold), and ATF3 (-7.5 fold). Up-regulated genes included a number of G-protein coupled receptors including LPAR5 (+7.3 fold), CYSLTR1 (+6.8 fold), and GPER (+16 fold). Other genes of interest included TLR9 (+3.9 fold), TLR10 (+2.8 fold), along with several anti-viral proteins including RANSEL (+6.9 fold), OAS1 (+7.8 fold), and OAS2 (+2.3 fold). Subgroup analysis revealed an up regulation of GP5 (+3.5 fold), LHX1 (+3.3 fold), ERG1 (+3.2 fold), FZD1 (+2.6 fold), and EFNB2 (+2.2 fold) in patients with a family history of WM and/or related B-cell disorders. For those with a high ISS score (≥3), we observed differences in WNT5A (+5.04 fold), CXCL12 (+3.5 fold), NOTCH4 (-2.6 fold) and IL2RA (-2.6 fold). Lastly, WM patients previously treated with rituximab displayed increased expression of BTG2 (+2.3 fold), MCL2 (+2.5 fold), and ARMCX2 (+5.5 fold). Conclusions The results of these studies demonstrate differential expression of several novel genes in WM including g protein coupled receptors and genes involved in interferon signaling. Importantly, these studies demonstrate for the first time differential expression of several gene candidates involved in B-cell differentiation that distinguish sporadic versus familial WM. Moreover, GEP revealed a unique profile for patients presenting with poor prognostic disease. Lastly, these studies reveal the up-regulation of 2 tumor suppressor genes, and the anti-apoptotic gene MCL-2 in WM patients treated with rituximab. The findings of these studies therefore have important implications in the pathogenesis, prognostication and treatment of WM. Disclosures: No relevant conflicts of interest to declare.

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Pavlakis, K. G., D. Hatzidimitriou, C. Matsoukas, E. Drakakis, N. Hatzianastassiou, and I. Vardavas. "Ten-year global distribution of downwelling longwave radiation." Atmospheric Chemistry and Physics Discussions 3, no. 5 (October 13, 2003): 5099–137. http://dx.doi.org/10.5194/acpd-3-5099-2003.

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Abstract. Downwelling longwave fluxes, DLFs, have been derived for each month over a ten year period (1984–1993), on a global scale with a resolution of 2.5° × 2.5°. The fluxes were computed using a deterministic model for atmospheric radiation transfer, along with satellite and reanalysis data for the key atmospheric input parameters, i.e. cloud properties, and specific humidity and temperature profiles. The cloud climatologies were taken from the latest released and improved International Satellite Climatology Project D2 series. Specific humidity and temperature vertical profiles were taken from three different reanalysis datasets; NCEP/NCAR, GEOS, and ECMWF (acronyms explained in main text). DLFs were computed for each reanalysis dataset, with differences reaching values as high as 30 Wm−2 in specific regions, particularly over high altitude areas and deserts. However, globally, the agreement is good, with the rms of the difference between the DLFs derived from the different reanalysis datasets ranging from 5 to 7 Wm−2. The results are presented as geographical distributions and as time series of hemispheric and global averages. The DLF time series based on the different reanalysis datasets show similar seasonal and inter-annual variations, and similar anomalies related to the 86/87 El Niño and 89/90 La Niña events. The global ten-year average of the DLF was found to be between 342.2 Wm−2 and 344.3 Wm−2, depending on the dataset. We also conducted a detailed sensitivity analysis of the calculated DLFs to the key input data. Plots are given that can be used to obtain a quick assessment of the sensitivity of the DLF to each of the three key climatic quantities, for specific climatic conditions corresponding to different regions of the globe. Our model downwelling fluxes are validated against available data from ground-based stations distributed over the globe, as given by the Baseline Surface Radiation Network. There is a negative bias of the model fluxes when compared against BSRN fluxes, ranging from −7 to −9 Wm−2, mostly caused by low cloud amount differences between the station and satellite measurements, particularly in cold climates. Finally, we compare our model results with those of other deterministic models and general circulation models.

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Kanan, Sandra, Kirsten Meid, Steven P. Treon, and Jorge J. Castillo. "Clinical Characteristics of Rituximab Intolerance in Patients with Waldenstrom's Macroglobulinemia." Blood 124, no. 21 (December 6, 2014): 2610. http://dx.doi.org/10.1182/blood.v124.21.2610.2610.

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Abstract Introduction: Rituximab is a chimeric anti-CD20 monoclonal antibody used for the treatment of both untreated and previously treated patients with Waldenström’s Macroglobulinemia (WM). Rituximab is often associated with infusion-related reactions (IRR) during the first infusion which is associated with a well described cytokine release syndrome. Rituximab is also associated with depletion of uninvolved immunoglobulins leading to symptomatic hypogammaglobulinemia associated with recurring infections in many patients. IRRs and hypogammaglobulinemia are common reasons for rituximab dicontinuation in patients with WM. In this study, we present data on WM patients who developed intolerance to rituximab defined as cessation of rituximab therapy outside of infusion related first-cycle IRRs, and symptomatic hypogammaglobulinemia. Methods: We performed a retrospective chart review within the clinical database of our center for patients with the consensus clinicopathological diagnosis of WM between 1996 and 2013, and for whom rituximab therapy was prematurely truncated. We excluded patients who experienced first-cycle IRRs and patients in whom rituximab was stopped due to symptomatic hypogammaglobulinemia. Clinical and laboratory data were collected and tabulated, and are presented using descriptive statistics. Results: From a database of 1,600 patients with WM, we have so far identified 40 WM patients who were considered intolerant to rituximab. The median age at WM diagnosis for these patients was 60.5 years (range 35-83 years). There was a male predominance of 2:1. The median number of therapies prior to becoming rituximab intolerant was 1 (range 0-5 lines). Fifty percent of patients were not previously exposed to rituximab. Fifty-three percent of patients became rituximab intolerant while receiving single agent rituximab, 18% while receiving bortezomib-based therapy, 15% while receiving cyclophosphamide-based therapy and 8% while receiving bendamustine-based therapy. Forty percent of patients developed rituximab intolerance while undergoing induction therapy, and the remaining 60% became intolerant during the maintenance phase. The most common reasons for stopping rituximab were fever, chills, facial swelling, shortness of breath, hypotension, back pain, hives, chest pain, and serum sickness-like symptoms. The median serum IgM prior to development of rituximab intolerance was 3,053 mg/dl (range 550-9,000 mg/dl), the median hemoglobin was 10.4 g/dl (8.2-14.5 g/dl), the median platelet count was 300 x 109/L (range 93-913 x 109/L), and the median bone marrow involvement was 35% (range 5-90%). Twenty-one percent of patients had familial WM, and 65% of patients were responding torituximab-based therapy at the time of intolerance. Importantly, 20% percent (n=8) of patients received ofatumumab, a fully human anti-CD20 monoclonal antibody, after developing rituximab intolerance, of whom 7 (87%) subsequently tolerated ofatumumab without incidence. Conclusions: We present data on 40 WM patients who became intolerant to rituximab outside of the context of first-cycle IRRs, and symptomatic hypogammaglobulinemia. Our study shows that rituximab can be associated with a variety of symptoms that prompt cessation of therapy, and that most patients show a response to therapy despite intolerance. The use of ofatumumab is feasible and well tolerated in WM patients intolerant to rituximab. Additional research is needed to better understand the pathophysiology behind rituximab intolerance in this patient population. Data collection continues. Disclosures No relevant conflicts of interest to declare.

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Journal articles on the topic 'Wm 203.5'

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