Citations

AbstractThe World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering, SM with an associated hematological neoplasm (SM‐AHN), aggressive (ASM) and mast cell leukemia (MCL). Recent studies have highlighted the prognostic importance of mutations in SM, including ASXL1, RUNX1, and SRSF2. In contrast, information on incidence of cytogenetic abnormalities in SM and their prognostic relevance, especially in the context of mutations, is limited. In the current study, we retrospectively reviewed the cytogenetic findings in 348 consecutive cases of SM (median age 59 years; 53% males); 41% constituted ISM, 45% SM‐AHN, 14% ASM and two cases of MCL. Karyotype was abnormal in 53 (15%) cases with incidences of 6% for ISM, 26% for SM‐AHN and 8% for ASM (P < .001); among SM‐AHN cases, abnormal karyotype incidences were 0% for SM‐AHN‐lymphoid and 28% for SM‐AHN‐myeloid (P < .001). Clinical correlative studies disclosed significant associations between abnormal karyotype and male sex (P = .002), age > 60 years (P = .04), thrombocytopenia (P < .001) and anemia (P < .001), but not with the presence of adverse mutations (P = .19). In univariate analysis, abnormal karyotype was associated with inferior survival (HR 3.0, 95% CI 2.0‐4.3), specifically confirmed for ASM (HR 4.9, 95% CI 1.1‐16.1) and SM‐AHN (HR 1.8, 95% CI 1.2‐2.7). Sample size adequacy allowed additional multivariable analysis in SM‐AHN‐myeloid, which disclosed independent prognostic contribution from adverse mutations (P = .003), anemia (P = .003) and thrombocytopenia (P = .001), but not from abnormal karyotype (P = .31). Our observations suggest that mutations are prognostically more relevant than karyotype in SM.

There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor–based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.

Abstract CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in &lt;1% of NC participants across all assays (representing potential undiagnosed cancers). An increasing trend was observed in NC vs stages I-III vs stage IV (nonsyn. SNVs/indels per Mb [Mean±SD] NC: 1.01±0.86, stages I-III: 2.43±3.98; stage IV: 6.45±6.79; WGS score NC: 0.00±0.08, I-III: 0.27±0.98; IV: 1.95± 2.33; methylation score NC: 0±0.50; I-III: 1.02±1.77; IV: 3.94±1.70). These data demonstrate the feasibility of achieving &gt;99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.

Abstract Introduction: Hyperdiploidy on FISH portends a good prognosis in myeloma. We compared hyperdiploidy determined by MFC to that by conventional FISH. Methods: We studied 1711 patients with plasma cell disorders who had simultaneous FISH and DNA index testing. Monotypic plasma cells in bone marrow are identified by MFC with antibodies to CD19, CD38, CD45, CD138, kappa and lambda; followed by staining by DAPI. DNA index is determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. Plasma cells with DNA content index of &lt;0.95 are hypodiploid and G0/G1 DNA content index of &gt;1.05 are considered hyperdiploid. Results: Distribution DNA index and FISH results are described in Table 1. Sensitivity and specificity of DNA index by hyperdiploidy was 86% and 83%. Cohen's Kappa coefficient for concordance was 0.69. Sensitivity increased to 94% for those with 2 or more trisomies and 97% for 3 or more trisomies. Of the 104 patients with trisomy and non-hyperdiploid DNA index, 62% patients had monosomy (mono) or deletion (del) 13q. Overall, DNA index was lower in patients with mono 13/del 13q (1.01; 0.97-1.11) compared to those without (1.07; 1.0-1.19), p&lt;0.001. After excluding patients with mono 13/del 13q, sensitivity and specificity of hyperdiploidy by DNA index were 92% and 82%, kappa = 0.73. Hyperdiploidy was seen in 55% of 272 patients with newly diagnosed myeloma. Sensitivity and specificity were 88% and 93%, kappa = 0.78. After median follow-up of 2.3 yrs, those with hyperdiploid DNA index had better progression free survival at 2,3 and 5 years, 62%, 45% and 21% compared to 50%, 33% and 13% in non-hyperdiploid group, p=0.05. Median overall survival (OS) was not reached; estimated 2, 3 and 5 year OS was 83%, 76% and 63% vs. 76%, 64% and 44%, respectively; p=0.08. Conclusions: DNA index by MFC is a rapid method to determine hyperdiploidy, with potential for replacing trisomy testing by FISH, especially when coupled with monosomy FISH probes. Hyperdiploid N=768 n/N (%)Diploid N=762 n/N (%)Hypodiploid N=78 n/N (%)P1P2Any trisomy 619/765 (81)96/758(13)8/76 (11)&lt;0.001&lt;0.001One chromosome42587733191429-111362Others12204Two chromosomes8525-Three or more chromosomes492131Any translocation124/744 (17)566/748 (76)53/74 (72)&lt;0.001&lt;0.001t(4;14)106313t(11;14)2240127t(14;16)5325t(14;20)38-t(6;14)8104Unknown partner76524Trisomy + Translocation95/743 (13)60/744 (8)6/74 (8)0.0090.002Monosomy 13/17 or deletion 13q/17p252/759 (33)295/744 (40)54/74 (73)&lt;0.0010.0001Monosomy 13/Deletion 13q208/717 (29)282/718 (39)20/70 (29)Monosomy 17/Deletion 17p70/749 (9)50/735 (7)20/72 (28)P1= three groups; P2= hyperdiploid vs. non-hyperdiploid Citation Format: Surbhi Sidana, Nidhi Tandon, Dragan Jevremovic, Rhett P. Ketterling, Angela Dispenzieri, Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, William Morice, Curtis A. Hanson, Michael Timm, Patricia Greipp, Linda B. Baughn, David Dingli, Suzanne R. Hayman, Wilson I. Gonsalves, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A. Lust, S.Vincent Rajkumar, Shaji K. Kumar. Hyperdiploidy in plasma cell disorders using multi-parametric flow cytometry (MFC) vs. FISH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 655.

Abstract Introduction: CLL phenotype (CD5+CD23+CD20dim) MBL is present in 5-10% of the general population. The prevalence and outcomes of adults with non-CLL like MBL (including CD5+CD23-, CD5+CD20bright, and CD5-) are not known. We screened for MBL using highly sensitive flow-cytometry in a clinic-based cohort of adults from the Mayo Clinic Biobank. Methods: The Mayo Clinic Biobank is a large scale bio-repository of 50,000 adults seen in primary care-based clinics. Herein, we focused on those adults ≥40 years who had stored peripheral blood mononuclear cells available (10% of the overall cohort). We screened for MBL using an 8 color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow cytometry assay validated to detect clonal B-cell events to the 0.005% level (1/20,000 events). Chi-square tests were used to assess associations with demographic characteristics. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for death. Results: A total of 2594 adults were screened; their median age was 63 years (range, 40-96) and 1111 (43%) were male. 2445/2594 (94%) individuals had interpretable flow cytometry results. A total of 336 (14%) individuals had MBL identified, of whom 276 (82%) had CLL-like MBL and 60 (18%) had non-CLL like MBL (including 39 adults with CD5- and 21 with CD5+CD23- or CD5+CD20 bright phenotype). A strong association between age and the prevalence of non-CLL like MBL was observed, with 0/278 (0%) in 40-49 years, 6/613 (1%) in 50-59 years, 20/674 (3%) in 60-69 years, 21/490 (4%) in 70-79 years, and 13/114 (11%) ≥80 years demonstrating non-CLL like MBL (p&lt;0.001). Non-CLL like MBL was more common in men compared to women (5% vs. 1%; p&lt;0.001). Compared to adults with no MBL, a higher proportion of non-CLL like MBL had a first-degree relative with a lymphoproliferative disorder (8% vs. 17%; p=0.03), and prior non-hematologic cancer (22% vs. 38%, p=0.006). The remainder of the present analysis is focused on adults with non-CLL like MBL (n=60). After a median follow-up of 5 years (range 0-8 years), 3/60 (5%) adults with non-CLL like MBL developed a hematologic malignancy (one myelodysplastic syndrome, two mantle cell lymphoma) compared to 5/2109 (0.2%) adults with no MBL (two large cell lymphoma, one multiple myeloma, one acute myeloid leukemia, one myelofibrosis). Among adults with non-CLL like MBL, the estimated 7-year overall survival (OS) was 79% compared to 94% in those with no MBL (p&lt;0.001, HR for death 3.8, 95% CI 1.98-7.3). After adjusting for age, sex, and self-reported prior non-hematologic cancer, the HR for death was 1.50 (95% CI 0.74-3.05, p=0.26). Conclusion: In this large study, ~1 of 40 adults seen in a primary care setting had non-CLL like MBL. The prevalence of the non-CLL phenotype MBL increased with age. With current follow-up, the risk of progression to an overt lymphoproliferative neoplasm appears to be low. Citation Format: Sameer A. Parikh, Sara J. Achenbach, Kari G. Chaffee, Neil E. Kay, Connie E. Lesnick, James R. Cerhan, Curtis A. Hanson, Tait D. Shanafelt, Susan L. Slager. The prevalence of non-chronic lymphocytic leukemia (CLL) phenotype monoclonal B-cell lymphocytosis (MBL) in a population-based cohort of U.S. adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3256.

SummaryThe effects of ibrutinib on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukaemia (CLL) patients treated in routine clinical practice require further investigation. Using the Mayo Clinical CLL Database, 193 CLL patients treated with ibrutinib between November 2013 and January 2017 outside the context of a clinical trial were identified; complete review of their medical records was performed for details of past history of AIC and treatment‐emergent AIC. We identified 29/193 (15%) patients with history of AIC prior to ibrutinib start. Of 12 patients requiring AIC therapy at ibrutinib start, 8 (67%) were able to discontinue or de‐escalate AIC treatment, and no patient had worsening of their AIC after initiating ibrutinib. Eleven (6%) patients developed treatment‐emergent AIC after a median of 59 (range, 6–319) days following the initiation of ibrutinib, 7 of whom (64%) were able to continue ibrutinib. Overall and event‐free survival from time of ibrutinib start were not significantly different between patients with history of AIC and those with no history of AIC. Treatment‐emergent AIC were seen exclusively in patients with unmutated IGHV and were associated with a shorter EFS. These results suggest a low rate of treatment‐emergent AIC and improvement in patients with existing AIC.

We consider the problem of model‐based clustering in the presence of many correlated, mixed continuous, and discrete variables, some of which may have missing values. Discrete variables are treated with a latent continuous variable approach, and the Dirichlet process is used to construct a mixture model with an unknown number of components. Variable selection is also performed to identify the variables that are most influential for determining cluster membership. The work is motivated by the need to cluster patients thought to potentially have autism spectrum disorder on the basis of many cognitive and/or behavioral test scores. There are a modest number of patients (486) in the data set along with many (55) test score variables (many of which are discrete valued and/or missing). The goal of the work is to (1) cluster these patients into similar groups to help identify those with similar clinical presentation and (2) identify a sparse subset of tests that inform the clusters in order to eliminate unnecessary testing. The proposed approach compares very favorably with other methods via simulation of problems of this type. The results of the autism spectrum disorder analysis suggested 3 clusters to be most likely, while only 4 test scores had high (>0.5) posterior probability of being informative. This will result in much more efficient and informative testing. The need to cluster observations on the basis of many correlated, continuous/discrete variables with missing values is a common problem in the health sciences as well as in many other disciplines.