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Background and Aims Portopulmonary hypertension (POPH) was previously associated with a single‐nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Approach and Results We performed a multicenter case‐control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn‐sec/cm−5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome‐wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12‐4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2‐hydroxyestrogen/16‐α‐hydroxyestrone (OR per 1‐ln decrease = 2.04; 95% CI, 1.16‐3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone‐sulfate (OR per 1‐ln decrease = 2.38; 95% CI, 1.56‐3.85; P < 0.001), and higher plasma levels of 16‐α‐hydroxyestradiol (OR per 1‐ln increase = 2.16; 95% CI, 1.61‐2.98; P < 0.001) were associated with POPH. Conclusions Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Abstract Background: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. Methods: A case–control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Results: Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03–1.54, Ptrend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02–1.28), but the association was restricted to cases with treatment-naïve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16–1.96, Ptrend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08–1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87–1.39, Ptrend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94–1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. Conclusions: Treatment-naïve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. Impact: Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.

Abstract BACKGROUND: The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients who have a circulating population of clonal B-cells, a total B-cell count of &lt;5 x 109/L, and no other features of another B-cell lymphoproliferative disorder. In most patients the immunophenotype is similar to that of chronic lymphocytic leukemia with co-expression of CD19 and CD5. The natural history of CLL-phenotype MBL is unclear. We used the Mayo Clinic hematopathology database to identify patients with CLL-phenotype MBL and abstracted clinical information on natural history and prognostic parameters from clinical and research records. METHODS: Using hematopathology records, we identified a cohort of 1820 patients seen at Mayo Clinic between August 1998 and May 2006 who underwent investigation using peripheral blood flow cytometry and who were found to have a clonal B-cell population of CLL phenotype. After elimination of patients with advanced stage (Rai I-IV), previously treated CLL, and individuals with an established diagnosis of CLL/MBL &gt;1 year prior to flow, 636 unique patients with isolated lymphocytosis were identified. Based on our prior analysis (Leukemia Research 32:1458) demonstrating that nearly all patients with an ALC &gt;10x109/L have a B-cell count &gt;5x109/L, we focused the remaining analysis on the 405/636 patients who had an ALC &lt;10x109/L and the necessary raw data from flow cytometry analysis to determine the B-cell count. RESULTS: Among the 405 individuals with an ALC &lt;10x109/L, 306 (76%) had a B-cell count &lt;5x109/L at the time of flow and met the current criteria for the diagnosis of MBL (BJH 130:325). Median age at the time of MBL diagnosis was 70 years (range 34 – 93). A slight male preponderance was observed (59% male). B-cell counts ranged from 0.02 to 4.99x109/L and ALC ranged from 0.3–9.6 x109/L. CD38 status was available for 268 (88%) MBL patients of whom 20% were CD38 positive using the 30% threshold. Cytogenetic analysis by fluorescent in situ hybridization (FISH) was available in 130 (42%) MBL patients. Using the hierarchical classification system of Dohner and colleagues, 57 (44%) were 13q-, 23 (18%) were trisomy 12, 5 (4%) were 11q-, 4 (3%) were 17p-, and 39 (30%) had no defect detected. ZAP-70 status was available for 77 (25%) patients of whom 13% were ZAP-70+ positive. Patients underwent sequential monitoring with a median follow-up of 1.7 yrs (range 0–8.1 yrs). Time from diagnosis to treatment for patients meeting criteria for MBL (n=306) as compared to Rai stage 0 CLL patients with B-cell counts between 5.0 and 10.0 x109/L (n=99) was not significantly different and is shown in Figure 1 (p=0.87). For individuals with MBL, survival free of treatment was 98% (95%CI: 96–100%) at 1 year, 93% (95%CI: 89–98%) at 2 years, and 77% (95%CI: 67–89%) at 5 years. While gender (p=0.10), and B-cell count as a continuous variable (p=0.15) were not found to be associated with time to treatment (TTT) among MBL patients, age (p=0.02, HR=0.94, 95% CI: 0.89–0.99) and CD38 status (p&lt;0.02, HR: 3.3, 95% CI: 1.2–9.2) did show a relationship with TTT. CONCLUSIONS: Although we observed a low rate of progression among individuals meeting criteria for MBL, TFS was similar to individuals meeting current criteria for Rai stage 0 CLL who had B-cell counts between 5.0 – 10.0 x109/L . Among individuals meeting criteria for MBL, younger patients and those who were CD38 positive had a shorter time to treatment. Additional studies are needed to determine what B-cell count or other characteristics should be used to distinguish between MBL and Rai stage 0 CLL. FIGURE: FIGURE:.

Abstract Figure Figure Background: An isolated 13q deletion in patients with chronic lymphocytic leukemia (CLL) is the single most common cytogenetic abnormality and is a favorable prognostic parameter (Dohner et al., NEJM3432:1910, 2000). Although 13q- can occur as either a heterozygous (13q-x1) or homozygous (13q-x2) deletion, it is unknown whether these two genetic types differ in their impact on clinical outcome. We previously postulated that 13q-x2 may be a more aggressive anomaly than 13q-x1 (Dewald et al., BJH121:287, 2003) and have undertaken a long-term clinical follow-up of patients with an isolated FISH detectable 13q- to test this hypothesis. Methods: We identified patients diagnosed with CLL between October 1992 to May 2008 and who had 13q deletion as their sole FISH abnormality. FISH was performed within 2 years of diagnosis and prior to treatment in all patients. Patients were sorted into three groups: 13q-x1 only, 13q-x2 only, or mosaic with both 13q-x1 and 13q-x2 cells. We assessed differences in percentage of abnormal cells, demographic characteristics, and clinical outcome among the three groups. Results: We identified 259 patients with isolated 13q deletion. Age ranged from 38 to 90 years (median=61) and included 99 women and 160 men. With respect to Rai stage, 142 patients (60%) had low risk [Rai 0], 81 (34%) intermediate risk [Rai I-II], and 13 (6%) high risk [Rai III-IV] disease. After a median follow-up of 1.9 years, 40 patients (15%) have been treated and 17 (7%) have died. Median TFS and OS for all patients were 6.9 and 9.3 years, respectively. The mean percentage of abnormal nuclei in the three groups was 44%, 53%, and 47% for 13q-x1 only, mosaic 13q-x1/13q-x2, or 13q-x2 only, respectively (p=0.22). No significant difference in age or gender was observed based on whether 13q- occurred as a heterozygous or homozygous deletion, or was mosaic. Likewise, no significant difference in survival (p=0.313, see Table) or time to treatment (p=0.53) was found among the three groups. Five year OS rates for the 13q- x1 only, 13q- x2 only, and mosaic 13q- x1/13q- x2 are 85%, 95%, and 83%, respectively Median time to treatment for 13q-x1 was not reached, and for the mosaic13q-x1/13q-x2 and 13q-x2 groups median time to treatment was 6.9 and 4.9 years, respectively. Conclusions: The presence of deletion in one versus two 13q- chromosomes in CLL patients appears to have no significant impact on treatment free or overall survival. This observation supports the grouping of CLL patients with isolated 13q- of one or both alleles into a single risk category as originally proposed in the risk categorization by Dohner et al. Taking the present findings together with those of Dohner et al and Dewald et al, we propose a hierarchical risk model of FISH abnormalities in CLL as 17p- à 11q- à 6q- à +12 à normal à 13q-, from most to least aggressive. The 13q- group would now include 13q-x1, 13q-x2, and the mosaic subgroups.

Abstract Background: The biology, pathology and clinical course of CD5+ chronic B cell lymphoproliferative disorders (CD5+ B-CLPD) excluding chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and mantle cell lymphoma (MCL) are poorly defined. These patients could either have a leukemic variant of a known B cell malignancy or a novel disease entity. Objective: To define the clinical features and pathology of CD5+ B-CLPD, compare these features to CLL, and test the hypothesis that at least some of these patients have a unique B cell malignancy. Methods: The study was conducted with Institutional Review Board permission. We studied 231 patients evaluated in the Division of Hematology at Mayo Clinic Rochester between 1996 and 2008 who had CD5+ monoclonal B cell population in the peripheral blood and/or bone marrow, and in whom CLL and MCL was not diagnosed after flow cytometry, histology and interphase fluorescence in situ hybridization (FISH) examinations. Data were abstracted from patient records and from the Mayo Clinic CLL database. Statistical analysis: To compare differences in characteristics between CD5+ and CLL patients, χ2 statistics were used for qualitative variables (gender, treatment, vital status) and t-tests were used for quantitative variables (age). We performed survival and time to treatment analyses with results displayed using Kaplan-Meier curves and p-values calculated using a log-rank test. Results: We analyzed data on 231 CD5+ B-CLPD patients diagnosed between 7/1/1976 and 5/2/2008 and 1572 CLL patients diagnosed in the same time period. Median follow-up from diagnosis was 2.5 years (range 0 to 25.1 years) for the CD5+ patients and 5.2 years (range 0 to 29.9 years) for CLL patients. CD5+ B-CLPD patients had a median age at diagnosis of 68 years (range 30–94 years) with male predominance (61.5%). One hundred and nine of 231 (52.4%) patients received treatment for their CD5+ B-CLPD and 162 (70.1%) patients were alive at the time of last follow-up. As a group, CD5+ B-CLPD patients had a similar male predominance to CLL but were older at diagnosis. CD5+ B-CLPD patients required their first treatment significantly sooner than CLL patients (median 2.0 years vs. 6.8 years, (p&lt; 0.001) and a higher percentage of CD5+ B-CLPD patients required treatment (52.4% vs. 37.5%, p&lt;0.0001). In addition, CD5+ B-CLPD patients had a shorter survival from diagnosis than CLL patients (median 8.4 years vs. 12.5 years, p&lt;0.001). In 60 patients the CD5+ B-CLPD disease was the leukemic phase of a known lymphoma (lymphoplasmacytic lymphoma, n=34; nodal marginal zone lymphoma, n=6; splenic marginal zone lymphoma, n=16; MALT lymphoma, n=4), 46 patients had incomplete data, and 125 patients did not have pathological and flow cytometry features of a known lymphoid malignancy. Next we compared clinical outcome among the 125 patients with unclassifiable CD5+ B-CLPD to the CLL patients. The unclassifiable CD5+B-CLPD patients were older at diagnosis (median 69 vs. 65 years, p=0.0003) but there were no significant differences in time to treatment (median 9.0 years vs. 6.8 years, p=0.93) or the proportion of patients receiving treatment (30% vs. 37.5%, p=0.11). The survival from diagnosis was shorter for unclassifiable CD5+ B-CLPD patients (median 6.3 vs. 12.5 years, p&lt;0.001). Conclusions: In this large series of CD5+ B-CLPD patients we found that a large subset did not meet diagnostic criteria for known B-cell malignancies and could have a novel disease. This will need to be investigated further. We reviewed the pathology of all available archived tissue and intend to examine additional clinical and prognostic information including molecular prognostic markers. Our data provide a clinical rationale for the careful differentiation between patients with CLL and CD5+ B-CLPD.

Abstract Next‐generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL‐IPI) in newly diagnosed CLL and high‐count monoclonal B‐cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi‐stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time‐to‐first treatment (TTT), adjusted for CLL‐IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17‐1.39, P = 2.6 × 10 −8 ; c ‐statistic = 0.76). When stratified by CLL‐IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37‐1.72, P = 7.0 × 10 −14 ). Overall, 80% of low/intermediate CLL‐IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12‐2.07, P = .007; c ‐statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL‐IPI, especially among low/intermediate CLL‐IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.

AbstractMost patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Abstract To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV , 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

7526 Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.