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BACKGROUND/PURPOSE Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. METHODS We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. RESULTS Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Assessment of measurable residual disease (often referred to as “minimal residual disease”) has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.

Smartwatch allows easy detection of arrhythmia. Such an approach is widely used for detecting atrial fibrillation. However, there has been no consensus on the diagnostic power of smartwatch-detected supraventricular tachycardia (SVT). We reported three patients of SVT presenting with infrequent palpitations. Their SVTs were not documented with single-lead or standard ECG in hospital before, but only recorded by the single-lead ECG on smartwatches. Electrophysiological studies confirmed the mechanisms of these SVTs and led to successful catheter ablations. In conclusion, in patients with recurrent symptomatic tachycardia and a smartwatch-detected SVT, an electrophysiological study is indicated rather than to wait for a standard ECG for clinical decision. This approach might prevent the delay for successful treatment.

Background Follicular lymphoma (FL) is less prevalent in Asians, but detailed epidemiological analyses were not available. This study aimed to characterize the epidemiologic features of FL in Taiwan to explore the factors relevant to disease development and prognosis. Methods We obtained epidemiological data for Taiwanese citizens during 1990‐2012 from Taiwan's National Cancer Registry Database, and the corresponding data for US Caucasians from the Surveillance, Epidemiology, and End Results Program. Changes in incidence rates were evaluated with age‐period‐cohort (APC) analyses. Patient outcomes were compared with 5‐year relative survival rates (RS) estimates. Results Incidence rates of FL in Taiwan increased continuously during the study period (0.34 to 0.91 per 100 000 person‐year from 1993‐1997 to 2008‐2012 in men, and from 0.29 [1993‐1997] to 0.81 [2008‐2012] in women), while rates in the US remained stable in both sexes, ranging between 3.73 and 3.96 in men and between 3.24 and 3.55 in women. Estimates of average annual percentage changes in incidence were significantly positive in Taiwan, but not in US Caucasians. Notably, the APC analysis identified a strong birth‐cohort effect in Taiwan, corresponding to environmental alterations present during the study period. The estimated 5‐year RS rates in both populations showed steady improvement, but the RS in Taiwanese patients was consistently 10% lower than in US Caucasians. Conclusion A distinct increasing trend of incidence with a strong birth‐cohort effect was identified in Taiwan, providing evidence of the association between environmental factors and disease development.

Reactivation of hepatitis B virus (HBV) by reverse seroconversion (HBV-RS) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) can occur in patients with resolved HBV infection (rHBV, defined as negative HBV surface antigen [HBsAg] and positive HBV core antibody), and may cause fatal hepatitis. To explore the risk factors, we retrospectively identified 817 consecutive patients who underwent allo-HSCT from 2005 to 2016 in this largest single centre cohort from National Taiwan Univerisity Hospital. Transplants using donors or recipients positive for HBsAg or HBV DNA were excluded, leaving 445 rHBV patients for analysis. The 3- and 5-year cumulative incidence of HBV-RS after allo-HSCT was 8·7% and 10·5%, respectively, at a median 16 months after allo-HSCT. All had concurrent HBV reactivation. HBV flares developed in 19% of HBV-RS cases, but none experienced hepatic failure. Neither did it impact non-relapse mortality or overall survival. Multivariate analysis revealed that patients with donor lacking hepatitis B surface antibody and extensive chronic graft-versus-host disease (cGVHD) have the highest risk for HBV-RS, with 5-year incidence of 24·2%. In conclusion, adoptive immunity transfer from the donor seems to have protective effects against HBV-RS, which may alter future donor selection algorithms, and combined with extensive cGVHD provides a good target for risk-adaptive HBV prophylaxis.

BACKGROUND Chronic hepatitis B has been linked to lymphoma with contradictory results. AIM To investigate the association between chronic hepatitis B and lymphoma by using a nationwide population-based cohort. METHODS Records of patients diagnosed with chronic hepatitis B (hepatitis B virus [HBV] cohort) or without (non-HBV cohort) during 2004-2007 were retrieved from the Taiwan National Health Insurance Research Database. Age, sex, comorbidities, and medical visits were matched using propensity scores between both cohorts, and they were followed up longitudinally until 2012 to determine any new lymphoma development. RESULTS A total of 203 031 patients were included in each cohort with a mean follow-up of 7-9 years. The lymphoma incidence rate was significantly higher in the HBV cohort than in the non-HBV cohort (29.4 vs 15.9 per 100 000 person-years, P

Background: Multicolor flow cytometry (MFC) analysis is widely used to identify minimal residual disease (MRD) after treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, current manual interpretation suffers from drawbacks of time consuming and interpreter idiosyncrasy. Artificial intelligence (AI), with the expertise in assisting repetitive or complex analysis, represents a potential solution for these drawbacks. Methods: From 2009 to 2016, 5333 MFC data from 1742 AML or MDS patients were collected. The 287 MFC data at post-induction were selected as the outcome set for clinical outcome validation. The rest were 4:1 randomized into the training set (n = 4039) and the validation set (n = 1007). AI algorithm learned a multi-dimensional MFC phenotype from the training set and input it to support vector machine (SVM) classifier after Gaussian mixture model (GMM) modeling, and the performance was evaluated in The validation set. Findings: Promising accuracies (84·6% to 92·4%) and AUCs (0·921–0·950) were achieved by the developed algorithms. Interestingly, the algorithm from even one testing tube achieved similar performance. The clinical significance was validated in the outcome set, and normal MFC interpreted by the AI predicted better progression-free survival (10·9 vs 4·9 months, p

OBJECTIVES Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the genetic landscape and clinical outcome in this group of patients are limited. METHODS A total of 693 newly diagnosed de novo non-M3 AML patients were consecutively enrolled. We compared relevant mutations in 20 genes between AML patients with or without HL and exposed their prognostic implications. RESULTS Hyperleukocytosis, defined as initial white blood cell counts above 50 000/μL, occurred in 28.9% of AML patients. HL patients had higher incidences of FLT3-ITD, NPM1, DNMT3A, CEBPA, and TET2 mutations. Multivariate analysis demonstrated that HL was an independent poor prognostic factor for overall survival and disease-free survival in total patients, those with intermediate-risk cytogenetics and normal karyotype irrespective of genetic alterations. Intriguingly, HL predicted poor survival in CEBPA double mutated, NPM1 + /FLT3-ITD- and NPM1-/FLT3-ITD- patients. Further, HL patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR) had a significantly longer overall survival and disease-free survival than those without allo-HSCT. CONCLUSIONS Hyperleukocytosis is an independent poor prognostic factor irrespective of cytogenetics and mutation status. Allo-HSCT in first CR seems to ameliorate the poor prognostic impact of HL.

Background DNMT3A gene mutation has been associated with poor prognosis in acute myeloid leukemia, but its clinical implications in myelodysplastic syndrome (MDS) and dynamic changes during disease progression remain controversial. Results In this study, DNMT3A mutation was identified in 7.9% of 469 de novo MDS patients. DNMT3A-mutated patients had higher platelet counts at diagnosis, and patients with ring sideroblasts had the highest incidence of DNMT3A mutations, whereas those with multilineage dysplasia had the lowest incidence. Thirty-one (83.8%) of 37 DNMT3A-mutated patients had additional molecular abnormalities at diagnosis, and DNMT3A mutation was highly associated with mutations of IDH2 and SF3B1. Patients with DNMT3A mutations had a higher risk of leukemia transformation and shorter overall survival. Further, DNMT3A mutation was an independent poor prognostic factor irrespective of age, IPSS-R, and genetic alterations. The sequential study demonstrated that the original DNMT3A mutations were retained during follow-ups unless allogeneic hematopoietic stem cell transplantation was performed, while DNMT3A mutation was rarely acquired during disease progression. Conclusions DNMT3A mutation predicts unfavorable outcomes in MDS and was stable during disease evolutions. It may thus be a potential biomarker to predict prognosis and monitor the treatment response. Electronic supplementary material The online version of this article (10.1186/s13148-018-0476-1) contains supplementary material, which is available to authorized users.

Background: FL is an indolent yet incurable disease characterized by recurrent relapses. Pts with R/R FL often have a poor prognosis and limited treatment options, particularly those who have progression of disease within 24 months of frontline treatment (POD24) or are refractory to multiple agent classes. Glofitamab is a T-cell-engaging, CD20xCD3 bispecific, full-length, 2:1 format antibody with bivalent binding to CD20 (B cells) and monovalent binding to CD3 (T cells). Glofitamab monotherapy with obinutuzumab pretreatment (Hutchings, et al. JCO 2021), or combined with obinutuzumab (Morschhauser et al, Blood 2019; NCT03075696), has shown efficacy and manageable safety in heavily pretreated R/R NHL. Here, we present updated results of glofitamab with three different step-up dosing (SUD) regimens as monotherapy (mono) or combined with obinutuzumab (combo) in R/R FL. Methods: Obinutuzumab (1000mg) was given 7 days prior to the first dose of glofitamab. For the 3 mono cohorts, intravenous glofitamab SUD was given on Days (D) 1 and 8 of Cycle (C) 1; then at target dose on C2, or as SUD on C1D1, C1D8, C2D1 and target dose on C3D1. For the combo cohort, glofitamab SUD was given on D1 and D8 of C1, then at target dose combined with obinutuzumab 1000mg from C2D1 and onwards (every 21 days for up to 12 cycles). Response rates were based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 53 pts received glofitamab mono SUD (2.5/10/16mg, n=3; 2.5/10/30mg, n=21; 0.5/2.5/10/30mg, n=29) and 19 pts received glofitamab combo SUD (2.5/10/30mg). All pts had FL Grade (Gr) 1-3A (FLIPI 1 high risk score: mono, 28 [53%] pts; combo, 11 [58%] pts). Median age was 64 years (range 33-83) in mono cohorts and 61 years (range 41-78) in the combo cohort; median number of prior therapies was 3 (range 1-12) and 2 (range 1-5), respectively. Twenty-eight (53%) pts in the mono cohorts and 8 (42%) pts in the combo cohort were refractory to last therapy; 16 (30%) and 7 (37%), respectively, were refractory to prior CD20 and alkylating therapy (double refractory). A total of 19 (36%) pts in the mono cohorts and 10 (53%) pts in the combo cohort had experienced POD24. In the mono cohorts, overall response rate (ORR) was 81% (n=43) and complete metabolic response rate (CMR) was 70% (n=37), with 72% (n=21) CMR in the 0.5/2.5/10/30mg cohort and 67% CMR in both the 2.5/10/16mg (n=2) and 2.5/10/30mg (n=14) cohorts. In the combo cohort, ORR was 100% (n=19) and CMR was 73.7% (n=14). In the mono cohorts 87% (32/37) pts were in CMR, while in the combo cohort 71% (10/14) pts were in CMR. Median follow-up of CMR ranged from 0-14 months (mono) and 0-5 months (combo), and at this cut-off the follow-up is insufficient to assess CMR duration. High CMR rates were observed in high-risk pts (Table). The most common adverse event (AE) was cytokine release syndrome (CRS): 66% and 79% in the mono and combo cohorts, respectively. CRS rates by mono cohort were as follows: 2.5/10/16mg cohort, 100% (3/3); 2.5/10/30mg cohort, 76% (16/21); 0.5/2.5/10/30mg cohort, 55% (16/29). With mono, CRS events (Lee et al. ASTCT 2019) were mostly Gr 1 (47.2%) and 2 (17.0%); 1 pt had a Gr 3 event (2.5/10/16mg cohort). With combo, 52.6% had Gr 1 CRS and 26.3% had Gr 2 CRS. There were no Gr 3 CRS events in the combo cohort and no Gr 4 or 5 CRS with either regimen. Of pts with CRS, tocilizumab was used to treat CRS in 22.9% pts in mono cohorts and 33.3% pts in the combo cohort. All CRS events were manageable and had resolved at data cut-off. Neurologic AEs were seen in 26 pts (16 mono, 10 combo; 36%); all Gr 1 (n=17) or Gr 2 (n=9). No ICANS-like events related to glofitamab were reported. Other common AEs were infusion related reactions and pyrexia (events separate from CRS; both 28%) and neutropenia (26%) with mono, and neutropenia (58%), anemia (37%) and thrombocytopenia (32%) with combo. Conclusions: Glofitamab SUD administered as monotherapy or in combination with obinutuzumab achieved high response rates in pts with heavily pretreated R/R FL, including high-risk subgroups. Response rates were comparable to those reported for CAR-T in R/R FL. The safety profile of glofitamab was manageable; CRS events were mostly low grade and occurred mainly in C1 and C2. Considering the short duration of follow-up, additional follow-up is required to further assess the safety and efficacy of glofitamab in this heterogeneously treated population. Further analyses will be presented. Figure 1 Figure 1. Disclosures Morschhauser: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carlo-Stella: AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Dickinson: Celgene: Research Funding; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Houot: Bristol-Myers Squibb: Honoraria; CHU Rennes: Current Employment; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Celgene: Honoraria; Jsnssen: Honoraria; Novartis: Honoraria. Haioun: Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding; Servier: Honoraria, Research Funding. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Incyte: Consultancy; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy. Hutchings: Novartis: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Mulvihill: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Obinutuzumab (Gazyva) is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of pts with previously untreated CLL; in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of pts with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemo followed by obinutuzumab monotherapy in pts achieving at least a PR, for the treatment of adult pts with previously untreated stage II bulky, III or IV FL

Chronic hepatitis C viral (HCV) infection has been associated with non-Hodgkin's lymphoma (NHL); however, the results are inconsistent among regions with different HCV prevalence rates. The temporal relationship, risk estimates, and association between HCV and lymphoid-neoplasms remain unclear. This study investigated the temporal relationship between HCV infection and lymphoid-neoplasms using a nationwide population-based cohort. Patients with chronic HCV infection were retrieved from the Taiwan National Health Insurance Research Database during 2001-2005 and designated as the HCV cohort. Those with prior malignancies or coinfected with hepatitis B or human immunodeficiency virus were excluded. The age, sex, and comorbidities, including rheumatological disorders and diabetes, were matched by propensity scores to another non-HCV cohort. Both cohorts were followed longitudinally until 2009 for a new diagnosis of any lymphoid-neoplasms or NHL. A total of 11,679 HCV and 46,716 non-HCV patients were included and followed for 8 years. The incidence rates of any lymphoid-neoplasms and NHL were significantly greater in the HCV cohort than the non-HCV cohort (48.4 versus 22.1, and 37.0 versus 17.5 per 100,000 person-years, respectively, both P < 0.001), even after we excluded lymphoid-neoplasms developed within the first year of follow-up. Cox proportional hazards regression analysis (after adjustment for age, sex, numbers of annual medical visits during follow-up, and comorbidities) indicated that HCV infection was associated with an increased risk of either any lymphoid-neoplasms (hazard ratio = 2.30, 95% confidence interval 1.55-3.43, P < 0.0001) or NHL (hazard ratio = 2.00, 95% confidence interval 1.27-3.16, P = 0.003). Conclusion: After adjustment for confounders and biases, chronic HCV infection is temporally associated with a two-fold increased risk of lymphoid-neoplasms, especially NHL, in Asian patients; additional large studies are needed to explore whether HCV eradication can reduce the incidence of lymphoid-neoplasms. (Hepatology 2016;63:721–730)

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy worldwide. A sizable fraction of these patients ended up succumbing to this fatal disease, so the standard of care after the second-line chemotherapy and/or autologous stem cell transplants (ASCT) remains to be improved. Polatuzumab vedotin-piiq (PoV), an anti-CD79b antibody-drug conjugate, gained accelerated approval by the U.S. Food and Drug Administration in June, 2019. The phase II randomized controlled study (GO29365) showed PoV in combination with bendamustine and rituximab (BR) conferred an additional 22% complete response rate for relapsed/refractory DLBCL, compared with BR alone (40% vs. 18%) . Interestingly, how PoV fares when combined with other salvage therapy remains as an open question. Method DLBCL patients who developed progressive diseases after at least 2 prior lines of therapy including R-CHOP and not previously treated with BR were enrolled into this study between Nov. 2018 and Apr. 2020 at the National Taiwan University Hospital. PoV was given at 1.8 mg/kg in combination with salvage chemotherapies based on clinicians' choices. The compassionate use of PoV was approved by the ethics committee, and clinical data were retrospectively analyzed. Results Thirty-two patients were enrolled in this study. According to the Hans' criteria of immunohistochemical subtypes, 13 patients were germinal center B cell-like (GCB), 17 were non-GCB, and 2 patients were unclassifiable. The median age was 62.5 years (range 20-82). At diagnosis, 26 (81%) patients had stage III or IV diseases, 22 (68.8%) had extranodal involvement, and 24 (75%) had the IPI scores equaled to 3 or higher. The median of failed prior lines of treatment was 4 (range 2-11), including 7 (21.9%) relapsing from ASCT and 16 (50%) were of primary refractory disease. Regarding combination therapies, 20 (62.5%) received BR, 5 (15.6%) had rituximab, 5 (15.6%) had rituximab/carmustine-containing regimens, and rituximab/gemcitabine-based ones were given to 4 (12.5%) patients. The median of cycles of PoV was 4 (range 1-7). Notably, the combinatory use of PoV and salvage chemotherapy helped transition 5 patients to ASCT and 4 to allogeneic SCT. The median overall survival (OS) was 8.9 months (95% confidence interval 6.2-not estimable) with the median follow-up of 11.4 months (range 0.3-20.7). The overall response rate (ORR) was 45.2%, including 29.1% complete response (CR) and 16.1% partial response (PR). The patients achieving CR or PR after PoV had better overall survival (OS) than those who did not (median OS: not reached (NR) vs. 5.6 months, p=0.0001, Figure A). The ORR for patients failing prior 2, 3, 4, and ≥5 lines of treatment were 50% (3/6), 40% (2/5), 50% (4/8), and 42% (5/12), respectively. The patients failing prior 4 lines of treatment had better OS than those with failed prior 5 or more lines (NR vs. 6.47 months). Non-GCB patients had better ORR (69.2% vs. 30.8%) and OS (NR vs. 6.23 months) than GCB ones did. Intriguingly, the patients received SCT had better OS compared with the others (NR vs. 6.23 months, p=0.011, Figure B). As for grade 3 & 4 hematological adverse effects, 16 (50%) patients developed anemia, 20 (62.5%) had thrombocytopenia, and 18 (56.3%) were neutropenic. Grade 5 toxicities included pneumonia (2 patients, 6.3%), fungemia (1, 3.1%), intracranial hemorrhage (1, 3.1%), and other infections (2, 6.3%). Conclusion As the third-line or above treatment for DLBCL in this study, the efficacy and safety associated with PoV-based therapies not only were encouraging but also helped bridge to transplants. The application of this monoclonal antibody-drug conjugate in future clinical trials for DLBCL is expected. Figure Disclosures Tsai: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Harvester: Honoraria; Janssen: Honoraria; Kirin: Honoraria; Takeda: Honoraria; BMS: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ko:Roche: Honoraria. Cheng:Roche: Honoraria. Huang:MundiPharma: Honoraria; Chugai: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol Meyer & Squibb: Honoraria.

With critical importance of medical healthcare, there exist urgent needs for in-depth medical studies that can access and analyze specific physiological signals to provide theoretical support for practical clinical care. As a consequence, obtaining the valuable medical data with minimal cost and impacts on hospital work comes as the first concern of researchers. Anesthesia plays a widely recognized role in surgeries, which attracts people to undertake relevant research. In this paper, a real-time physiological medical signal data acquisition system (PMSDA) for the multi-operating room applications is proposed with high universality of the hospital practical settings and research requirements. By utilizing a wireless communication approach, it provides an easily accessible network platform for collection of physiological medical signals such as photoplethysmogram (PPG), electrocardiograph (ECG) and electroencephalogram (EEG) during the surgery. In addition, the raw data is stored on a server for safe backup and further analysis of depth of anesthesia (DoA). Results show that the PMSDA exhibits robust, high quality performance and efficiently reduces costs compared to previously manual methods and allows seamless integration into hospital environment, independent of its routine work. Overall, it provides a pragmatic and flexible surgery-data acquisition system model with low impact and resource cost applicable to research in critical and practical medical circumstances.

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment.

BACKGROUND Chronic hepatitis C infection is linked to lymphoma development. AIM To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma. METHODS Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL). RESULTS In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43-0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C

Diagnosis of depth of anaesthesia (DoA) plays an important role in treatment and drug usage in the operating theatre and intensive care unit. With the flourishing development of analysis methods and monitoring devices for DoA, a small amount of physiological data had been stored and shared for further researches. In this paper, a critical care monitoring (CCM) system for DoA monitoring and analysis was designed and developed, which includes two main components: a physiologic information database (PID) and a DoA analysis subsystem. The PID, including biologic data and clinical information was constructed through a browser and server model so as to provide a safe and open platform for storage, sharing and further study of clinical anaesthesia information. In the analysis of DoA, according to our previous studies on approximate entropy, sample entropy (SampEn) and multi-scale entropy (MSE), the SampEn and MSE were integrated into the subsystem for indicating the state of patients underwent surgeries in real time because of their stability. Therefore, this CCM system not only supplies the original biological data and information collected from the operating room, but also shares our studies for improvement and innovation in the research of DoA.

The revised International Prognostic Scoring System (IPSS-R) was recently developed to better assess the clinical outcome of adult patients with myelodysplastic syndrome (MDS). In this study, we aimed to investigate the prognostic impact of this new risk model on 555 MDS patients in Taiwan. Generally, the IPSS-R could discriminate MDS patients regarding risk of leukemia evolution and overall survival in our cohort and it further refined prognostic stratification in all IPSS risk categories. However, we could not find the inter-group difference between IPSS-R very low and low risk subgroups in both leukemia-free survival (LFS) and overall survival (OS). IPSS-R couldn't distinguish the prognosis between very good and good and between good and intermediate risk cytogenetic categories in OS, and between very good and good and between intermediate and poor cytogenetic-risk categories in LFS, either. On the other hand, incorporation of monosomal karyotype (MK) into IPSS-R could further stratify MDS patients with higher-risk IPSS-R (intermediate, high and very high risk) into four groups, rather than three groups, with different OS (P

Summary: Next-generation sequencing is producing vast amounts of sequence information from natural and engineered ecosystems. Although this data deluge has an enormous potential to transform our lives, knowledge creation and translation need software applications that scale with increasing data processing and analysis requirements. Here, we present improvements to MetaPathways, an annotation and analysis pipeline for environmental sequence information that expedites this transformation. We specifically address pathway prediction hazards through integration of a weighted taxonomic distance and enable quantitative comparison of assembled annotations through a normalized read-mapping measure. Additionally, we improve LAST homology searches through BLAST-equivalent E-values and output formats that are natively compatible with prevailing software applications. Finally, an updated graphical user interface allows for keyword annotation query and projection onto user-defined functional gene hierarchies, including the Carbohydrate-Active Enzyme database. Availability and implementation: MetaPathways v2.5 is available on GitHub: http://github.com/hallamlab/metapathways2. Contact: shallam@mail.ubc.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Allogeneic hematopoietic stem cell transplantation is a curative-intent treatment for patients with high-risk hematologic diseases. However, interstitial pneumonitis (IP) and other toxicities remain major concerns after total body irradiation (TBI). We have proposed using linear accelerators with rice-bag compensators for intensity modulation (IM-TBI), as an alternative to the traditional cobalt-60 teletherapy with lung-shielding technique (Co-TBI). Patients who received a TBI-based myeloablative conditioning regimen between 1995 and 2014 were recruited consecutively. Before March 2007, TBI was delivered using Co-TBI (n = 181); afterward, TBI was administered using IM-TBI (n = 126). Forty-four patients developed IP; of these cases, 19 were idiopathic. The IP-related mortality rate was 50% in the total IP cohort and 63% in the idiopathic subgroup. The 1-year cumulative incidences of IP and idiopathic IP were 16.5% and 7.4%, respectively; both rates were significantly higher in the Co-TBI group than in the IM-TBI group. Multivariate analysis revealed that Co-TBI was an independent prognostic factor for both total and idiopathic IP. In the acute myeloid leukemia subgroup, patients with different TBI techniques had similar outcomes for both overall and relapse-free survival. In conclusion, IM-TBI is an easy and effective TBI technique that could substantially reduce the complication rate of IP without compromising treatment efficacy.

Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but the prognostic relevance of these genes mutations in acute myeloid leukemia (AML) remains unclear. In this study, we investigated mutations of three SF genes, SF3B1, U2AF1 and SRSF2, by Sanger sequencing in 500 patients with de novo AML and analysed their clinical relevance. SF mutations were identified in 10.8% of total cohort and 13.2% of those with intermediate-risk cytogenetics. SF mutations were closely associated with RUNX1, ASXL1, IDH2 and TET2 mutations. SF-mutated AML patients had a significantly lower complete remission rate and shorter disease-free survival (DFS) and overall survival (OS) than those without the mutation. Multivariate analysis demonstrated that SFmutation was an independent poor prognostic factor for DFS and OS. A scoring system incorporating SF mutation and ten other prognostic factors was proved very useful to risk-stratify AML patients. Sequential study of paired samples showed that SF mutations were stable during AML evolution. In conclusion, SF mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. These mutations may be potential targets for novel treatment and biomarkers for disease monitoring in AML.

Introduction Recent advances in the discovery of the genomic landscape in AML prompts necessity to re-examine the 2017 European LeukemiaNet (ELN) recommendation. In this study we aimed to validate the usefulness of 2017 ELN risk stratification in a large Taiwan cohort with special focus on the prognostic relevance of FLT3-ITD allelic ratio and its interaction with other mutations. Methods We retrospectively included 1040 de novo non-M3 AML patients. AML was risk-stratified according to the 2017 ELN recommendation. 739 (71.1%) patients who received standard chemotherapy were included for survival analysis. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 293 (39.6%) patients. Mutational analyses of fifteen genes, including CEBPA, NPM1, FLT3, RUNX1, ASXL1, TP53, splicing factors (SF), such as SRSF2, U2AF1, and SF3B1, as well as KIT, NRAS, KRAS, DNMT3A, TET2, and WT1 were performed. FLT3-ITD/wild allelic ratios were calculated as the ratio of the area under the curve by fragment analysis. High FLT3-ITD allelic ratio (FLT3-ITDhigh) was defined as ³ 0.5 and low allelic ratio (FLT3-ITDlow) defined as < 0.5. Results According to the 2017 ELN risk classification, favorable, intermediate and adverse categories comprised 34.6%, 29.2% and 36.2% patients, respectively. NPM1 mutations and FLT3-ITD, the most common mutations in this cohort, were detected in 217 (20.9%) and 216 (20.8%) patients, respectively, with a significant association between each other. The median value of the FLT3-ITD/wild ratio was 0.68 without difference between NPM1-mutated and NPM1-wild group. Of note, patients with FLT3-ITDhigh had higher WBC count and LDH level than those with FLT3-ITDlow. Overall, the CR rate and relapse rate were 74.2% and 54.7%, respectively and 5-year overall survival (OS) was 43.2±1.9%. The CR rate (92.3%) was higher in the 2017 ELN favorable risk group than in the intermediate (73.0%) and adverse groups (52.0%, P As to the prognostic impact of FLT3-ITD, we showed that FLT3-ITD patients had significantly lower CR rate, higher relapse rate, reduced DFS and OS than those without. There was a strikingly difference in treatment response between the low and high FLT3-ITD allelic ratio groups: CR rate (80.7% vs. 63.6%, P=0.0319), relapse rate (56.5% vs. 66.2%, P=0.329), DFS (14.2 vs. 4.6 months P=0.011) and OS (24.0 vs. 11.9 months, P=0.048). Interestingly, patients with FLT3-ITDhigh had a better OS if they received allogeneic HSCT than those who did not. Among the 2017 ELN favorable-risk category, we found that patients with mutated NPM1 and FLT3-ITDlow had significantly shorter OS (median, not reached vs. 31.6 months, P=0.003, Figure. 1A) and a trend of shorter DFS (median 14.9 months vs. 93.9 months, P=0.089, Figure. 1B) compared to other ELN favorable subgroups. To find the cause of the difference, we investigated the concurrent mutations in the patients with mutated NPM1 and FLT3-ITDlow. 46.2% of them had concurrent poor-risk mutations, such as ASXL1, RUNX1, TP53, WT1, TET2, DNMT3A, and SF mutations. Similarly, among the 2017 ELN intermediate-risk category, patients with mutated NPM1 and FLT3-ITDhigh had more unfavorable outcomes compared to those with wild-type NPM1 and without FLT3-ITD (DFS, median 3.7 vs. 11.6 months, P=0.028 and OS, median, 11.4 vs. 26.5 months, P=0.067). Presence of concurrent poor-risk mutations were also identified in 72.9% of these patients. Based on these findings, we postulated that concomitant poor-risk genetic alterations at least partially affected the prognosis of FLT3/ITD patients. In the cohort of FLT3-ITD patients, patients harboring poor-risk mutations had shorter DFS and OS than those without (P=0.028 and P=0.031, respectively). Further, co-occurrence of FLT3-ITDhigh and poor-risk mutations that predicted a worst outcome, seemed to define a highly adverse prognostic group. Conclusions We showed that ELN 2017 risk classification could well stratify AML patients in Taiwan. The prognostic relevance of FLT3-ITD may further depend on the presence or absence of co-occurring poor-risk genetic alterations, which seemed to add an adverse effect in patients with FLT3-ITD. These observations warrant confirmation in other prospective and large-scale studies. Disclosures Ko: Roche: Research Funding; GNT Biotech & Medicals Crop.: Research Funding; Abbevie: Research Funding; Mumdipharma Taiwan: Consultancy.

The immunomodulating effect of human leukocyte antigen (HLA)-DR and the central role of CD4 T cells in alloimmunity provide clues suggesting that HLA-DR-matched, partially mismatched related donors could be feasible alternative donors of allogeneic hematopoietic stem cells for transplantations (allo-HSCT). We describe our experience with allo-HSCT in eight patients with high-risk acute leukemia; donors included one of each of the parents. Among the eight patients, seven were identical HLA-DR matches with the donors. The stem cells were not manipulated in vitro. Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, cyclosporine, and methotrexate. All patients had successful trilineage engraftment. Only one patient had grade 2–4 acute GVHD. Two patients died before day +100 due to complications. At the end of follow-up, four patients had survived for 18–48 months and three are alive and without relapse. Our results suggest that HLA-DR fully-matched parents are feasible alternative donors for allo-HSCT in patients with high-risk acute leukemia under an intensive conditioning regimen.

Background/Purpose Hodgkin's lymphoma (HL) is particularly rare in Asia, including Taiwan. The report concerning its clinical features and treatment outcomes in Asians is limited. An exploration of the characteristics of HL in this area is of importance for future studies. Methods In this study, 133 patients with HL diagnosed between January 1985 and December 2004 at National Taiwan University Hospital were analyzed retrospectively. Results The age distribution revealed a young-adult peak at the age around 20 years. The nodular sclerosis type (NS-HL) was the most common histopathogic subtype (45%), followed by mixed cellularity (29%), lymphocyte predominant (13%), and lymphocyte depleted subtype (2%). The incidence of NS-HL was, however, lower compared with that in the West (around 70%). The male to female ratio was approximately 1:2 in patients with NS-HL, in contrast to the male predominance in patients with other subtypes. Induction therapy led to complete remission (CR) in 87% of patients. At a median follow-up of 78 months, the 10-year overall survival (OS) was 79% in all HL patients and was 90% in those who achieved first CR. In multivariate analysis, the achievement of CR was the only independent factor associated with good OS. Conclusion The treatment response of HL in Taiwan is good and comparable to that in Western countries. The epidemiologic differences between Taiwan and the West mandate further studies.

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.

Invasive fungal infections (IFIs) is an important complication for acute myeloid leukemia (AML) patients receiving induction chemotherapy. However, the epidemiological information is not clear in Southeastern Asia, an area of potential high incidences of IFIs. To clarify it, we enrolled 298 non-M3 adult AML patients receiving induction chemotherapy without systemic anti-fungal prophylaxis from Jan 2004 to Dec 2009, when we applied a prospective diagnostic and treatment algorithm for IFIs. Their demographic parameters, IFI characters, and treatment outcome were collected for analysis. The median age of these patients was 51 years. Standard induction chemotherapy was used for 246 (82.6%) patients, and 66.8% of patients achieved complete remission (CR) or partial remission. The incidence of all-category IFIs was 34.6% (5.7% proven IFIs, 5.0% probable IFIs and 23.8% possible IFIs). Candida tropicalis was the leading pathogen among yeast, and lower respiratory tract was the most common site for IFIs (75.4%, 80/106). Standard induction chemotherapy and failure to CR were identified as risk factors for IFIs. The presence of IFI in induction independently predicted worse survival (hazard ratio 1.536 (1.100–2.141), p value = 0.012). Even in those who survived from the initial IFI insults after 3 months, the presence of IFIs in induction still predicted a poor long-term survival. This study confirms high incidences of IFIs in Southeastern Asia, and illustrates potential risk factors; poor short-term and long-term outcomes are also demonstrated. This epidemiological information will provide useful perspectives for anti-fungal prophylaxis and treatment for AML patients during induction, so that best chances of cure and survival can be provided.

The development of high-throughput sequencing technologies over the past decade has generated a tidal wave of environmental sequence information from a variety of natural and human engineered ecosystems. The resulting flood of information into public databases and archived sequencing projects has exponentially expanded computational resource requirements rendering most local homology-based search methods inefficient. We recently introduced MetaPathways v1.0, a modular annotation and analysis pipeline for constructing environmental Pathway/Genome Databases (ePGDBs) from environmental sequence information capable of using the Sun Grid engine for external resource partitioning. However, a command-line interface and facile task management introduced user activation barriers with concomitant decrease in fault tolerance. Here we present MetaPathways v2.0 incorporating a graphical user interface (GUI) and refined task management methods. The MetaPathways GUI provides an intuitive display for setup and process monitoring and supports interactive data visualization and sub-setting via a custom Knowledge Engine data structure. A master-worker model is adopted for task management allowing users to scavenge computational results from a number of worker grids in an ad hoc, asynchronous, distributed network that dramatically increases fault tolerance. This model facilitates the use of EC2 instances extending ePGDB construction to the Amazon Elastic Cloud.

Introduction Acute myeloid leukemia (AML) with hyperleukocytosis (HL), commonly defined as white blood cell (WBC) counts >100,000/uL, are intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the clinical characteristics, genetic alterations in this group of patients are limited, and the role of hematopoietic stem cell transplantation (HSCT) is controversial. Method A cohort of 755 de novo AML patients diagnosed from 1994 to 2011 who had cryopreserved cells for analysis were enrolled. The mutation status of 18 genes was determined by Sanger sequencing and/or next generation sequencing (NGS). We compared cytogenetics and relevant mutations in these genes between AML patients with and without HL, and exposed their prognostic implications. Results The median age was 54 (range 15-94). 101 (13.4%) patients had HL. HL was associated with younger age (median age 47 vs. 54, P=0.022), higher peripheral blast percentage (77.6% vs. 39%, P Survival analysis was performed on the 525 patients who received standard intensive chemotherapy; among whom 69 patients had HL. The HL patients had lower complete remission (CR) rates compared to those without (63.8% vs. 78.2%, P=0.009). Further, the HL patients had significantly poorer overall survival (OS) and disease-free survival (DFS) than those without (median 24 months vs. not reached (NR), P=0.042; 6.5 vs. 11.8 months, P=0.005, respectively, Figure 1). Older age, poor-risk cytogenetics, RUNX1, TP53 and WT1 mutations were other poor prognostic factors for OS (median, 18.1 months vs. NR, P Conclusion The HL patients represented 13.4% of our AML cohort and showed distinct clinic features and genetic alterations compared to those without HL. HL was an independent poor prognosis factor irrespective of cytogenetics change or mutation status, and the HL patients may potentially benefit from HSCT. Figure 1 The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy (A) (B) Figure 1. The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy. / (A). / (B) Figure 2 The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 2. The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome (MDS) and its stability during disease progression. We checked mutation status of the U2AF1 by direct sequencing in 478 de novo MDS patients and correlated with the clinical characteristics and outcomes. We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the disease courses. Thirty-six patients (7.5%) were found to have U2AF1 mutations, which occurred more frequently in younger patients (P = 0.033). U2AF1 mutation was an independent poor-risk factor for overall survival (OS) in all patients (P = 0.030) and younger patients (P = 0.041). U2AF1 mutation could also predict shorter time-to-leukemia transformation (TTL) in younger patients (P = 0.020). In addition, U2AF1 mutation was associated with shorter TTL in lower-risk MDS patients. Sequential analyses showed all original U2AF1 mutations in U2AF1-mutated patients were retained during follow-ups unless complete remission was achieved, whereas none of the U2AF1-wild patients acquired a novel mutation during disease evolution. U2AF1 mutation is more prevalent in younger MDS patients and associated with inferior outcomes although it is stable during the clinical course. The mutation may be used as a biomarker for risk stratification. Am. J. Heamtol. 88:E277–E282, 2013. © 2013 Wiley Periodicals, Inc.

Alterations of galectin-3 expression are often seen in cancers and may contribute to tumorigenesis, cancer progression, and metastasis. The studies concerning clinical implications of galectin-3 expression in patients with acute myeloid leukemia (AML) are scarce. We investigated the expression of LGALS3, the gene encoding galectin-3, in the bone marrow (BM) mononuclear cells from an original cohort comprising 280 adults with primary non-acute promyelocytic leukemia. Higher LGALS3 expression was closely associated with older age, French-American-British M4/M5 subtypes, CD14 expression on leukemic cells, and PTPN11 mutation, but negatively correlated with CEBPA mutation and FLT3-ITD. Compared with patients with lower LGALS3 expression, those with higher expression had lower complete remission rates, higher primary refractory rates, and shorter overall survival. This result was validated in an independent validation cohort. A scoring system incorporating higher LGALS3 expression and 8 other risk factors, including age, white blood cell count, cytogenetics, and gene mutations, into survival analysis proved to be very useful to stratify patients with AML into different prognostic groups (P < .001). In conclusion, BM LGALS3 expression may serve as a new biomarker to predict clinical outcome in patients with AML, and galectin-3 may serve as a potential therapeutic target in those patients with higher expression of this protein.

Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger ( Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

The incidence of chronic lymphocytic leukemia (CLL) in Taiwan is markedly lower than that in Western countries, but we have seen a drastically increasing trend. We explored this distinct incidence trend of CLL for Taiwanese. The epidemiologic data of CLL for Taiwanese and Caucasian Americans during 1986 to 2005 were obtained from the Taiwan National Cancer Registry and Surveillance, Epidemiology, and End Results Program, respectively. The individual effects of time period and birth cohort on the incidence trends were analyzed using an age-period-cohort model. Although there was a weak period effect corresponding to the increased applications of immunophenotyping in 1991 to 1995 in Taiwan, evidences suggested that the age-adjusted incidence rate of CLL for Taiwanese was continuously increasing during the 20-year period while that for Caucasian Americans remained steady. In addition, a much stronger birth-cohort effect was identified for Taiwanese but not for Caucasian Americans. This effect corresponded to the westernization of lifestyle in Taiwan since 1960. We conclude that, in addition to the ethnic difference of incidence, there is distinct increasing incidence trend of CLL in Taiwan. The strong birth-cohort effect underlying this increasing trend indicates that lifestyles and environmental factors may play a role in the development of CLL for Taiwanese.

Primary effusion lymphoma (PEL) is a rare form of nonodgkin’s lymphoma (NHL) that involves serous body cavities, uch as the pleural, pericardial, and abdominal cavities, with ymphomatous effusions in the absence of lymphadenopathy or rganomegaly.1–3 Morphologically the lymphoma cells of PEL xhibit high-grade cytological features, including immunoblastic o anaplastic appearances, large nuclei with prominent nucleoli, nd abundant basophilic cytoplasm.1,2 Although there are some eported cases of T-cell PEL,4,5 the lymphoma cells of PEL are hought tobeofB-cell origin.2,3,6 The lymphomacells of PELexpress ommon leukocyte antigen CD45 but usually lack other pan-Bell or pan-T-cell surface antigens. Instead, activated plasma cell elated markers, such as CD30, CD38 or CD138, are frequently emonstrated.6 Previously, PEL was reported primarily in human mmunodeficiency virus (HIV)-infected patients, which was excluively linked to human herpesvirus type-8 (HHV-8) infection.2,7 ore recently, PEL has been reported to occur in HIV-negative atients with chronic hepatitis C virus (HCV) infection.8–11 In this eport, we aimed to describe three cases of PEL in patients who had o-infection with HHV-8 and hepatitis B virus (HBV).

The growth of myeloma cells depends on bone marrow (BM) stroma consisting of stromal cells, secreted cytokines and the extracellular matrix (ECM). Decorin, a small leucine-rich proteoglycan in the ECM, is a signaling ligand and native anti-tumor agent. However, the role of decorin in patients with myeloma is not clear. We evaluated the correlation between the decorin levels measured by enzyme-linked immunosorbent assay in BM plasma from 121 patients with newly diagnosed myeloma based on their clinical features and treatment response. The median decorin levels in the patients and the normal control group were 12.31 ng/mL [standard deviation (SD), 7.50 ng/mL; range, 2.45 to 44.46 ng/mL] and 10.31 ng/mL (SD, 2.42 ng/mL; range, 4.85-15.14 ng/mL), respectively (P < 0.001). Using 15.15 ng/mL as a cut-off, 46 patients (38%) exhibited higher decorin levels (H-DCN), whereas the other patients exhibited normal to lower decorin levels (NL-DCN). Except for the median age, which was significantly younger in the H-DCN than in the NL-DCN group (60.6 ± 14.0 vs. 65.8 ± 12.2 years, respectively; P = 0.034), there were no differences between the two groups. However, in 79 patients who had received novel agent-based induction, the overall response rate was significantly better in the H-DCN than in the NL-DCN (97 vs. 63%, respectively; P < 0.001), as was the depth of responses (P = 0.008), which were not observed in those who had received chemotherapeutic agents alone. Progression-free survival (PFS) was significantly longer in H-DCN than NL-DCN (not reached vs. 19.5 mo, respectively; P = 0.0003). Multivariate analyses indicated that H-DCN, as a significantly independent factor, was associated with better treatment response (odds ratio, 20.014; 95% CI, 2.187-183.150; P = 0.008) and longer PFS (hazard ratio, 0.135; 95% CI, 0.051-0.361; P < 0.001). These findings disclose the potential role of decorin in myeloma and provide a basis for further study on possible synergistic anti-myeloma effects between decorin and the novel agents that target BM stroma.

The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

To the Editor: Lymphomatoid granulomatosis (LYG) involves a B-cell lymphoproliferative process associated with Epstein-Barr virus (1). The disease is characterized predominantly by lung involvement, and the pathologic findings show an angiocentric pattern with lymphoid cell clustering. Patient median survival time is ≈14 months (2). Treatment commonly consists of corticosteroids and cyclophosphamide, but a literature review did not demonstrate any benefit from corticosteroid therapy, cytotoxic chemotherapy, or radiation (3). Rituximab, a monoclonal antibody, targets a B-cell surface molecule, CD20. Recently, several case reports have been published about the effectiveness of rituximab for LYG (4,5). We report acute cytomegalovirus pneumonitis in a patient with LYG. In May 2005, a 40-year-old woman with no history of systemic disease had experienced intermittent dry cough for 1 month. Her cough was not associated with any specific environmental exposure or location. Computed tomographic (CT) scan of the chest showed bilateral multiple lung nodules, and a lung biopsy sample showed lymphohistiocytic and lymphoplasmacytic cell infiltrates with some fibrous material. Prednisolone was prescribed for suspected cryptogenic organizing pneumonitis, but her symptoms improved only partially. One year later, her symptoms worsened. Chest CT scan showed more nodules in both lungs (Figure, panel A). A repeat lung biopsy sample showed large abnormal lymphoid cells clustering in pink-white nodules around and within blood vessel walls. The abnormal lymphocytes were positive for CD20 and Epstein-Barr virus–encoded RNA. The patient was HIV negative, and her bone marrow showed no evidence of lymphoma. Abdominal and pelvic CT scans did not show other abnormal lymph nodes or organ involvement. LYG was diagnosed. Figure Chest computed tomography scan of a 40-year-old woman with no history of systemic disease. A) Bilateral multiple lung nodules and lymphomatoid granulomatosis were diagnosed after lung biopsy. B) After rituximab treatment, the prior nodular lung lesions ... The patient’s condition did not respond well to induction chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, and her dyspnea persisted. One week later, rituximab was prescribed; dyspnea dramatically improved after 1 day, and she could tolerate room air without oxygen support. However, 1 day later, severe respiratory distress with hypoxemia suddenly occurred. Although chest CT scan disclosed dramatic resolution of the previously found nodular lung lesions, it also showed newly developed interstitial ground glass opacities (Figure, panel B). A diagnosis of interstitial pneumonitis was considered. Serum cytomegalovirus (CMV) DNA quantification by pp65 gene PCR was performed; the amount was high, up to 2 × 105 copies/mL. Acute CMV pneumonitis was diagnosed. Although the patient received mechanical ventilatory support, CMV intravenous immunoglobulin administration, and ganciclovir therapy, she died 5 days after the onset of acute CMV pneumonitis. CMV pneumonitis is a common presentation of CMV disease in immunocompromised patients. Host factors, such as presence of cancers or compromised immune function, play a major role in determining pathogenicity of the virus. Respiratory failure is the leading cause of death among patients with rapidly progressive interstitial pneumonitis related to CMV, especially among recipients of renal and bone marrow transplants (6). The patient reported here received chemotherapy and steroids; both treatments would render the patient immunocompromised, a condition that may lead to such a rapidly progressive course. This patient had no identifiable concurrent illnesses that might have been associated with compromised immunity or development of LYG. However, fatal CMV pneumonitis, a complication usually associated with extremely impaired immunity, developed. The case suggests that, even without an identifiable immunocompromised condition, a patient with LYG should be considered an immunocompromised host, and rituximab or other immunosuppressive treatments should be prescribed cautiously; the possibility for rare complications should be recognized. Because of massive ablation of humoral immunity, the relationship between rituximab and virus infection has been addressed, including varicella–zoster infection, parvovirus B19 infection, and CMV reactivation (7). In immunocompromised patients, rituximab might lead to higher risk for virus infection. This issue has been addressed with HIV/AIDS patients with high-grade B-cell lymphoma for whom rituximab is not generally recommended because B-cell ablation could result in more opportunistic infections. For LYG, increased frequency is associated with both congenital and acquired immunodeficiency, such as X-linked lymphoproliferative syndrome, Wiskott–Aldrich syndrome, and HIV/AIDS in which T-cell surveillance is deficient (8). Thus, for a patient with LYG whose immune system might be abnormal (9), the risks associated with rituximab therapy should be considered the same as the risks for HIV/AIDS patients, and the risk for viral infection or reaction to rituximab should be recognized, particularly in areas where CMV seropositivity in the population is high (10). In addition, especially for adult and elderly patients, the gradual increase of CMV seroprevalence with age should be recognized (10). Moreover, the patient reported here had previously received cytotoxic drugs as well as maintenance steroid therapy, both of which contributed to a severely compromised immune system. These factors may have led to her acute CMV pneumonitis after receipt of rituximab. In conclusion, the potential for acute CMV reactivation should recognized during use of rituximab to treat patients with LYG. During rituximab treatment of LYG, routine monitoring for CMV reactivation and other viral infections is warranted.

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.

Rituximab improves response to treatment and outcome for patients with CD20+ B-cell lymphoma. Herein, however, we report the occurrence of severe pulmonary complications shortly after rituximab infusion in three patients with the newly diagnosed Asian variant of intravascular lymphoma. It is suggested that patients with this subtype of lymphoma are monitored carefully for possible drug reactions during the use of rituximab.

Background Chronic lymphocytic leukemia (CLL) is much less prevalent in Asian countries. Whether there are differences in survival outcomes between the East and West, however, remain unclear. Methods The survival data for CLL patients identified in the Taiwan Cancer Registry database between 1990 and 2004, together with corresponding data in the US Surveillance, Epidemiology, and End Results database, were retrieved. The relative survivals (RS, adjusted for the expected survival in the general population) were estimated in patients diagnosed in three 5-year periods of time. Results CLL drastically shortened patients’ life expectancy; more importantly, this negative impact in Taiwan was much larger than that in the US: the 5-year RS in Taiwan and US were 59% and 76%, and the 10-year RS, 45% and 56%, respectively. Nevertheless, survival in Taiwan was better in the periods after 1995 (5-year RS, from 53.0% to 60.6%), a time period corresponding to the introduction of the Taiwan National Health Insurance scheme. Such improvement was largely due to decreased mortality in patients younger than 65 (5-year RS, from 53.5% to 69.1%). Despite the improvement, patients’ RS in Taiwan in recent periods remain steadily 15~20% inferior to that in the US in both younger and older patient groups. Conclusions The improved RS in Taiwan implies that therapeutic advances are changing the prognosis of CLL. The stable RS gap between Taiwanese and the US patients suggests the existence of an ethnic difference in CLL patients’ outcomes.

Abstract 3018 Background and Purposes Epstein-Barr virus (EBV)-associated PTLD is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Independent risk factors include use of ATG, acute GVHD, CMV antigenemia, T-depleted graft, and unrelated donor in our previous study. Quantitative real-time polymerase chain reaction (Q-PCR) was developed for early detection and intervention of EBV reactivation to prevent PTLD-related mortality. Patients and Methods Between Apr 2004 and Oct 2010, EBV viral load in plasma was monitored by Q-PCR in 222 HSCT patients (total 2945 samples) in NTUH. EBV reactivation was defined as > 500 copies/mL in two consecutive assays or > 10-fold elevation than baseline level. Results EBV reactivation occurred in 50 (22%) patients. The cumulated incidence of EBV reactivation was 28% at 1-year and 32% at 2-year. Median time to EBV reactivation was 40 days (ranges, 26–406) after SCT and median peak EBV-viral load, 10888 copies/ml (ranges, 948–3×107). The risk of EBV reactivation was significantly higher in patients receiving ATG (52% vs. 13%, p< 0.001), use of TBI (58% vs. 26%, p Conclusions Monitoring of EBV viral load is a sensitive and useful tool in the surveillance of EBV-reactivation. Frequent monitoring in high-risk patients is important to prevent occurrence of EBV-PTLD. Disclosures: No relevant conflicts of interest to declare.

Abstract 4378 Chronic lymphocytic leukemia (CLL) is a prevalent leukemia in western countries. However, the incidence of CLL in Taiwan, is markedly lower but shows an increasing trends. We explored the incidence of CLL in Taiwan during the past two decades and compared it with Caucasian Americans. The epidemiologic data of CLL (1979-2003) in Taiwan was obtained from Taiwan Cancer Registry, and the corresponding data of Caucasian Americans was from the Surveillance, Epidemiology, and End Results Program (SEER). From 1979-2003, the age-adjusted annual incidence (with WHO 2000 standard population) of CLL in Taiwan increased from 0.08 to 0.36 per 100,000 people with about 4.5 folds increment, while that in Caucasian Americans was much higher but remained in steady state in this period (2.6 to 3.1 per 100,000 people). Age-specific incidence rate of CLL plotted by calendar year at diagnosis revealed a stronger period effect in Taiwanese (Figure 1A). The estimation of age-specific annual percentage changes (AAPC) of incidences revealed that, in every age group, the annual increase of the overall incidence throughout the past 2 decades was much higher for Taiwanese compared with that for Caucasian Americans (Figure 1B). Age-specific incidence rates plotted by birth cohort showed that the CLL incidence was higher for later birth cohorts for every age group in Taiwanese but not in Caucasian Americans (Figure 1C). The individual effects of time period and birth cohort on the trends of incidence of CLL in both populations were analyzed using the age-period-cohort analysis for comparison. These analyses showed a much stronger birth-cohort effect on the incidence trend of CLL in Taiwanese than in Caucasian Americans. This strong birth-cohort effect corresponded to the Westernization of lifestyle in Taiwan since 1960. This finding suggests that, in addition to the racial differences of genetic backgrounds that may be responsible for the differences in the CLL incidence, the environmental effects also play some roles. We also analyzed the cytogenetic abnormalities (CA) by conventional cytogenetics (CG) and fluorescence in situ hybridization (FISH) and assessed their clinical significance in Taiwanese patients who were diagnosed and treated at National Taiwan University Hospital. Thirty-nine patients (45.9%) out of 85 patients possessed CG-CA and 58 (69.9%) out of 83 patients had FISH-CA. FISH was more sensitive to detect CA than CG. Those who had neither CG-CA nor FISH-GA had excellent overall survival (OS). Patients with hypodiploidy or complex CG-CA had poorer prognosis than others (p=0.043 and 0.037, respectively). Among those specific chromosome changes detected by CG, trisomy 12 was the most common CA (14.1% among 85 patients). Detection of 17p- by CG was independently associated with poor prognosis. By FISH, 13q- was the most common CA (45.8% among 83 patients), followed by trisomy 12 (20.5%); the frequencies of these two abnormalities were similar to those reported in western countries. Both FISH-CA of 17p- and 11q- were significantly independent factors for poor prognosis. Trisomy 3 was found in five patients; all were of Binet A stage but had a poor prognosis, suggesting that CLL with trisomy 3 may be a distinct disease entity. From these data we conclude that the incidence of CLL in Taiwan was dramatically increased in recent years and was associated with a birth-cohort effect. The CA of CLL in Taiwanese patients are similar to those in Western countries, indicating that although the incidence of CLL is lower in Taiwan than in the West, the pathogenesis of this disease in these two areas is similar. The finding from combined CG and FISH analysis can help predict prognosis. The clinical significance of trisomy 3 in CLL needs to be further investigated. Disclosures: No relevant conflicts of interest to declare.

Purpose: In patients of acute myeloid leukemia (AML) with mutations in Nucleophosmin (NPM), minimal residual disease (MRD) can be quantified by real-time polymerase chain reaction (qPCR). However, the validity of MRD detection by qPCR on a long-term basis and its prognostic significance remain undetermined. Patients and Methods: We quantified NPM mutants by qPCR in genomic DNA of 202 bone marrow samples serially collected during a median follow-up of 21.9 months (range 2.5 to 204) from 40 AML patients bearing this mutation. Results: With a relatively homogeneous number of mutants at diagnosis, induction chemotherapy resulted in a median of 2.78 logs of reduction (p Conclusion: Quantification of MRD by qPCR on genomic DNA in AML bearing NPM mutation predicts outcomes of this group of patients.

Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0-8) and a score ≥4.5 was used for CRBN positivity (CRBN(+)) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN(+) NDMM patients, CRBN(-) NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN(+) patients than CRBN(-) patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN(+) for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN(+) was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.