Polymorphisms in the CYP450 Genes Influences Regimen Related Toxicity and Outcome in Patients with Beta Thalassaemia Major Undergoing HSCT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 869-869
Author(s):  
Poonkuzhali Balasubramanian ◽  
Salamun Desire ◽  
Vikram Mathews ◽  
Kavitha M Lakshmi ◽  
Shaji R Velayudhan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Annual Meeting ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
P Value ◽  
Thalassaemia Major ◽  
Hematopoietic Stem ◽  
Beta Thalassaemia ◽  
Variant Genotype ◽  
The Impact

Abstract Abstract 869 Polymorphisms in drug metabolizing enzymes are known to contribute to inter-individual differences in the pharmacokinetics (PK) of the two most commonly used drugs for conditioning for hematopoietic stem cell transplantation (HSCT), busulfan (Bu) and cyclophosphamide (Cy) and their metabolites in plasma. We have previously reported the impact of CYP genes on the PK of Cy, [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 99] and the influence of Cy PK on transplant outcome [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 1820]. We have now extended this study to evaluate a total of 19 polymorphisms in 11 genes that are known to be involved in the metabolism of Bu and Cy. 180 of the 276 patients with thalassemia major who underwent HSCT between March 1991 and Dec 2008 and for who genomic DNA was available were included in the study. The following polymorphisms were screened using PCR followed by RFLP and/ or gel electrophoresis: GSTA1*B, GSTM1 and GSTT1 deletion, GSTP1*B, CYP2B6*2, *3, *4, *5 and *6, CYP2C9*2, *3 and *4, CYP2C19*2, *3, CYP3A4*1B, CYP3A5*3, *6 and ALDH1A1*2 and ALDH3A1*2. Polymorphism frequencies were associated with regimen related toxicities, other transplant related complications using Fischer's Exact test and Cox-proportional hazard's model.. Significant associations are shown in the Table. On univariate analysis, CYP2B6*4 variant genotype was associated with incidence of hemorrhagic cystitis (HC); CYP2C9*3 variant genotype was associated with the severity of HC; CYP2C19*3 and 2C9*2 genotypes were associated with overall and even-free survival (OS and EFS) and CYP2C9*2 and CYP2C9*3 genotype was associated with transplant related mortality (TRM). Multivariate analyses performed adjusting for known clinical risk factors still showed these genotypes to be significantly associated with outcome parameters. Variant genotypes of polymorphisms that result in decreased metabolism of Cy are protective against regimen related toxicities while these polymorphisms were risk factors for EFS and OS in the present study. This is the first report on the influence of common GST, CYP and ALDH polymorphisms on outcome of HSCT in patients with thalassaemia major. Screening for these polymorphisms in patients with beta thalassaemia undergoing HSCT can help identify patients at higher risk of complications.Table:EndpointGenotypeRelative risk (95% CI)P- value HCCYP2B6*4 variant0.3 (0.13-0.889)0.028 HC grade 1 vs. HC grade 2-4CYP2C9*3 variant0.2 (0.073-0.962)0.043 TRM2C9*2 variant2.7 (1.08-6.77)0.034 2C9*3 variant2.3 (1.0-5.7)0.049 OS and EFS2C19*3 variant3.3 (1.2-9.3)0.018 2C9*2 variant1.3 (0.93-2.03)0.070 Disclosures: No relevant conflicts of interest to declare.

Effects of Multiple Myeloma (MM) Therapy and Type of Thromboprophylaxis On the Incidence and Timing of Venous Thromboembolism (VTE) and Factors Predictive of VTE.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2244-2244
Author(s):  
Jatin J. Shah ◽  
Aparna Hegde ◽  
Xiao Zhou ◽  
Sheeba K. Thomas ◽  
Michael Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Cancer Center ◽  
Hematopoietic Stem ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Multivariate Proportional Hazard ◽  
The Impact

Abstract Abstract 2244 Background: Patients (pts) with MM are at increased risk for VTE due to various risk factors related to the host, disease, and treatment. Immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide have further increased the risk of VTE. Several studies have shown the VTE risk can be reduced with the use of low molecular weight heparin (LMWH) or aspirin thromboprophylaxis. Based on these findings, VTE thromboprophylaxis has been recommended in pts receiving IMiDs + Dexamethasone (Dex), but the impact of these guidelines on patient outcomes in clinical practice is unclear. The objective of this observational study was to evaluate the incidence, timing and risk factors of VTE and the impact of different types of thromboprophylaxis on the incidence of VTE. Methods: This was a retrospective cohort study, and included all MM pts newly referred to the M.D. Anderson Cancer Center in 2006. Medical records of these pts were reviewed for the type and site of VTE, the incidence and timing of VTE during the five-year period from the referral date, and the risk factors, including pt demographics, co-morbidities, baseline laboratory values, types of MM and treatment, and types of thromboprophylaxis. Univariate and multivariate proportional hazard models were fitted to find the independent risk factors predictive of VTE. The stepwise selection method was employed to build a multivariate model using variables with p<0.15 in univariate analysis. Results: The cumulative incidence of VTE was 24% (38/159 pts) during the 5-year follow up period. Of the 38 pts with VTE, 25 (66%) had deep vein thrombosis (DVT), 11 (29%) had pulmonary embolus (PE), and 2 had concurrent DVT and PE. Most of the pts (32/38, 84%) had VTE within 1 year from the referral date. The incidence of recurrent VTE among these pts was 27.5% (11/38 pts), for a total of 52 episodes. Since the majority of VTEs and recurrences were within one year, we examined the risk factors for VTE during this period. Treatment with IMiDs + Dex and thromboprophylaxis with LMWH or Coumadin were independent predictive factors as shown below. The incidence of VTE was highest in pts exposed to IMiDs + Dex (30/38 pts), even after discontinuation of treatment, with most episodes (17/30) occurring during the preparation (7/30) or within 30 days (10/30) following hematopoietic stem cell transplantation (HSCT), when most (16/17) pts were not receiving anti-coagulants. Conclusions: These findings suggest that patients treated with IMiDs + Dex are at high risk for VTE, even after discontinuation of this treatment, especially, during and after the HSCT period. Future studies are needed to investigate VTE prevention strategies for this high-risk pt population. Disclosures: No relevant conflicts of interest to declare.

Population Pharmacokinetics of Cyclophosphamide in Patients with Thalassaemia Major Undergoing HSCT Shows Body Weight, CYP450, GST and ALDH Polymorphisms as Covariates Explaining Inter-Individual Variation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1182-1182 ◽  
Author(s):  
Poonkuzhali Balasubramanian ◽  
John Carl Panetta ◽  
Salamun Desire ◽  
Shaji R Velayudhan ◽  
Vikram Mathews ◽  
...  
Keyword(s):  
Body Weight ◽  
Individual Variation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Thalassaemia Major ◽  
Hematopoietic Stem ◽  
Beta Thalassaemia ◽  
Population Pk

Abstract Abstract 1182 Poster Board I-204 Cyclophosphamide (Cy) in combination with busulfan is an important component of myeloablative conditioning regimen used prior to hematopoietic stem cell transplantation (HSCT) for both malignant and non-malignant conditions. We have previously reported up to 20 fold inter-individual variation in the pharmacokinetics (PK) of Cy in patients with beta thalassaemia undergoing HSCT [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 99]. PK parameters of Cy have been shown to be associated with regimen related toxicity and outcome of transplant. To explain the basis of the inter-individual variation in Cy PK, we have developed a population PK model. We analyzed the PK of Cy in consecutive children with beta thalassaemia major who received HSCT from HLA identical matched sibling donor at the Christian Medical College, Vellore from 2001 till 2004. A total of 900 cyclophosphamide concentration measurements from 55 patients were included and correlated with age, sex, body weight and 10 polymorphisms in enzymes involved in the metabolism or biotransformation of Cy namely GST A1, M1, T1, P1, CYP2B6, CYP2C9, CYP2C19 and ALDH genes. Non-linear mixed effects modeling analysis was performed with Monolix (version 2.4, www.monolix.org) to investigate the effect of patient covariates on PK, and to estimate the relative magnitude of inter-individual and inter-occasion variability. A two-compartment pharmacokinetic model was used to describe the data. The pharmacokinetic parameters estimated included elimination rate constant and volume (ke (1/hr), V (L or L/kg)), and the inter-compartmental parameters (k12 and k21 (1/hr)). The distribution of the parameters was assumed log-normal. Body weight was the main covariate which explained the largest portion of the IIV (28% and 20% of V and ke IIV, respectively). In addition, the following genotypes showed differences in the pharmacokinetics: GSTP1*B (1.7X higher ke in MUT versus WT or HET; p<0.05), CYP3A4*1B (2X higher ke in HET versus WT; p<0.05), and ALDH1A1*2 (2X higher ke in HET versus WT; p<0.05). We have developed a population PK model for Cy in thalassaemic children by considering morphological and biological covariates, which explains more than 45% and 22% (V and ke IIV, respectively) of the variation in Cy PK in these patients. This model-based algorithm may be used to design and plan targeted dose therapy in this group of pediatric patients and to predict the risk of toxicity and outcome of HSCT. Disclosures: No relevant conflicts of interest to declare.

Large Conserved Domains Of Low DNA Methylation Maintained By 5-Hydroxymethycytosine and Dnmt3a

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2406-2406
Author(s):  
Mira Jeong ◽  
Deqiang Sun ◽  
Min Luo ◽  
Yun Huang ◽  
Myunggon Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Hox Genes ◽  
Conflicts Of Interest ◽  
P Value ◽  
Genomic Feature ◽  
Conserved Domains ◽  
Hematopoietic Stem ◽  
Genome Wide ◽  
The Impact

Abstract Identification of recurrent leukemia-associated mutations in genes encoding regulators of DNA methylation such as DNMT3A and TET2 have underscored the critical importance of DNA methylation in maintenance of normal physiology. To gain insight into how DNA methylation exerts the central role, we sought to determine the genome-wide pattern of DNA methylation in the normal precursors of leukemia cells: the hematopoietic stem cell (HSC), and investigate the factors that affect alterations in DNA methylation and gene expression. We performed whole genome bisulfite sequencing (WGBS) on purified murine HSCs achieving a total of 1,121M reads, resulting in a combined average of 40X coverage. Using Hidden Markov Model we identified 32,325 under-methylated regions (UMRs) with average proportion of methylation ≤ 10% and by inspecting the UMR size distribution, we discovered exceptionally large “methylation Canyons” which span highly conserved domains frequently containing transcription factors and are quite distinct from CpG islands and shores. Methylation Canyons are a distinct genomic feature that is stable, albeit with subtle differences, across cell-types and species. Canyon-associated genes showed a striking pattern of enrichment for genes involved in transcriptional regulation (318 genes, P=6.2 x 10-123), as well as genes containing a homeobox domain (111 genes, P=3.9 x 10-85). We compared Canyons with TF binding sites as identified from more than 150 ChIP-seq data sets across a variety of blood lineages (>10)19 and found that TF binding peaks for 10 HSC pluripotency TFs are significantly enriched in entirety of Canyons compared with their surrounding regions. Low DNA methylation is usually associated with active gene expression. However, half of Canyon genes associated with H3K27me3 showed low or no expression regardless of their H3K4me3 association while H3K4me3-only Canyon genes were highly expressed. Because DNMT3A is mutated in a high frequency of human leukemias24, we examined the impact of loss of Dnmt3a on Canyon size. Upon knockout of Dnmt3a, the edges of the Canyons are hotspots of differential methylation while regions inside of Canyon are relatively resistant. The methylation loss in Dnmt3a KO HSCs led Canyon edge erosion, Canyon size expansion and addition of 861 new Canyons for a total of 1787 Canyons. Canyons marked with H3K4me3 only were most likely to expand after Dnmt3a KO and the canyons marked only with H3K27me3 or with both marks were more likely to contract. This suggests Dnmt3a specifically is acting to restrain Canyon size where active histone marks (and active transcription) are already present. WGBS cannot distinguish between 5mC and 5hmC, so we determined the genome-wide distribution of 5hmC in WT and Dnmt3a KO HSCs using the cytosine-5-methylenesulphonate (CMS)-Seq method in which sodium bisulfate treatment convert 5hmC to CMS; CMS-containing DNA fragments are then immunoprecipitated using a CMS specific antiserum. Strikingly, 5hmC peaks were enriched specifically at the borders of Canyons. In particular, expanding Canyons, typically associated with highest H3K4me3 marking, were highly enriched at the edges for the 5hmC signal suggesting a model in which Tet proteins and Dnmt3a act concomitantly on Canyon borders opposing each other in alternately effacing and restoring methylation at the edges, particularly at sites of active chromatin marks. Using Oncomine data, we tested whether Canyon-associated genes were likely to be associated with hematologic malignancy development and found Canyon genes were highly enriched in seven signatures of genes over-expressed in Leukemia patients compared to normal bone marrow; in contrast, four sets of control genes were not similarly enriched. Further using TCGA data, we found that expressed canyon genes are significantly enriched for differentially expressed genes between patients with and without DNMT3A mutation (p value<0.05) Overall, 76 expressed canyon genes, including multiple HOX genes, are significantly changed in patients with DNMT3A mutation (p=0.0031). Methylation Canyons, the novel epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development. Disclosures: No relevant conflicts of interest to declare.

PS02.181: RISK FACTORS AND TREATMENT OF DIAPHRAGMATIC HERNIA FOLLOWING IVOR-LEWIS OESOPHAGECTOMY FOR CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 173-173
Author(s):  
Francesco Puccetti ◽  
Paolo Parise ◽  
Uberto Fumagalli Romario ◽  
Andrea Cossu ◽  
Stefano De Pascale ◽  
...  
Keyword(s):  
Risk Factors ◽  
Oesophageal Cancer ◽  
Diaphragmatic Hernia ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Neoadjuvant Chemoradiotherapy ◽  
Occurrence Rate ◽  
P Value ◽  
Ivor Lewis

Abstract Background Oesophagectomy is the mainstay of curative treatment for oesophageal cancer and post-oesophagectomy diaphragmatic hernia (PODH) represents a potentially life-threatening surgical complication characterized by an underestimated occurrence rate and unknown related risk factors. This study analyses the experience of two tertiary designated centers in order to evaluate key elements concerning development and treatment of PODH. Methods A cohort of consecutive patients affected by a clinically resectable oesophageal cancer (any T, any N and M0) underwent Ivor-Lewis oesophagectomy between March 1997 and April 2017 according to three different approaches: totally open incision procedure (OILO), hybrid (HILO) and totally mininvasive to esophagectomy (MILO). All patients were retrospectively observed in the context of a postoperative calendarised follow-up in order to record the incidence and postrepair results of PODH. Results 414 patients underwent Ivor-Lewis oesophagectomy for cancer and 22 (5.3%) developed PODH within a median follow-up period of 16 months (6 - 177). Surgical repair was generally applied by the mean of laparoscopic cruroplasty (77%) with a conversion rate of 24%. Postoperative morbidity did not include early recurrences but exclusively cardio-pulmonary complications (5 patients) with one case of respiratory failure leading to death. The discharge was reached after a median hospital stay of 6 days (2 - 95) while 3 recurrences (14%) occurred over a median follow-up period of 10.1 months. A wide univariate analysis identified statistically significant associations between PODH occurrence and the administration of preoperative chemoradiotherapy, the complete pathological response (CPR) and a lymph node harvest (LNH) larger than 33 stations (p-value of 0.016, 0.001 and 0.024 respectively). The strong influence of an extended LNH was confirmed by the multivariable analyses (0.026) along with CPR which should however be considered as longer survival-related bias. Conclusion The minimally invasive surgery and the neoadjuvant chemoradiotherapy represent a considerable part of multimodal treatment for oesophageal cancer presenting a not statistically significant association with PODH development while a LNH including more than 33 nodes resulted to be an independent risk factor mirroring the extent of surgical demolition in oesophagectomy. Disclosure All authors have declared no conflicts of interest.

scholarly journals Efficacy of Yttrium-90 Iburitumomab Tiuxetan for Early Relapsed/Refractory Indolent B-Cell Lymphoma: A Single Institute Retrospective Analysis in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5333-5333
Author(s):  
Keiichi Nakata ◽  
Shigeo Fuji ◽  
Ryo Nakata ◽  
Kazuhito Tsutsumi ◽  
Shuhei Kida ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Significant Prognostic Factor ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Yttrium 90

Abstract Introduction: Indolent B-cell lymphoma is a type of non-Hodgkin's lymphoma that grows slowly and is not a curative disease. Yttrium-90 (90Y) iburitumomab tiuxetan is used in patients with relapsed/refractory indolent B-cell lymphoma, data is still limited in the rituximab era. In addition, previous studies did not assess the impact of early progression of disease within 2 years (POD24) which was reported to be associated with a poor prognosis in follicular lymphoma (Casulo et al, J Clin Oncol 2015) on the efficacy of 90Y iburitumomab tiuxetan. Thus, here we assessed the efficacy of 90Y iburitumomab tiuxetan in relapsed/refractory indolent B-cell lymphoma, and analyzed the impact of POD24 in this setting. Methods: We retrospectively analyzed the clinical outcomes of 51 patients with a relapsed/refractory indolent B-cell lymphoma who received 90Y iburitumomab tiuxetan at our institute from February 2009 to January 2018. POD24 was defined as progression within 24 months from the beginning of induction chemotherapy. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Results: The median age was 64 years (range 37-88 years) at the time of receiving 90Y iburitumomab tiuxetan, and 29 (56.9%) were male. Disease subtypes were as follows: follicular lymphoma (n=44, 86.3%), mantle cell (n=4, 7.8%), marginal zone (n=2, 3.9%), and MALT lymphoma (n=1, 2.0%). The median number of previous regimens was 2 (range 1-9) and included rituximab-based therapy in all patients. Disease status at the time of receiving 90Y iburitumomab tiuxetan were as follows: complete remission (CR n=3, 5.9%), partial remission (PR n=13, 25.5%), stable disease (SD n=3, 5.9%), progression disease (PD n=32, 62.7%). The median follow-up time was 3.7 years (range 0.3-8.8 years) and overall response rate (ORR) was 94.1% (CR 56.9%, PR 37.3%). The ORR in patients with POD 24 was 95.0% (CR 60.0%, PR 35.0%), compared to 93.5% (CR 54.8%, PR 38.7%) with non-POD24. The 3-year OS and PFS rates for all patients receiving 90Y iburitumomab tiuxetan were 83.6% and 41.0%, respectively. POD24 was a significant prognostic factor for PFS in univariate analysis (1.2 years in patients with POD24 vs. 3.3 years in patients with non-POD24, (P=0.02) (Figure1). In multivariate analysis, POD24 was an independent prognostic marker of PFS (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.22-0.87, P=0.02). Conclusion: 90Y iburitumomab tiuxetan was highly effective in patients with relapsed/refractory indolent B-cell lymphoma patients. However, in patients with POD24, duration of response was short. Thus, another treatment strategy including hematopoietic stem cell transplantation should be considered. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Previous Invasive Fungal Infections on the Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5748-5748
Author(s):  
Gaetano Maffongelli ◽  
Gaetano Maffongelli ◽  
Gaetano Maffongelli ◽  
Laura Cudillo ◽  
Fabio Di Piazza ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
P Value ◽  
Period Range ◽  
European Organization ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
The Impact

Abstract Introduction: Outcome in allogeneic HSCT varies widely depending on disease type, stage, stem cell source, HLA-matched status and conditioning regimen. IFI is a possible complication of HSCT and a prior IFI increases the patient's risk for transplant related mortality due to the possibility of reactivation of the fungal infection. This study aimed to evaluate the impact of a previous IFI history on transplant outcome Methods: We retrospectively collected the clinical data of patients considered eligible for allogeneic HSCT during 2014 at the Rome Transplant Network (RTN), a JACIE accredited metropolitan transplant program established in Rome since 2006. The observation of patients was continued until 31 December 2015. The diagnosis of IFI were defined as possible, probable and proven as established by European Organization for Research and treatment of Cancer. Results: Twenty-one (37%) out of 57 eligible patients had an IFI episode before transplant: 6 of the episodes were proven, 4 probable and 11 possible. Overall, 10 (47%) pneumonia, 4 (19%) gastroenteritis, 3 sinusitis, 2 candida sepsis, 1 meningitis and 1 cutaneous abscess were registered. Five out of 21 patients (23%) died before HSCT versus 2 of 36 patients (5%) without previous documented IFI, [OR 5.31 95% CI 0.93- 30.40 , p value 0.06 Fisher Test], . A larger percentage of patients with past IFI waited HSCT over 6 months from the date of eligibility in comparison with those without previous IFI [43% vs 30% ; OR 1.87 95% CI 0.54-6.40 , p value 0.5 Yates test]; Sixteen (57%) out of 28 dead patients in the pre-transplant period have had a previous IFI episode vs 5(17%) out of patients alive [OR 6.4, 95% CI 1.89-21.68, p value: 0.004 Yates Test]. In the post-transplant period, only 6% of patients with a past IFI, experienced an engraftment in a time of < 15 days, vs 30% of patients without past IFI [OR 4.86 CI 95% 0,5-43,2, p value 0,2 Yates test]. In the post-transplant period, a IFI was diagnosed in 13 (26%) patients; ten (76%) out of 13 patients had a past IFI versus 9 (24%) of the patients without IFI.. [OR 7.87, CI 95% 1,8-34,2, p value 0,005 Yates test].Among the dead HSCT patients, those who had a previous IFI had a lower median survival [160 days (range 22- 480)] compared to patients without a previous IFI who died [196.5 days period (range 20-820)]. Conclusions: A previous IFI episode in the pre transplant period slow the accessibility to the transplant, adversely affects the engraftment, and is significantly associated with increased post-transplant mortality Disclosures No relevant conflicts of interest to declare.

scholarly journals The Risk Factors of the Venous Thromboembolism in Hospitalized Patients with Hematologic Malignancies in the United States: National Inpatient Sample Analysis, 2011-2015

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2310-2310
Author(s):  
Veli Bakalov ◽  
Amy Tang ◽  
Amulya Yellala ◽  
Robert B. Kaplan ◽  
John Lister ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Hematologic Malignancies ◽  
The United States ◽  
Hospitalized Patients ◽  
Lymphocytic Leukemia ◽  
P Value

Abstract Background. Hospital course of patients with hematologic malignancies associated with multiple complications, such as venous thromboembolism (VTE) which significantly affects morbidity and mortality. Compared to the general population patients with hematologic malignancies carry series of risk factors of VTE. Goals of this study were to describe demographic characteristics as well as define the risk factors of VTE in hospitalized patients with hematologic malignancies. Our study was focused on acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Non-Hodgkin's lymphoma (NHL), Hodgkin's Disease (HD), multiple myeloma (MM). Methods. Cohort selection. The Nationwide Inpatient Sample (NIS) database from the Healthcare Cost and Utilization Project (HCUP) of the Agency for Healthcare Research and Quality (AHRQ) for the years 2011 to 2015 was queried for the analysis. We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and corresponding ICD-10-CM codes (for the period of 0ctober 1 - December 31, 2015) in order to identify patients with hematologic malignancies as a primary diagnosis for the hospitalization, and VTE as secondary diagnosis of the hospitalization. In order to determine comorbidities in selected population we used Clinical Classifications Software (CCS) in conjunction with ICD-9-CM codes. Statistical Analysis. Complex weights were used throughout all calculations, enabling appropriate national projections. Percentages in all tables and figures reflect national estimates. Chi-squared and independent t-tests were used for univariate analysis where appropriate. We performed logistic regression analyses to examine the association between risk factor and VTE. In our study p-value <0.05 was considered statistically significant. Data were analyzed using SAS v9.4 (SAS Institute, Cary, NC). Results. A total of 80,078 patients with hematologic malignancies were hospitalized from 2011 to 2015. Males represented 56.1% of the population, majority of the patients were white (69.5%), greater part of the patients were older than 35 years of age (35-65 42.6%, >65 48.8%) (Table 1). Main comorbidities during hospitalization were anemia (58.1%), followed by hypertension (49.1%), fluid disorders (40.1%) and coagulopathies (24.5%) (data not shown). Rate of VTE in all patients was 5.3% and was evenly distributed among genders and races. Rate of VTE was highest in patients with AML (6.6%) followed by ALL (6.1%), and NHL (6.0%), and lowest in patients with MM (3.49%) followed by CLL (3.31%), and CML (3.31%) (Table 2). The highest risk of VTE among patients with hematologic malignancies were in patients receiving chemotherapy (OR=1.684 95% CI=1.567-1.809) followed by infections such as pneumonia (OR 1.313 95% CI 1.201-1.436) and sepsis (OR=1.66 95% CI=1.524-1.621). Other comorbidities such as congestive heart failure, liver disease, coagulation disorders and acute renal failure were associated with significantly higher risk of VTE with OR varying from 1.1 to 1.2. (Table 3) Conclusions. In this retrospective large US inpatient database analysis, we found that average rates of VTE in patients with hematologic malignancies was 5.3% and was highest in patients with AML. Patients receiving chemotherapy had highest risk of developing VTE during hospitalization followed by patients with infections such as sepsis and pneumonia. Higher rates of VTE in patients receiving chemotherapy and patients with sepsis was previously described, however our findings indicate that rate of VTE remain high in these population. Findings of our study can be used for development of the appropriate antithrombotic prophylactic strategies in hospitalized patients with hematologic malignancies. Disclosures No relevant conflicts of interest to declare.

Analysis of Risk Factors for Overall Survival at 5 Years in 96 Patients after Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4669-4669
Author(s):  
Jiahua Ding ◽  
Jiahua Ding
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Blood Type ◽  
Hematopoietic Stem

Abstract Abstract 4669 The aim was to analyze the risk factors for overall surrival at 5 years in 96 patients undergoing allogeneic hematopoietic stem cell transplantation by retrospec- tive analysis. 11 clinical parameters were selected for univariate analysis by using a Cox regression: age, sex, morbid rate, HLA locus, donor type, donor-recipient blood type, conditioning regimen, aGVHD, HC, VOD and IP. Factors significant at the 0.1 level on univariate analysis were evaluated by multivariate analysis by a Cox regres- sion. The cumulative incidence of aGVHD and patients survival rate were calculated by the method of Kaplan and Meier. 95 patients achieved sustained donor engraftment except one patients not. The median time of leukocyte engraftment was 13 days. The incidence rates of grades I∼IV acute GVHD was 43.75%.one of grades I aGVHD was 11.46%,gradesIIaGVHD was 19.79%,grades III∼‡WaGVHD was 12.50%. Ten patients relapsed and 38 dead,the overall survival at 5 years was 60.42%. The COX method analysis showed that aGVHD and disease states at transplant significantly im- proved OS. In conclusions, The key to improve the outcome of allo-HSCT is to red- uce the incidence and severity of aGVHD, meanwhile selecting the suitable disease state of CR1 at transplantation to treat the patients in advanced refractory and recure- nt situation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Human Genetic Diversity Alters Therapeutic Gene Editing Off-Target Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3993-3993
Author(s):  
Linda Yingqi Lin ◽  
Samuele Cancellieri ◽  
Jing Zeng ◽  
Francesco Masillo ◽  
My Anh Nguyen ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Clinical Trials ◽  
Genome Editing ◽  
Gene Editing ◽  
Conflicts Of Interest ◽  
African Ancestry ◽  
Great Promise ◽  
Personal Genome ◽  
Hematopoietic Stem ◽  
The Impact

Abstract CRISPR gene editing holds great promise to modify somatic genomes to ameliorate disease. In silico prediction of homologous sites coupled with biochemical evaluation of possible genomic off-targets may predict genotoxicity risk of individual gene editing reagents. However, standard computational and biochemical methods focus on reference genomes and do not consider the impact of genetic diversity on off-target potential. Here we developed a web application called CRISPRme that explicitly and efficiently integrates human genetic variant datasets with orthogonal genomic annotations to predict and prioritize off-target sites at scale. The method considers both single-nucleotide variants (SNVs) and indels, accounts for bona fide haplotypes, accepts spacer:protospacer mismatches and bulges, and is suitable for personal genome analyses. We tested the tool with a guide RNA (gRNA) targeting the BCL11A erythroid enhancer that has shown therapeutic promise in clinical trials for sickle cell disease (SCD) and β-thalassemia (Frangoul et al. NEJM 2021). We find that the top predicted off-target site is produced by a non-reference allele common in African-ancestry populations (rs114518452, minor allele frequency (MAF) = 4.5%) that introduces a protospacer adjacent motif (PAM) for SpCas9. We validate that SpCas9 generates indels (~9.6% frequency) and chr2 pericentric inversions in a strictly allele-specific manner in edited CD34+ hematopoietic stem/progenitor cells (HSPCs), although a high-fidelity Cas9 variant mitigates this off-target. This report illustrates how population and private genetic variants should be considered as modifiers of genome editing outcomes. We expect that variant-aware off-target assessment will be required for therapeutic genome editing efforts going forward, including both ongoing and future clinical trials, and we provide a powerful approach for comprehensive off-target prediction. CRISPRme is available at crisprme.di.univr.it. Disclosures No relevant conflicts of interest to declare.

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