Investigation of CLL-Susceptibility Loci with Monoclonal B-Cell Lymphocytosis (MBL) Risk and Confirmation of Recently Reported CLL-Susceptibility Loci

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2443-2443
Author(s):  
Susan Slager ◽  
Kari Rabe ◽  
Sara Achenbach ◽  
Celine Vachon ◽  
Lynn Goldin ◽  
...  
Keyword(s):  
Mayo Clinic ◽  
Conflicts Of Interest ◽  
The United States ◽  
European Population ◽  
Lymphocytic Leukemia ◽  
Control Measures ◽  
Trend Test ◽  
P Value ◽  
Susceptibility Loci ◽  
Single Nucleotide Variants

Abstract Abstract 2443 Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association (GWA) study of CLL identified genetic variants located on chromosomes 2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13 that increased the risk of CLL within a European population. We replicated 5 of these 6 loci in an independent sample of CLL cases and controls from the United States. We now investigate whether these loci also influences MBL, a reported precursor condition of CLL. In addition, a follow-up analysis of the initial GWA study identified four more CLL-susceptibility loci on 2q37.3, 8q24.21, 15q21.3, and 16q24.1. Herein, we also evaluate the association of these four loci with risk of CLL. Methods: Peripheral blood samples were obtained from three ongoing studies: the Genetic Epidemiology CLL (GEC) Consortium, the Mayo Clinic non-Hodgkin lymphoma (NHL)/ CLL study, and the Mayo Clinic Biobank. We implemented rigorous genotyping quality-control measures, and successfully genotyped a total of 407 CLL patients, 965 controls, and 60 MBLs from these studies. Within each locus, the previously reported single nucleotide variants (SNPs) or variants in high linkage disequilibrium (LD) with the previously reported SNPs were evaluated with risk of MBL or CLL. Tests for association was done using the Cochran-Armitage trend test, and unconditional logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for CLL or MBL risk Results: In our evaluation of the six initially reported CLL-susceptibility loci (2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13) with MBL risk, we found three of the six had suggestive associations (p-value < 0.20) with ORs comparable to and in the same direction as those observed from CLL risk. Our strongest finding was with rs13397985 at locus 2q37.1 (OR= 1.56; 95% CI: 1.05, 2.31; p-trend = 0.041), followed by rs17483466 at locus 2q13 (OR= 1.49; 95% CI: 0.99, 2.24; p-trend = 0.074). As expected given our previously reported findings with CLL risk, the association between rs11083846 on chromosome 19q13 and MBL risk was not significant (p-trend = 0.70). Of the four recently reported CLL-susceptibility loci SNPs located on 2q37.3, 8q24.21, 15q21.3, and 16q24.1, we found all to be associated with CLL risk but one. Specifically, the strongest association was seen for locus 8q24.21 (best tagged SNP rs1021955; OR = 1.37; 95% CI: 1.10, 1.70; p-trend = 0.005), followed by locus 16q24.1 (best tagged SNP rs305065; OR= 0.77; 95% CI: 0.61, 0.97; p-trend = 0.024). However, we found no associations for locus 15q21.3 for the previously reported SNP nor for any SNPs in LD with the previously reported SNP. Conclusions: Our MBL results provide additional robust genetic evidence that MBL is a precursor to CLL and that it shares similar underlying genetic predisposition. Also our results confirm three of the four recently reported CLL-susceptibility loci and further support the role of a genetic basis in the etiology of CLL. More research is needed to elucidate the potential manner in which these genetic loci function in CLL or MBL. 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.

Increasing Genetic Complexity Predicts for Inferior Outcomes Following Reduced-Intensity Conditioning Allogeneic Transplant for Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3090-3090 ◽  
Author(s):  
Samantha M. Jaglowski ◽  
Nyla A. Heerema ◽  
Patrick Elder ◽  
John C. Byrd ◽  
Steven Devine ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Allogeneic Transplant ◽  
Reduced Intensity Conditioning ◽  
Genetic Complexity ◽  
Reduced Intensity

Abstract Abstract 3090 Several biologic markers have been identified which predict an unfavorable course in CLL. Reduced-intensity conditioning (RIC) allogeneic transplant may be able to overcome some of these. This retrospective analysis evaluates the effect of cytogenetics, including metaphase cytogenetics, on outcomes with RIC-allogeneic SCT. From 2005–2011, 51 RIC-allogeneic SCTs were performed at The Ohio State University for CLL. There were 38 males (74.5%) and 13 females (25.5%) with a median age of 58 (range 37–73). The median interval between diagnosis and SCT was 48 months (range 9–270). Before SCT, a median 4 lines of chemotherapy were given (range 1–11). One patient was in CR at the time of SCT, 39 were in PR, and 11 had stable or progressive disease; the median CMI was 3 (range 0–7). Fifty-nine percent of patients had del17; 53% had 3 or more abnormalities on metaphase cytogenetics, and 37% had 5 or more abnormalities. The source was PBSC in 48 (94%), BM in 1 (2%) and CB in 2 (4%). Of the PB or BM SCTs, 19 donors (39.6%) were related and 29 (60.4%) were volunteer; 45 (92%) were matched and 4 (8%) had a 1 allele mismatch. There were 21 (41%) pairs with an ABO mismatch and 16 (31.4%) pairs with a gender mismatch. Conditioning was Flu/Bu +/− ATG in 42 patients (82.2%), FluCamTBI in 6 (11.8%), FluCy in 1 (2%), and FluCyTBI-based in 2 receiving CB (4%). Following transplant, 34 (66.6%) developed AGVHD (gr 1–2: 28, gr 3–4: 6) and 27 of 48 evaluable patients (56.3%) developed CGVHD (limited: 7, extensive: 20). With a median follow-up of 17.3 months (range 1–60), the estimated 3-year OS and PFS following transplant were 56.5% and 42.9% respectively. Table 1 lists variables which had a p-value of ≤0.1 on univariate analysis. The presence of del13 and ≥5 karyotype abnormalities remained significant on multivariate analysis for OS while ≥5 karyotype abnormalities and conditioning with an alemtuzumab-containing regimen were significant for PFS (Table 2). The estimated 3 year OS for patients with del13 was 32.2% and 23% for patients with ≥5 karyotype abnormalities, compared with 72.7% and 73.5% for those without, respectively. The estimated 3-year PFS was 21.5% for patients with ≥5 karyotype abnormalities and 0% for patients with an alemtuzumab-containing regimen and 53.9% and 49.3% for those without, respectively.Table.Variables included in multivariate analysis model.Variablelogrank p-valuePFSOSAge ≥550.0072*…Del13 ≥4.7%0.0039*Del17p ≥5.7%0.0019*0.0878Karyotype abnormalities ≥50.0002*0.0138*Karyotype abnormalities ≥30.0186*0.0623Largest node ≥4 cm0.0277*…Marrow involvement ≥50%0.0752…Alemtuzumab conditioning…0.0001*GVHD prophylaxis0.0001*0.0374*HLA mismatch<0.0001*…*statistically significant at p<0.05Table 2.Multivariate analysis of OS, PFS.OSVariableHR95% CIp-valueDel13q<4.7%1≥4.7%3.581.36 to 9.420.01Karyotype<41≥55.161.97 to 13.560.001PFSVariableHR95% CIp-valueConditioningno alemtuzumab1alemtuzumab9.83.28 to 29.290Karyotype<41≥54.351.67 to 11.280.002 Due to small numbers, the alemtuzumab data should be interpreted with caution, but are consistent with previous reports. Increasing genomic complexity is known to predict for diminished chemosensitivity. Accordingly, the presence of 5 or more abnormalities on metaphase cytogenetics was demonstrated to be a poor prognostic indicator for both PFS and OS following SCT. There was substantial, but not universal, overlap among patients with del17, del13, and highly complex karyotype; this interplay merits further consideration. Better understanding of the evolution of genetic complexity will better define how to time transplant to allow for maximum benefit to those patients likely to evolve.Figure 1.OS and PFS by KaryotypeFigure 1. OS and PFS by Karyotype Disclosures: No relevant conflicts of interest to declare.

Vegf and bFGF Single-Nucleotide Polymorphisms In Chronic Lymphocytic Leukemia: Impact On Susceptibility

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5287-5287
Author(s):  
Sandra Ballester ◽  
Begoña Pineda ◽  
Eduardo Tormo ◽  
Blanca Navarro ◽  
Ariadna Perez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Expression Patterns ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Exact Test ◽  
Cd38 Expression ◽  
Mutational Status ◽  
The Individual

Abstract Background B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical outcome. Recent studies have identified a number of different molecular prognostic markers (including mutational status of the IgVH gene, ZAP70 and CD38 expression) that allow to discriminate patients in prognostic subgroups. However, different expression patterns of angiogenic factors as VEGF, VEGFR1 and bFGF have been related with B-CLL susceptibility and treatment requirements. We have analyzed the polymorphisms: -710 C/T in VEGFR1, rs1109324, rs1547651, rs3025039 (936C/T) and rs833052 in VEGF and rs1449683 (223 C/T) in bFGF in order to determine the possible association with susceptibility in B-CLL. Methods Peripheral blood samples from 230 B-CLL patients and 476 healthy controls were genotyped using probes TaqMan SNP Genotyping Assays. Samples were providing from the Hospital Clinic of Valencia. Four SNPs in the VEGF gene, one SNP in the bFGF gene and one SNP in the VEGFR1 gene were evaluated. Statistical analysis was performed using SNPStats program (Catalan Institute of Oncology) and Fisher's exact test was applied to evaluate the significance. Results We have observed an increased frequency of the T allele in the rs1449683 SNP [OR 1.62 (95% CI: 0.98-2.66) p-value =0.063] and in the rs1547651 SNP [OR 0.72 (95% CI: 0.51-1.03), p-value=0.072] in our B-LLC patients when compared to control subjects. Moreover we observed that T allele carriers of rs3025039 (VEGF) have a significant protective effect concerning this disease [OR 0.59 (95% CI: 0.39-0.89) p-value=0.009]. Conclusion Our data indicate an increased frequency of the T allele in polymorphisms rs1449683 (bFGF) and rs1547651 (VEGF) in the group of patients, which possibly account for the individual susceptibility to develop B-CLL. On the other hand the data provided suggest that the T allele of VEGF rs3025039 is likely important genetic marker of susceptibility to B-CLL. Further studies regarding the role of pro-angiogenic markers in B-CLL would be beneficial to help elucidate pathogenic pathways in this disease. Disclosures: No relevant conflicts of interest to declare.

Baseline Symptoms, Female Sex, and Younger Age Are Correlated with Higher Levels of Peri-Collection Pain, Symptoms, and Persistent Discomfort One Year after Related Donor BM and PBSC Donation: An Analysis of the Related Donor Safety Study (RDSafe)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3847-3847
Author(s):  
Michael A. Pulsipher ◽  
Brent R. Logan ◽  
Deidre M. Kiefer ◽  
Pintip Chitphakdithai ◽  
Galen E. Switzer ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
The United States ◽  
P Value ◽  
Unrelated Donor ◽  
Moderate Pain ◽  
Safety Study ◽  
Peripheral Blood Stem Cells ◽  
Donor Safety ◽  
Related Donor ◽  
Pain Symptoms

Abstract Prospective data regarding donation related toxicities and time to recovery in related donors (RDs) of bone marrow (BM) and peripheral blood stem cells (PBSC) are limited, in contrast to significant data available regarding unrelated donor experiences. To address this lack of data in RDs, the NHLBI-funded Related Donor Safety Study (RDSafe; NCT00948636) prospectively enrolled RDs of all ages between 2010 and 2013 at 54 transplant centers in the United States. RDs were assessed for pre-donation comorbidities and health status, and then followed for 1 year after donation, collecting detailed information on adverse events, pain levels and 10 collection-related NCI-CTC symptoms. This report describes baseline, peri-donation, and through 1 year post pain/symptoms for RDs aged 18-60: 124 BM (38 centers, med age 33, 48% female) and 919 PBSC (42 centers, med age 49, 44% female). Results: About 20% of RDs reported pain and NCI-CTC symptoms at baseline, mostly grade 1, with females reporting pain/symptoms more often than males (see figures). Pain occurred in approximately 80% of donors surrounding collection with other symptoms occurring in 50-70% of donors. Pain and symptoms persisted in 10-20% of RDs at 1, 6, and 12 months; pain/symptoms returned to baseline in only a few categories assessed, but mostly remained elevated from baseline at 1 year. In addition, for both males and females, at 1 year grade 2-4 pain or symptoms were 2-3 times baseline rates. Multivariate analysis was performed on PBSC donors, where numbers were sufficient to look at key risk factors (see table). Females had more grade 3-4 pain at collection, and grade 2-4 pain and symptoms at 1 year. Age differences were noted, with RDs age 30-39 experiencing the highest amount of pain and symptoms and RDs age 50-60 experiencing less pain compared to donors aged 18-29. Pain or symptoms at baseline were important predictors of higher levels of reported pain/symptoms, respectively, during the collection and also higher risk of grade 2-4 pain at 1 year. Conclusions: One in 5 RDs have mild/moderate pain and/or symptoms at baseline, and the presence of pain/symptoms at baseline increases risk for experiencing higher levels of pain/symptoms during collection. Although the majority of RDs return to baseline status within a month of donation, >10-20% of RDs have lingering pain/symptoms 6-12 months after donation, and rates of grades 2-4 pain and symptoms at 1 year are more than double baseline. Females have higher grades of pain with collection and more grade 2-4 pain and symptoms at 1 year compared to males. RDs should be informed of the risk of mild/moderate pain/symptoms lingering through the first year after donation. Ongoing efforts to correlate baseline comorbidities of RDs with outcomes should allow RDs to be better informed of risk and potentially identify clinical risk profiles where RDs should be deferred. *Pain = max grade 2-4 or 3-4 2 days post-donation of BM or day+5 of PBSC collection (collection day 1). **Symptoms = fever, fatigue, rash, local site reactions, nausea, vomiting, anorexia, insomnia, dizziness, and syncope Table 1. MV Analysis of PBSC RDs for pain and donation-related symptoms: Odds Ratio (p-value). Pain* Symptoms** day+5 Grd 2-4 day+5 Grd 3-4 1yr Grd 2-4 day+5 Grd 2-4 1yr Grd 2-4 Female 1.667 (0.010) 1.667 (0.016) 1.887 (0.041) Age (0.001) (0.008) (<0.001) Age 18-29 1.0 1.0 1.0 Age 30-39 0.76 (0.306) 2.2 (0.036) 2.48 (0.008) Age 40-49 0.68 (0.115) 1.46 (0.283) 1.49 (0.216) Age 50-60 0.45 (<0.001) 0.93 (0.836) 0.93 (0.830) Baseline pain overall (0.001) (0.004) (<0.001) Baseline pain Grd 0 1.0 1.0 1.0 Baseline pain Grd 1 2.2 (<0.001) 2.6 (0.06) 2.95 (<0.001) Baseline pain Grd 2-4 4.73 (<0.001) 4.4 (0.002) 3.95 (<0.001) Baseline sx overall (<0.001) Baseline sx Grd 0 1.0 Baseline sx Grd 1-4 2.16 (<0.001) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3323-3323 ◽  
Author(s):  
Lorenzo Falchi ◽  
Michael Keating ◽  
Susan Lerner ◽  
Xuemei Wang ◽  
Kplola Y Elhor Gbito ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Prognostic Impact ◽  
Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

scholarly journals Predictors of Increase in Emergency Room (ER) Visits and Hospitalizations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Chemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4509-4509
Author(s):  
Bruce Feinberg ◽  
Brad Schenkel ◽  
Ali McBride ◽  
Lorie Ellis ◽  
Menaka Bhor ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Healthcare Resource ◽  
The United States ◽  
Healthcare Resource Utilization ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Oncology Care ◽  
Comorbidity Index ◽  
Significant Covariates

Abstract Background: Acute care interventions negatively impact patients' quality of life and represent one of the major cost drivers in oncology care. Understanding the predictors for increased healthcare resource utilization is essential for better management of patients with CLL. This study evaluated predictors for ER visits and hospitalizations in patients with CLL treated with chemotherapy. Methods: Using claims data (MORE2 Registry®), patients receiving chemotherapy for CLL were retrospectively identified by ICD-9 codes (204.1X) during a 48-month period (August 2009-2013). Patients with secondary malignancies, pregnancy codes, and age <18 were excluded. Univariate regression analysis was conducted to determine covariates associated with an increase in ER visits and hospitalizations. Results for significant variables were reported as odds ratio/p-value. Odds ratio >1 indicates increase in chance of event. Results: A total of 2,013 patients with CLL were identified. Median age at diagnosis was 72 years, 61% were male, 34% were treated in the relapsed setting, 42% had ER visits, and 39% were hospitalized throughout their treatment history. Significant increases in ER visits and hospitalizations were associated with the following variables (OR/p-value): age (ER: 1.015/.001, hospitalization: 1.001/.038), Charlson comorbidity index (ER: 1.253/.013, hospitalization: 1.038/.018), supportive care use (ER: 2.087/<.001, hospitalization: 2.429/<.001), number of CLL related adverse events (ER: 12.311/<.001, hospitalization: 29.467/<.001), chemotherapy duration (ER: 1.001/<.001, hospitalization: 1.001/<.001), bendamustine use (ER: 1.404/.001, hospitalization: 1.381/.002), fludarabine use (ER: 1.405/<.001, hospitalization: 1.395/.001), Northeast region of the United States (ER: 1.293/.008, hospitalization: 1.321/.005), and treatment following relapse (ER: 3.413/<.001, hospitalization: 4.018/<.001). Significant covariates associated with a decrease in hospitalizations or ER visits were not found. Conclusions: This retrospective study demonstrated that patient demographic and clinical characteristics as well as chemotherapy choice were associated with ER visits and hospitalizations in patients with CLL. ER visits and hospitalizations have similar drivers. These data warrant consideration of age and comorbidity-adjusted treatment choice in CLL patients who need active treatment with antineoplastics. Disclosures Feinberg: Janssen Scientific Affairs, LLC: Consultancy. Schenkel:Janssen Scientific Affairs, LLC: Employment. McBride:Janssen Scientific Affairs, LLC: Consultancy. Ellis:Janssen Scientific Affairs, LLC: Employment. Bhor:Janssen Scientific Affairs, LLC: Consultancy. Radtchenko:Janssen Scientific Affairs, LLC: Consultancy. Lal:Janssen Scientific Affairs, LLC: Consultancy.

scholarly journals Cost and Efficacy of Upfront Plerixafor Versus a “Just-in-Time” (JIT) Approach in Hematopoietic Progenitor Cell (HPC) Mobilization

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1127-1127 ◽  
Author(s):  
Lauren Westfall Veltri ◽  
Aaron Cumpston ◽  
Alexandra Shillingburg ◽  
Christopher Lipinski ◽  
Sijin Wen ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Karnofsky Performance Status ◽  
Wholesale Price ◽  
The United States ◽  
Cell Yield ◽  
Hematopoietic Progenitor Cell ◽  
Just In Time ◽  
P Value ◽  
The Mean

Abstract HPC mobilization with plerixafor (Plex) plus G-CSF (G+P) results in superior CD34+ cell yield, when compared to mobilization with G-CSF alone in patients with myeloma and lymphoid malignancies. However, Plex-based approaches are associated with high mobilization costs. To circumvent higher costs, several institutions use a so-called JIT approach, where Plex is only administered to patients likely to fail mobilization with G-CSF alone. Whether such a JIT-Plex approach is cost effective has not been confirmed to date. We present here, a single institution comparative analysis of 137 patients with myeloma and lymphoma who underwent mobilization with 2 different approaches of Plex utilization. Between Jan 2010-Oct 2012 (n=77) patients received mobilization G-CSF (10 μg/kg) for 5 days and Plex (0.24 mg/kg) on the evening of day four, 11 hours before apheresis the following day (G+P). To reduce mobilization costs between Nov 2012-Jun 2014 (n=60) patients were mobilized with JIT-Plex where Plex was only administered to patients likely to fail mobilization with G-CSF alone (i.e. patients with a day 4 peripheral blood (PB) CD34+ count of <10/μL, or those with day 1 yield of < 1.0 X 106 cells/kg or day 1+2 yield of <1.5 X 106 cells/kg ABW. Mobilization failure was defined as inability to collect at least 2 X 106 /kg CD 34+ cells. Patients in G+P had a higher mean peak PB CD34+ cell count (77 vs. 33.1 cells/μL, p<0.001) and a higher mean CD34+ cell yield on day 1 of collection (4.4 X 106 vs. 2.4 X 106 cells/kg ABW, p=0.0005). The mean total CD34+ cell collection was also higher in G+P (6.64 X 106 vs. 4.81 X 106 cells/kg ABW, p=0.0068). In the JIT-Plex group 41% (n=24) completed adequate HPC collection without Plex. Mobilization failure was noted in 5 patients in the G+P group (3 were salvaged with bone marrow harvest) and 2 patients in the JIT-Plex group. Two patients in either group did not proceed to AHCT as a result of mobilization failure. The mean Plex doses utilized in JIT-Plex was lower (1.3 vs. 2.1, p=0.0002), however 21% (n=16) in the G+P group completed apheresis on day 1 compared to only 6.9% (n=4) in JIT-Plex, p=0.0094. Cost analysis was estimated based on actual sales price (actual wholesale price AWP – (AWP X 0.2)) for mobilization agents and the United states (US) Department of Health and Human Services Centers for Medicaid Services (HHS/CMS) reimbursement rates for procedural costs associated with mobilization, apheresis or cryopreservation. The mean estimated cost was higher in the G+P group ($28,448 vs. $24,852, p=0.0315). Our analyses, for the first time confirms that mobilization with JIT-Plex allows for a safe, adequate and cost efficient strategy for HPC collection. Baseline Patent Characteristics at Time of Mobilization Table Mobilization Strategy Upfront Plerixafor + G-CSF (n=77) G-CSF + Just-in-time Plerixafor (n=60) p-value Disease Myeloma Lymphoma 46 (60%) 31 (40%) 30 (50%) 30 (50%) 0.29 Mean age, years (range) 58 (23-75) 57 (22-75) 0.45 Male gender 42 (55%) 33 (57%) 0.92 Race: Caucasian 73 (97%) 57 (98%) 1.0 Lines of prior therapy, mean 1.5 1.8 0.3 Prior Radiation 13 (18%) 12 (21%) 0.66 Mean KPS (range) 80 (70-100) 80 (60-100) 0.75 HCT-CI Score (mean) 2 2 0.36 Abbreviations: G-CSF-granulocyte-colony stimulating factor (filgrastim); KPS-Karnofsky performance status; HCT-CI- hematopoietic cell transplantation-specific comorbidity index Disclosures No relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia Treatment in México: Up to Half Patients May Not Requiere Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Luisa Fernanda Sánchez-Valledor ◽  
Carmina Alejandra Córdova-Ramírez ◽  
Gilberto David Elias-de-la-Cruz ◽  
Montserrat Rivera-Álvarez ◽  
Antonio Cruz-Mora ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Hematologic Malignancy ◽  
Stage Iv ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Simplified Approach ◽  
Anti Cd20

Introduction Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm which represents the most frequent hematologic malignancy in Caucasians. Every year, there are15,000 new diagnoses and 5000 CLL deaths in the United States. Its prevalence in México and other non-Caucasian populations is substantially lower and the clinical course of CLL patients has been described to be less aggressive Methods All consecutive patients seeking medical care after 1983 in our institution as a result of CLL and followed for at least 3 months were entered in the study. The study was approved by the institutional review board. The treatment of patients was withheld in: (a) Persons with CLL Rai stage 0 or 1, until progression; (b) Persons with CLL Rai stage 2-4, with a negative expression of ZAP-70 until progression. Progression was defined by: Anemia, thrombocytopenia, massive symptomatic or progressive splenomegaly and or adenopathy, progressive lymphocytosis (&gt;50% increase in two months or lymphocyte doubling timeless than 6 months), autoimmune hemolytic anemia not responding to standard therapies, or constitutional symptoms: Weight loss greater than 10% in 6 months, unexplained night sweats or unexplained fever for 2 or more weeks. Refractoriness of the disease was defined as progression despite treatment for a minimum of 3 months. Results Among 98 patients with CLL who were accrued in the study between 1983 and 2019, 49 (50%) were followed for three or more months and accordingly, entered in the study. Median follow up time of the patients is 61 months (95% CI 46.1-75.8). There were 15 females and 34 males, the median age was 65 years (range 23-86). According to the Rai staging system, there were 24 stage 0, 7 stage I, 8 stageII, 0 stage III and 10 stage IV; 80% of patients were identified in stages 0-II. In 28 patients a complete immune phenotype of the malignant cells was analyzed: 89% of patients were ZAP-70 negative (ZAP expression in less than 20% of malignant cells), 79% expressed CD5, 100% CD19 and 86% CD23. Three patients were born in European countries, whereas 6 had an immediate European ancestor, indicating that a Caucasian background was identified in 9/49patients (18%). There were no instances of T-cell CLL. Median OS for all the patients has not been reached, being above 247 months (20 years). The OS of patients given or not any treatment was not statistically different (p= 0.09). It is clear that patients who needed treatment did worse than those not needing treatment but the differences were not significant. Patients with advanced stages (III and IV) had a worse outcome than those in early stages. Median OS for patients given no treatment at all has not been reached and is above 247 months; median OS for patients given CP was 115 months, median OS for those given FC has not been reached and is above 132 months, whereas median OS for persons given FCR has not been reached, being above 136 months; all these differences are not statistically significant. Eight of 49 patients were found to be refractory to treatment; they were receiving CP (5 cases); FC (2 cases) and FCR (one case); these refractory patients were given, FCR (7 cases) and rituximab/ifosfamide/carboplatin/etoposide (one case). No patient had to be given cladribine, pentostatin, alemtuzumab (anti-CD52), bendamustine, ofatumumab (anti-CD20), obinutuzumab (anti-CD20), lenalidomide, ibrutinib nor idelalisib. Conclusion In the era of novel anti-CLL drugs, we have found that the clinical course of these patients in México seems to be less aggressive than in Caucasian populations and that, in consequence, circa 50% of them do not need any treatment at all. In those needing treatment, the use of a simplified approach and taking advantage of improved supportive care measures, acceptable results are obtained even if all of the new CLL drugs are not employed. These observations may be critical in developing countries, where the cost of the drugs will continue to be a major factor in choosing therapies. Disclosures No relevant conflicts of interest to declare.

Identification of New Recurrent Multiple Small Interstitial Deletions Affecting Genes Coding for Kinases in Chronic Lymphocytic Leukemia (CLL): a New Pathogenic Mechanism?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 672-672
Author(s):  
Andrea Rinaldi ◽  
Michael Mian ◽  
Davide Rossi ◽  
Francesco Forconi ◽  
Clara Deambrogi ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Gene Activation ◽  
Copy Number Variations ◽  
Current Data ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
P Value

Abstract Abstract 672 BACKGROUND: CLL is the most common adult-onset leukemia in the Western world. The most common known genetic lesion is the 13q14.3 deletion targeting MIR15/MIR16. We applied a very high resolution array to identify new genetic lesions in CLL. METHODS: 266 CLL samples were analyzed with Affymetrix Human Mapping 6.0 arrays, comprising over 1,8 million probes with a median distance of less than 1 Kb. Copy number was inferred using the circulary binary segmentation (CBS) algorithm. Minimal common regions (MCR) were defined using a modified version of the algorithm by Lenz et al. (PNAS 2008), specifically altered to identify very small genomic losses covered by only 2-9 probes and occurring in at least 5% of the cases (mMCRs). mMCRs having 100% overlap with known copy number variations were discarded. RESULTS: mMCRs occurred in 75 known genes. The most commonly affected genes were CDC73 (cell division 73; 63% of the cases, 3 probes), RREB1 (ras responsive element binding protein 1; 60%, 5 probes), JAK2 (47%, 8 probes), CCDC88A (AKT-phosphorylation enhancer,; 47%, 3 probes), AKT3 (43%, 4 probes). Other affected genes at a lower frequency were PIK3CA (26%), EGFR (25%), XRCC4 (18%), JAK1 (18%), PTPRK (15%), RB1 (14%), ERBB2 (10%), PDGFRA (8%), FHIT (7%). A functional analysis performed with DAVID 2008 (http://david.abcc.ncifcrf.gov/) identified the terms “anti-oncogene” and “tyrosine-protein kinase” and five KEGG (http://www.genome.jp/kegg/) pathways (“prostate cancer”, “non-small cell lung cancer”, “pancreatic cancer”, “endometrial” cancer”) as enriched among the 75 genes with a statistically significant p-value <0.05 after Benjamini multiple test correction. Besides tumor suppressor genes such as RB1 and FHIT, very interestingly, many of the genes appeared to code for kinases and for oncogenes. The mMCRs occurred in intronic regions, and apparently targeted highly conserved regions. These regions might represent regulatory loci and their loss may cause gene activation. Validation of selected genes is on-going. CONCLUSIONS: The application of high resolution arrays on a large series of CLL samples has shown frequent small interstitial deletions targeting a discrete number of genes, highly enriched for transcripts coding for kinases. A potential mechanism of action might be the loss of regulatory regions determining gene activation. Once validated, the current data would provide the basis to explore the rationale for the use of kinase inhibitors in the treatment of CLL. Disclosures: No relevant conflicts of interest to declare.

Over Expression of MN1 Accelerates Leukemia Onset and Confers Resistance to Chemotherapy by Suppression of p53 and Bim

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2501-2501
Author(s):  
Timothy Pardee
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
The United States ◽  
Retroviral Vectors ◽  
Genetic Alterations ◽  
P Value ◽  
Over Expression ◽  
Resistance To Chemotherapy ◽  
Worse Prognosis

Abstract Abstract 2501 Acute myeloid leukemia (AML) is an aggressive malignancy of immature myeloid precursors that leads to progressive marrow failure and death. This disease will affect approximately 12,950 people this year in the United States, causing 9,050 deaths. The most common treatment is combination chemotherapy containing cytarabine (Ara-C) and an anthracycline. Resistance to these therapies is a major problem and most patients diagnosed with AML will ultimately die from resistant disease. AML is a genetically diverse malignancy and karyotype can be used to delineate prognosis. There is a clear link between chromosomal abnormalities and resistance to chemotherapy as complete remission rates are significantly different between groups. Additionally, there are now multiple submicroscopic genetic alterations that have been found to effect prognosis. These alterations can be mutations, over or under expression of a particular gene. MN1 is a transcription co-factor and several studies have demonstrated its over-expression confers a worse prognosis. High MN1 expressers were less likely to achieve a remission and had lower 3 year survival rates. Additionally, over expression of MN1 in murine bone marrow leads to AML in transplanted recipients and predicts for resistance to ATRA in elderly AML patients. The effect of MN1 on response to standard chemotherapy is currently unknown. To determine the effect of MN1 expression on therapy response we infected murine MLL-ENL driven AML cells with retroviral vectors that expressed MN1. When partially infected populations were exposed to a titration of either Ara-C or doxorubicin MN1 expressing cells were significantly enriched compared to untreated controls. When cells were exposed to a titration of Ara-C the MN1 expressing cells were enriched up to1.69 fold and when exposed to doxorubicin were enriched up to 3.80 fold. Both results were highly statistically significant with p values of 0.004 and < 0.0001. Consistent results were obtained with repeated infections and with separately derived MLL-ENL lines. Additionally, MN1 was able to confer therapy resistance to anthracycline resistant Flt3-ITD expressing cells suggesting non-overlapping mechanisms. Purified populations of cells expressing MN1 were resistant to Ara-C when compared to the parental leukemia (IC50 175.6nM vs 67.28nM) and highly resistant to doxorubicin. Consistent with these results human OCI-AML3 cells expressing MN1were enriched by 1.6 fold when exposed to doxorubicin, a highly significant result with a p value of 0.0002. In contrast a control vector without MN1 was not significantly enriched. In vivo when mixed leukemia cells were injected into syngeniec recipients MN1 expressers were significantly enriched in the femoral bone marrow of treated animals compared to controls. Treated animals had 90.58% (+/−0.66) MN1 expressing blasts compared to 55.38% (+/−5.25) in controls. This result was highly statistically significant with a p value of < 0.0001. This observation was reproducible in a separately derived MLL-ENL driven cell line. Additionally, the engraftment of MLL-ENL and Flt3-ITD expressing cells was significantly increased by MN1 expression leading to shorter survival in recipient animals despite the already highly aggressive nature of the parental leukemia. When MN1 expressing cells were exposed to doxorubicin or Ara-C they displayed significantly lower Annexin V positivity consistent with an attenuated apoptotic response (3.65 vs 34.79, p=<0.0001). When we examined BH3 only family member induction following exposure to Ara-C and doxorubicin we found significantly decreased levels of Bim induction by QPCR in cells expressing MN1. Similarly, stabilization of p53 following treatment was blunted in MN1 expressers as was induction of its downstream targets p21 and MDM2. Importantly the amount of DNA damage induced by doxorubicin as assessed by γH2AX foci was not different between MN1 expressing cells and the parental leukemia. These data suggest that over expression of MN1 confers resistance to both Ara-C and doxorubicin in vitro and in vivo by suppression of Bim induction and p53 response. These observations suggest a biological explanation for the clinical observation that it confers a worse prognosis. Disclosures: No relevant conflicts of interest to declare.

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