Statins Use Improves the Clinical Outcomes of Salvage Therapy in Relapsed/Refractory CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3931-3931
Author(s):  
Long Xuan Trinh ◽  
Young Kwang Chae ◽  
Preetesh Jain ◽  
Ohad Benjamini ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Clinical Outcomes ◽  
Salvage Therapy ◽  
Older Patients ◽  
Conflicts Of Interest ◽  
Young Patients ◽  
The Other ◽  
Concurrent Use ◽  
The Impact

Abstract Abstract 3931 Introduction - Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase. In addition, statins possess anti-inflammatory, immunomodulatory, antioxidant, and cell growth inhibitory properties. In B- CLL cells, statins induce in-vitro apoptosis (Daphne Chapman-Shimshon et-al), suggesting that statins might possess properties. We noticed a high prevalence of dyslipidemia in patients with chronic lymphocytic leukemia (CLL). However the impact of dyslipidemia and its modulation by statins on clinical outcomes of patients with CLL remains unclear. Therefore, we conducted a retrospective analysis to assess the effect of statins in patients with CLL who received salvage (fludarabine, cyclophosphamide and rituximab) FCR chemotherapy. Methods - We analyzed the clinical outcome of relapsed/refractory patients with CLL (n=284) who underwent FCR salvage therapy at our institution between 1999 and 2012. Patients who were uninterruptedly treated with statins at least one month prior to and during salvage therapy (n=35) were assigned to the statins arm, whereas the other arm consisted of 249 patients who were not treated with statins. The Cox proportional hazards regression model was used to assess the association between patient characteristics and progression-free survival (PFS) and overall survival (OS). Actual survival and PFS were estimated using the method of Kaplan-Meier, and OS and PFS were compared among two groups of patients using log-rank test. Results - All pretreatment characteristics of the patients with concurrent use of statins were similar to those who were not treated with statins except for their age. Patients in the statins arm were older: 21 patients (60%) were older than 65 compared to 74 patients of 249 (30%) in the other group (p<0.05). The median OS and PFS of all 284 patients were 3.9 years (95% CI: 3.4–4.5) and 1.74 years (95% CI: 1.6–2.3), respectively. PFS was significantly longer in patients treated with statins. Fifteen of the 35 statin-treated patients (43%) as opposed to only 36 of 249 (14%) in the non-statins group experience no disease progression. Concurrent use of statins significantly prolonged PFS. The median PFS for statin-treated v/s. untreated was 4.6 and 1.7 years, respectively (p<0.05). This significantly improved PFS was consistent in young and elderly patients. In young patients (age < 65) with statins, the median PFS was not reached whereas in patients who were not treated with statins it was 2 years (p<0.05). In older patients (age ≥ 65), PFS was significant longer with concurrent use of statins than without statins; estimated PFS were 2 and 1.6 years, respectively (p<0.05). With the median follow-up of 5 years, the median overall survival was significantly longer in patients treated with statins, with 17 of 35 (49%) patients of the statins group and 59 (24%) of 249 in patients who were not treated with statins alive at the end of study. Concurrent use of statins significantly prolonged OS with an estimated median OS for the two groups of 6.9 years and 3.9 years, respectively (p<0.05). This significantly improved OS was consistent in young and elderly patients. Young patients (age <65) with statins had a significant prolonged survival with an estimated OS of 8.6 years whereas estimated OS in young patients without statins (p<0.05) was only 4 years. In older patients (age ≥65) the median OS was significantly longer with the concurrent use of statins than without statins; estimated OS in the two subgroups were 6.9 and 2.6 years respectively, (p<0.05). Conclusions - In conclusion, concurrent use of statins significantly improved OS, PFS in relapsed/refractory CLL patients treated with salvage FCR therapy. Further studies to determine the role of statins and mechanism of action in patients with CLL are warranted. Disclosures: No relevant conflicts of interest to declare.

Outcome of Elderly Patients with Acute Myeloid Leukemia (AML) Post Hypomethylating Agent (HMA) Failure.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2627-2627 ◽  
Author(s):  
Koichi Takahashi ◽  
Hagop M. Kantarjian ◽  
Hady Ghanem ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Salvage Therapy ◽  
Research Funding ◽  
Objective Response ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Investigational Agents ◽  
The Impact

Abstract Abstract 2627 Background and Aims: HMA such as 5-azacitadine or decitabine have been increasingly used as induction therapy in elderly patients with AML. The prognosis of such patients who failed initial HMA and the impact of subsequent chemotherapy on outcome are unknown. Therefore the aims of the current analysis are 1) to evaluate the prognosis of elderly patients with AML post HMA failure and 2) to evaluate the efficacy of using intensive cytarabine-based salvage therapy vs. low intensity investigational therapy. Methods: We analyzed 54 patients older than 60 years old with AML who received induction treatment with HMA using either 5-azacitadine (n=17; 31%) or decitabine (n=37; 69%) under various clinical trials. Result: Median age of the group was 68 years (range; 60–84); 39% patients were female. Forty three patients (77%) had performance status (PS) ≤1 and 11 patients had PS of 2 (23%). Mean initial white blood cell count was 10.9 ± 3.2 (x103/μl), hemoglobin 9.9 ± 0.2 (g/dl), platelet count 77 ± 9 (x103/μl), and bone marrow blast count 44 ± 2.9 (%). Cytogenetic category was classified as intermediate in 30 (55%) patients and poor in 24 (45%) based on the MRC criteria. Six patients (11%) carried FLT3-ITD mutation and 1 carried FLT3 D835 mutation. Complete remission (CR) was achieved in 24 patients (44%) with median numbers of cycles required to achieve CR being 3 (range; 1–6). All patients received further salvage therapies, at the time of failure, with a median of 2.5 (range, 2–5) salvage regimens. As part of the salvage regimen, high-dose cytarabine-based regimen (HDAC) was given to 32 patients (59%). Objective response rate to HDAC was 53%, with 18 pts achieving CR. Median number of courses given was 2 (range, 1–7) with a median duration of response of 3 months. No induction death was reported. Stem cell transplant was performed in total of 9 patients (17%) as a consolidation post HDAC (n=4) or as salvage therapy (n=5). With a median follow-up of 5 months post HMA failure, 5 (9%) patients remained alive receiving therapy. The median overall survival (OS) was 5.4 months (range, 2.3–8.5). The 1-year overall survival rate was 26%. There was no difference in OS between patients who received HDAC versus those who received investigational agents (p=0.25). Conclusion: The outcome of untreated elderly patients with AML who failed HMA is poor with a median survival of 5 months. HDAC based regimen, although active with low treatment related morbidity, yielded no survival improvement compared to investigational agents. Such patients should benefit from more innovative approaches. Disclosures: Ravandi: Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding.

scholarly journals Impact of cardiovascular disease and risk factors on fatal outcomes in patients with COVID-19 according to age: a systematic review and meta-analysis

Heart ◽  
2020 ◽  
pp. heartjnl-2020-317901
Author(s):  
SungA Bae ◽  
So Ree Kim ◽  
Mi-Na Kim ◽  
Wan Joo Shim ◽  
Seong-Mi Park
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Relative Risk ◽  
Elderly Patients ◽  
Meta Analysis ◽  
Fatal Outcome ◽  
Young Patients ◽  
Lower Prevalence ◽  
Prevalence Rates ◽  
The Impact

ObjectivePrevious studies that evaluated cardiovascular risk factors considered age as a potential confounder. We aimed to investigate the impact of cardiovascular disease (CVD) and its risk factors on fatal outcomes according to age in patients with COVID-19.MethodsA systematic literature review and meta-analysis was performed on data collected from PubMed and Embase databases up to 11 June 2020. All observational studies (case series or cohort studies) that assessed in-hospital patients were included, except those involving the paediatric population. Prevalence rates of comorbid diseases and clinical outcomes were stratified by mean patient age in each study (ranges: <50 years, 50–60 years and ≥60 years). The primary outcome measure was a composite fatal outcome of severe COVID-19 or death.ResultsWe included 51 studies with a total of 48 317 patients with confirmed COVID-19 infection. Overall, the relative risk of developing severe COVID-19 or death was significantly higher in patients with risk factors for CVD (hypertension: OR 2.50, 95% CI 2.15 to 2.90; diabetes: 2.25, 95% CI 1.89 to 2.69) and CVD (3.11, 95% 2.55 to 3.79). Younger patients had a lower prevalence of hypertension, diabetes and CVD compared with older patients; however, the relative risk of fatal outcomes was higher among the former.ConclusionsThe results of the meta-analysis suggest that CVD and its risk factors (hypertension and diabetes) were closely related to fatal outcomes in COVID-19 for patients across all ages. Although young patients had lower prevalence rates of cardiovascular comorbidities than elderly patients, relative risk of fatal outcome in young patients with hypertension, diabetes and CVD was higher than in elderly patients.Prospero registration numberCRD42020198152.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9544-9544
Author(s):  
Nienke A De Glas ◽  
Esther Bastiaannet ◽  
Frederiek van den Bos ◽  
Simon Mooijaart ◽  
Astrid Aplonia Maria Van Der Veldt ◽  
...  
Keyword(s):  
Older Adults ◽  
Overall Survival ◽  
Metastatic Melanoma ◽  
Older Patients ◽  
Regression Models ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Toxicity Response ◽  
Grade 3 ◽  
The Impact

9544 Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]

scholarly journals Impact of Age on Short- and Long-Term Outcomes after Pancreatoduodenectomy for Periampullary Neoplasms

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Mario Gruppo ◽  
Francesca Tolin ◽  
Boris Franzato ◽  
Pierluigi Pilati ◽  
Ylenia Camilla Spolverato ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Adjuvant Treatment ◽  
Long Term Outcomes ◽  
Group I ◽  
Periampullary Neoplasms ◽  
Short And Long Term ◽  
Group Ii ◽  
The Impact

Background. Although mortality and morbidity of pancreatoduodenectomy (PD) have improved significantly over the past years, the impact of age for patients undergoing PD is still debated. This study is aimed at analyzing short- and long-term outcomes of PD in elderly patients. Methods. 124 consecutive patients who have undergone PD for pancreas neoplasms in our center between 2012 and 2017 were analyzed. Patients were divided into two groups: group I (<75 years) and group II (≥75 years). Demographic features and intraoperative and clinical-pathological data were collected. Primary endpoints were perioperative morbidity and mortality; complications were classified according to the Clavien-Dindo Score. Secondary endpoints included feasibility of adjuvant treatment and overall survival rates. Results. A total of 106 patients were included in this study. There were 73 (68.9%) patients in group I and 33 (31.1%) in group II. Perioperative deceases were 4 (3.6%), and postoperative pancreatic fistulas were 34 (32.1%). Significant difference between two groups was demonstrated for the ASA Score (p=0.004), Karnofsky Score (p=0.025), preoperative jaundice (p=0.004), and pulmonary complications (p=0.034). No significance was shown for diabetes, radicality of resection, stage of disease, operative time, length of stay, postoperative complications according to the Clavien-Dindo Score, postoperative mortality, pancreatic fistula, and reoperation rates. 69.9% of the patients in group I underwent adjuvant treatment vs. 39.4% of the older ones (p=0.012). Mean overall survival was 28.5 months in group I vs. 22 months in group II (p=0.909). Conclusion. PD can be performed safely in elderly patients. Advanced age should not be an absolute contraindication for PD, even if greater frailty should be considered. The outcome of elderly patients who have undergone PD is similar to that of younger patients, even though adjuvant treatment administration is significantly lower, demonstrating that surgery remains the main therapeutic option.

Low-grade astrocytoma: a decade of experience at St. Jude Children's Research Hospital.

1997 ◽  
Vol 15 (8) ◽  
pp. 2792-2799 ◽  
Author(s):  
A Gajjar ◽  
R A Sanford ◽  
R Heideman ◽  
J J Jenkins ◽  
A Walter ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cerebral Hemisphere ◽  
Young Patients ◽  
Age At Diagnosis ◽  
Cerebellar Hemisphere ◽  
Low Grade ◽  
Tumor Site ◽  
Primary Tumor Site ◽  
Significant Difference ◽  
The Impact

PURPOSE To evaluate the impact of primary tumor site, age at diagnosis, extent of resection, and histology on progression-free survival (PFS) in pediatric low-grade astrocytoma. PATIENTS AND METHODS Medical, pathologic, and imaging information were reviewed for 142 children (ages 2 months to 19 years) with low-grade astrocytoma treated between January 1984 and July 1994. Gross total resection (GTR) was attempted for cerebellar and cerebral hemisphere tumors, with biopsy or less aggressive resection used predominantly for tumors in other sites. Surgery was followed by observation in 107 cases, radiation therapy in 31, and chemotherapy in four. RESULTS The overall survival rate was 90% +/- 3% (SE) at 4 years. PFS was significantly better for patients with cerebellar and cerebral hemisphere tumors (n = 75) than those with tumors in all other sites (P = .0006). Within the former group, there was no significant difference in PFS for patients in whom GTR was achieved versus those with incomplete resections (4-year estimates, 89% and 77%, respectively). Histology (juvenile pilocytic v astrocytoma not otherwise specified [NOS]) was not related to PFS in an analysis that controlled for tumor site and patient age. Patients younger than 5 years at diagnosis had a significantly poorer PFS than older children, regardless of histology (P < .03) or tumor site (P < .002). Treatment for progressive/recurrent disease was effective in a majority of patients, but appeared more successful in patients with hemispheric than thalamic or hypothalamic tumors. CONCLUSION The overall survival in this series of pediatric low-grade astrocytomas is excellent. Age at diagnosis and tumor location, but not histology, had a significant impact on PFS. Efforts to improve treatment outcome should focus on young patients (< 5 years) and on those with central midline tumors. The majority of patients with completely resected hemispheric tumors were monitored without further therapy, which supports attempted GTR of cerebral and cerebellar hemisphere low-grade astrocytoma.

PS01.162: IS THERE A DIFFERENCE IN SURVIVAL BETWEEN YOUNGER AND OLDER GASTRIC CANCER (INCLUDING AEG II AND AEG III) PATIENTS AFTER GASTRECTOMY?

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 95-95
Author(s):  
Benjamin Babic ◽  
Florian Matthias Corvinus ◽  
Edin Hadjijusufovic ◽  
Evangelos Tagkalos ◽  
Hauke Lang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Elderly Patients ◽  
Conflicts Of Interest ◽  
Subtotal Gastrectomy ◽  
Young Patients ◽  
Western World ◽  
Old Patients ◽  
Younger Patients ◽  
Significant Difference

Abstract Background The incidence of gastric cancer decreases in the western world, however, it remains one of the most common diseases (1). There is just little data from Europe comparing the outcome of young and elderly gastric cancer patients. This study compares, depending on the age of 266 patients, the outcome of 266 consecutive gastrectomy cases due to gastric cancer Methods 266 consecutive patients with gastric cancer received a gastrectomy between 2008–2016 at our comprehensive cancer centre. The mean age of the patients in this study was 64 years old (21- 93 years). All patients were followed up regarding survival. The patients were separated in 6 different groups, depending on the age at the time of operation. The different groups were re-analysed and compared to each other regarding median and 5-year survival. Results In this collective the 5-year survival rate for all patients was 43%. There were more diffuse type adenocarcinomas in Patients < 40 years. In younger patients the tumour was staged in an advanced stadium compared to the elderly patients group. There is a significantly higher 5-year survival rate for younger patients after gastrectomy. There is no significant difference, when separating patient groups in to decades of age. Conclusion Young patients have a higher 5-year survival rate after gastrectomy compared to old patients. However, comparing patients from chronologic age in decades, the significance is not reproducible. Therefore gastrectomy or subtotal gastrectomy is the determining therapeutic approach for gastric cancer with an acceptable outcome in both young and elderly patients. Older patients might have an lower 5 year survival rate not only due to the cancer or the surgical therapy itself, it is related to comorbidities and a lower rate in neoadjuvant therapy as well Disclosure All authors have declared no conflicts of interest.

Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1616-1616 ◽  
Author(s):  
Eyal C. Attar ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
Susan P. Whitman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Advanced Pancreatic Cancer ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
Expression Levels ◽  
The Impact ◽  
Disease Free

Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

Tet2 Loss Accelerates The Myeloproliferative Neoplasm (MPN) Phenotype Of Jak2V617F Knockin Mice But Is Insufficient To Cause Leukemic Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4095-4095
Author(s):  
Edwin Chen ◽  
Lawrence J Breyfogle ◽  
Rebekka K. Schneider ◽  
Luke Poveromo ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Conditional Knockout ◽  
The Other ◽  
Myelogenous Leukemia ◽  
Leukemic Transformation ◽  
The Impact

Abstract TET2 mutations are early somatic events in the pathogenesis of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) and are one of the most common genetic lesions found in these diseases. In MPN, TET2 mutations are enriched within more advanced disease phenotypes such as myelofibrosis and leukemic transformation and often co-occur with the JAK2V617F mutation, which is present in the majority of MPN patients. We have developed and characterized a Jak2V617F conditional knockin mouse (Jak2VF/+), the phenotype of which closely recapitulates the features of human MPN. To determine the impact of Tet2 loss on Jak2V617F-mediated MPN, we crossed Tet2 conditional knockout mice with Jak2VF/+ knockin and Vav-Cre transgenic mice and backcrossed the compound mutant animals. We then characterized the effects of heterozygous and homozygous loss of Tet2 on the phenotype of Jak2VF/+ mice. We assessed peripheral blood counts, histopathology, hematopoietic differentiation using flow cytometry, colony formation and re-plating capacity. We also evaluated the effects of Tet2 loss on the transcriptome of the HSC compartment using gene expression microarrays and on HSC function using competitive bone marrow transplantation assays. Similar to Jak2VF/+/VavCre+ mice, Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice develop leukocytosis, elevated hematocrits (HCT) and thrombocytosis. Tet2-/-/Jak2VF/+/VavCre+ mice demonstrate enhanced leukocytosis and splenomegaly compared to the other groups. All groups demonstrate myeloid expansion, erythroid hyperplasia and megakaryocytic abnormalities consistent with MPN in the bone marrow and spleen, while more prominent myeloid expansion and megakaryocytic morphological abnormalities are observed in Tet2-/-/Jak2VF/+/VavCre+ mice as compared to the other groups. Notably, we do not see the development of acute myelogenous leukemia (AML) in Tet2-/-/Jak2VF/+/VavCre+ mice at 6 months. We see enhanced expansion of lineagelowSca1+cKithigh (LSK) cells (enriched for HSC) most prominently in the spleens of Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice as compared to Jak2VF/+/VavCre+ mice. In colony forming assays, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced re-plating activity compared to Jak2VF/+/VavCre+ LSK cells and that Tet2-/-/Jak2VF/+/VavCre+ LSK cells form more colonies that Tet2-/-/Jak2+/+/VavCre+ cells. Gene expression analysis demonstrates enrichment of a HSC self-renewal signature inTet2-/-/Jak2VF/+/VavCre+ LSK cells. Concordant with this, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced competitive repopulation at 16 weeks as compared to Jak2VF/+/VavCre+ and Tet2+/-/Jak2VF/+/VavCre+ LSK cells. In aggregate these findings demonstrate that Tet2 loss promotes disease progression in MPN but is insufficient to drive full leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

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