Expression of the Bcl-2 Family of Regulatory Proteins by Quantitative Immunohistochemistry (AQUA) in Follicular Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4996-4996
Author(s):  
Julie E Chang ◽  
Songwon Seo ◽  
Kyungmann Kim ◽  
Adam M Petrich ◽  
David T Yang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Follicular Lymphoma ◽  
Tissue Microarray ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Continuous Variable ◽  
Expression Levels ◽  
Wide Range ◽  
Apoptotic Proteins ◽  
Diagnostic Biopsies

Abstract Abstract 4996 Introduction The indolent and incurable nature of follicular lymphoma (FL) is characterized by defects in cellular apoptosis. The ubiquitous overexpression of bcl-2 in FL favors cell survival, but differences in the expression levels and interactions with other bcl-2 family members may account for the clinical heterogeneity observed in FL. Regulation of apoptosis is the result of the interaction of multiple anti-apoptotic and pro-apoptotic members. We evaluated the use of high through-put quantitative immunofluorescence staining with automated quantitative analysis (AQUA) technology to evaluate multiple pro- and anti-apoptotic bcl-2 proteins on a FL tissue microarray. Quantitative levels of apoptotic proteins were correlated with IPI and FLIPI scores and survival. Patients and methods Seventy-six FL patients evaluated at our institution between 1986 and 1996 with diagnostic biopsies available in paraffin tissue were identified, and diagnostic biopsies incorporated into a tissue microarray. Immunofluorescent antibodies to the anti-apoptotic proteins bcl-2, mcl-1, bcl-XL and the pro-apoptotic proteins BAX, BAD, BAK were applied to the tissue microarray and expression quantified by AQUA technology. Each section was co-stained with CD20, and a CD20 mask or gate applied to limit examination of protein expression to tumor cells. Intensity of fluorescence staining in each sample was expressed as an AQUA score. The AQUA score was analyzed for each protein as a continuous variable. Results The mean age was 56.7 years (range 21.7-84.8), with 55% of patients under the age of 60. Sixty-two percent of patients were men and 66% of patients had stage ≥3 disease at diagnosis. Median duration of follow-up was 9.4 years (range 0.7-33.6 years). Complete data for determining IPI and FLIPI status were available for 63 patients. All bcl-2 family protein biomarkers were expressed as logarithms of the AQUA score. There was a wide range of expression of both pro- and anti-apoptotic proteins between cases, with up to 1000 fold differences in expression levels for all proteins, including bcl-2. In general, there was no association between levels of pro- and anti-apoptotic protein expression and IPI or FLIPI score or survival. In univariate analysis, the hazard ratio for individual biomarkers shows the estimated relative risk of dying for patients, estimating risk based on a one unit increase in the log expression for a biomarker. No individual biomarker was predictive of survival. Age and IPI and FLIPI risk groups were predictive of survival (Table 1). Multivariate analysis showed that biomarkers were not predictive for survival after adjusting for other variables. Conclusions AQUA quantification of pro- and anti-apoptotic proteins identified marked heterogeneity in protein expression, including bcl-2, in these follicular lymphoma samples. However, there was no clear relationship between the bcl-2 family of biomarkers and FLIPI/IPI status or survival. Use of AQUA technology on a microarray of paraffin-embedded tissue was feasible, but was not useful in predicting clinical outcome in these cases. Disclosures No relevant conflicts of interest to declare.

Functional Proteomic Profiling of Myelodysplastic Syndromes Reveals Distinct Protein Expression Signatures and Identifies Candidate Therapeutic Targets

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1975-1975
Author(s):  
Brittany Knick Ragon ◽  
Fieke W Hoff ◽  
Chenyue W Hu ◽  
Yihua Qiu ◽  
Suk-Young Yoo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Expression ◽  
Myelodysplastic Syndromes ◽  
Conflicts Of Interest ◽  
Cell Type ◽  
Disease Heterogeneity ◽  
Cluster Membership ◽  
Protein Clusters ◽  
Wide Range ◽  
Genetic Events

Abstract Background: Myelodysplastic syndromes (MDS) are heterogeneous clonally derived bone marrow disorders characterized by ineffective hematopoiesis and propensity to transform to acute myeloid leukemia. With greater than 15,000 new cases identified yearly, patients (pts) with MDS have a wide range of clinical manifestations and outcomes. Challenges in treating MDS include disease heterogeneity and a small number of effective treatments, particularly beyond first-line approaches and supportive care. Although mutational analysis of MDS provides prognostic information, the plethora of genetic events in a single case complicates using this information for guiding clinical therapy. We hypothesized that these genetic events coalesce into a finite number of protein expression signatures and that these would guide individualized therapy. Methods: A custom Reverse Phase Protein Array (RPPA) with 378 samples (including replicates) from 123 newly diagnosed and 76 relapsed/refractory MDS pts as well as 20 normal CD34+ bone marrow samples was created and probed with 136 antibodies to determine relative protein expression. To assess impact of source cell type on protein expression, 112 of the 378 samples (representing some replicates from 95 pts) had paired CD34+ and CD34+CD38- samples. Since proteins interact with each other and function within networks, proteins were first divided into 25 Protein Functional Groups (ProFnGp) based on their known functionality in the literature. Progeny clustering was then performed for each ProFnGp to determine the optimal number of protein clusters. Principal component analysis (PCA) was used to map global differences and similarities between protein clusters and normal CD34+ samples. Hierarchical clustering (HC) was performed on a compilation of all protein clusters in one binary matrix to identify recurrent protein expression signatures (PrSIG)that comprised similar combinations of protein constellations (PrCON). Associations between signature membership, clinical and molecular features, and outcome were assessed. Proteins that were universally over or under expressed and specific for a given signature were identified. Results: Clustering of pts for each ProFnGp revealed distinct relative expression and activation states compared to normal CD34+ samples. For each ProFnGp, 2 to 6 distinct expression clusters were identified, providing 110 protein clusters for HC. Of the 25 ProFnGp, all had MDS specific patterns and 19 had at least one cluster similar to normal CD34+ cells. HC revealed strong co-correlation between multiple groups of protein clusters from various ProFnGp and suggested 11 PrCON. Pts that expressed similar recurrent combinations of PrCON formed 11 PrSIG (Figure 1). Within PrSIG, no bias was observed in sample status (fresh or cryopreserved), source (peripheral blood or bone marrow), gender, or relapse status. Analysis of paired samples revealed 84% of CD34+ samples were present in separate PrSIG from corresponding CD34+CD38- samples, suggesting cases where CD34+ samples were distinct from CD34+CD38- samples. This suggests cell type should be considered in future analyses. Structured cluster memberships were identified, suggesting ProFnGp targets. The distinct cluster identified in PrCON 4 x PrSIG 1 revealed associations with ProFnGp including apoptosis, SMAD, PKC, mTOR, MEK, and Hippo pathways. Within this cluster, upregulation was identified in proteins including PKCα, PI3Kp110α, and SMAD6 and downregulation in SMAC, PKCd, SMAD1, SMAD4, TSC2, and NF2, suggesting targets for directed combination therapy with agents such as selective PKCα and PI3K inhibitors or SMAC mimetics. Overall summation of expression for each protein across each signature revealed many proteins with either significantly higher or lower expression relative to CD34+ controls. Conclusions: Analysis of protein expression levels in a network-based approach revealed classification of MDS pts into finite protein expression signatures based on the existence of recurrent protein constellations. Recognition of universal differentially expressed proteins, together with signature specific proteins, suggests targets for personalized and directed combinatorial therapeutics. Figure 1 HC based on binary ProFnGp cluster membership. Each vertical pt column consists of 25 of 110 protein clusters. Blue squares indicate positive cluster membership. Figure 1. HC based on binary ProFnGp cluster membership. Each vertical pt column consists of 25 of 110 protein clusters. Blue squares indicate positive cluster membership. Disclosures No relevant conflicts of interest to declare.

The Importance of Age in Prognosis of Follicular Lymphoma: Clinical Features and Life Expectancy of Patients Younger Than 40 Years

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1593-1593 ◽  
Author(s):  
Chiara Lobetti-Bodoni ◽  
Paola MV Rancoita ◽  
Silvia Montoto ◽  
Armando Lopez-Guillermo ◽  
Annarita Conconi ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Follicular Lymphoma ◽  
Clinical Features ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Bone Marrow Involvement ◽  
Interquartile Range ◽  
Survival Duration ◽  
Strong Impact ◽  
Histological Transformation

Abstract Abstract 1593 Background The median age at presentation of follicular lymphoma (FL) is around 60 years (yrs). Despite recent reports of general improvement of overall survival (OS) in the last decade, the outcome of younger patients (pts) with FL has not been extensively investigated. Patients and methods Our study aimed to investigate possible differences in clinical features, therapy and outcome in FL pts younger than 40 yrs compared to the older ones. Consecutive FL cases from 4 different European centers (Barcelona, Spain; Bellinzona, Switzerland; London, UK; Novara, Italy) diagnosed in the last 25 yrs were retrospectively analyzed. For each patient data on clinical features at diagnosis, treatment and outcome were retrieved. Results A total of 1003 FL pts (452 males and 551 females; median age: 56.5 yrs, interquartile range 46–67 yrs) were collected, 153 of them were ≤40 yrs at the time of diagnosis. Comparing clinical features at diagnosis of pts >40 and of pts ≤40 yrs, some differences were observed. In younger pts there was a lower incidence of elevated LDH (14% vs. 23%, p=0.02), and a less frequent primary extra nodal localization (7% vs. 13%, p=0.03), but a more frequent bone marrow involvement (57% vs. 44%, p=0.003) and involvement of more than 4 nodal lesions (43% vs. 25%, p<0.001). Information concerning first line treatment was available for >95% of pts. At a median follow-up of 9.3 yrs (interquartile range, 5–15 yrs) 91% of pts ≤40 yrs have received treatment for their lymphoma, compared to 84% of pts >40 yrs (p=0.02). An initial wait and see policy was applied in 11% of the younger pts and in 19% of the remainder (p=0.03). No differences in the two populations were observed in the type of chemotherapy given as first FL treatment, but pts >40 yrs received more frequently rituximab, alone or in combination, than younger pts (26% vs. 13%, p=0.001). At a univariate analysis younger pts had longer OS, and longer cause-specific survival (CSS, defined by deaths due to FL or acute toxicity of its treatment). In particular, the 10-yrs OS was 81% for pts ≤40 yrs (95%CI: 75–88%), vs 51% in the older ones (95%CI: 47–55%) (p<0.001). The 10-yrs CSS was 82% for pts ≤40 yrs (95%CI: 75–89%) compared to 60% in the older ones (95%CI: 56–64%) (p<0.001). 10-yr PFS was 39% for pts ≤40 yrs (95%CI: 31–48%), vs 24% in the older ones (95%CI: 21–28%) (p<0.001). Notably, when stratifying pts by age (≤40, 41–59 and ≥60 yrs) those ≤40 yrs-old at diagnosis had a CSS similar to that of pts of 41–59 yrs, but longer OS (figure 1). Even in this younger group, OS (median, 24 yrs) was, however, dramatically shorter than the life expectancy for the general population of the same age (approx. 45 yrs for males and 50 yrs for females in the UK, according to the Office for National statistics -www.statistics.gov.uk). At multivariate analysis, the features at diagnosis significantly influencing OS and CSS were B symptoms, stage ≥III, hemoglobin<12 g/dl, elevated LDH, period of diagnosis (≤1990, between 1991 and 1999, and >2000), age>60 yrs. No differences between age groups (≤40 yrs vs. >40 yrs) were observed in the incidence of second tumors (8% vs. 11%) and histological transformation (18% in both populations). Conclusions In this multicentre study younger pts with FL presented with different clinical features than those >40 yrs. As expected the CSS of pts >60 is strongly impaired, but interestingly the CSS of pts ≤40 yrs was similar to that of pts 41–59 yrs. Despite some limitations due to the fact that many pts were treated in the pre-rituximab era, these data suggest that FL still has a strong impact on survival duration of younger pts, who otherwise would have a long life expectation. Disclosures: No relevant conflicts of interest to declare.

Coexpression of MYC and BCL-2 Predicts Inferior Survival in Pgi-DLBCL Treated with CHOP-like Regimen/Rituximab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5404-5404 ◽  
Author(s):  
Le Zhang ◽  
Bing Xia ◽  
Shanqi Guo ◽  
Xiaowu Li ◽  
Fulian Qu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Chemotherapy Response ◽  
Prognostic Impact ◽  
Mrna Levels ◽  
Expression Levels ◽  
Stage Disease

Abstract MYC protein expression has been identified to be associated with inferior overall survival (OS) and progression-free survival (PFS) when coexpressed with BCL-2 protein in patients with diffuse large B cell lymphoma (DLBCL). But the concurrent expression of MYC and BCL-2 proteins in primary gastrointestinal (PGI)-DLBCL has not been clearly understood. Here, we investigated whether this coexpression has prognostic significance in PGI-DLBCL patients and explored its associations with patients’ clinical parameters. We enrolled 60 PGI-DLBCL patients and 30 age- and sex-matched healthy controls. Expression levels of MYC and BCL-2 were detected from both protein and mRNA levels by immunohistochemistry and real-time RT-PCR. Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein were correlated with high MYC and BCL-2 mRNA expression, respectively (both p<0.05). We found that patients with advanced-stage disease (at IIE-IV) having higher MYC and BCL-2 coexpression levels (p<0.05). In addition, MYC+/BCL-2+ patients had more difficulty achieving complete remission than others (p<0.05). Presence of MYC protein expression only affected OS and PFS when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (p<0.05) even after adjusting for age, Lugano stage, IPI, and BCL-2 protein expression in a multivariable model. MYC+/BCL-2+ patients have poorer chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting prognosis of PGI-DLBCL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Activation of JAK2/STAT5 Pathway Reduces Expression Level of DNMT3a in MPN Cell Line

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5394-5394
Author(s):  
Jie Zhou ◽  
Aibin Liang ◽  
Shaoguang Li ◽  
Wenjun Zhang ◽  
Jianfei FU
Keyword(s):  
Protein Expression ◽  
Cell Line ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Expression Level ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Increased Risk

Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to acute myeloid leukemia (AML), and JAK2V167F is the most frequent MPN driving mutation detected in >95% of PV and 50-60% ET and PMF. DNMT3A is a de novo DNA methyltransferase that catalyzes the addition of methyl groups into active chromatin in CpG-rich regions leading to gene inactivation. Dnmt3a-/- HSC have enhanced self-renewal and a block in differentiation in vivo. Previous study showed that JAK2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation, while whether JAK2V617F regulates DNMT3a still remains unclear. AZ960 is a potent and selective ATP competitive inhibitor of the JAK2 kinase, and previous studies reported that AZ960 possessed the activity selectively against JAK2. LY2784544 has been identified as a selective inhibitor of JAK2V617F and has undergone clinical trials for the treatment of several myeloproliferative disorders. Methods: Empty vector (control) and mutant JAK2V617F were transduced into BaF3 cells using a lentivirus system. JAK2V617F-expressing BaF3 cells grow IL-3 independent and were selected by fluorescence-activated cell sorting (FACS) for GFP expression. The protein expression levels of p-STAT5 and DNMT3a were detected by western blotting. JAK2V617F-expressing and control BaF3 cells were incubated with gradient concentration of LY2784544 or AZ960 to inhibit JAK2/STAT5 pathway. Results: The expression levels of p-STAT5 were obviously up-regulated in the JAK2V617F-expressing BaF3 cells, and DNMT3a was down-regulated. After 1-hour incubation in the serial diluted LY2784544, p-STAT5 were reduced in JAK2V617F-expressing BaF3 cells, with expression of DNMT3a elevated. To further confirm the correlation between JAK2/STAT5 pathway and expression of DNMT3a, another JAK2 inhibitor AZ960 was tested similar to LY2784544. With p-STAT5 expression suppressed, protein level of DNMT3a showed significantly promotion. Conclusion: We observed that JAK2V167F mutation suppresses protein expression levels of DNMT3a in MPN cell lines. JAK2 inhibition by AZ960 and LY2784544 significantly improved expression levels of DNMT3a. The activation of JAK2/STAT5 pathway reduces expression level of DNMT3a in MPN cell line, and the specific mechanism still needs to be explored. Figure Disclosures No relevant conflicts of interest to declare.

Absolute Monocyte Count in Follicular Lymphoma Patients Treated with Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1574-1574
Author(s):  
Reina Watanabe ◽  
Naoto Tomita ◽  
Kumiko Kishimoto ◽  
Satoshi Koyama ◽  
Eriko Ogusa ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Clinical Stage ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
World Health ◽  
Serum Lactate Dehydrogenase ◽  
Monocyte Count ◽  
Chop Therapy

Abstract Abstract 1574 Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL), with a highly variable natural history ranging from an indolent disease to a rapidly progressive one such as its transformation to aggressive NHL. We have used the Follicular Lymphoma International Prognostic Index (FLIPI) that uses patient- or tumor-specific characteristics for the risk-stratification of patients with FL at the time of diagnosis. The tumor microenvironment, including variable monocyte-derived cell infiltration, has recently shown to play an important role in the clinical course of FL patients. Wilcox et al. showed that an elevated absolute monocyte count (AMC) is associated with inferior overall survival of FL patients receiving varying treatment strategies (Wilcox RA, et al. Leuk Lymphoma 2012). We retrospectively evaluated the prognostic changes in AMC at diagnosis in FL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy alone. This study included 157 consecutive FL patients treated with the R-CHOP therapy at 1 of the 7 participating hospitals between 2001 and 2009. Since 2001, the Yokohama City University Hematology Group in Japan uniformly and curatively treated patients with FL, except for those with stage 1 FL; the patients were treated with 6 cycles of standard R-CHOP therapy for 21 days. Patients who showed partial response (PR) after the initial 4 cycles were administered a total of 8 R-CHOP cycles, and those who did not show PR after the initial 4 cycles or patients in whom the disease progressed at any given time received salvage therapy. Patients who had bulky masses at diagnosis received involved field radiation following 6—8 cycles of R-CHOP therapy. Patients for whom the doses had to be reduced by more than 20% were excluded from the study. The study included 80 men and 77 women, with a median age of 63 years at diagnosis (range, 18—80 years). The FL of the 157 patients were classified as grade 1 (n = 65), grade 2 (n = 60), grade 3a (n = 20), and grade 3b (n = 12) according to the World Health Organization (WHO) scheme. The median AMC at diagnosis was 349 cells/μL (range, 10—1110 cells/μL). The median observation period for surviving patients was 45 months. The 5-year progression-free survival (PFS) estimated for the entire cohort was at 71.3%. The differences in the PFS when patients were stratified according to their AMCs were not significant. The effect of the following variables on PFS were assessed: (1) AMC > 390 cells/μL; (2) age > 60 years; (3) hemoglobin level < 120 g/L; (4) elevation of serum lactate dehydrogenase levels; (5) nodal areas > 4; and (6) advancement of clinical stage. In the univariate analysis, the presence of more than 4 nodal areas (hazard ratio [HR] = 2.65, 95% CI, 1.58—4.47, P < 0.001) and advanced clinical stage (HR = 2.75, 95% CI, 1.26—6.03, P= 0.01) were associated with inferior PFS. However, in the multivariate analysis, the association between the presence of more than 4 nodal areas and survival was found to be significant (HR = 2.33, 95% CI, 1.28—4.24, P = 0.006). Therefore, both univariate and multivariate analyses indicate that AMC was not a prognostic factor for PFS. There was no statistically significant correlation between AMC and FL patients' clinical outcome. AMC is not a prognostic factor in FL patients treated by R-CHOP. Disclosures: No relevant conflicts of interest to declare.

Long-Term Remissions Of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophospamide, Doxorubicine, Vincristine and Prednisone (R-CHOP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3028-3028
Author(s):  
Paolo Strati ◽  
Jorge Enrique Romaguera ◽  
Larry W. Kwak ◽  
Fredrick B Hagemeister ◽  
Maria Alma Rodriguez ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Follicular Lymphoma ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Single Agent ◽  
World Health ◽  
Cell Transplant ◽  
Baseline Characteristics ◽  
Grade 3

Abstract Background Follicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. FLG3 are defined as > 15 centroblasts per high power field and are further subdivided into A or B on the basis of the presence of centrocytes. Their natural history is similar to that of diffuse large B cell lymphomas (DLBCL) and there is still debate about their optimal management. Methods We conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004. Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression with backward stepwise selection. Logistic regression with odds ratio (OR) was used for MVA of categorical variable. Results Patient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. In particular, patients with stage I/II disease (9) all received 5-6 cycles, with additional radiation therapy consolidation in 4 patients. The overall response rate was 100% and 43 (96%) patients achieved complete remission (CR). After a median follow-up of 9 (2-12) years, median PFS has not been reached with 14 (31%) patients relapsing. Nearly all relapses occurred within 3 years, except for 1 patient who relapsed after 8 years and achieved a second durable CR with single agent Rituximab (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p=0.03). Among relapsed patients, 3 (21%) transformed to DLBCL (1 at first relapse) and died. Six (43%) relapsed patients received stem cell transplant (1 allogeneic) and 5 (36%) received more than 2 salvage regimens. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate analysis, the only factor associated with a shorter OS after relapse was transformation (p=0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p=0.004) and elevated LDH (OR 2.4, p=0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p=0.02) and LDH > 618 IU/L (HR 5.9, p=0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p=0.04). Conclusions R-CHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients. Disclosures: No relevant conflicts of interest to declare.

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.

Treatment Outcome of Acute Myeloid Leukemia Patients From Brazil According to Karyotype, Presence or Not of FLT3-ITD and NPM1 Mutations, and BAALC Gene Expression.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3836-3836
Author(s):  
Mariana Tereza Lira Benício ◽  
Ana Flávia Leonardi Tibúrcio Ribeiro ◽  
Ana Beatriz Firmato Glória ◽  
Antonio R Lucena-Araujo ◽  
Bárbara A Santana-Lemos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developing Countries ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Developed Countries ◽  
University Hospitals ◽  
Expression Levels ◽  
High Doses ◽  
Wbc Count

Abstract Abstract 3836 Current results regarding AML treatment in developed countries have shown that the estimate five-year overall survival (OS) is around 40–50%. In contrast, the few existing studies concerning the outcome of AML patients in developing countries reported OS values around 18–25%, despite the fact that there is a relative excess of acute promyelocytic leukemia (APL) cases, which are associated with favorable prognosis. In addition, the studies conducted in developing countries have not taken into account recently reported molecular markers, such as mutations in the NPM1 gene and expression levels of the BAALC gene, which were demonstrated to impact on outcome. The present study aimed to evaluate the effects of karyotype, NPM1 and FLT3-ITD mutations, and BAALC gene expression on the outcome of AML Brazilian patients. One hundred and fifty-eight patients were enrolled in two University Hospitals of the Southeast Region of the country. The median age was 43 years (range:12–92 y) with 78 males (49%). Patients were treated with conventional chemotherapy consisting of daunorubicin (60mg/m2/d for 3 days) and cytarabin (200mg/m2/d for 7 days) as induction, followed by two or three cycles of consolidation therapy with high doses of cytarabin (above 1g/m2/d). The following variables were analyzed: age, gender, WBC count, karyotype, NPM1 and FLT3-ITD mutations, and the quantitative evaluation of the BAALC gene expression. Pretreatment bone marrow samples were analyzed by G-banding cytogenetic, of which 143 were successful, and so allowed the stratification of patients in groups according to prognosis, as proposed by the Medical Research Council (MRC) in: favorable (n=48), intermediate (n=77) and adverse (n=18). A combination of ASO-RT-PCR and sequencing was performed to detect NPM1 mutations. FLT3-ITD detection was performed by PCR. The relative expression levels of BAALC gene were measured by RQ-PCR, according to the comparative cycle threshold (Ct) method and patients were classified as presenting high or low expression using the median as the cut-off value. The estimated five-year OS for all patients was of 15.3% (S.D.: ± 3.4%). The median OS according to cytogenetic stratification was of 1234, 593 and 230 days for favorable, intermediate and adverse groups, respectively (p=0.04). Univariate analysis detected as significant the following variables: age, cytogenetic risk group and presence of FLT3-ITD (p=0.03). Indeed, patients harboring FLT3-ITD patients presented a mean OS of only 300 days (range: 116–485 days) in comparison with 770 days (531 – 1010) in patients without FLT3 mutations. Besides, FLT3-ITD was associated with genre (more common in females, p=0.02) and with cytogenetics (more frequent in the favorable and intermediate cytogenetic risk groups). When only cytogenetically normal patients were analyzed (n=55), NPM1 mutations were significantly associated with longer OS (mean: 1058 days, range: 449–1666 days vs. 276 days, range: 145–406 days; p=0.03). Patients expressing high BAALC levels presented shorter OS (p=0.04). The multivariate analysis revealed FLT3-ITD as an independent prognostic factor for OS (p=0.007). Our results provide important insights into the characterization of AML patients in Brazil, suggesting that the frequency of cytogenetic abnormalities and FLT3-ITD mutations are similar to those in developed countries, whereas NPM1 mutations are less frequent. Importantly, the outcome was inferior to that reported in Europe and US, thus suggesting that multicentric collaborative efforts are urgently needed. Disclosures: No relevant conflicts of interest to declare.

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