Impact of Complete Kariotypic Remission (CKR) and Sokal Risk on Overall Survival in Chronic Myelogenous Leukemia (CML) Patients: A Monocentric Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4803-4803
Author(s):  
Lorenzo Falchi ◽  
Monica Schippa ◽  
Debora Luzi ◽  
Rita Emili ◽  
Viola Festuccia ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Acquired Resistance ◽  
Response Duration ◽  
Myelogenous Leukemia ◽  
Response To Treatment ◽  
Line Therapy ◽  
Number Of Patients ◽  
Sokal Score ◽  
The Impact

Abstract Introduction Progressive improvement has been observed in CKR and survival of CML patients (pts) in response to interferon (IFN)a-based regimens, or imatinib. The purpose of this study is the evaluation of: rate of, time to and duration of CKR in accordance to first line therapy employed and Sokal score; impact on overall survival of CKR, and Sokal score, separately considered or combined together. Patients. 109Ph’+ and 5Ph’−, (BCR-ABL positive), CML pts were treated at diagnosis with allogeneic transplantation (3 pts), hydroxyurea (HU) (19 pts), INFa (51pts, G1), INFa associated with ARA-C (20 pts, G2), imatinib alone (18 pts, G3), or imatinib combined with INFa (3 pts, G4). INFa was employed as second line therapy in 12 pts initially treated with hydroxyurea (G5), while INFa/ARA-C combination or imatinib alone was given to 24 (G6) and 23 (G7) pts with de novo or acquired resistance or intolerance to INFa. Third line therapy, consisting of the combination of imatinib with IFNa, was employed in 11 (G8) pts with no CKR (5 pts) or in complete cytogenetic, but not in molecular remission (6 pts). Results. 40 of 94 Ph’+ evaluable non-allotransplanted pts obtained one or more (overall 47) CKRs to INFa-based regimens or imatinib. CKR rate, median time to CKR and response duration are shown in table 1. In the analysis according to Sokal score 82/94 pts, with complete prognostic data at diagnosis, were included. The percentage of responders was higher in the low compared to the non-low Sokal risk group (57% vs. 31%). Irrespective of the treatment, median duration value of the first CKR was also better in the former [18+mths(1–64)] than in the latter group [6mths(2–54)] with 16 vs.4 pts still in first or subsequent remission. Overall survival for CKRs was 68+mths(5–275) vs. 52mths(5–270) for CKRs with 35 vs. 6 pts still alive respectively. Overall survival according to Sokal score at diagnosis was 61+ mths(5–275) for low vs 53mths(5–212) for non-low risk patients. The impact on survival of CKR and Sokal risk were then analyzed simultaneously. The median survival of 27 CKRs and 20 not CKRs with low Sokal risk were 61+mths(5–275)and 63 mths(14–270) respectively as compared to 73+mths(11–212) of 11 CKRs and 36mths(5–139) of 24 not CKRs with unfavourable characteristics at diagnosis. The number of patients still alive in these 4 groups were 24/27, 3/20, 8/11, 3/24 respectively at the time when this analysis was performed. Conclusions. The present data not only confirm the effectiveness of imatinib-over the INFa-based regimens in inducing CKR, but also suggest that response to treatment may be better than Sokal risk in predicting patient survival. Rate,time to and duration of CKR according to treatment PT Group CKR rate(%) time to CKR( months) Duration of CKR (months) N° of pts in cCKR Median Range Median Range G1 17 16 (3–28) 6 (2–53) 0 G2 30 11 (3–24) 15,5 (2–33) 0 G3 85 6 (2–14) 10+ (1–44) 11 G4 100 4 (4–5) 48 (2–50) 1 G5 0 0 G6 9 9,5 (7–12) 40,5 (17–64) 1 G7 54 9 (4–38) 21,5+ (3–54) 6 G8 80 3 (2–4) 26+ (4–48) 9

scholarly journals Choice of Hypomethylating Agent (HMA) for Initial Treatment Does Not Influence Outcome or Survival for Therapy-Related Myeloid Neoplasms (t-MN)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1718-1718
Author(s):  
Charlene C. Kabel ◽  
Debra A. Goldman ◽  
Larry W. Buie ◽  
Virginia M. Klimek
Keyword(s):  
Retrospective Study ◽  
Tp53 Mutation ◽  
De Novo ◽  
Response Duration ◽  
Myelogenous Leukemia ◽  
World Health ◽  
Survival Outcomes ◽  
Cell Transplant ◽  
Tp53 Mutations ◽  
The Impact

Introduction: T-MN is a serious complication of prior chemotherapy and/or radiation therapy. In 2008, the World Health Organization created a new category for t-MN due to the distinct variance in etiology when compared to de novo myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Compared to de novo MDS/AML, t-MN characteristically has poor risk cytogenetics and a higher incidence of TP53 mutations which are both associated with inferior survival. Small, retrospective analyses have evaluated the efficacy of front-line HMA therapy for t-AML and t-MDS, with response rates of approximately 38% (Klimek et al. Leukemia Res, 2012 and Bally et al, Leukemia Res, 2013). However, the response duration (RD), progression-free survival (PFS), and overall survival (OS) outcomes are poorly characterized in t-MN treated with HMA. This retrospective study evaluates the efficacy and survival of t-MN patients (pts) treated with azacitidine (AZA) or decitabine (DAC) in the largest cohort analyzed to-date. Methods: Our cohort included pts with t-MN at Memorial Sloan Kettering Cancer Center treated with either AZA or DAC from January 1, 2002 to September 30, 2016. The primary objective was to compare the best overall response rate (ORR) between AZA and DAC, including complete remission (CR), marrow CR (mCR), hematologic improvement (HI), and partial response (PR). The best ORR was then compared to stable disease (SD), treatment failure (TF), and progressive disease (PD). Secondary objectives included OS, PFS, and RD. Responses were assessed using the 2006 MDS International Working Group (IWG) guidelines and 2003 AML IWG guidelines. We also assessed the impact of TP53 mutations on response to HMA and survival outcomes. Results: Of the 118 pts (56% male), 76 pts received DAC and 42 pts received AZA. Median age was 70 years (yrs) (range, 25-90). DAC recipients were younger (median 67 yrs, range, 25-85) compared to AZA (median 73 yrs, range, 42-90). More pts with AML were treated with DAC (n=27, 35.5%) and more pts with MDS were treated with AZA (n=36, 85.7%). Most MDS pts had Poor (19.3%) or Very Poor (42%) risk cytogenetics, resulting in a High (23.9%) or Very High (54.5%) overall IPSS-R risk category. Time to response was faster with DAC (9.4 weeks) versus (vs.) AZA (13.3 weeks) with more pts proceeding to hematopoietic cell transplant (HCT) in the DAC group (n=19, 25%) vs. AZA (n=3, 7.1%). Overall, there were no statistical differences in response between AZA and DAC when we analyzed combined TF/PD (45.2% and 32.9%, respectively), SD (14.3% and 25%, respectively), and combined CR/HI/PR (40.5% and 42.1%, respectively) with a p-value of 0.28 (Table 1). However, more patients receiving DAC achieved CR and mCR (18.4% and 14.5%, respectively) vs. AZA (4.8% and 7.1%, respectively) and AZA had a higher HI rate (28.6%) vs. DAC (5.3%). DAC pts also appeared to have higher TF rates (25%) vs. AZA (19%) with more PD in the AZA group (26.2%) vs. DAC (7.9%). Median OS was 10.9 months (mo) and PFS was 5.3 mo (Figure 1). There was no difference in median OS between AZA (11.2 mo) and DAC (10.9 mo, p=0.61) and no difference in the median PFS between AZA (5.1 mo) and DAC (5.3 mo, p=0.83). Lastly, there was no difference in median RD between AZA (4.5 mo) and DAC (3.4 mo, p=0.39). Of the 58 pts with known TP53 mutation status, 29 (50%) had ≥1 TP53 mutation(s). There was no difference in OS and PFS between mutant and wildtype TP53 pts, and no difference in survival between AZA and DAC recipients in the mutant TP53 cohort (Figure 2). Conclusions: This large, retrospective study showed no difference in the ORR between AZA and DAC. The faster response and higher rates of CR and mCR may favor the use of DAC as a bridge to HCT in eligible pts. Conversely, the higher rates of HI seen with AZA can improve the quality of life in MDS pts who are ineligible for HCT. Our results confirm prior reports of poor OS seen in t-MN. In our cohort, we showed no difference in survival outcomes between AZA and DAC. There was also no statistical difference in OS/PFS between DAC and AZA in mutant TP53 pts, however point estimates may indicate a pattern favoring DAC over AZA that needs to be explored in a larger sample size. Although we confirmed the efficacy of HMA in this difficult to treat population, response duration and survival outcomes remain poor. Development of more effective therapies that specifically target the biology of t-MN are needed to improve survival outcomes.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

scholarly journals T stage-dependent lymph node and distant metastasis and the accuracy of lymph node assessment in rectal cancer

2021 ◽  
Author(s):  
Henry Ptok ◽  
Frank Meyer ◽  
Roland S. Croner ◽  
Ingo Gastinger ◽  
Benjamin Garlipp
Keyword(s):  
Rectal Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Lymph Nodes ◽  
False Negative ◽  
Cumulative Risk ◽  
Distant Metastases ◽  
Number Of Patients ◽  
Tumor Stages ◽  
The Impact

Summary Objective To analyze data obtained in a representative number of patients with primary rectal cancer with respect to lymph node diagnostics and related tumor stages. Methods In pT2-, pT3-, and pT4 rectal cancer lesions, the impact of investigated lymph nodes on the frequency of pN+ status, the cumulative risk of metachronous distant metastases, and overall survival was studied by means of a prospective multicenter observational study over a defined period of time. Results From 2000 to 2011, the proportion of surgical specimens with ≥ 12 investigated lymph nodes increased significantly, from 73.6% to 93.2% (p < 0.001; the number of investigated lymph nodes from 16.2 to 20.8; p < 0.001). Despite this, the percentage of pN+ rectal cancer lesions varied only non-significantly (39.9% to 45.9%; p = 0.130; median, 44.1%). For pT2-, pT3-, and pT4 rectal cancer lesions, there was an increasing proportion of pN+ findings correlating significantly with the number of investigated lymph nodes up to n = 12 investigated lymph nodes. Only in pT3 rectal cancer was there a significant increase in pN+ findings in case of > 12 lymph nodes (p = 0.001), but not in pT2 (p = 0.655) and pT4 cancer lesions (p = 0.256). For pT3pN0cM0 rectal cancer, the risk of metachronous distant metastases and overall survival did not depend on the number of investigated lymph nodes. Conclusion In rectal cancer, at least n = 12 lymph nodes are to be minimally investigated. The investigation of fewer lymph nodes is associated with a higher risk of false-negative pN0 findings. In particular, in pT3 rectal cancer, the investigation of more than 12 lymph nodes lowers the risk of false-negative pN0 findings. An upstaging effect by the investigation of a possibly maximal number of lymph nodes could not be detected.

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

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.

Outcomes of IDH1/2 mutant AML patients treated with IDH1/2 inhibitors: A single institutional experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19010-e19010
Author(s):  
Constantine Nick Logothetis ◽  
Chetasi Talati ◽  
Gregoire Calon ◽  
Nathan P Horvat ◽  
Virginia Olivia Volpe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Somatic Mutations ◽  
Demographic Data ◽  
Response Duration ◽  
Initial Response ◽  
Median Number ◽  
Resistance Mechanisms ◽  
Overall Response ◽  
Line Therapy ◽  
Number Of Patients

e19010 Background: Recent studies showed that IDH1/2 are frequently mutated in AML and that aberrant 2-HG elevation driven by the mutant IDH1/2 proteins plays a pivotal role in AML development. Subsequent clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. In this single institutional retrospective study, we explored the efficacy and safety outcomes of IDH1/2mut AML patients treated with Ivosidenib or Enasidenib. Methods: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Results: A total of 43 ( IDH1mut, n = 12; IDH2mut, n = 33; both IDH1/2mut, n = 2) patients were included in the study. Median age at AML diagnosis was 67.6 (24.2-83.3) years and 24 (55.8%) patients were male. Eighteen (42%) patients had secondary AML and 13 (34.2%), 17 (44.7%), and 8 (21.1%) patients had favorable, intermediate, and adverse risk, respectively. A total of 23 (53.5%) and 9 (20.9%) patients received intensive chemotherapy and hypomethylating agents as their 1st line therapy. One patient received Enasidenib as the 1st line therapy and the rest of the patients had relapsed/refractory disease prior to IDH1/2 inhibitor therapy. Median number of treatment prior to IDH1/2 inhibitors was 4 (0-8). The median duration of IDH1/2 inhibitor treatment was 3.2 (0.2-31.6) months ( IDH1 mut, 2.5 [0.7-13.5]; IDH2 mut, 3.4 [0.2-31.6]). Treatment response was assessed in 38 patients and 18 had overall response (CR, n = 7 [18.4%]; PR, n = 11 [28.9%]). Among these, 13 patients had concurrent somatic mutations in FLT3, KRAS, NRAS, or PTPN11. The overall response rate in these patients was not statistically different compared to patients who did not have these mutations (38.5% vs. 40%, p > 0.05). The median PFS was 3.9 (0.4-14.7) months ( IDH1 mut, 5.6 [1.7-11.5] vs. IDH2 mut, 3.7 [0.4-14.7], p > 0.05) and median OS was 7.6 (0.4-44.1) months. The most common reason for IDH1/2 inhibitor discontinuation was disease progression (n = 21) followed by adverse events (n = 3) and allogeneic transplant (n = 2). The adverse events were assessed in 41 patients and the most common adverse events were differentiation syndrome ( IDH1 mut, n = 3; IDH2 mut, n = 5) and leukocytosis ( IDH1 mut, n = 4; IDH2 mut, n = 4) followed by hepatic toxicity ( IDH2 mut n = 7), and QTc prolongation ( IDH1 mut, n = 3). Conclusions: Our study indicates that IDH1/2 inhibitors remain a reasonable option for the refractory/relapsed IDH1/2mut AML. However, significant number of patients failed to show any response and many of the patients who showed initial response had short response duration. These findings warrant further studies to identify underlying resistance mechanisms of IDH1/2 inhibitors and the optimal combination therapeutic strategies.

Weekly Irinotecan in Patients with Metastatic Colorectal Cancer Failing 5-Fluorouracil-Based Chemotherapy: Efficacy and Prognostic Factors

2003 ◽  
Vol 89 (2) ◽  
pp. 141-145 ◽  
Author(s):  
Aziz Karaoğrlu ◽  
Suayib Yalcin ◽  
Gülten Tekuzman ◽  
Ayse Kars ◽  
Ismail Çelik ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Objective Response ◽  
Response Duration ◽  
Response To Treatment ◽  
Time To Progression ◽  
Median Response ◽  
Poor Prognostic Factor ◽  
Histologic Subtype

Aims and background We evaluated the efficacy and tolerability of weekly irinotecan as a second-line treatment in patients with colorectal cancer failing 5-fluorouracil-based chemotherapy and searched for predictive and prognostic factors. Methods A total of 36 patients were included. Median age was 53 years (range, 33-72). One treatment cycle consisted of irinotecan, 100 mg/m2 weekly, for 4 weeks followed by a 2-week rest. Gender, age, primary site, number of metastatic sites, histologic subtype, differentiation, pretreatment CEA, CA 19-9 and lactate dehydrogenase levels and marker response to treatment were investigated as predictive factors for response to treatment and as prognostic factors in the overall survival and time to progression of the patients. Results A total of 120 cycles (median, 3 cycles) was delivered. An overall 14% objective response rate (1 complete and 4 partial responses) was achieved. The median response duration was 4 months (range, 2-7). Another 36% of the patients had stable disease for a median duration of 4 months (range, 2-8). Median time-to-disease progression was 4 months and overall median survival was 12 months (95% confidence interval, 9-15). Pretreatment serum CA 19-9 level and marker response to two courses of treatment were found to be clinically significant in time to progression and overall survival. Younger age (≤45 years) was a poor prognostic factor associated with a shorter time to progression. The major toxicity was grade 3-4 diarrhea, which occurred in 28% of the patients, and treatment was discontinued in 3 (8%) patients due to toxicity. Other hematological and non-hematological toxicities were mild and manageable. Conclusions We concluded that weekly irinotecan at the dose of 100 mg/m2 is an effective and tolerable treatment option, with a 50% disease control rate, for patients with colorectal cancer failing previous 5-fluorouracil-based chemotherapy.

scholarly journals HLA-E⁎01:03 Allele in Lung Transplant Recipients Correlates with Higher Chronic Lung Allograft Dysfunction Occurrence

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Julie Di Cristofaro ◽  
Mathieu Pelardy ◽  
Anderson Loundou ◽  
Agnès Basire ◽  
Carine Gomez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Study ◽  
Viral Infections ◽  
De Novo ◽  
Therapeutic Option ◽  
Univariate Analysis ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Hematopoietic Stem ◽  
The Impact

Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. HLA-E seems to play a major role in the immune response to different viral infections and to affect transplantation outcome, in Hematopoietic Stem Cell Transplantation, for example. Two nonsynonymous alleles, HLA-E⁎01:01 and HLA-E⁎01:03, have functional differences, involving relative peptide affinity, cell surface expression, and potential lytic activity of NK cells. The aim of this retrospective study was to determine the impact of these two alleles for LTx recipients on anti-HLA alloimmunization risk, overall survival, and chronic rejection (CLAD). HLA-E was genotyped in 119 recipients who underwent LTx from 1998 to 2010 in a single transplantation center. In univariate analysis, both HLA-E homozygous states were associated with impaired overall survival compared to heterozygous HLA-E alleles (p=0.01). In multivariate analysis, HLA-E⁎01:03 allele showed increased CLAD occurrence when compared to homozygous HLA-E⁎01:01 status (HR: 3.563 (CI 95%, 1.016–12),p=0.047). HLA-E allele did not affect pathogen infection or the production ofde novoDSA. This retrospective study shows an uninvestigated, deleterious association of HLA-E alleles with LTx and requires verification using a larger cohort.

scholarly journals Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

2014 ◽  
Vol 32 (10) ◽  
pp. 1020-1030 ◽  
Author(s):  
Suzanne L. Topalian ◽  
Mario Sznol ◽  
David F. McDermott ◽  
Harriet M. Kluger ◽  
Richard D. Carvajal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Clinical Trials ◽  
Objective Response ◽  
Response Duration ◽  
Advanced Melanoma ◽  
Immune Memory ◽  
Drug Discontinuation ◽  
Median Response ◽  
The Impact

PurposeProgrammed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued.Patients and MethodsPatients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation.ResultsMedian overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative.ConclusionOverall survival following nivolumab treatment in patients with advanced treatment–refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2343-2343
Author(s):  
Jingmei Hsu ◽  
Anita J. Kumar ◽  
Martin P. Carroll ◽  
Noelle V. Frey ◽  
Nirav N. Shah ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Myeloproliferative Neoplasm ◽  
Molecular Characteristics ◽  
Intermediate Risk ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

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