scholarly journals Second-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia with Additional Chromosomal Abnormalities

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1640-1640
Author(s):  
Naoto Takahashi ◽  
Tomoko Yoshioka ◽  
Masahiro Kizaki ◽  
Tatsuya Kawaguchi ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Observational Study ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Rank Test ◽  
Log Rank Test ◽  
Cytogenetic Analyses ◽  
Tki Treatment

Background: In the New TARGET observational study, 452 newly diagnosed chronic myeloid leukemia chronic phase (CML-CP) patients were analyzed and the results reported recently in International Journal of Hematology (IJH). The median follow-up period was 5.4 years, and eight patients progressed to AP/BC and six had a CML-related death. Herein, we evaluated the impact of additional chromosomal abnormalities (ACAs) on the clinical outcomes of participants in this study. Methods: Cytogenetic analyses of bone marrow aspiration were performed at enrollment and every 6 months until complete cytogenetic response (CCyR) was achieved. If physicians switched to TKI because of resistance or intolerance to the first TKI, cytogenetic analyses of bone marrow aspiration were performed at baseline of the second-line treatment. Chromosome banding analysis was performed on bone marrow cells after short-term culture (24 hours). At least 20 metaphases were analyzed by the G-banding method according to the International System for Human Cytogenetic Nomenclature. This sub-analysis in the New TARGET observational study 1 was approved by the ethics committee of Akita university school of medicine (No. 2178). Results: For cytogenetic analyses, 1,732 samples were collected over the entire observation period from 452 patients. Chromosomal abnormalities, besides standard Ph translocation, were identified in 164 samples from 61 patients. Constitutional alterations (n=7) and single abnormality with -Y at the onset of CML (n=11), clonal chromosomal abnormalities in Ph negative metaphases during TKI treatment (n=10) and t(v;22) including three-way Ph translocation at the onset of CML (n=9) were excluded from patients with ACAs. ACAs were detected in 24 patients either at the onset of CML (n=19) or over the duration of TKI treatment (n=5). Among them, i(17q), monosomy7/7q-, chromosome3q26, and complex karyotype composed of these 3 abnormalities, which were proposed as a high-risk ACAs in a previous study were identified in three patients. Among 24 patients with ACAs, 8 patients received imatinib(IM) and 16 patients 2G-TKI. There were no statistically significant differences in the clinical background between the group with and without ACAs.Six patients with TKI resistance could hardly achieve MMR, and 4 patients died after progression to AP/BC. In a multivariate analysis of prognostic factors for predicting the clinical outcomes, including age, 2G-TKI, Charlson Comorbidity Index (CCI) score, performance status (PS), EUTOS long-term survival score (ELTS), and the presence of ACAs (Table), ACAs was one of the independent adverse prognostic factors for OS (HR 3.701 [95%CI: 1.175−11.660] P= 0.025), EFS (HR 3.920 [95%CI: 1.563−9.833] P= 0.036), PD (HR 39.02 [95%CI: 7.103−214.30] P< 0.0001), and loss of response (HR 8.346 [95%CI: 3.221−21.630] P<0.0001). The 2G-TKI was also a prognostic factor for OS (HR 0.36 [95%CI: 0.156−0.831] P= 0.017), PFS (HR 0.35 [95%CI: 0.158−0.775] P= 0.0095), and PD (HR 0.108 [95%CI: 0.021−0.558] P= 0.0079). CCI and PS were independent prognostic factors for each survival, but not for MMR, loss of response or PD, which is associated with TKI response or resistance. The Kaplan-Meier curve for PFS, and OS were significantly lower for the group with ACAs than without (Figure A, D: Log-rank test P= 0.00842, 0.00408, respectively); the 5-year PFS and OS rates of the group with ACAs were 81.3% (95%CI: 56.6−92.7), and 77.6% (95%CI: 49.8−91.2), respectively. Although there were statistically significant differences in PFS, and OS between the group with and without ACAs in imatinib arm (Figure B, E: Log-rank test P= 0.00007, 0.00007, respectively), there were no differences in 2G-TKI arm (Figure C, F: Log-rank test P= 0.478, 0.515, respectively). Conclusions: In the present cytogenetic analysis of the New TARGET observational study 1, ACAs had a negative impact on clinical outcomes. However, we discovered that 2G-TKI might be able to overcome the poor prognosis of CML patients with ACAs in 2G-TKI era. Therefore, cytogenetic analysis at CML diagnosis and during TKI treatment is very important for the prediction of outcome and the selection of TKI. Acknowledgments: This study was supported by research fundingfrom Novartis Pharmaceuticals and Bristol-Myers Squibb to Japanese Society of Hematology. Disclosures Takahashi: Pfizer: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Chug Pharmaceuticals: Research Funding; Asahi Kasei Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau. Kizaki:Daiichi Sankyo: Research Funding; Janssen Pharm: Speakers Bureau; Takeda Pharm: Research Funding, Speakers Bureau; Ono Pharm: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Kyowa Kirin: Research Funding; Chugai Pharm: Research Funding; Celgene: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sumitomo Dainippon Pharm: Consultancy. Kawaguchi:Pfizer: Honoraria; Novartis: Honoraria; Alexion: Honoraria. Suzuki:AbbVie: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; Bristol-Myers Squibb: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Yamamoto:Meiji Seika Pharma: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Bayer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; SymBio: Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1538-1538
Author(s):  
Aristoteles Giagounidis ◽  
Alan List ◽  
Eva Hellström-Lindberg ◽  
Mikkael A. Sekeres ◽  
Ghulam J. Mufti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Rank Test ◽  
Employment Equity ◽  
Advisory Committees ◽  
Log Rank Test ◽  
Equity Ownership ◽  
Baseline Characteristics ◽  
Rbc Transfusion

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

scholarly journals Prognostic Impact of Chromosomal Variation in Patients with Acute Promyelocytic Leukemia (APL); Analysis of 775 Cases Enrolled in the Japan Adult Leukemia Study Group APL Studies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2329-2329
Author(s):  
Miwa Adachi ◽  
Akihiro Takeshita ◽  
Tomohiko Taki ◽  
Shigeki Ohtake ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Clinical Outcomes ◽  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Leukocyte Count ◽  
Promyelocytic Leukemia ◽  
Chromosome 9 ◽  
Chromosome 15 ◽  
Free Survival

Abstract Background: A combination of all-trans retinoic acid (ATRA) and chemotherapy (CT) has dramatically improved the prognosis of acute promyelocytic leukemia (APL). Nevertheless, considerable number of patients are either refractory to the treatment or relapse after an initial complete remission (CR). Although prognostic factors for APL have been studied, the influence of chromosomal variations in addition to t(15;17) remains controversial. One of the reasons is due to the numbers of cases studied were relatively small (47 to 513 cases). Here, we analyzed clinical features and outcomes of 775 APL caseswith or without additional chromosome abnormalities (ACAs) who were treated with ATRA and CT in the JALSG-APL studies including a large number of cases analyzed for karyotype. Methods: 1,024 cases aged between 15 and 70 yrs with newly diagnosed APL were enrolled in the JALSG APL92, 95, 97 and 204 studies and 775 patients were assessable for karyopypes. All protocols included induction therapy with ATRA and CT, following several courses of post-remission chemotherapy including anthracyclines. Arsenic trioxide (ATO) was not included. Clinical and biological characteristics such as age, gender, initial leukocyte count, platelet count, number of APL cells, DIC score, lack of Auer-rod and incidence of variant type were analyzed in relation to chromosomal abnormalities in 766 cases. CR rate, relapse rate (RR), overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were assessed and compared between patients with or without ACAs. Each variation of ACAs was also analyzed with clinical and biological features. This work was supported in part by the National Cancer Center Research and Development Fund (26-A-24), Grants-in-Aid from the Cancer Research from the Japanese Ministry of Health, Labor and Welfare (#23-004 and #25100501). These studies were approved by our IRB. Results: ACAswere noted in 235 patients (30%). Sanz score and the initial leukocyte count were significantly lower in patients with ACAs (p=0.027 and p=0.027, respectively). No other clinical or biological differences were found between patients with and without ACAs. The subgroups of ACAs were shown in Figure 1. Trisomy 8 was found in 76 cases (32%). Other ACAs were found involving chromosome 15 in 37 cases (16%), both chromosomes 15 and 17 in 31 cases (13%), chromosome 7 in 19 cases (8%), chromosome 9 in 12 cases (5%), chromosome 6 in 8 cases (3%), chromosome 21 in 7 cases (3%) and alternative ACAs in 43 cases (18%). A low initial leukocyte count (<3,000/µl) was significantly associated with an abnormality of chromosome 15 (p=0.039) and a high initial leukocyte count (≥10,000/µl) was associated with other unspecified chromosomal abnormalities (p=0.010). In all cases, CR rate, OS, EFS and DFS were not different between patients with and without ACA (p=0.341, p=0.694, p=0.414, p=0.852, respectively). However, in elderly patients (≥50 yrs) with ACAs, OS, EFS and DFS were significantly lower compared to younger patients (<50 yrs) (p=0.019, p=0,023 and p=0.030, respectively) (Figure 2). No such age related difference was observed for patients without ACAs (OS, p=0.068; EFS p=0.485; DFS, p=0.672). In each risk group divided by initial leukocyte count, clinical outcomes were not different between patients with and without ACAs. In patients without ACAs, OS, EFS and DFS of patients assigned to no maintenance or retinoid maintenance were significantly better than in those allocated to the maintenance CT (p<0.001, for all). (Figure 3) The significance was not observed in patients with ACAs except DFS (OS, p=0.161; EFS p=0.293; DFS p=0.043). Conclusions: The present study is the largest to date to focus on the influence of ACAs on clinical outcomes of patients with APL treated with ATRA and CT. The analysis revealed exact variation and frequency of ACAs. We found that patients with ACAs were associated with the lower initial leukocyte count and the lower survival outcomes in elderly patents, suggesting a possible link to age and post-remission chemotherapy. Some promising agents, such as ATO, tamibarotene and gemtuzumab ozogamicin might change the prognostic factors, including ACAs. Careful chromosomal analyses, especially ACAs related to chromosome 15 and/or 17, need to be analyzed by molecular methods and performed in future prospective studies with alarge number of cases. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Kiyoi: Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD.: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding. Kobayashi:Ohtsuka: Research Funding; Behringer: Research Funding; Simic: Research Funding. Asou:Chugai Pharmaceutical Co., Ltd.: Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria.

Results of a Phase I-II Clinical Trial of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab (OFAR) Combination Therapy In Patients with Aggressive, Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Syndrome (RS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 923-923 ◽  
Author(s):  
Apostolia Maria Tsimberidou ◽  
William G. Wierda ◽  
Sijin Wen ◽  
William Plunkett ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Median Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Rank Test ◽  
Advisory Committees ◽  
Log Rank Test

Abstract Abstract 923 Background: To enhance the response rate with a decrease in myelosuppression that were observed with oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) (Tsimberidou et al, J Clin Oncol, 2008;26:196), the daily dose of oxaliplatin was increased from 25 to 30mg, the daily dose of Ara-C was decreased from 1 g/m2 to 0.5 g/m2 and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: OFAR2 consisted of oxaliplatin 30mg/m2 D1-4; fludarabine 30mg/m2; Ara-C 0.5g/m2; rituximab 375mg/m2 D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2-3 (level 1) D2-4 (level 2) or D2-5 (level 3) every 4 weeks. Tumor lysis, DNA virus, and PCP prophylaxis was administered. A “3+3” design was used (Phase I) and and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results: Overall 102 patients (rel. CLL 67, RS 35) were treated. Twelve patients were treated in the Phase I portion of the study. Dose-limiting toxicities were noted in 2/3 patients at level 3 (G4 diarrhea and G4 sepsis). Level 2 was the maximum tolerated dose. Ninety patients (CLL, 60; RS, 30) were treated in Phase II portion of the study (age > 60 years 67%, 17p del 37.5%, 11q del 15%, 13q del 18%, +12, 17%; neg. 12.5%; unmutated IgVH 81.5%, ZAP70-positive 77%, and CD38 30%, 63%). Response in 80 of 90 patients (Phase II) is shown in Table (too early, n=10). The overall response rates in patients (Phase II) with 17p deletion and 11q deletion were 29% and 41%, respectively. Twenty-nine patients underwent SCT after OFAR2 (response status to OFAR2 at the time of SCT: CR, n=3; nPR, n=2; 15; no response, n=9). With a median follow-up of 20.8 months, the median survival was 19 months (95% CI, 13–37+) and the median FFS was 6 months (95% CI, 3.4 – 8.2). Overall, 238 cycles were administered. G3-4 neutropenia, thrombocytopenia, and anemia were noted in 67%, 74%, and 44% of patients (51%, 64%, and 25% of cycles); and G3-4 infections in 19% of patients. Clinical outcomes of OFAR2 were compared with those of OFAR1. In patients with RS, the overall response rate was 41% (11/27) with OFAR2 and 50% (10/20) with OFAR1 (p = 0.57, Fisher's test); the median survival with OFAR2 and OFAR1 was 8.3 months and 18+ months, respectively (p = 0.92, log-rank test); and the respective median FFS was 3.0 months and 4.1 months (p = 0.40, log-rank test). In patients with CLL, the overall response rate was 55% (29/53) with OFAR2 and 33% (10/30) with OFAR1 (p = 0.36, Fisher's test); the median survival with OFAR2 was 21.4 months and 13.8 months with OFAR1 (p = 0.19, log-rank test); and the respective median FFS was 6.6 months and 4.9 months (p = 0.69, log-rank test). Conclusion: OFAR2 induced response in 41% of patients with RS and 55% of patients with relapsed/refractory CLL in the phase II study. Antileukemic activity was also noted in patients with 17p deletion. Although the numbers of patients are small, OFAR1 was associated with a trend towards superior clinical outcomes in patients with RS compared to OFAR2; and OFAR2 was associated with a trend towards superior clinical outcomes compared to OFAR1 in patients with relapsed/refractory CLL. Disclosures: Tsimberidou: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; ASCO: Career Development Award, Research Funding. Off Label Use: Drug: Oxaliplatin. Oxaliplatin combined with fludarabine, cytarabine, and rituximab has antileukemic activity in patients with relapsed/refractory Chronic Lymphocytic Leukemia and Richter Syndrome. Wierda:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Micromet: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Abbott Laboratories: Research Funding. O'Brien:Biogen Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Kipps:Sanofi Aventis: Research Funding. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

A Retrospective Analysis on Prognostic Factors of Angioimmunoblastic T-Cell Lymphoma: a Multicenter Cooperative Study In Japan

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3117-3117
Author(s):  
Takashi Tokunaga ◽  
Kazuyuki Shimada ◽  
Kazuhito Yamamoto ◽  
Dai Chihara ◽  
Takuji Ichihashi ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
T Cell Lymphoma ◽  
Rank Test ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Log Rank Test ◽  
Number Of Patients

Abstract Abstract 3117 Background: Angioimmunoblastic T-cell lymphoma (AITL) is one of the major types of peripheral T-cell lymphoma (PTCL), with T follicular helper cells (TFH) reported to be the normal counterpart cell type. The disease generally presents with poor prognosis following conventional chemotherapy treatments. Furthermore, existing prognostic factors or predictive models for non-Hodgkin lymphoma are not useful in the prognostification of AITL. Identification of novel prognostic factors is therefore vital. Unfortunately, the number of studies using a large cohort of patients with AITL has so far been limited. Patients and Method: To elucidate the clinicopathological characteristics of AITL in Japan, we retrospectively analyzed 213 patients who were diagnosed with AITL between January 1990 and September 2008 from 31 participating hospitals. Patients with AITL were eligible for analysis only if their diagnosis was confirmed by histopathological and immunohistochemical criteria in accordance with the WHO classification. For immunohistochemical analysis, we evaluated CD10, CXCL13, PD-1 and EBER-ISH in addition to routine immunostaining. Clinical data was retrospectively collected from case reports. Patients received treatment for AITL according to the respective institutional protocols. Overall survival (OS) and progression free survival (PFS) were analyzed by using the log-rank test, and results expressed as Kaplan-Meier plots. Cox proportional hazard regression analysis with OS and PFS was performed to identify potential independent prognostic factors. This study was approved by the institutional review board of participating hospitals and complied with the provisions of the Declaration of Helsinki. Result: The median patient age was 67 years (range: 34–89 years), with 74% of patients older than 60 years. The female:male ratio was 1:1.8. Ninety percent of patients displayed Stage III or IV disease, and 23% of patients involved more than 1 extranodal site. B-symptoms and bone marrow involvement were present in 60% and 30% of patients, respectively. Laboratory findings showed anemia (male: Hb <13.0 g/dl, female: Hb <11.0 g/dl) in 61% of patients, a positive Coombs test in 47%, hypergammaglobulinemia (IgG >1700 mg/dl) in 54%, IgA >400 mg/dl in 37%, and elevated serum LDH levels in 75% of patients, respectively. According to the international prognostic index (IPI) and prognostic index for PTCL-NOS (PIT) score, patients were categorized as follows; IPI: Low (L), 10% (22/199); Low-intermediate (LI), 20% (39/199); High-intermediate (HI), 39% (77/199); and High (H), 31% (61/199), respectively, and PIT: Group1 (G1), 4% (8/201); Group2 (G2), 19% (38/201); Group3, 42% (85/201); and Group4, 35% (70/201), respectively. In terms of the initial series of treatments, 84% of patients received anthracycline-based chemotherapies. With a median follow-up duration of 42 months in surviving patients, 3-year OS and PFS were 54% and 39%, respectively. IPI was predictive for OS (3-years OS: L, 84%; LI, 65%; HI, 54%; H, 38%; Log-rank test, p<0.001), however, PIT was less predictive than IPI according to the distribution of the number of patients and survival in each group (3-years OS: G1, 88%; G2, 65%; G3, 57%; G4, 42%; Log-rank, p=0.014). Immunohistochemical staining revealed positivity for CD10 in 31% (40/130), EBER-ISH in 68% (108/160), CXCL13 in 92% (76/83), and PD-1 in 61% of patients (51/83), respectively. Multivariate analysis revealed total protein (TP) (<6.5 g/dl), {hazard ratio (HR), 2.12; 95% confidence interval (CI), 1.20–3.72; p=0.010}, IgA (>400 mg/dl) (HR, 2.00; 95% CI, 1.19–3.34; p=0.009), anemia (male, Hb <13.0 g/dl; female, Hb <11.0 g/dl) (HR, 1.95; 95% CI, 1.11–3.52; p=0.020), CRP (>1.0 mg/dl) (HR, 1.84; 95% CI, 1.05–3.35; p=0.033), and performance status (>2) (HR, 1.73; 95% CI, 1.03–2.92; p=0.040) were identified as significant prognostic factors for OS. IgA (HR, 1.94; 95% CI, 1.25–2.98; p=0.003), and anemia (HR, 1.65; 95% CI, 1.03–2.66; p=0.036) were significant prognostic factors for PFS. Conclusion: Prognosis of patients with AITL in Japan is poor. Although IPI was useful in prognostification of AITL, other factors including those not adopted in IPI, such as IgA, anemia, TP and CRP, significantly affected the prognosis in this analysis. Further validation studies of these criteria should be performed. Disclosures: Naoe: Chugai Pharmaceutical Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.,Ltd.: Research Funding; Dainippon Sumitomo Pharma Co.,Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Kinoshita:Chugai Pharmaceutical Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.,Ltd.: Research Funding.

Treatment of Diffuse Large B-Cell Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2684-2684
Author(s):  
Aminat U Magomedova ◽  
Sergey K Kravchenko ◽  
Alexandra Kremenetskaya ◽  
Evgenyi Zvonkov ◽  
Elena Baryakh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
B Cell ◽  
Intensive Therapy ◽  
Adult Patients ◽  
Rank Test ◽  
Bulky Disease ◽  
Direct Invasion ◽  
Log Rank Test ◽  
Large B Cell

Abstract Abstract 2684 Introduction: diffuse Large B-cell lymphoma (DLBCL) are aggressive but potentially curable with multi-agent chemotherapy. The R-CHOP regimen is standard therapy for treatment of DLBCL patients. Whereas attempts to improve outcome with more intensive chemotherapy failed to show additional benefit. Aims: to set the indications to standard or intensive therapy in patients with nodal DLBCL and to evaluate the efficiency of modified protocol NHL-BFM-90 in adult patients. Patients and methods: 139 patients with newly diagnosed nodal DLBCL were included in the study since January 2002 till December 2010. The diagnosis was established according to the criteria of the WHO classification. Diagnostic methods include neck, thorax, abdomen and pelvis CT scan, tumor biopsy bilateral bone marrow (BM) biopsy, lumbal puncture, MRT or scintigraphy of bones. Bone marrow involvement was found in 18 cases and confirmed by immunohistochemistry. Bulky disease, direct invasion to adjacent organs, III-IV stage according Ann-Arbor and increased level LDH were considered as the unfavorable prognostic factors. The patients were stratified into 2 groups: the first group with unfavorable prognostic factors (86 patients), the second group without unfavorable prognostic factors (53 patients). Median age in the first group was 53 years. There were 46 men and 40 women. The level of LDH was elevated in the 61 patients. III-IV stage without involvement of BM was diagnosed in the 35 patients, IV stage with BM involvement-in the 18 patients, bulky disease and direct invasion to adjacent organs-in the 33 patients. Median age in the second group was 55 years. There were 28 men and 25 women. All patients in the first group received intensive therapy by modified protocol NHL-BFM-90. The patients in the second group received chemotherapy CHOP-21(n=28) or R-CHOP-21 (n=25). The program NHL-BFM-90 was modified: the dose of methotrexate was 1,5 g/m2 for 12 hours and adriamycin 25 mg/m2 was infused in 1–2 days of course AA. All patients treated with this protocol gave written informed consent. We made spleneectomy to all the patients of splenic DLBCL before chemotherapy (n=20). The estimation of the chemotherapy efficiency was carried out according to the criteria of the International Working Group: rate of complete remissions (CR), overall (OS) and relapse-free (RFS) survival. The data were analyzed with SAS statistical package program. Statistical significance of the difference in the survival curves for two groups was calculated with Log-rank Test. Results: 64 patients in the first group (74,4%) and 53 patients (100%) in the second group achieved CR. 5-year OS and RFS were 65% and 86% in the first group 96% and 100% in the second group, accordingly. In the first group the best results were obtained in patients without BM involvement. 5-year OS was 84% in these patients comparing 12% in patients with BM involvement–figure 1 (Log-Rank Test=0,0001). The rate of CR and OS were the same in CHOP-21 group and R-CHOP-21 group–figure 2 (Log-Rank Test=0,8). Conclusion: The stated unfavorable prognostic factors allowed to stratify patients into prognostic groups. Modified program NHL-BFM-90 is effective treatment for adult patients with DLBCL with unfavorable prognostic factors. The concordant of BM involvement is the most strict prognostic factor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Predictive impact of PVL assessments on clinical outcomes in patients undergoing TAVR

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Matsushita ◽  
B Marchandot ◽  
M Kibler ◽  
C Sato ◽  
J Heger ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cox Regression ◽  
Adenosine Diphosphate ◽  
Rank Test ◽  
Multicenter Studies ◽  
Cox Regression Analysis ◽  
Paravalvular Leakage ◽  
Transcatheter Aortic Valve ◽  
Log Rank Test ◽  
Cerebrovascular Events

Abstract Introduction Paravalvular leakage (PVL) following transcatheter aortic valve replacement (TAVR) is associated with greater mortality. In clinical practice, determining PVL severity after TAVR remains challenging and often requires multiparametric assessment. Purpose This study sought to evaluate the respective value of various modalities of PVL assessments, including transthoracic echocardiography (TTE), cine-angiography, aortic regurgitation index (ARI), and closure time with adenosine diphosphate (CT-ADP), in the prediction of adverse clinical outcomes. Methods We included 1044 patients from our prospective TAVR registry between February 2010 and May 2019. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization within 1-year. Established cutoff values of ARI (&lt;25) and CT-ADP (&gt;180 sec) were used to assess the presence of PVL after TAVR. Results Moderate to severe PVL occurred in 14.2% and 5.2% of patients as measured by TTE and angiography. The rate of patients with ARI &lt;25 and CT-ADP &gt;180 sec were 36.5% and 24.9%, respectively. Among the four modalities, PVL evaluated by angiography predicted poorer clinical outcomes (Log rank test; p=0.001), whereas TTE, ARI &lt;25, and CT-ADP &gt;180 sec were not associated with 1-year MACCE. By multivariate Cox regression analysis, moderate to severe PVL by angiography was an independent predictor of 1-year MACCE (hazard ratio: 1.96; 95% confidence interval: 1.22–3.00; p=0.007). Conclusions Paravalvular leakage measured by angiography was evidenced as the most meaningful modality in the prediction of adverse clinical outcomes. Future multicenter studies are warranted to ensure these findings in the current TAVR era. Figure 1 Funding Acknowledgement Type of funding source: None

Interferon Adjuvant to Radical Nephrectomy in Robson Stages II and III Renal Cell Carcinoma: A Multicentric Randomized Study

2001 ◽  
Vol 19 (2) ◽  
pp. 425-431 ◽  
Author(s):  
Giorgio Pizzocaro ◽  
Luigi Piva ◽  
Maria Colavita ◽  
Sonia Ferri ◽  
Raffaella Artusi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factors ◽  
Protective Effect ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Radical Nephrectomy ◽  
Rank Test ◽  
Event Free Survival ◽  
Free Survival ◽  
Log Rank Test

PURPOSE: Because interferon gave promising results in the management of metastatic renal cell carcinoma in the 1980s, a multicentric randomized controlled trial was planned to compare adjuvant recombinant interferon alfa-2b (rIFNα2b) with observation after radical nephrectomy in patients with Robson stages II and III renal cell carcinoma. Overall and event-free survival were to be evaluated together with prognostic factors. PATIENTS AND METHODS: Overall and event-free survival curves for 247 patients (124 controls and 123 treated) were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox’s multiple regression models were adopted to perform a joint analysis of treatment and prognostic factors. RESULTS: The 5-year overall and event-free survival probabilities were 0.665 and 0.671, respectively, for controls and 0.660 and 0.567, respectively, for the treated group; the differences were not statistically significant (2P = .861 for overall and 2P = .107 for event-free survival with the log-rank test). Regarding prognostic factors, only grade, pT, and pN demonstrated a significant prognostic role. First-order interactions of treatment with pT and pN category were investigated; a significant interaction was found between pN and treatment. A harmful effect of rIFNα2b in the 97 treated pN0 patients and a protective effect in the 13 treated pN2/pN3 patients were statistically significant. CONCLUSION: Adjuvant rIFNα2b is not indicated after radical nephrectomy for renal cell carcinoma. The protective effect in the small group of pN2/pN3 patients requires further investigation.

Does Age Itself Have an Adverse Effect on Survivorship of Meniscal Allograft Transplantation? A Cartilage Status and Time From Previous Meniscectomy–Matched Cohort Study

2020 ◽  
Vol 48 (7) ◽  
pp. 1696-1701 ◽  
Author(s):  
Ju-Ho Song ◽  
Seong-Il Bin ◽  
Jong-Min Kim ◽  
Bum-Sik Lee ◽  
Dong-Wook Son
Keyword(s):  
Clinical Outcomes ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Rank Test ◽  
Meniscal Allograft Transplantation ◽  
Log Rank Test ◽  
Meniscal Allograft ◽  
Age Related ◽  
Significant Difference ◽  
Operating Characteristic Curve

Background: The aging process is accompanied by several conditions that could affect the outcome of meniscal allograft transplantation (MAT). These conditions have made it difficult for clinicians to determine the effect of chronologic age on survivorship after MAT. Hypothesis: Advanced age does not have an adverse effect on survivorship of MAT when controlling for age-related factors, such as cartilage status and time from previous meniscectomy. Study Design: Cohort study; Level of evidence, 3. Methods: The records of 264 consecutive patients who underwent primary medial or lateral MAT were reviewed. To check whether there was a difference in MAT survivorship according to age, a cutoff value was calculated from a time-dependent receiver operating characteristic curve. Survival rates, as well as clinical improvement as determined using the Lysholm score, were compared between groups divided by the cutoff value. Patients were matched for cartilage status and elapsed time from previous meniscectomy. Differences in survivorship and clinical outcomes were assessed between the matched groups. Results: A time-dependent receiver operating characteristic curve showed that the difference in MAT survivorship was maximized with a cutoff age of 43 years. Kaplan-Meier analysis showed a significant difference in MAT survivorship between the older and younger groups (log-rank test, P = .01). However, after matching for cartilage status and time from previous meniscectomy, which left 56 patients per group, there was no significant difference in MAT survivorship (log-rank test, P = .10) between the groups. Regarding clinical outcomes, the mean Lysholm scores were not significantly different between the older and younger groups ( P = .19, before matching; P = .39, after matching). Conclusion: MAT survivorship was more affected by age-related prognostic factors, such as cartilage status and time from previous meniscectomy, than age itself. Clinical outcomes did not show differences according to age, either.

The Prognostic Value of Serum APRIL Levels in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5648-5648
Author(s):  
Sinem Nihal Esatoglu ◽  
Dilek Keskin ◽  
Muge Kutnu ◽  
Tugrul Elverdi ◽  
Ayse Salihoglu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Demographic Data ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Healthy Controls ◽  
Log Rank Test ◽  
Treatment Naïve ◽  
Group A ◽  
Group B ◽  
Time To First Treatment

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with variable clinical course. Several studies have been conducted to predict outcome in patients with CLL and also have been going on. A proliferation inducing ligand (APRIL) has been shown to involve in survival and resistance to apoptosis in CLL, and APRIL molecule has been investigated as a prognostic marker in CLL patients. However, there are limited and controversial data regarding APRIL and its impact on prognosis in CLL. We aimed to compare serum APRIL levels in CLL patients with those of age and gender matched healthy subjects, and to investigate the relationship between APRIL and the other common prognostic factors, and to determine whether serum APRIL levels predict time to first treatment in CLL. Methods: After ethical approval and informed consent were obtained, between May and December 2012, venous blood samples were driven from 96 CLL patients’ and 25 healthy controls’, and serum APRIL levels were measured by ELISA. Demographic data and the prognostic markers were obtained from the patients’ files, and patients have been followed for a minimum of 12 months. We tested the correlation between APRIL with the, clinical and biological parameters, and used the log rank test to compare their Kaplan Meier curves. Results: Patients were divided into three groups: Treatment naive (group A, n=49), chemotherapy receiving (group B, n=25) and who had previously received chemotherapy (group C, n=22). Median APRIL level was higher in group A (2.78 vs 1.29; p=0.034) and group C (3.54 vs 1.29; p=0.001) when compared to healthy controls, but was not different in group B (1.56 vs 1.29; p=0.3) (Figure 1). Serum APRIL level in group A was negatively correlated with hemoglobin levels (r=-0.298; p=0.037) and platelet counts (r=-0.321; p=0.025) whereas no correlation with age, Rai and Binet stages, lymphocyte counts, β2-microglobulin and CD38 levels were detected. Group A patients were also divided into 2 subgroups (APRIL levels low, n=20 and APRIL levels high, n=29) using median natural logarithm of serum APRIL level as cut off. April low and high subgroups were similar with respect to demographic data and prognostic factors. Median time to first treatment was not reached in the APRIL low group, but was 104 months in the APRIL high group (p=0.13, log-rank test). Conclusions: Among the treatment naive patients, serum APRIL levels only negatively correlate with hemoglobin levels and platelet counts. These correlations seem to be associated with tumor burden rather than the prognosis, because APRIL levels were not different in chemotherapy receiving patients compared to healthy controls. Since a median survival time could not be reached in the APRIL low group, short follow up time might be an explanation why the APRIL levels did not predict the time to first treatment. In conclusion, our findings let us to think APRIL levels are not a useful marker to predict prognosis in patients with CLL. Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Disclosures No relevant conflicts of interest to declare.

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