Lower Complete Response Rate Research Articles

The impact of the neutrophil:lymphocyte ratio in response and survival of patients with de novo diffuse large B-cell lymphoma

The neutrophil:lymphocyte ratio (NLR) has emerged as prognostic in patients with hematological malignancies. We aimed at evaluating the NLR as predictive for complete response (CR) and prognostic for progression-free (PFS) and overall survival (OS) in a study cohort of 121 Peruvian patients with diffuse large B-cell lymphoma (DLCBL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients with an NLR ≥6 (n = 28) were more likely to have a performance status ECOG ≥2 (74% vs. 23%; p < 0.001). NLR ≥6 was associated with lower CR rate to R-CHOP (46% vs. 74%; p = 0.02) and there was a trend towards significance in multivariate regression analyses (OR 0.36, 95% CI 0.11–1.00; p = 0.05). Patients with NLR ≥6 had lower 5-year PFS rate (39% vs. 72%; p < 0.001) and lower 5-year OS rate (46% vs. 75%; p = 0.001) than patients with NLR <6 and was an independent adverse factor for PFS (HR 2.43, 95% CI 1.21–4.87; p = 0.01) and OS (HR 2.68, 95% CI 1.31–5.47; p = 0.007) in multivariate Cox regression analyses. NLR ≥6 was prognostic of PFS and OS after adjusting for the International Prognostic Index and the NCCN-IPI scores. In conclusion, the NLR could add predictive and prognostic value to well established prognostic tools in DLBCL.

High frequency of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute myeloid leukemia.

AIMTo evaluate the importance of the CD34+CD38- cell population when compared to the CD34+CD38+/low and CD34+CD38+/high leukemic cell sub-populations and to determine its correlations with leukemia characteristics and known prognostic factors, as well as with response to therapy and survival.METHODSTwo hundred bone marrow samples were obtained at diagnosis from 200 consecutive patients with newly diagnosed acute myeloid leukemia (AML) were studied between September 2008 and December 2010 at our Institution (Hematology Department, Lyon, France). The CD34/CD38 cell profile was analyzed by multiparameter flowcytometry approach using 8C panels and FACS CANTO and Diva software (BD Bioscience).RESULTSWe analyzed CD34 and CD38 expression in bone marrow samples of 200 AML patients at diagnosis, and investigated the prognostic value of the most immature CD34+CD38- population. Using a cut-off value of 1% of CD34+CD38- from total “bulk leukemic cells” we found that a high (> 1%) level of CD34+CD38- blasts at diagnosis was correlated with advanced age, adverse cytogenetics as well as with a lower rate of complete response after induction and shorter disease-free survival. In a multivariate analysis considering age, leukocytosis, the % of CD34+ blasts cells and the standardized cytogenetic and molecular risk subgroups, a percentage of CD34+CD38- leukemic cells > 1% was an independent predictor of DFS [HR = 2.8 (1.02-7.73), P = 0.04] and OS [HR = 2.65 (1.09-6.43), P = 0.03].CONCLUSIONTaken together, these results show that a CD34/CD38 “backbone” for leukemic cell analysis by multicolour flowcytometry at diagnosis provides useful prognostic information.

Re-irradiation of Vertebral Body Metastases: Treatment in the Radiosurgery Era

Vertebral bodies remain one of the most common sites of metastases. In cases where surgical intervention is not indicated or appropriate, conventional external radiation therapy (cEBRT) has been the standard treatment modality. Unfortunately, cEBRT is typically limited, with low complete response and poor local control rates. Disappointing results with re-irradiation using cEBRT highlight the need for innovative salvage therapeutic strategies, such as stereotactic body radiotherapy. A detailed description of this complex treatment strategy is outlined, as is a systematic review of current literature. Although data are limited to single institution series, re-irradiation has consistently been found to be effective with respect to local control (1 year rates range from 66 to 90%) and pain response. Importantly, the treatment is shown to be safe, with the crude rate of radiation myelopathy <1% and a rate of vertebral compression fracture of 12%. As further research and technologic advances continue to refine therapy, stereotactic body radiotherapy is now a recommended option for the treatment of previously irradiated vertebral body metastases.

Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: Randomized controlled trial.

Nocturnal enuresis (NE) is a common pediatric developmental disorder. Desmopressin is frequently used for NE and is an evidence-based therapy. Suoquan capsule is a Chinese medicine commonly used for treating NE in children but is poorly understood by most scholars. A total of 369 children with NE were randomized to receive either suoquan, desmopressin plus suoquan, desmopressin, or behavioral intervention for 2months, and the response rates evaluated. Subsequently, the viable demographic factors that could lead to success were investigated on logistic regression analysis. Moreover, after 3months of follow up, the relapse rate was investigated. The complete response (CR) rate in the desmopressin plus suoquan group (37.5%) was higher than that in the behavioral intervention group (6.3%, P<0.007). The desmopressin group had a lower CR rate (22.5%) and a higher non-response rate (25.0%) than the desmopressin plus suoquan group (non-response rate, 21.9%; P>0.007). The relapse rate in the desmopressin group was significantly higher than that in the desmopressin plus suoquan group (72.2% vs. 30.6%, P<0.007). On Multivariate analysis, treatment group, NE frequency, and age were independent predictors of CR at 2months (P<0.05). Combined traditional Chinese and Western treatment in children with NE is effective and has a low relapse rate. NE frequency, treatment method, and age are important predictive factors for CR after treatment.

Pathologic Response and Acute Toxicity: Planned Interim Analysis of the Phase 2 NeoRT Trial Evaluating Preoperative Single Fraction Partial Breast Radiation Therapy in Early Stage Breast Cancer

Pre-operative partial breast irradiation (PBI) has been explored as an alternative to adjuvant breast radiotherapy. Practically, this approach has the potential to limit treatment volumes while simultaneously providing an avenue to study breast cancer radiation response. In this Phase II study, we hypothesized that 20% of patients would have a complete pathologic response at surgical resection six weeks after preoperative radiation. Histologically confirmed breast cancer patients with ER(+) or PR(+), Her2(-) T1N0 invasive breast cancer or Tis <2cm were enrolled in this single institution, IRB approved, Phase II study delivering 21Gy preoperatively to the intact tumor. Toxicity was scored using CTCAE version 4.0. Any toxicity possibly, probably or definitely related to radiotherapy is reported. Interim analysis was planned to assess complete pathologic response rates, defined as no residual invasive or in-situ tumor. Residual cancer burden (RCB) was also calculated. 20 of 40 planned patients have been enrolled. Three patients were subsequently ineligible on MRI but fifteen have proceeded to surgical resection. Two patients have received radiation but not surgery at the time of this analysis. The median age was 61 (range 58-77), 87% of patients were white and 87% had invasive ductal carcinoma. One patient had a post-operative wound infection and grade 3 seroma requiring drain placement. A second patient had a small area of wound dehiscence with seroma leakage. Remaining toxicities were grade 1-2 and consisted primarily of discomfort, seroma, fatigue and skin change. Pathologic complete response was noted in 1 patient (7%). Another had a pCR by RCB assessment, both with DCIS on pre-treatment biopsy. 5 patients (33%) had an RCB of I, and 8 patients (53%) an RCB of II. Fifteen women with early stage breast cancer have completed a single preoperative fraction of 21Gy followed by surgical resection at six weeks. Two (13%) grade 3 post-operative toxicities and one (7%) pathologic complete response were noted. This interim analysis suggests an increase in post-operative complications relative to our Phase I experience and a low rate of complete pathologic response in invasive disease. We plan to increase accrual in order to better define the optimal timing of surgical excision relative to operative complications and tumor response.

Differences in the immune microenvironment and genomic characteristics of TNBC in African American women compared to other races.

e13028 Background: African American (AA) women are more likely to be diagnosed with triple negative breast cancer (TNBC) compared to other races and have lower pathologic complete response rate to neoadjuvant therapy. Our goal was to assess differences in the immune microenvironment and genomic characteristics of TNBC by race using the TCGA data set. Methods: We compared the expression levels of 13 previously reported immune metagenes (CTL, Mphages, MHC1, Tregs, IF1, NK, STAT1, MHC2, Giam, Tfh, Tinh, Tstim, LCK), histologic tumor infiltrating lymphocyte (TIL) count and overall mutational load, neoantigen load, clonal heterogeneity assessed using the MATH score, amplification and deletion loads of between AA (n = 58) and non-AA TNBC (n = 114). Data was downloaded from the TCGA website, immune metagene expression and MATH scores were calculated as previously reported. Distributions between cohorts were compared using the Mann-Whitney U-test. Results: Among the immune metagenes only the cytotoxic T cell (CTL) metagene showed lower expression in AA patients (3.64 versus 4.08, unadjusted p = 0.046). TIL count was available in 51 of 58 AA and 91 of 114 of non-AA cases, and no significant difference was observed between the racial groups (p = 0.55). We also did not observe statistically significant differences in the mutational load (p = 0.36), neoantigen load (p = 0.38), clonal heterogeneity represented by the MATH score (p = 0.54), and amplification and deletion loads (p = 0.23 and 0.83 respectively) between the two TNBC race groups. We also assess the expression distribution of the immune signatures in an independent Affymetrix gene expression dataset including 40 AA and 323 non-AA patients with TNBC. Similar to the TCGA, there were no significant race differences in the immune signatures, including in the CTL metagene. Conclusions: These results suggest that the differences in prevalence and treatment response seen between TNBC in AA and non-AA patients are unlikely to be due to differences in the immune microenvironment and the genomic landscape of TNBC. However, more subtle comparison in the immune biology of these cancers can only be studies with more focused methods.

Systemic Inflammatory Response After Preoperative Chemoradiotherapy Can Affect Oncologic Outcomes in Locally Advanced Rectal Cancer.

Systemic inflammatory response (SIR) has been reported to be an important determinant of disease progression and survival in patients with colorectal cancer. This study investigated the prognostic relevance of changes in the platelet count on survival and the predictive value of changes in platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) on the pathological tumor response to preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). From 2006 to 2015, 291 consecutive patients with LARC who were treated with preoperative CRT followed by curative surgery at the Kyungpook National University Medical Center (Daegu, Korea) were retrospectively analyzed. A cut-off value of 370×103/μl for the platelet count was used and a PLR ≥235 was defined as high. Any change in the PLR or NLR was calculated based on subtracting the pre-CRT PLR or NLR from the post-CRT values. A total of 17.5% patients had stage II and 82.5% had stage III LARC. Initially high NLR and PLR were significantly associated with poor clinical outcomes. Patients who maintained a high platelet count after CRT also had an advanced pathological stage (p=0.028), low pathological complete response rate (p=0.048), and high relapse rate (p=0.021). For patients with an initially low PLR, the multiple logistic regression analysis revealed that a high PLR change (odds ratio (OR)=2.301, 95% confidence interval (CI)=1.269-4.174; p=0.006) and clinical stage II compared to stage III (OR=1.878, 95% CI=1.231-2.865; p=0.003) were significant independent markers predictive of a good response to CRT. The present results suggest that platelet and PLR change after preoperative CRT, along with the initial platelet count, can be used as prognostic and predictive markers for the oncological outcomes in patients with LARC.

Abstract P3-16-01: Immune characterization of inflammatory breast cancer and correlation to pathological complete response

Abstract Background: Treatment of inflammatory breast cancer (IBC) includes neoadjuvant chemotherapy (NAC) followed by mastectomy and radiation. Responses are limited however with low pathological complete response (pCR) rates and poor survival. Recent RNA expression studies suggest that activated T cell signaling pathways and immunomodulatory markers such as PD-L1 are associated with a higher pCR rate in IBC; however comprehensive studies of tumor infiltrating lymphocytes (TIL) and protein expression of immunomodulatory molecules are lacking. There is a critical need therefore to study molecular and immune determinants of therapeutic response in IBC, with the goal of identifying biomarkers and actionable strategies to improve treatment outcomes. Methods: Baseline core biopsies from 36 IBC patients, 22 with stage III and 14 with stage IV disease were evaluated. Of these, 21 stage III and 10 stage IV patients underwent mastectomy following NAC, the latter for palliative purposes. Tumor subtype distribution was 14 patients with HER2-/HR-, 6 with HER2+/HR-, 11 with HER2-/HR+, and 5 with HER2+/HR+ disease. TIL infiltration in the tumor stroma was quantified on H&amp;E slides based on consensus guidelines as well as by immunohistochemistry (IHC) staining for CD8. PD-L1 expression in the TIL and invasive tumor was evaluated by IHC in tumors with &amp;gt;1%TIL. Results: Stromal TIL were found in the invasive tumor on pretreatment biopsies in 26 (72%) patients, with TIL percentages ranging from 1% to 60% (mean=11.6; sd=13.8); of note, 1 patient biopsy sample only had tumor emboli on the tissue block and therefore was not evaluable. Higher TIL infiltrate was noted in stage III versus stage IV disease (mean TIL 11.6% versus 3.5%, p=0.028). Mean TIL infiltrate was 11.5% in HER2-/HR-, 10.0% in HER2+/HR-, 10.4% in HER2+/HR+, and 3.6% in HER2-/HR+ tumors (p=NS). At mastectomy, 7/21 stage III patients and 1/10 stage IV patients achieved a pCR. Mean TIL was 13.4% in the pCR group versus 8.2% in the non-pCR group (p=0.37) CD8 and PD-L1 staining was performed on samples with &amp;gt;1%TIL (n=15, of which 14 samples were available for additional staining). An average of 42% of TIL stained positive for CD8 (range 10-80%). There was no significant relationship between %CD8 and pCR, stage, or receptor status. None of these 14 patients demonstrated membranous PD-L1 positivity but all had focal weak cytoplasmic staining in the lymphocytes. Conclusions: Differences exist in the presence of stromal TIL in distinct groups within IBC (stage III versus stage IV disease and across histologic subtypes) and may contribute to differential responses to therapy. When comparing these results to published non-IBC literature (FinHER trial), our IBC patient cohort had lower TIL infiltrate in several histologic subtypes (HER2-/HR- 11.5% vs 25%, p=0.015), HER2+/HR-(10% vs 20%, p=0.10), and HER-/HR+ disease (3.6 vs 7.5%, p=0.01); TIL was comparable for HER2+/HR+ disease. Additional studies are underway (including multiplex analysis of myeloid and lymphoid markers, T cell receptor sequencing, and molecular profiling) in pre-treatment and surgical samples to better understand mechanisms of treatment response and resistance. Citation Format: Reddy SM, Wargo JA, Reuben A, Reuben J, Woodward W, Ueno N, Mittendorf EA, Krishnamurthy S. Immune characterization of inflammatory breast cancer and correlation to pathological complete response [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-16-01.

Impact of CD44 expression on radiation response for bladder cancer.

Background Identification of potential factors that can stratify tumors' response to specific therapies will aid in the selection of cancer therapy. Radioresistance is the major obstacles to positive outcomes in bladder cancer patients after definite chemotherapy. CD44, a cancer stem cell surface marker, is relevant in treatment resistance. In the present study, we examined the role of CD44 in bladder cancer.Methods We retrospectively analyzed the clinical outcomes of 85 bladder cancer patients treated with definite chemoradiotherapy, and correlated the expressions of CD44 with IL-6 and treatment response. Furthermore, the bladder cancer cell lines HT1197 and MB49 were selected for cellular and animal experiments to investigate the links between the CD44, IL-6 and radiation response.Results Analyzing the clinical specimen, the staining of CD44 was significantly linked with higher clinical stage, lower complete response rates, higher loco-regional failure rate and lower survival rate with intact bladder for patients treated with definite CCRT. In addition, the frequency of CD44 immunoreactivity was significantly higher in IL-6-positive bladder cancer specimens. By cellular experiments, the expression of CD44 was stimulated by IL-6 and linked with the cancer stem cell-like property. As demonstrated through in vitro and animal experiments using immunocompromised and immunocompetent hosts, CD44+ bladder cancer cells appeared more resistant to irradiation, associated with less RT-induced cell death.Conclusions Our findings suggested that CD44 is important in predicting the radiation response of bladder tumor cells. If overexpressed CD44 and/or IL-6 were noted in pre-surgical specimens, radical cystectomy is more likely to be preferred.

The Meningioma 1 (MN1) Gene is an Independent Poor Prognostic Factor in Adult Egyptian Acute Myeloid Leukemia Patients

Aim:To determine the prognostic importance of meningioma 1 (MN1) gene expression levels in the context of other predictive markers for acute myeloid leukemia (AML) cases.Methods:MN1 expression was measured in 85 newly diagnosed adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction.Results:At diagnosis 67.4% of cases had elevated MN1 expression, this being associated with a worse prognosis, higher incidence of lymphadenopathy and CD34 transcript expression (p=0.02 and <0.001, respectively). No other molecular or clinical characteristics were significantly associated with MN1expression. Patients with high MN1 expression had lower complete response rate at day 15 compared to patients with low MN1 expression (p=0.09) and a significantly higher relapse rate (21.1% versus 7.7%, respectively, p=0.04). Patients with high MN1 expression had shorter TTP compared to those with low expression, p= 0.07.Conclusion:MN1 expression may predict outcome in AML patients. The MN1 gene and micro RNA expression suggest a biological feature that could be used as therapeutic targets.

Soluble Interleukin-2 Receptor and C-Reactive Protein Levels Are Associated with the Efficacy of Bendamustine As a Salvage Treatment for Indolent Lymphoma

Background:Bendamustine has demonstrated a favorable efficacy and toxicity profile in relapsed or refractory indolent lymphoma. Limited information is available regarding the prognostic factors (particularly laboratory parameters) of bendamustine treatment, although studies have shown a relationship between the hampered effect of bendamustine and an increase in lactate dehydrogenase (LDH) levels. Therefore, we retrospectively evaluated clinical and laboratory factors immediately prior to initiating bendamustine treatment and analyzed its correlation with the clinical outcome among patients with relapsed or refractory indolent lymphoma.Patients and methods:We analyzed 55 relapsed or refractory indolent lymphoma patients who had been treated with bendamustine alone (n = 19) or rituximab plus bendamustine (n = 36) at our hospital from 2000 to 2015. The median age at diagnosis was 65 years and the median follow-up period was 552.5 days. Histological analysis revealed follicular lymphoma (n = 21), mantle cell lymphoma (n = 10), MALT lymphoma (n = 7), lymphoplasmacytoid lymphoma (n = 5), and other low-grade B cell lymphomas (n = 4). We further analyzed the relationships between the clinical outcome [overall response rate (ORR), complete response (CR), progression-free survival (PFS), and overall survival (OS)] and clinical data, including sex, patient age (≥65 years), performance status (≥2), IPI (≥HI), FLIPI (≥HI), no. of previous therapies (≥2), prior purine analogue treatment, response to last treatment, and laboratory parameters [white blood cell count (≥5000/µl), lymphocyte count (≥1000/µl), platelet count (≥10000/µl), LDH (elevated or normal), sIL-2R (elevated or normal), and CRP (elevated or normal)], before starting bendamustine treatment.Results:The median number of cycles of bendamustine was 4 (range: 1-8). The ORR was 80.3% with a CR of 39.2%. Moreover, the CR rate was significantly worse in patients who had elevated sIL-2R and CRP, high or high-intermediate IPI scores, and a high WBC count (P = 0.002, P < 0.001, P = 0.072, and P < 0.046, respectively). Among follicular lymphoma patients, elevated CRP was only associated with a low CR rate (P = 0.028). In multivariate analysis, sIL-2R, CRP, and a high WBC count were all significantly associated with a worse CR rate (P = 0.044, P = 0.002, and P = 0.032, respectively). The 1- and 2- year OS rates were 80.3% and 76.1%, respectively. The OS was significantly higher in a group of the patients who obtained CR after bendamustine, were treated with rituximab plus bendamustine, and did not receive prior purine analogue treatment (P = 0.007, P = 0.008, and P < 0.001, respectively). An elevated CRP was associated with worse OS (P = 0.055). In multivariate analysis, only CR after bendamustine was significantly associated with improved OS (P = 0.023).The 1- and 2-year PFS rates were 69.2% and 60.5%, respectively. PFS was significantly better in patients who obtained CR after bendamustine treatment, had a normal CRP, had not received more than 2 previous therapies, and had a good performance status (P < 0.001, P = 0.007, P = 0.031, and P = 0.033, respectively). In multivariate analysis, any prognosis factors were significantly associated with PFS.Conclusion:This is the first study to demonstrate a correlation between laboratory parameters (i.e., CRP and sIL-2R) and the clinical outcome in patients with relapsed or refractory indolent lymphoma who were treated with bendamustine. In this study, CRP and sIL-2R levels as well as the WBC count were associated with the CR rate. In addition, the CRP levels were associated with OS and PFS, but LDH levels were not associated with any clinical outcomes. Previous studies have reported that the elevation of serum CRP and sIL-2R levels were associated with poor OS or PFS in patients who were treated with rituximab combined with CHOP in diffuse large B-cell lymphoma or follicular lymphoma. Our study indicates that serum CRP and sIL-2R levels are also important laboratory parameters for patients with indolent lymphoma who underwent bendamustine treatment. DisclosuresNo relevant conflicts of interest to declare.

RUNX1 Mutation in Cytogenetically Normal Acute Myeloid Leukemia : Clinical Implications, Co-Mutation Analysis

Background and ObjectivesAcute Myeloid Leukemia (AML) is a cytogenetically and molecularly heterogeneous disease. In the recent decades, many genetic mutations and their clinical significances in AML have been identified with the development of new genomics technology. Based on these advances, new 2 entities were added to the WHO 2008 classification : AML with mutated NPM1 and AML with mutated CEBPA. Likewise, AML with RUNX1 mutation are now considered as a new provisional entity in the next update of WHO classification. In this work, we characterized patients with cytogenetically normal AML according to RUNX1 mutational status and analyzed several co-mutations by next generation sequencing.Patients and MethodsA total of 419 patients were included in the present study who met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of AML with normal karyotype confirmed by conventional cytogenetic analysis. Analysis of genetic mutations were performed using targeted resequencing by Illumina Hiseq 2000 (Sureselect custom probe set targeting 94 myeloid gene panel including RUNX1 mutation). Samples for the confirmation of first complete response were also analyzed in 163 patients. The majority of patients (97%) received ’3+7’ standard induction chemotherapy. Median age was 53(range 15-84).ResultsOverall, most common mutations for this cohort were NPM1(33.9%), DNMT3A(30.3%), NRAS(20.2%), IDH2(15.0%), FLT3(12.2%), CEBPA(11.1%). RUNX1 mutations were found in 22 of 419 (5.4%) patients. 7 of 13 available samples in complete remission still had RUNX1 mutation. The patients with RUNX1 mutations were older than those with wild-type RUNX1. (p=0.006) and RUNX1 mutation had a trend of male preponderance. The WBC count and blast percentage of peripheral blood and bone marrow were not different according to RUNX1 mutational status. The complete response rate was significantly lower in RUNX1 mutated group compared with wild-type group. (57% vs. 84%, p=0.005) In univariable survival analysis, RUNX1 mutations were significantly associated with inferior event-free survival (EFS) (p<0.001), relapse-free survival (RFS) (p=0.009) and overall survival (OS) (p=0.002). However, in multivariable analysis, RUNX1 mutation was not an independent prognostic factor for inferior EFS (hazard ratio(HR) 1.48, p=0.286), RFS (HR 2.15, p=0.057) OS (HR 1.14, p=0.716). Co-mutation analysis revealed that ASXL1 (26%,p=0.001), KRAS (26%, p=0.009), BCOR (16%, p=0.032) were correlated with RUNX1 mutation. None of the patients with RUNX1 mutation had NPM1 mutation and only one patient had CEBPA mutation.ConclusionIn cytogenetically normal AML, RUNX1 mutation is observed in 5.4% and is mutually exclusive of the NPM1 and CEBPA mutation. Older age and lower complete response rate is correlated with RUNX1 mutation. In univariable survival analysis, RUNX1 mutation is associated with poor clinical outcomes. DisclosuresNo relevant conflicts of interest to declare.

Pure Erythroid Leukemia Is Characterized By TP53mutations, a Complex Karyotype with Chromosome 17 Abnormalities, and Adverse Risk Independent of Therapy Type

INTRODUCTION: Pure erythroid leukemia (PEL) is a rare form of acute leukemia characterized by a neoplastic proliferation of immature erythroblasts with an extremely aggressive clinical course. Although there are previous reports describing its association with a complex karyotype and chromosome 5 and 7 abnormalities, there is no knowledge on the mutational landscape of this disease. Also, further evaluation of the optimal treatment strategy for this subset of patients is still required.METHODS: We retrospectively evaluated all patients with pure erythroid leukemia treated at The University of Texas MD Anderson Cancer Center from 1980 to 2016. Cytogenetic analysis was reported following the ISCN 2013 nomenclature. Sequencing data was obtained by use of a 28-gene targeted PCR-based next generation sequencing (NGS) platform. Clinical and demographic data was obtained from clinical records. Response was defined following 2003 IWG criteria. Generalized linear models were used to study the association of overall response (OR), complete response (CR) and risk factors. Kaplan-Meier produce limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS).RESULTS: A total of 27 patients had PEL. Patient characteristics are shown in Table 1. Median age at diagnosis was 67 years (range 33-65). Eleven (41%) patients had therapy related disease, 10 (37%) evolved from a prior myelodysplastic syndrome and 1 (4%) from chronic myeloid leukemia. Presence of a complex karyotype was observed in 96% (25/26) patients. A total of 13 (48%) patients with PEL had mutation analysis available. Twelve (92%) had at least one detectable mutation. Median number of mutations was 1 (range 0-3). TP53 mutations were found in 11/12 (92%) patients, and ASXL1, PTPN11 and DNMT3A each found in 1 (8%) patient. Type and frequency of TP53 mutations is shown in Figure 1A. Fifteen (58%) patients with PEL had chromosome 17 abnormalities including monosomy 17, del(17p) and add(17)(p11.2). Five (50%) patients with cytogenetic and mutation data available had both TP53 mutation and chromosome 17 abnormalities. Nine (27%) patients were treated with hypomethylating agent based therapy, 11 (41%) with intensive chemotherapy, 1 (4%) with targeted therapy and 6 (22%) died before receiving any form of therapy. We compared clinical characteristics and outcomes of patients with PEL with that of 162 patients with acute erythroid/myeloid leukemia (AEL) treated at MDACC during the same time period. Patients with PEL tended to be older (p=0.006), have lower platelet count (p=0.009) and lower peripheral blast percentage (p=0.022), higher LDH levels (p<0.001) and a higher frequency of a complex karyotype (96 vs 61%, p<0.001) (Table 1). Patients with PEL were less frequently treated with intensive chemotherapy (p<0.001) and had lower CR rates compared to patients with AEL treated with chemotherapy (OR 0.23, 95% CI 0.58-0.90, p=0.051). Median follow up was 8 months (range 0-269 months). The median OS for patients with PEL was 3.8 months compared to 10 months for AEL (HR 2.895, 95% CI 1.843-4.55, p<0.001) (Figure 1B). No differences in survival were observed with chemotherapy compared to hypomethylating agents for both patients with PEL (median OS 4.4 months vs 3.9 respectively, p=0.794) (Figure 1C) or AEL (median OS 10 vs 6.9 months respectively, p=0.556) (Figure 1D).CONCLUSION: Pure erythroid leukemia represents 14% of cases of all erythroid leukemia. We establish, in the largest series to date, PEL is characterized by a very complex karyotype. There is also a high prevalence of chromosome 17 abnormalities and mutations in TP53; interestingly, in several patients, there was co-occurrence of both, or double TP53 mutations. Our data demonstrates that severely impaired and completely lost of TP53 function, resulting in genomic instability, is a strong influential factor for PEL pathogenesis in particular, and is consistent with its associated dismal prognosis irrespective of currently available therapies. In view of PEL outcomes and older age at diagnosis, enrollment in clinical trials targeting or circumventing mutant p53, and less intensive approaches is the current optimal strategy for this subset of patients. [Display omitted] [Display omitted] DisclosuresRavandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Daver:Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Kantarjian:Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Neoadjuvant chemotherapy with methotrexate/vinblastine/doxorubicin/cisplatin vs. gemcitabine/cisplatin for muscle-invasive bladder cancer: a review and meta-analysis

Objective To systematically assess the efficacy of neoadjuvant chemotherapy (NAC) with methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) vs. gemcitabine/cisplatin (GC) for muscle-invasive bladder cancer (MIBC). Methods Randomized controlled trials (RCTs) or non-RCTs regrading the efficacy of NAC with MVAC vs. GC for MIBC were retrieved in Pubmed, Cochrane library, Sciverse, CNKI, VIP and Wanfang database from databases establishment to May 2016. According to the including and exclusion criterion, two reviewers independently reviewed the trials, conducted the Meta-analysis with RevMan 5.3 soft ware. Results A total of 13 non-randomized clinical controlled trials were eligible for the study including 1690 cases. The pooled results showed that MVAC group had a lower down staging rate (RR=0.77, 95%CI 0.61-0.97, P=0.03) and complete response rate (RR=0.70, 95%CI 0.53-0.93, P=0.01). Statistically significant were observed. However, there was no significant difference in disease free survival (RR=0.88, 95%CI 0.60-1.29, P=0.53). Conclusion Compared with MVAC, NAC with GC had higher down staging rate and complete response rate. Therefore, NAC with GC should be considered as a preferable option for MIBC. Key words: Muscle invasive bladder cancer; Methotrexate/vinblastine/doxorubicin/cisplatin (MVAC); Gemcitabine/cisplatin (GC); Neoadjuvant chemotherapy; Meta analysis

Differences in outcome of patients with syncytial variant Hodgkin lymphoma compared with typical nodular sclerosis Hodgkin lymphoma

Nodular sclerosis Hodgkin lymphoma (NS-HL) is the most common subtype of HL and usually has a good prognosis. A variant of NS, the syncytial variant (SV) has well-established histopathologic features but little is known about its clinical behavior. Small case series have suggested that SV patients present with advanced disease and have a comparatively aggressive course. The objective of this study was to determine the clinical characteristics and outcome of SV patients. A total of 167 adult patients with NS-HL including 43 patients with SV and 124 patients with typical NS (t-NS) were included in our analysis following institutional review board (IRB) approval. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine the differences in survival. Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) was the most frequent induction regimen administered in 91% of all patients. The rate of complete response (CR) in the SV group was 74% versus 87% in the t-NS group (p = 0.05). At 49 months follow up, the PFS was 17 months in the SV group and not reached in the t-NS group [p < 0.0001; hazard ratio (HR) = 3.695; 95% confidence interval (CI) = 3.0, 11.07]. The median OS was not reached in both groups (p = 0.32). Our results show that SV histology represents a poor risk group with lower CR rate and shorter PFS and this should be considered in the risk stratification of classical HL patients.

Differences in Outcome of Patients with Syncytial Variant Hodgkin Lymphoma (HL) Compared with Typical Nodular Sclerosis HL

Abstract Introduction: Syncytial variant of nodular sclerosis HL (SV) is a well-described distinct pathologic entity characterized by prominent aggregates of Hodgkin/Reed- Sternberg cells in nodules separated by fibrous collagen bands. Despite its well-known morphologic description, little is known regarding the clinical behavior of the SV. Previous reports suggest that patients with SV often presented with B symptoms and advanced stage disease, however, large series defining the clinical outcome have not been reported so far. We systematically studied the clinical features and outcome of patients with SV and further compared them with patients with typical nodular sclerosis HL (t-NS). Patients and Methods: 167 adult patients (pts.) with Nodular Sclerosis HL were included in our analysis following institutional IRB approval. Differences between the two groups (SV vs. t-NS) were analyzed using Chi- square and t -Student tests. Statistical significance was set at P Results: Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. The median age at diagnosis was 31 yrs. (range: 18-75 yrs.) and 85 patients were male (51%). At diagnosis, 100% patients had an ECOG status of 0-1; 39 % had advanced stage disease (stage III and IV); and 48% had B symptoms. 23 % patients presented with bulky disease defined as a mass > 10 cm or a mediastinal mass >1/3 of thorax at T5-T6. 90% patients received ABVD as their initial treatment. The remaining were treated with Stanford V, MOPP or on a clinical trial. 37 % patients received radiation therapy. Furthermore, 63% patients with SV and relapsed disease were treated with high dose therapy followed by stem cell transplant (ASCT). In the SV vs. t-NS comparison, no statistically significant differences were observed between the two groups with regards to age, gender, stage at presentation, B symptoms, bulky disease or favorable features. The rate of complete response (CR) in the SV group was 74% vs. 87% in the t-NS group (P=0.05). Moreover, at a median follow up of 49 months, the median progression free survival (PFS) was inferior in the SV group (17.02 months) compared with the t-NS group (not reached) (P Discussion: In summary, our results suggest that SV was associated with a lower rate of complete response to standard ABVD chemotherapy +/- radiation and inferior PFS. Despite the high rate of relapse associated with SV, these patients can be salvaged with standard salvage regimens, ASCT or newer immunomodulatory agents and therefore not compromising OS. Our report suggests that patients with SV should be considered for novel combination immuno-chemotherapies to improve the rate of complete remission and subsequently avoid the need for ASCT. Download : Download high-res image (86KB) Download : Download full-size image Figure 1 . PFS in patients with SV vs. t-NS Download : Download high-res image (59KB) Download : Download full-size image Figure 2 . OS in patients with SV vs. t-NS Disclosures Reddy: PCYC: Consultancy; ImmunoGen: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.

The role of PD-L1 in the radiation response and clinical outcome for bladder cancer.

Identification of potential factors that can stratify a tumor’s response to specific therapies will aid in the selection of cancer therapy. The aim was to highlight the role of programmed cell death 1 ligand 1 (PD-L1) in bladder cancer. In this study, 92 of muscle-invasive bladder cancers and 28 of non- muscle invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human and murine bladder cancer cell lines were used to examine the correlation between PD-L1 and radiation response. Our data revealed that PD-L1 was overexpressed in the bladder tumor specimens compared with adjacent non-malignant specimens. Furthermore, the staining of PD-L1 was significantly linked to higher clinical stage, lower complete response rates and reduced disease-free survival rates. By in vitro and in vivo experiments, irradiation up-regulated the expression of PD-L1 in tumor cells, and its increase correlated with the irradiation dose. In immunocompetent mouse models, blocking PD-L1 induced a longer tumour growth delay following irradiation. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells was responsible to the effects of PD-L1 on radiation response. In conclusion, PD-L1 could be a significant clinical predictor for clinical stage and treatment response of bladder cancer.

Abstract IA13: Engineered T cells for cancer therapy

Abstract Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a limited survival. Chimeric antigen receptor (CAR)-modified T cells targeting CD19 may overcome the limitation of low complete response rates with conventional therapies with the potential to induce sustained remissions in patients with refractory B-cell malignancies. We previously reported preliminary results on three patients with refractory CLL. Here we report the mature results from our initial trial using CAR modified T cells to treat 14 patients with relapsed and refractory CLL (1). Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14–11 ×108 CTL019 cells (median 1.6 x 108 cells). Patients were monitored for toxicity, response, expansion and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8/14 (57%), with 4 complete remissions (CR), and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and CAR T cells have persisted and remain functional beyond 4 years in the first two patients achieving CR; no patient in CR has relapsed. All responding patients have developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease is not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL. In separate studies we have asked whether the same CD19 CAR may have activity in tumors that do not express CD19. A patient with refractory multiple myeloma was treated with CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, following myeloablative chemotherapy (melphalan 140 mg/m2) and autologous stem cell transplantation (2). Four years earlier, autologous transplantation with a higher melphalan dose (200 mg/m2) had induced only a partial, transient response. Autologous transplantation followed by CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at last evaluation, 12 months after treatment. This response was achieved despite absence of CD19 expression in 99.95% of this patient's neoplastic plasma cells.

Differences in Outcome of Patients with Syncytial Variant Hodgkin Lymphoma (HL) Compared with Typical Nodular Sclerosis HL

▪Introduction: Syncytial variant of nodular sclerosis HL (SV) is a well-described distinct pathologic entity characterized by prominent aggregates of Hodgkin/Reed- Sternberg cells in nodules separated by fibrous collagen bands. Despite its well-known morphologic description, little is known regarding the clinical behavior of the SV. Previous reports suggest that patients with SV often presented with B symptoms and advanced stage disease, however, large series defining the clinical outcome have not been reported so far. We systematically studied the clinical features and outcome of patients with SV and further compared them with patients with typical nodular sclerosis HL (t-NS).Patients and Methods: 167 adult patients (pts.) with Nodular Sclerosis HL were included in our analysis following institutional IRB approval. Differences between the two groups (SV vs. t-NS) were analyzed using Chi- square and t -Student tests. Statistical significance was set at P <0.05. Kaplan Meier method was used to calculate the Progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine the differences in survival. Statistical analysis was performed using SPSS.22 software.Results: Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. The median age at diagnosis was 31 yrs. (range: 18-75 yrs.) and 85 patients were male (51%). At diagnosis, 100% patients had an ECOG status of 0-1; 39 % had advanced stage disease (stage III and IV); and 48% had B symptoms. 23 % patients presented with bulky disease defined as a mass > 10 cm or a mediastinal mass >1/3 of thorax at T5-T6. 90% patients received ABVD as their initial treatment. The remaining were treated with Stanford V, MOPP or on a clinical trial. 37 % patients received radiation therapy. Furthermore, 63% patients with SV and relapsed disease were treated with high dose therapy followed by stem cell transplant (ASCT). In the SV vs. t-NS comparison, no statistically significant differences were observed between the two groups with regards to age, gender, stage at presentation, B symptoms, bulky disease or favorable features. The rate of complete response (CR) in the SV group was 74% vs. 87% in the t-NS group (P=0.05). Moreover, at a median follow up of 49 months, the median progression free survival (PFS) was inferior in the SV group (17.02 months) compared with the t-NS group (not reached) (P<0.0001; HR = 3.695; 95% CI=3.0-11.07). The median overall survival (OS) was not reached in both groups and was not statistically different [Fig.1&2, P=0.32]. Significant differences in PFS and OS were observed based on stage of disease (early vs. advanced) and achievement of complete response at end of treatment by univariate analysis. In the corresponding multivariate analysis, achievement of CR following completion of treatment was the only independent predictor for OS.Discussion: In summary, our results suggest that SV was associated with a lower rate of complete response to standard ABVD chemotherapy +/- radiation and inferior PFS. Despite the high rate of relapse associated with SV, these patients can be salvaged with standard salvage regimens, ASCT or newer immunomodulatory agents and therefore not compromising OS. Our report suggests that patients with SV should be considered for novel combination immuno-chemotherapies to improve the rate of complete remission and subsequently avoid the need for ASCT. [Display omitted] [Display omitted] DisclosuresReddy:PCYC: Consultancy; ImmunoGen: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.

Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.

Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)-modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 10(8) to 11 × 10(8) CTL019 cells (median, 1.6 × 10(8) cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL.