Expression of the Cancer-Testis Antigens, SEMG 1 and Protamine 1, in Early CLL: Their Relationship to Disease Stage and Zap 70 Expression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4680-4680
Author(s):  
Farouk Meklat ◽  
Yana Zhang ◽  
Zhiqing Wang ◽  
Jian Zhang ◽  
Sukhrob Mustalov ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Tumor Vaccine ◽  
Early Stage ◽  
Disease Stage ◽  
Early Disease ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Ct Antigen ◽  
Cancer Testis ◽  
Protamine 1

Abstract Despite advances in modern chemotherapy, CLL remains incurable. CLL is an indolent disease. It expresses a panel of Cancer-Testis (CT) antigens. CLL leukemia cells are susceptible to the cytotoxicity of T cells. CLL is, therefore, an ideal disease for immunotherapeutic approaches. Immunotherapy, in addition to being less toxic and more specific than chemotherapy, provides a different mode of cytotoxicity that may synergize with that induced by chemotherapeutic agents. Immunotherapy also offers the prospect of inducing immune memory that may be important for long term disease-free survival of patients with CLL. However, there are obstacles that may prevent successful immunotherapy. CLL patients are generally immunosuppressed even before any therapy is given and the immunosuppression increases as the disease progresses. Therefore, any immunotherapeutic approaches for CLL should be aplied in early disease when immunosuppression is least encountered. We previously demonstrated the expression of a CT antigen, SEMG 1, in 3/9 patients with CLL. Furthermore, we also demonstrated that the presence of high titer IgG in the serum of patients expressing SEMG 1, suggesting the in vivo immunogenicity of SEMG 1 in the cancer-bearing autologous host. We have also recently used SEMG 1 as the bait in a yeast two-hybrid system of testicular cDNA library and identified that Protamine 1 is the interacting ligand of SEMG 1 and that Protamine 1 is also a novel CT antigen, suggesting that both SEMG 1 and Protamine 1 may be suitable antigens for tumor vaccine development. However, the expression of SEMG 1 and Protamine 1 in early CLL is unknown. We have in this study set out to determine whether or not SEMG 1 and/or Protamine 1 could be used for the design of tumor vaccine for the targeting of patients with early CLL, in particular, those with poor risk disease, as predicted by Zap 70 expression. Using pairs of sequence-specific primers in RT-PCR on a cohort of CLL (41 Stage 0/I and 6 Stage II/III), we found that SEMG 1 gene is expressed in 24/47 (51%) and Protamine 1 in 16/47 (34%) of CLL patients. Gene expression in most cases was associated with the detection by immunocytochemistry of SEMG 1 and/or Protamine 1 in the CLL cells. The expression frequency of SEMG1 and Protamine 1 in CLL did not appear to differ between early and late stage disease. 19/41 of patients with early stage disease and 5/6 of patients with late disease expressed SEMG 1; 12/41 of patients with early stage disease and 4/6 patients with late disease expressed Protamine 1. Furthermore, the expression of these antigens was equally distributed between Zap 70+ and Zap 70− CLL. SEMG 1 was expressed in 4/6 of Zap 70+ CLL (all 6 had early disease) and 2/9 of Zap 70− CLL (1/8 early disease and 1/1 late disease). Interestingly, although Protamine 1 expression in CLL predicted for SEMG 1 co-expression, only 67% of SEMG 1+ CLL expressed Protamine 1. Our results, therefore, suggest that both SEMG 1 and Protamine 1 are suitable targets for tumor vaccine development for some patients with early CLL, especially those with high risk disease, as predicted by Zap 70 expression.

scholarly journals A Retrospective Analysis of Outcomes of Diffuse Large B Cell Lymphoma (DLBCL) in the Elder Patients in China

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5410-5410
Author(s):  
Peng Liu ◽  
Ying Han ◽  
Jianliang Yang ◽  
Xiaohui He ◽  
Changgong Zhang ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Early Stage ◽  
B Cell Lymphoma ◽  
Disease Stage ◽  
Early Stage Disease ◽  
Large B Cell Lymphoma ◽  
Elder Patients ◽  
Stage Disease ◽  
Ann Arbor ◽  
Advanced Disease Stage

Abstract Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have a worse prognosis compared to the younger population, since older age is associated with comorbidity and suboptimal performance status leading to intolerance of chemo-immunotherapy. The outcome of DLBCL in the older patients (> 60 years) was well described in clinical trials with reported 5-year overall survival (OS) of 50-80% (Coiffier et al., N Engl J Med 2002). Since this group is often precluded from clinical trials and population-based studies are limited, optimal treatment strategy for the old patients with DLBCL remains controversial. Here, we describe a Chinese real-world experience of management of elderly DLBCL patients treated at National Cancer Hospital, China. Methods: This is a single-center, retrospective analysis of consecutive DLBCL patients aged ≥60 who planned to receive chemotherapy +/- rituximab. The standard regimens included 3-4 cycles (early stage disease) or 6 cycles (advanced) of R-CHOP like regimens (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) followed by two rituximab doses in fit patients; R-miniCHOP for unfit and R-CE(etoposide)OP for frail elder patients. Patient data including baseline characteristics, histology, clinical parameters, and treatment outcomes were extracted from hospital medical records. The primary endpoint was progression-free survival (PFS); secondary endpoint was OS. Statistical analyses included descriptive statistics and Kaplan Meier estimates. Results: From June 2006 to December 2012, 349 patients aged ≥60 years were included, in which 204 patients were aged <70 years (Table 1). 326 patients received chemotherapy or chemo-immunotherapy with rituximab. Median follow up was 82 months. Five year PFS and OS of the elder patients were 45.8% and 51.9%, respectively. Significant difference was seen between patients < 70 years and those ≥70 years in terms of PFS (51.0% vs 38.6%, p=0.030) and OS (58.3% vs 42.8%, p=0.007) (Figure 1). Patients with early-stage disease (Ann Arbor StageⅠ/Ⅱ) had better 5-year PFS (60.1% vs 23.5%, p<0.001) and OS (65.3% vs 30.9%, p<0.001) than patients with advanced disease stage (Ann Arbor Stage III/IV) (Figure2). In addition, regimen including rituximab significantly improved the survival than chemotherapy alone (5-year PFS: 37.3% vs 64.0%, p<0.001; 5-year OS: 44.5% vs 69.3%, p<0.001), especially in patients ≥70 years, which almost doubled 5-year PFS and OS (5-year PFS: 25.4% vs 50.7%, p<0.001; 5-year OS: 28.8% vs 56.0%, p<0.001) (Figure3). Conclusions: Elder age (≥70 years) and advanced disease stage (Ann Arbor Stage III/IV) are associated with poor PFS and OS in Chinese elder DLBCL patients. The addition of rituximab significantly improves the survival compared to chemotherapy alone, especially in patients aged ≥70 years. These findings underscore the importance of personalized evaluation and treatment in elder patients with DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Recent advances in understanding and managing cutaneous T-cell lymphomas

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 331
Author(s):  
Patrick M. Brunner ◽  
Constanze Jonak ◽  
Robert Knobler
Keyword(s):  
T Cell ◽  
Early Stage ◽  
Disease Stage ◽  
Treatment Modalities ◽  
Early Stage Disease ◽  
T Cell Lymphomas ◽  
Stage Disease ◽  
Related Quality ◽  
Health Related ◽  
Stage Ivb

Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of extranodal non-Hodgkin lymphomas involving primarily the skin and mycosis fungoides is its most frequent entity. Whereas most patients show an indolent course in early disease (clinical stages IA to IIA), some patients progress to advanced disease (stage IIB or higher), and the 5-year survival rate is unfavorable: only 47% (stage IIB) to 18% (stage IVB). Except for allogeneic stem cell transplantation, there is currently no cure for CTCL and thus treatment approaches are palliative, focusing on patients’ health-related quality of life. Our aims were to review the current understanding of the pathogenesis of CTCL, such as the shift in overall immune skewing with progressive disease and the challenges of making a timely diagnosis in early-stage disease because of the lack of reliable positive markers for routine diagnostics, and to discuss established and potential treatment modalities such as immunotherapy and novel targeted therapeutics.

Matching for 12 HLA Alleles Is Associated with a Significantly Superior Survival Due to a Lower Mortality in Recipients of Unrelated Donor Haematopoietic Cell Transplants for Early but Not Late Stage Leukaemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3056-3056
Author(s):  
B.E. Shaw ◽  
N.P. Mayor ◽  
A.-M. Little ◽  
Nigel H. Russell ◽  
A. Pagliuca ◽  
...  
Keyword(s):  
Late Stage ◽  
Early Stage ◽  
Disease Stage ◽  
Unrelated Donor ◽  
Disease Relapse ◽  
Early Stage Disease ◽  
Hla Alleles ◽  
Graft Versus Host ◽  
Multiple Loci ◽  
Stage Disease

Abstract Recipient/donor HLA matching is an important determinant of outcome in transplantation using volunteer unrelated donor (VUD). The degree of matching remains controversial. Some data suggest that disease stage is an important factor to consider when assessing the need for a well-matched donor. We analysed the impact of matching for 12 HLA alleles at six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) in a cohort of 458 patients receiving VUD transplants for leukaemia (142 CML, 170 AML, 146 ALL). Of the pairs, 84 were matched for 12/12 alleles, 250 and 124 were mismatched for one locus or more than one locus respectively (graft versus host vector). Most single locus mismatches were at DPB1 (218/250, 87%). In multiply mismatched pairs the loci were: DPB1 plus one other locus (81), 2 other loci excluding DPB1 (10) and more than 2 loci (33). Patients receiving 12/12 matched grafts had a significantly better survival than those who had mismatched grafts (7 years: 45% vs 30%, p=0.022) and those matched for 10/10 alleles (p=0.050). The outcome was not significantly different dependent on whether the mismatch was at single or multiple loci, nor whether the single mismatch was at DPB1 compared to any other HLA locus. Disease stage was a significant determinant of outcome, with patients transplanted in early stage disease (defined as CR1 or CP1, N=222) having a superior outcome to those with late stage disease (N=236) (7 year: 42% vs 28%; p=0.002) In patients with early stage disease, the survival was significantly better if 12/12 matched compared to the mismatched group (7 years: 62% vs 36%; p=0.005). Other factors associated with a significantly improved survival in this cohort were: patient age below the median (32 years), patient CMV seronegativity and CML (rather than acute leukaemia). In multivariate analysis, pairs matched for less than 12/12 HLA alleles (HR=1.8; CI 1.0–3.0; p=0.034) and acute leukaemia (HR=1.8; CI 1.2–2.6; p=0.003) had a significantly worse survival. The reason for the inferior outcome was a significantly worse transplant related mortality (TRM) in the mismatched pairs (p=0.006). This was 16%, 32% and 48% at 100 days, 1 and 7 years in the mismatched group, compared to 9%, 13% and 21% in the matched group. While the incidence of acute graft versus host disease (GvHD) overall was not increased in the mismatched group, the incidence of grade III/IV GvHD was higher (12/12 match = 0%, single locus mismatch = 2%, multiple loci=13%; p=0.002) and this was associated with a higher TRM (p=0.002). There was no significant impact of mismatching on chronic GvHD or disease relapse. Unlike these data, in the late disease stage cohort there was no effect of 12/12 matching status on survival (7 years: 25% vs 28%, NS) or TRM. However, there was an increase in GvHD in HLA mismatched pairs (acute, p=0.012; chronic, p=0.015) and the presence of cGvHD was protective against disease relapse (p=0.044). These data suggest that in patients transplanted at an early disease stage, matching for 12 HLA alleles is important to improve survival. In later stage disease the presence of an HLA mismatch may increase the incidence of GvHD and consequently of the graft versus leukaemia effect and hence be tolerated overall.

Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6005-6015 ◽  
Author(s):  
Stephen J. Proctor ◽  
Jennifer Wilkinson ◽  
Gail Jones ◽  
Gillian C. Watson ◽  
Helen H. Lucraft ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cox Regression ◽  
Early Stage ◽  
Univariate Analysis ◽  
Central Element ◽  
Disease Stage ◽  
Advanced Stage ◽  
Early Stage Disease ◽  
Large Patient ◽  
Stage Disease

Abstract The SHIELD program for Hodgkin lymphoma in patients 60 years of age or older, prospectively evaluated clinical features and outcome in a large patient cohort (n = 175). The central element was a phase 2 study of VEPEMB chemotherapy (n = 103, median age 73 years) incorporating comorbidity assessment. A total of 72 other patients were treated off-study but registered prospectively and treated concurrently with: ABVD (n = 35); CLVPP (n = 19), or other (n = 18). Of VEPEMB patients, 31 had early-stage disease (stage 1A/2A) and received VEPEMB 3 times plus radiotherapy. Median follow-up was 36 months. Complete remission (CR) rate (intention-to-treat) was 74% and 3-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. A total of 72 patients had advanced-stage disease (stage 1B/2B/3 or 4) and received VEPEMB 6 times. CR rate was 61% with 3-year OS and PFS of 66% and 58%, respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. Overall treatment-related mortality was 7%. In patients treated with curative intent with VEPEMB, ABVD, and CLVPP (n = 157), CR linked to several factors in univariate analysis. In a Cox regression model only, obtaining CR remained significant for OS and CR plus comorbidity and age for PFS. RS-EBV status had no significant effect on outcome.

scholarly journals Molecular estimation of neurodegeneration pseudotime in older brains

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sumit Mukherjee ◽  
Laura Heath ◽  
Christoph Preuss ◽  
Suman Jayadev ◽  
Gwenn A. Garden ◽  
...  
Keyword(s):  
Late Stage ◽  
Late Onset ◽  
Early Stage ◽  
Disease Onset ◽  
Postmortem Brain ◽  
Disease Stage ◽  
Rna Seq ◽  
Early Stage Disease ◽  
Molecular Changes ◽  
Stage Disease

AbstractThe temporal molecular changes that lead to disease onset and progression in Alzheimer’s disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage–or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10−5), Aβ (CERAD score, P = 1.8 × 10−5), and cognitive diagnosis (P = 3.5 × 10−7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.

Practice patterns in children, adolescents, and young adults with mycosis fungoides: Single institution study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19553-e19553
Author(s):  
Madeline Hooper ◽  
Yumeng Zhang ◽  
Eric Taylor ◽  
Lucia Seminario-Vidal ◽  
Lubomir Sokol
Keyword(s):  
Young Adults ◽  
Early Stage ◽  
Adolescents And Young Adults ◽  
Disease Stage ◽  
Topical Steroids ◽  
Second Line ◽  
First Line ◽  
Early Stage Disease ◽  
Disease Response ◽  
Stage Disease

e19553 Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, but management remains heterogenous. MF management is based on disease stage, comorbidities, availability, and physician preference. Few studies have assessed treatment in children, adolescents, and young adults because prognosis in these groups is generally favorable; however, optimizing therapeutic protocols for these patients will improve clinical care and reduce adverse effect incidence. Here, we retrospectively describe the practice patterns and disease response for the child, adolescent, and young adult with MF. Methods: We retrospectively reviewed clinical data on 46 patients younger than 40 years with MF treated at Moffitt Cancer Center between 2009 and 2019. Mean time to next therapy (mTTNT) was used as a surrogate marker for the duration of clinical benefit. Group differences in mTTNT for patients with early-stage MF was assessed using Kaplan-Meier analysis. P-values were calculated using the log-rank test. Results: Overall, mean age was 29.2 years (range: 6.6-39.8). Topical steroids (47.8%) and narrowband-UVB (nbUVB) (19.6%) were the most utilized first line treatments regardless of disease stage. Forty patients had early-stage MF (stage IA-IIA). Among them, mean age was 27.8 years (6.6-36.6); 55% received topical steroids and 22.5% received nbUVB first line. These patients received a mean of three (1-7) unique therapies throughout their treatment course. Other reported topicals were retinoids, nitrogen mustard and pimecrolimus. Systemic retinoids were used in one early-stage case. Used first line in early-stage disease, topical therapy resulted in a mTTNT of 25 months ( p= 0.015); mTTNT after combination and systemic therapy was 12 and 5.5 months. As second line treatment, phototherapy resulted in a mTTNT of 58 months, but this finding was not statistically significant ( p= 0.11). Topical and systemic agents used second line resulted in mTTNT of 34 and 33 months. Six patients had advanced-stage MF (stage IIB-IVB) with a mean age of 27.6 years (19.9-35.8), two of which died from the disease. Each patient received a different first line therapy: topical nitrogen mustard, systemic steroids, systemic retinoids, radiation, psoralen and UVA light, or CHOP chemotherapy. Mean number of therapies administered to this cohort was five (2-9). Conclusions: In children, adolescents, and young adults with MF, topical and phototherapies were used more frequently than systemic therapies or radiation. In early-stage disease, the longest clinical response was achieved with topical treatments. Used second line, phototherapy demonstrated promising disease response trends compared to those of other modalities. Systemic therapy does not produce durable disease response in the first line setting; however, its utility in advanced-stage disease and as a second line agent requires further research.

Disease complexity and economic burden on patients with colon cancer in the SEER-Medicare population.

2017 ◽  
Vol 35 (8_suppl) ◽  
pp. 30-30 ◽  
Author(s):  
Maria Alma Rodriguez ◽  
Lee Cheng ◽  
Alma Yvette DeJesus ◽  
Hui Zhao ◽  
Sharon Hermes Giordano
Keyword(s):  
Colon Cancer ◽  
Survival Time ◽  
Cancer Care ◽  
Early Stage ◽  
Stage Iv ◽  
Disease Stage ◽  
Comorbid Conditions ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Stage Iv Disease

30 Background: The relatively high cost of cancer care is receiving national attention. Treating cancer includes not only managing this illness, but also the complications and exacerbation of the patients’ underlying comorbid conditions. The purpose of this study was to analyze how the charges for colon cancer care are affected by the complexity of the patients’ underlying health problems. Methods: We searched the Surveillance, Epidemiology, and End Results-Medicare database to identify patients diagnosed with colon cancer from 2009 through 2011. The estimated charges of the patients’ Medicare claims were stratified by survival time, disease stage, patient age, and comorbidity number. We defined patients’ 12 months of care as the 1 month immediately preceding cancer diagnosis plus the 11 months immediately following diagnosis. Results: We identified 10,822 patients newly diagnosed with colon cancer during the study period. Of those patients, one quarter died within 11 months after diagnosis. Treatment for early-stage cancer was significantly less expensive than treatment for advanced disease. For patients with early-stage disease, the charges for surgery, chemotherapy, and/or radiation therapy constituted a smaller contribution to the overall care charges. For patients with advanced-stage disease, the substantially higher overall care charges were largely due to charges for chemotherapy and/or biotherapy. Among patients with the same disease stage at diagnosis (except for patients stage IV disease), those with a survival time of less than 12 months incurred higher charges than those with a survival time of 12 months or more did. Regardless of disease stage, survival time, or age, patients with one and two or more comorbid conditions incurred statistically significant higher charges (7.0% and 29.7%, respectively) than those with no comorbid conditions. Conclusions: These findings demonstrate the important contribution of disease complexity among patients with cancer to the analysis of resource utilization. Using overall cancer care cost or reimbursement models that do not incorporate disease complexity may negatively affect hospitals that care for a high proportion of patients with complex conditions.

scholarly journals Overall Survival and Adjuvant Therapy in Women with Ovarian Carcinosarcoma: A Single-Institution Experience

Diagnostics ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 200 ◽  
Author(s):  
Aaron Nizam ◽  
Bethany Bustamante ◽  
Weiwei Shan ◽  
Karin K. Shih ◽  
Jill S. Whyte ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Early Stage ◽  
Age At Diagnosis ◽  
Disease Stage ◽  
Tumor Board ◽  
Single Institution ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Platinum Based Chemotherapy

Background: Carcinosarcoma of the ovary (CSO) is a rare and aggressive variant of ovarian cancer. Due to the rare nature of the disease there is insufficient evidence to make recommendations regarding standard management and overall prognosis. Methods: An Institutional Review Board-approved study identified all our patients with CSO between January 2011 and May 2018. Demographic and outcome measures were abstracted from the medical records and tumor board files. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). Results: 27 women with CSO were identified. The median age at diagnosis was 65 years (range 48–91). Five women (18%) presented with early stage disease (Stage I or II) and 22 patients (82%) presented with late stage III or IV disease. Twenty patients (74%) received intravenous platinum-based combination chemotherapy. Seven patients did not receive chemotherapy during their treatment course. The median overall survival was 23 months (range 2–68 months). Overall survival was not significantly worsened by the stage of disease at diagnosis. There was no difference in survival based on the age at diagnosis, tobacco status or ethnicity (p > 0.05). Conclusion: This is one of the largest single institution experiences with CSO. The majority of our patients presented with advanced stage disease and received adjuvant platinum-based chemotherapy after cytoreductive surgery. The median overall survival of 23 months was not affected by the stage of the disease. The optimal management of this rare disease needs further study with collaborative, prospective multi-institutional trials.

Semg 1 Expression in Early Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4175-4175
Author(s):  
Farouk Meklat ◽  
Sharif Uddin Ahmed ◽  
Masum Shahriar ◽  
Jian Zhang ◽  
Suhkrob Mastulov ◽  
...  
Keyword(s):  
Tumor Vaccine ◽  
Early Stage ◽  
Low Frequency ◽  
Disease Stage ◽  
Leukemia Cells ◽  
Immune Repertoire ◽  
Early Stage Disease ◽  
Chromosome 20 ◽  
Ct Antigens ◽  
Reactive Lymphocytes

Abstract SEMG 1 is major protein of semen coagulum shown to inhibit human sperm capacitation. It plays an important role in sperm clotting and is normally degraded into smaller fragments by prostate-specific antigen. The gene encoding SEMG 1 has been localized to the long arm of chromosome 20, a region of chromosome 20 that is frequently deleted in myeloproliferative diseases and myelodysplastic syndrome. We previously found SEMG 1 to be a Cancer-Testis (CT) antigen that was immunogenic in the cancer-bearing patients, supporting its potential as a target for tumor immunotherapy. CLL patients are generally immunosuppressed even before any therapy is given. The immunosuppression increases as the disease progresses and may prevent successful immunotherapy unless the therapeutic approach is used to patients with early stage disease (Stage 0 or I), even prior to use of any immunosuppressive chemotherapy. However, most CT antigens are expressed in low frequency in early stage cancer. Accordingly, we set out to determine the expression frequency, variant and pattern of expression of SEMG 1 in patients with early CLL. Using a pair of sequence-specific primers in RT-PCR on total RNA derived from patients with early CLL, we found that SEMG 1 transcripts could be detected in 19/41 (46%) patients. The high frequency at which SEMG 1 is expressed in early CLL is in contrast to the generally low frequency of expression of other CT antigens in early malignancies. SEMG 1 expression not only occurred at the transcript level but also protein level, as determined by immunocytochemistry using SEMG 1 MoAbs. These results indicate that SEMG 1 could potentially be a suitable target for the design of tumor vaccine that could be applicable to a large proportion of patients with early CLL. Of the 19 patients expressing SEMG 1, eight expressed Zap 70 protein and 11 did not (p = 0.4; N.S.). Therefore, any SEMG 1-based tumor vaccine could be applicable even to patients with early poor risk CLL (as determined by Zap 70 expression). However, SEMG 1 expression, as determined by immunocytochemistry, within individual CLL patients was heterogeneous, suggesting that tumor vaccine targeting SEMG 1 may have to be administered with therapeutic agents that upregulate SEMG 1 expression to overcome the potential problem of tumor antigen heterogeneity that could prevent the success of the tumor vaccine. Since SEMG 1 exists in two variants, we next determined which SEMG 1 variant was expressed in CLL cells. Using a primer pairs in PCR to amplify across the 180 bp transcript that is deleted in SEMG 143, we showed that in all cases of SEMG 1-positive CLL specimens, only the non-truncated transcripts were detected, indicating the expression of SEMG 150 variant in CLL. Finally, applying diluted patient serum to an ELISA system, we found that high titers SEMG 1 IgG antibodies could be detected in six of these 41 patients but not in any of the 20 healthy donors. Leukemia cells from three of these patients expressed SEMG 1. These results, therefore, suggest that SEMG 1-reactive lymphocytes are present in the immune repertoire of patients with early CLL, irrespective of whether the leukemia cells express SEMG 1, and further support the feasibility of applying a SEMG 1-based tumor vaccine to these patients. In conclusion, SEMG 150 is expressed by the leukemia cells in a high proportion of patients with early CLL, irrespective of the Zap 70 expression status. SEMG 1 may be an immunological target for immunotherapy of nearly half of early CLL patients, especially when SEMG 1-reactive lymphocytes are present in the immune repertoire of these patients.

Response Rate of 16% and High Incidence of Adverse Events In Placebo-Treated Patients with CD25 Assay-Positive Cutaneous T-Cell Lymphoma (CTCL): An Analysis of Patient Characteristics and Predictors of Response

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4158-4158
Author(s):  
Miles Prince ◽  
Madeleine Duvic ◽  
Ann Martin ◽  
Wolfram Sterry ◽  
Chalid Assaf ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Adverse Events ◽  
Active Treatment ◽  
Response Rate ◽  
Early Stage ◽  
Disease Stage ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Hodgkin's Lymphomas ◽  
Systemic Antibiotics

Abstract Abstract 4158 Background: CTCLs are rare, extranodal non-Hodgkin's lymphomas characterized by the accumulation of malignant T lymphocytes in the skin; mycosis fungoides (MF) and Sézary syndrome (SS) are the most common variants. Their clinical course is typically chronic and progressive, despite multiple therapeutic interventions. Observational studies of patients with CTCL, although limited by rarity, are necessary to improve understanding of prognostic factors. Aims: The goals of this analysis were to describe the initial disease characteristics, prognostic factors, and natural history of disease observed in 44 patients with CD25-positive, recurrent/persistent CTCL included in the placebo arm of Study L4389-11. We were particularly interested to determine if there were any characteristics peculiar to the 16% of patients treated with placebo who were observed to have a response in this study. Methods: This multicenter, randomized, double-blind, placebo-controlled phase III trial compared 2 different doses of denileukin diftitox (9 or 18 μ g/kg/day) with placebo in 144 patients with histopathologically confirmed stage IA to III MF/SS who had received ≤3 previous therapies. Medications essential for patient welfare (cardiac medications, narcotics, anti-nausea agents, vitamins, or laxatives) and transfusions were also allowed. The primary efficacy endpoint was overall response rate (ORR); progression-free survival (PFS) was a secondary endpoint. Relationships between baseline covariates and clinical outcomes were assessed by multivariate regression analyses. Results: Placebo-treated patients had a median age of 59.0 years, and the majority were white (77.3%), had early-stage disease (stage <IIA; 68.2%), had a diagnosis of MF (84.1%), and had <20% circulating abnormal lymphocytes (85.4%) at baseline. The ORR was 15.9% (95% exact confidence interval [CI]: 6.6%-30.1%) for patients receiving placebo (complete response: 2.3%; partial response: 13.6%), reflecting a possible baseline rate of spontaneous disease remission expected in untreated CTCL. Of the 7 responding patients, 3 were treated during the trial with systemic anti-staphylococcal antibiotics (2 pts with IIB, 1pt with erythroderma). Of the remaining 4 pts the stages were 1A (1), IB (2), IIB (1). Median PFS according to Kaplan-Meier analysis was 124 days (4.1 months) (95% exact CI: 92–176 days (3.0-5.8 months)), and the median values for patients with stage ≤IIA disease and stage ≥IIB disease at baseline were 107 days (3.5 months) and 211 days (6.9 months), respectively. Multivariate analyses identified no significant effects of any baseline factors on either ORR or PFS, although there was a trend toward poorer PFS associated with advanced age (hazard ratio: 1.21; 95% CI: 0.97–1.52; P=.0947). These analyses were likely limited by small sample size. A total of 95.5% of patients in the placebo arm used rescue medications (skin moisturizers etc.) at least once during the treatment period. Adverse events (AEs) and treatment-related AEs occurred in 90.9% and 59.1% of placebo-treated patients, respectively. General disorders and administration site conditions were the most common types of treatment-related AEs (52.3%), which included fatigue (22.7%), rigors (15.9%), peripheral edema (15.9%), pyrexia (13.6%), and pain (2.3%). Sepsis occurred significantly more often with placebo versus active treatment (6.8% vs. 0%; P < .05). Three of the 7 (43%) responders had received systemic antibiotics and 14/37 non-responders had received systemic antibiotics (38%). Conclusion: The findings from this study demonstrate that responses can be observed in patients with MF/SS in the absence of anti-tumor treatment. Likely contributing factors to these ‘spontaneous responses' are the use of systemic antibiotics, aggressive ‘rescue medication' use and the waxing and waning nature of skin lesions, particularly in early-stage disease. All future studies should carefully document the use of systemic antibiotics during therapy. These results can serve as standard comparators for other active-treatment studies that lack a placebo control arm. Disclosures: Prince: Eisai: Consultancy, Honoraria. Duvic:Eisai: Consultancy, Research Funding, Speakers Bureau. Assaf:Eisai: Consultancy, Honoraria. Straus:Eisai: Consultancy, Honoraria.

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