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Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma

Jain, Salvia; Diefenbach, Catherine; Zain, Jasmine; O'Connor, Owen A
Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naive and bortezomib-exposed populations
PMCID:3102580
PMID: 21654882
ISSN: 1555-175x
CID: 134321

Hodgkin's Lymphoma Cell Lines Have up-Regulated IL-3 Receptor alpha (IL-3R alpha) Expression and Are Sensitive to SL-401, An IL-3R alpha Targeted Drug [Meeting Abstract]

Diefenbach, Catherine S; Sabado, Rachel; Brooks, Christopher L; Baquero-Buitrago, Jairo; Cruz, Crystal; Vengco, Isabelita; Montanari, Francesca; Marchi, Enrica; Scotto, Luigi; Cirrito, Thomas P; Bergstein, Ivan; O'Connor, Owen A
ISI:000299597105465
ISSN: 0006-4971
CID: 2209832

Preliminary Results of An Ongoing Phase I Trial of Oral Belinostat a Novel Histone Deacetylase Inhibitor in Patients with Lymphoid Malignancies [Meeting Abstract]

Zain, Jasmine M; Foss, Francine M; Diefenbach, Catherine S; Petrylak, Daniel; Narwal, Ameet; Neylon, Ellen; Knoblauch, Poul; O'Connor, Owen A
ISI:000299597105438
ISSN: 0006-4971
CID: 2209922

Interim Results of a Phase 1 Trial of An Oral Histone Deacetylase Inhibitor Belinostat In Patients with Lymphoid Malignancies [Meeting Abstract]

Zain, Jasmine M.; Foss, Francine M.; de Bono, Johann S.; Narwal, Ameet; Neylon, Ellen; Blumenschein, George; Lassen, U.; Knoblauch, Poul; Diefenbach, Catherine S.; O'Connor, Owen A.
ISI:000289662202011
ISSN: 0006-4971
CID: 134501

Mantle cell lymphoma in relapse: the role of emerging new drugs

Diefenbach, Catherine S M; O'Connor, Owen A
PURPOSE OF REVIEW: Despite current advances in the therapy for newly diagnosed mantle cell lymphoma (MCL), relapsed MCL continues to have a poor prognosis. Advances in our understanding of the molecular pathogenesis of MCL are yielding many promising novel therapies. RECENT FINDINGS: This article reviews the unique biology of MCL and describes how our understanding of its cell cycle dysregulation, and impaired apoptotic pathways is yielding many potential therapeutic targets including cyclin D1 and the cell cycle regulatory proteins, inhibitors of mammalian target of rapamycin, the proteasome, and proapoptotic family members. Recent preclinical and clinical data with cdk inhibitors, histone deacetylase inhibitors, the proteasome inhibitor bortezomib, mammalian target of rapamycin inhibitors, and other experimental strategies such as immunotherapy and microRNA are discussed. SUMMARY: Understanding these targeted therapies in the context of the biology of MCL, has the potential to develop novel therapeutic platforms for the treatment of relapsed MCL, and will hopefully change the outcome for patients with this challenging clinical condition
PMID: 20679769
ISSN: 1531-703x
CID: 111588

Monomorphic T-cell post-transplant lymphoproliferative disorders exhibit markedly inferior outcomes compared to monomorphic B-cell post-transplant lymphoproliferative disorders [Letter]

Montanari, Francesca; Bhagat, Govind; Clark-Garvey, Sean; Seshan, Venkatraman; Zain, Jasmine; Diefenbach, Catherine; McCormick, Erin; Crook, Meaghan; Conroy, Meghan; O'connor, Owen A
PMID: 20807097
ISSN: 1029-2403
CID: 112051

Post Transplant Lymphoproliferative Disorders: Prognostic Features and Rituximab Impact In a 120 Case Single Institution Series [Meeting Abstract]

Montanari, Francesca; Bhagat, Govind; Seshan, Venkatraman; Clark-Garvey, Sean; Zain, Jasmine M; Diefenbach, Catherine S; McCormick, Erin; Conroy, Meaghan; Crook, Meghan; Alobeid, Bachir; O'Connor, Owen A
ISI:000289662204570
ISSN: 0006-4971
CID: 2209802

Safety and immunogenicity study of NY-ESO-1b peptide and montanide ISA-51 vaccination of patients with epithelial ovarian cancer in high-risk first remission

Diefenbach, Catherine S M; Gnjatic, Sacha; Sabbatini, Paul; Aghajanian, Carol; Hensley, Martee L; Spriggs, David R; Iasonos, Alexia; Lee, Helen; Dupont, Bo; Pezzulli, Sandra; Jungbluth, Achim A; Old, Lloyd J; Dupont, Jakob
PURPOSE: The cancer-testis antigen NY-ESO-1 is expressed by >40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with the HLA-A*0201-restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission. EXPERIMENTAL DESIGN: After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16. RESULTS: Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months-not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months. CONCLUSION: Vaccination of high-risk HLA-A*0201-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Additional study is warranted
PMID: 18451240
ISSN: 1078-0432
CID: 81151

Preoperative serum YKL-40 is a marker for detection and prognosis of endometrial cancer

Diefenbach, Catherine S M; Shah, Zharna; Iasonos, Alexia; Barakat, Richard R; Levine, Douglas A; Aghajanian, Carol; Sabbatini, Paul; Hensley, Martee L; Konner, Jason; Tew, William; Spriggs, David; Fleisher, Martin; Thaler, Howard; Dupont, Jakob
OBJECTIVE: YKL-40 is a secreted glycoprotein of the chitinase family that has been previously described as a diagnostic and prognostic marker for a number of cancers, including epithelial ovarian cancer. In this study, we examined the frequency of serum elevation as well as the diagnostic and prognostic significance of this serum marker in endometrial cancer. MATERIALS AND METHODS: Preoperative serum levels of YKL-40 and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) for all endometrial cancer patient samples (34) available in the Memorial Sloan-Kettering Cancer Center Gynecology Service Tissue Bank between the years 1987 and 2002, and compared to a cohort of normal individuals. A YKL-40 value of 61 ng/mL has previously been determined to represent the upper limit of normal. YKL-40 values were correlated with clinical characteristics, including patient age, tumor grade, histology, clinical stage, and clinical outcome (progression-free survival [PFS] and overall survival [OS]). RESULTS: YKL-40 was elevated (>61 ng/mL) in 26 (76%) of 34 endometrial cancer patients compared with elevations of CA125 in 21 (62%) of 34 patients (P=0.09). Twenty-eight (82%) of all 34 patients had elevations of either CA125 or YKL-40 or both; 16 (89%) of 18 advanced-stage endometrial cancer patients had elevation of at least one of these two markers. Median preoperative YKL-40 value was 137 ng/mL (range, 22-1738 ng/mL) for endometrial cancer patients compared with 28 ng/mL (range, 15-72 ng/mL) for normal healthy subjects (P<0.0001). There was no statistically significant association of YKL-40 with patient age, tumor grade, histology, or stage. Elevation of YKL-40 (>80 ng/mL) was correlated with poor clinical outcome in univariate analysis, but was not demonstrated in multivariate analysis. At 5 years' follow-up, the PFS rate was 80% for patients with YKL-40<80 ng/mL compared with 43% for patients with YKL-40>80 ng/mL (P=0.004). The 5-year OS rate for patients with YKL-40<80 ng/mL was 79% compared with 48% for patients with YKL-40>80 ng/mL (P=0.047). CONCLUSION: Preoperative serum YKL-40 is frequently elevated and may represent a novel marker for the detection of endometrial cancer and the identification of high-risk subsets of patients with worse clinical outcome. Further investigation of this promising endometrial cancer marker in larger studies is warranted
PMID: 17023034
ISSN: 0090-8258
CID: 81143

Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is highly expressed in advanced ovarian cancer and is associated with aggressive histology and poor survival

Diefenbach, Catherine S M; Soslow, Robert A; Iasonos, Alexia; Linkov, Irina; Hedvat, Cyrus; Bonham, Lynn; Singer, Jack; Barakat, Richard R; Aghajanian, Carol; Dupont, Jakob
BACKGROUND: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) tumor expression is an emerging prognostic, diagnostic, and therapeutic target in early epithelial ovarian cancer (EOC). The significance of tumor overexpression of LPAAT-beta was investigated in a large number of advanced- and early-stage EOC patients. METHODS: LPAAT-beta expression was analyzed by immunohistochemistry (IHC) in 158 ovarian tumors, including 68 advanced and 90 low-stage tumors, representing all grades and histologies (including 33 borderline tumors). In advanced-stage patients, tissue from multiple sites was evaluated to assess differential expression of LPAAT-beta in local tumor and distant metastases. RESULTS: LPAAT-beta was overexpressed in 90 (57%) of all 158 ovarian tumors. Forty-nine (72%) of 68 advanced tumors overexpressed LPAAT-beta. LPAAT-beta was associated with the presence of carcinoma versus borderline histology (67% vs. 18%, P < .0001), high histologic grade [according to the Silverberg Grading Scheme] (Grade 1, 25%; Grade 2, 21%; and Grade 3, 54%; P < .0001), and with papillary-serous histology. In an analysis of the 125 carcinoma patients, LPAAT-beta increased with but was not significantly associated with advanced clinical stage (P = .1431). LPAAT-beta expression was associated with shortened progression-free survival (PFS) (5-year PFS, 32% for LPAAT-beta-positive vs. 60% for LPAAT-beta-negative; P = .0318) and decreased overall survival (OS) (5-year OS, 54% for LPAAT-beta-positive vs. 74% for LPAAT-beta-negative; P = .0173). CONCLUSIONS: LPAAT-beta is highly expressed in advanced ovarian tumors and is associated with aggressive histology and decreased PFS and OS. LPAAT-beta is an intriguing prognostic tool for the identification of high-risk EOC and a potential target for directed therapy that warrants further study
PMID: 16944535
ISSN: 0008-543x
CID: 81142