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ABSTRACT: Mycosis fungoides (MF) and Sezary Syndrome (SS) represent the most common subtypes of primary Cutaneous T-cell lymphoma (CTCL). Patients with advanced MF and SS have a poor prognosis leading to an interest in the development of new therapies with targeted mechanisms of action and acceptable safety profiles. In this review we focus on such novel strategies that have changed the treatment paradigm of this rare malignancy.
Journal of Hematology & Oncology 05/2012; 5:24. · 3.99 Impact Factor
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ABSTRACT: Plasmablastic lymphoma (PBL) is an aggressive lymphoma classified by the World Health Organization as a subtype of diffuse large B-cell lymphoma that shares many morphologic and immunophenotypic features with multiple myeloma. It is extremely rare in immunocompetent patients. Because of the small number of patients reported, this rare lymphoma remains a poorly characterized and understood entity with presently no standard recommendations regarding the optimal treatment. Herein, we report a dramatic clinical response coupled with tumor lysis syndrome to a bortezomib-based treatment in an HIV-negative patient with refractory plasmablastic lymphoma.
Clinical lymphoma, myeloma & leukemia 10/2010; 10(5):E43-6.
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ABSTRACT: Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This is the only approved therapy for patients with PTCL.
This review describes the clinical development of PDX from its synthesis to its FDA approval. It details the biochemical basis of the differences between PDX and other antifolates that form the basis of the superiority of its activity. This is followed by a description of the preclinical data that led to early-phase clinical trials in lung cancer and lymphoma and, finally, the definitive trial that led to its approval in PTCL. The review also describes how PDX is being combined with other agents in both the preclinical and clinical arenas.
These trials have been instrumental in defining a safe dose as well as the safety profile of the agent. FDA approval for the use of PDX in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients.
PDX is a unique antifolate that has been rationally designed to have a high affinity for the reduced folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase. It is active in T-cell lymphomas and non-small-cell lung cancer. It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.
Expert Opinion on Pharmacotherapy 07/2010; 11(10):1705-14. · 3.20 Impact Factor
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ABSTRACT: Mature T-cell and NK-cell lymphomas are increasingly being recognized as unique biological entities distinguishable from other forms of lymphomas. Treatment paradigms developed for B-cell lymphomas are considered inadequate for application to these diseases, as indicated by the poor outcome of these patients with the overall 5-year survival remaining below 30% for most histologies. There is a tremendous need for newer treatment options both in the upfront and relapsed setting for T-cell lymphomas. In recent years, there has been a plethora of new targeted agents that have shown promising activity in T-cell lymphomas. The most notable is the novel antifolate pralatrexate that has been approved for the treatment of relapsed and refractory T-cell lymphoma. Other agents include histone deacetylase inhibitors (vorinostat, romidepsin, belinostat), proteosome inhibitors (bortezomib), immunomodulatory agents (lenalidomide), nucleoside analogs (gemcitabine, nalarabine) and targeted antibodies. An improved understanding of the molecular pathogenesis of T-cell lymphomas will help define the role of these agents in the treatment paradigms of T-cell lymphomas both as single agents and as rationally designed combinations and will lead to curative treatments for these difficult diseases.
International journal of hematology 07/2010; 92(1):33-44. · 1.17 Impact Factor
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ABSTRACT: A patient with chronic hepatitis C virus (HCV) presented to our clinic with a hepatic mass as well as lymphocytosis. Biopsy of the hepatic mass revealed apposed hepatocellular carcinoma (HCC) and small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL). Dramatic examples of lymphoma regression during treatment with antiviral medication in chronic HCV patients have suggested an etiologic role for HCV in lymphomagenesis. A growing body of research seeks to clarify the details of the interaction between HCV and B-cell lymphomas. This case of adjacent SLL/CLL and HCC is the first published diagnosis of these two diseases in the liver at one time, and the only published example of the physical apposition of any lymphoma and HCC. The case is provocative in light of recent evidence that local interactions between HCV-infected hepatocytes and B cells may contribute to lymphomagenesis.
Acta Haematologica 12/2009; 123(2):77-80. · 1.35 Impact Factor
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Annals of Surgical Oncology 08/2009; · 4.17 Impact Factor
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ABSTRACT: T-cell lymphomas (TCLs) classically have a poorer response to therapy when compared with B-cell lymphomas and account for only 10-15% of all lymphoid malignancies. Hepatosplenic TCLs are a rare subset of this group that usually present with hepatosplenomegaly, B-symptoms, and only rarely with lymphadenopathy.
This disease process, also known as gamma/delta (gamma/delta) TCL because of the expression of the T-cell receptor gamma/delta chain, tends to present in young male patients. Hepatosplenic TCLs have recently gained notoriety because of the realization that patients with long-term treatment of some immunomodulators can develop this potentially fatal disease. These facts are exacerbated by the fact that patients with this disease rarely enjoy remissions of more than brief duration with common chemotherapeutic agents or bone marrow transplants. A novel agent, pralatrexate, has recently been found to have a dramatic activity in this patient population with refractory/relapsed disease. Unfortunately, patients with hepatosplenic TCL often present with thrombocytopenia and this new agent is contraindicated in these patients because of the potential exacerbation of thrombocytopenia with this agent.
Because of this we attempted a laparoscopic-assisted splenectomy in one patient with grade 4 thrombocytopenia.
Postoperatively the patient's thrombocytopenia resolved, permitting him to begin treatment with this potentially life-saving agent.
Due to the lethality of this disease and potential efficacy of new therapies, we believe splenectomy should be considered in patients with hepatosplenic lymphoma in an effort to improve the treatment options and survival of patients with this challenging disease.
Annals of Surgical Oncology 06/2009; 16(7):2014-7. · 4.17 Impact Factor
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Leukemia & lymphoma 05/2009; 50(6):1039-42. · 2.40 Impact Factor
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ABSTRACT: Dr. O'Connor delivered the following material as a poster at the 2003 American Society of Hematology meeting highlighting results from his work with bortezomib in the treatment of non-Hodgkin's and mantle cell lymphoma. A full publication of his results will appear later this year. Abstract #2346 appears in Blood, Volume 102, issue 11, November 16, 2003. The American Society of Hematology Poster Session "Lymphoma: Treatment and Supportive Care" took place on Sunday, December 7, 2003.
Journal of the National Comprehensive Cancer Network: JNCCN 11/2004; 2 Suppl 4:S21-2. · 4.41 Impact Factor
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Tarun Kewalramani,
Andrew D Zelenetz,
Stephen D Nimer,
Carol Portlock,
David Straus,
Ariela Noy, Owen O'Connor,
Daniel A Filippa,
Julie Teruya-Feldstein,
Alison Gencarelli,
Jing Qin,
Alyson Waxman,
Joachim Yahalom,
Craig H Moskowitz
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ABSTRACT: Patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) who achieve complete response (CR) before autologous stem cell transplantation (ASCT) generally have better outcomes than those who achieve only partial response (PR). We investigated whether adding rituximab to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy regimen (RICE) could increase the CR rate of patients with DLBCL under consideration for ASCT. Thirty-six eligible patients were treated with RICE, and 34 received all 3 planned cycles. The CR rate was 53%, significantly better than the 27% CR rate (P =.01) achieved among 147 similar consecutive historical control patients with DLBCL treated with ICE; the PR rate was 25%. Febrile neutropenia was the most frequent grade 3 or 4 nonhematologic toxicity; it occurred in 7.5% of delivered cycles. No patient had RICE-related toxicity that precluded ASCT. The median number of CD34(+) cells per kilogram mobilized was 6.3 x 10(6). Progression-free survival rates of patients who underwent transplantation after RICE were marginally better than those of 95 consecutive historical control patients who underwent transplantation after ICE (54% vs 43% at 2 years; P =.25). RICE appears to induce very high CR rates in patients with relapsed and refractory DLBCL; however, further studies are necessary to determine whether this treatment regimen will improve outcomes after ASCT.
Blood 06/2004; 103(10):3684-8. · 9.90 Impact Factor
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Carol S Portlock,
Gerard B Donnelly,
Jing Qin,
David Straus,
Joachim Yahalom,
Andrew Zelenetz,
Ariela Noy, Owen O'Connor,
Steven Horwitz,
Craig Moskowitz,
Daniel A Filippa
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ABSTRACT: The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively identified (5/92-11/00); the samples were immunostained, and clinical data ascertained. Cases were re-reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow-up of 29.2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time-to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age >/=45 years. TTF was significantly poorer for ABVD-treated patients with CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC, both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+) patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.
British Journal of Haematology 06/2004; 125(6):701-8. · 4.94 Impact Factor
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Wm Kevin Kelly,
Victoria M Richon, Owen O'Connor,
Tracy Curley,
Barbara MacGregor-Curtelli,
William Tong,
Mark Klang,
Lawrence Schwartz,
Stacie Richardson,
Eddie Rosa,
Marija Drobnjak,
Carlos Cordon-Cordo,
Judy H Chiao,
Richard Rifkind,
Paul A Marks,
Howard Scher
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ABSTRACT: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer.
SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues.
No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms.
Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
Clinical Cancer Research 09/2003; 9(10 Pt 1):3578-88. · 7.74 Impact Factor
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ABSTRACT: PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.
Leukemia and Lymphoma 07/2003; 44(6):1027-35. · 2.58 Impact Factor
