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Biomedical subjects

Claire E Dearden

Publications and source records attributed to Claire E Dearden.

8 recordsLinked to original sources
PubMed2006

Alemtuzumab in T-cell lymphoproliferative disorders.

The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation.

Alemtuzumab↗
PubMed2006

Role of single-agent purine analogues in therapy of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of lymphomas with different clinical presentation and morphologic, immunophenotypic, and cytogenetic markers. Many of these malignancies follow an aggressive course and current therapeutic strategies are limited. The prognosis for these patients is usually very poor. The purine analogues are a class of drugs that have been shown to be active in patients who have T-cell lymphoma. T cells have a very high concentration of adenosine deaminase (ADA), a key enzyme in the purine degradation pathway, which is blocked by this class of agent. Pentostatin has been the most extensively studied of these drugs in PTCL and has shown variable response rates. However, many of the reports are limited to small single-center studies. Larger prospective randomized trials will be necessary to examine this therapy and to further explore combination regimens, which may result in increased responses.

Adenosine Deaminase Inhibitors↗
PubMed2006

T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive post-thymic malignancy with poor response to conventional treatment and short survival. It can readily be distinguished from other T-cell leukemias on the basis of the distinctive morphology, immunophenotype, and cytogenetics. Consistent chromosomal translocations involving the T-cell receptor gene and one of two protooncogenes (TCL-1 and MTCP-1) are seen in the majority of cases and are likely to be involved in the pathogenesis of the disorder. The CD52 antigen is expressed at high density on the malignant T-cells and therapy with alemtuzumab, a humanized IgG1 antibody that targets this antigen, has produced promising results. In relapsed/refractory patients overall and complete response rates have been seen in up to 76% and 60%, respectively. In previously untreated patients, complete remission rates of 100% have been reported. These responses are durable and translate into improved survival for responders. However, relapse is inevitable and strategies using both autologous and allogeneic stem cell transplantation are currently being explored. Additional clinical trials are investigating the use of alemtuzumabin combinations with chemotherapy, either concurrent or sequential. In the future we hope to have a betterunderstanding of how best to integrate these therapeutic approaches to further prolong survival for patients with T-PLL.

Adult↗
PubMed2005

Long-term outcomes of previously untreated myeloma patients: responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments.

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

Adult↗
PubMed2003

Peripheral T-cell lymphomas: diagnosis and management.

Peripheral T-cell lymphomas are a diverse group of diseases with varying clinical manifestations. Response to conventional chemotherapy generally is poor. Treatment using purine analogs has achieved response rates between 25% and 60% in relapsed/refractory patients, with minimal toxicity. The highest response rates were seen with pentostatin and gemcitabine. Using purine analogs in combination therapy may improve response rates, albeit with an increased risk of toxicity. The role of purine analogs as first line therapy in patients who have otherwise favorable prognostic factors has not been defined. Monoclonal antibody therapy has emerged in the last decade as a promising approach in treating T-cell malignancies. Campath-1H is an effective and well-tolerated therapy in these diseases. Durable remissions have been seen in heavily pretreated patients and in up to two thirds of patients who had T-PLL, which is the largest disease group studied. These results in T-PLL are significantly better than those reported with other therapies; this suggests that Campath-1H should be moved to first line therapy in this aggressive disease. The way in which monoclonal antibodies work indicate that they may be particularly useful in treating patients who have minimal residual disease, and, in this setting, facilitate stem cell transplantation. In addition, the activity of Campath-1H to deplete T cells has been exploited in preparative regimens before allogeneic bone marrow transplantation. These approaches may be worth further investigation in patients who have T-cell lymphomas. None of the therapies that are available to treat the mature T-cell neoplasms seems to be curative, other than in selected patients who have favorable ALCL. Much of the data have been drawn from small, non-randomized studies. There is a need for larger, prospective, randomized trials to examine these novel therapies and to further explore combination regimens, which may exploit potential synergism.

Antibodies, Monoclonal↗
PubMed2002

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta.

BACKGROUND: A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL-positive chronic myeloid leukemia. METHODS: We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated skin lesions that had been present for a long time. RESULTS: In all four patients, a normal blood count was achieved within four weeks after treatment began. In the patient with skin disease, the lesions began to resolve shortly after treatment began. The t(5;12) translocation was undetectable by 12 weeks in three patients and by 36 weeks in the fourth patient. In the three patients with the ETV6-PDGFRB fusion gene, the transcript level decreased, and in one patient, it became undetectable by 36 weeks. All responses were durable at 9 to 12 months of follow-up. CONCLUSIONS: Imatinib mesylate induces durable responses in patients with chronic myeloproliferative diseases associated with activation of PDGFRB.

Adult↗
PubMed2002

Alemtuzumab in T-cell malignancies.

Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen, which is abundantly expressed on all normal and most malignant T-lymphocytes. We summarize the results of our experience using alemtuzumab to treat a range of clinically aggressive, mature, post-thymic, T-cell malignancies, including T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), T-cell large granular lymphocyte (T-LGL) leukemia, and human T-cell lymphotropic virus I (HTLV-I) associated adult T-cell leukemia-lymphoma (ATLL). Alemtuzumab was administered at a dose of 30 mg, three times a week until maximum response. Apart from first-dose reactions, which were common, treatment was well tolerated, the main complication being infection and viral reactivation associated with the prolonged lymphopenia. Overall response rates were 76% (60% complete response) in 39 patients with T-PLL and 100% in 3 patients with CTCL, of duration up to 4 yr. Experience in T-LGL and ATLL is limited to single cases only and further studies are required to better define the role of alemtuzumab in these subgroups. Our results indicate that alemtuzumab has activity in T-cell malignancies, particularly in T-PLL and in patients with predominantly blood and bone marrow disease. It may be possible to prolong response duration by the use of high-dose therapy and stem cell transplantation. Alemtuzumab may also have a role in purging minimal residual disease following other chemotherapy and prior to transplantation. We conclude that treatment with alemtuzumab may offer new hope to patients who otherwise have a bleak prognosis.

Aged↗