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Biomedical subjects

Ian W Flinn

Publications and source records attributed to Ian W Flinn.

11 recordsLinked to original sources
PubMed2003

Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance.

PURPOSE: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy. PATIENTS AND METHODS: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome. RESULTS: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 +/- 0.28 v 0.39 +/- 0.29, P <.016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P =.02). CONCLUSION: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.

Antibodies, Monoclonal↗
PubMed2003

Interphase cytogenetic abnormalities in chronic lymphocytic leukemia may predict response to rituximab.

Select cytogenetic abnormalities such as del(17)(p13.1) and del(11)(q22-q23)predict rapid disease progression and inferior survival in chronic lymphocytic leukemia (CLL). We sought to determine the impact of the four most common interphase cytogenetic abnormalities in 28 CLL patients relative to response to three-times-a-week rituximab therapy. Abnormalities were noted in 25 of the 28 patients to include del(13)(q14.3) [n = 16 (57%)], del(11)(q22.3) [n = 10 (36%)], +12 [n = 6 (21%)], del(17)(p13.1) [n = 5 (18%)], and normal [n = 3 (11%)]. Only a minority of each of these occurred as sole abnormalities. To categorize patients into one specific group, we used the hierarchical order del(17)(p13.1) > del(11)(q22.3) > trisomy 12 > del(13)(q14.3) to prioritize. Response to rituximab was noted to vary by cytogenetic group: del(17)(p13.1), 0% [n = 5]; del(11)(q22.3), 66% [n = 9]; del(13)(q14.3), 86% [n = 7]; +12, 25% [n = 4], and normal, 0% [n = 3]. Response was significantly lower (P = 0.05) in patients with del(17)(p13.1) as compared with those with other abnormalities. These data suggest that interphase cytogenetics in CLL may be predictive of a response to rituximab therapy and provide support for additional studies validating risk-adapted therapy in this disease.

Antibodies, Monoclonal↗
PubMed2003

MALT Lymphomas.

Mucosa-associated lymphoid tissue (MALT) lymphomas occur in a variety of organs, including the orbit, conjunctiva, salivary glands, skin, thyroid gland, lungs, stomach, and intestine. These tumors are often localized and of indolent clinical behavior. Diagnosis is made by pathologic evaluation of a tissue biopsy. Careful staging is mandatory and tailored to the initial presentation. Staging includes a history and physical, chemistries, computed tomography scan, and bone marrow biopsy. This information is supplemented with an ear, nose, and throat consultation, esophagogastro-duodenoscopy, colonoscopy, endoscopic ultrasound of the stomach, and cytogenetic/immunohistochemical analysis of the tumors. Treatment is tailored to organ involvement and stage at presentation. Eradication of Helicobacter pylori using a triple anti-H. pylori regimen approved by the US Food and Drug Administration is standard therapy for all H. pylori-positive gastric MALT lymphomas. Endoscopic ultrasound- and computed tomography-staged gastric MALT stage IE tumors will achieve a complete response with this approach in approximately 60% to 90% of patients (the more superficial the tumor, the better the response). Patients with tumors that are T4 node-positive Musshoff stage IIE1 and IIE2 or tumors with adverse cytogenetics should receive radiotherapy or surgery with or without radiotherapy. Tumors with a significant high-grade component or large cell tumors with a minor low-grade MALT component should receive CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy. Localized MALT lymphomas of the orbit, conjunctiva, salivary glands, and thyroid gland are treated successfully with radiotherapy. Surgery as first-line therapy for gastric MALT lymphomas was replaced by attempts at organ preservation. In the past, margin-free surgical excision or tumor debulking followed by radiation therapy and chemotherapy has been highly effective for gastric MALT lymphomas. Therefore, surgical excision of large cell or bulky tumors of the stomach, thyroid, lung, and salivary gland, followed by adjuvant radiotherapy or chemotherapy, may still be an important consideration in selected patients. Surgery still has a role for patients with relapsed or refractory low-grade disease and life-threatening hemorrhage. Disseminated MALT lymphomas are incurable and are treated primarily with chemotherapy according to symptoms.

Humans↗
PubMed2003

Incorporating monoclonal antibodies in blood and marrow transplantation.

The development of therapeutic monoclonal antibodies had been a significant advance in the treatment of B-cell non-Hodgkin's lymphoma (NHL). In the setting of blood and marrow transplantation (BMT), initial research was focused on in vitro graft purging. More recently, investigators have designed in vivo purging protocols using rituximab with the goal of obtaining tumor-free grafts. Exciting developments stem from the use of iodine 131 ((131)I)-tositumomab as well as yttrium 90 ((90)Y)-ibritumomab in myeloablative doses in blood and marrow transplantation protocols for high-risk patients. Finally, vigilance towards complications in particular unusual infections is advised given the profound immunosupressive state caused by these antibodies.

Antibodies, Monoclonal↗
PubMed2003

Chronic lymphocytic leukemia: advances in biology and therapeutics.

Recent advances in our understanding of the biology of chronic lymphocytic leukemia have made it possible to stratify patients according to risk. In addition, advances in the therapy of patients have improved responses and have for the first time allowed for a risk adapted approach to patients with chronic lymphocytic leukemia similar to that which has been used for acute leukemia for years. Tumor cell differentiation status and presence of specific somatic and immunoglobulin gene mutations have been shown to be reliable predictors of disease behaviors. This knowledge could provide clinicians with tools to better stratify patients and eventually affect their clinical outcomes. Furthermore, new therapeutic agents and treatment combinations that appear to have increased efficacy have been developed.

Antineoplastic Agents↗
PubMed2002

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma.

PURPOSE: Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin's lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-naïve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS: Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m(2) weekly for 4 weeks) or time to progression (TTP) of < or = 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m(2) intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS: Fifty-seven patients were treated. The median age was 54 years, 74% had tumors > or = 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier-estimated TTP was 6.8 months (range, 1.1 to > or = 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION: Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.

Adult↗
PubMed2002

The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction.

Rituximab is a chimeric monoclonal antibody directed at CD20 with significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a proportion of patients with CLL receiving rituximab treatment have in vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a pathway similar to fludarabine and other chemotherapeutic agents is intricately involved in the blood elimination of tumor cells after rituximab treatment. Patients having caspase-3 activation and PARP cleavage in vivo had a significantly lower blood leukemia cell count after treatment as compared to those without caspase activation. Significant down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also noted, possibly explaining in part how rituximab sensitizes CLL cells to the cytotoxic effect of chemotherapy in vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on induction of apoptosis and provides another area of focus for studying mechanisms of antibody-resistance in neoplastic cells.

Antibodies, Monoclonal↗
PubMed2002

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience.

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group. The median time to an absolute neutrophil count of 0.5 x 109/l was 45 d (range 20-185). Relapse was the major cause of failure with a relapse rate of 55% in CR2 and 44% in CR3, while the non-relapse, transplant-related mortality rate was 15% in CR2 and 33% in CR3. In univariate analysis, patient age, cytogenetics, white blood cell count at presentation, CR1 duration and the sensitivity of clonogeneic leukaemia (CFU-L) in the graft to 4HC were all prognostic for EFS. Using each of these significant variables in multivariate modelling, patient age and sensitivity of CFU-L to 4HC were determined to be predictors of EFS. 4HC-purged autologous BMT produced results similar to allogeneic BMT for AML patients beyond first remission.

Acute Disease↗
PubMed2002

Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma.

The treatment of malignant lymphoma has improved over the past 20 years, but the majority of patients are not cured. New modalities using targeted therapy based on new information in molecular biology and immunology hold promise for better outcomes with less toxicity. We review data on the use of radiolabeled monoclonal antibodies directed against the CD20 antigen on malignant B cells. We discuss the major radionuclides available, iodine 131 ((131)I), tositumomab, and yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA) and present data on new approaches in labeling antibodies that have facilitated their use. Clinical trial data with the yttrium-labeled antibodies are discussed. The use of dosimetry as a means for predicting toxicity is discussed, and the questions of long-term toxicity (late effects) are addressed. These targeted approaches to the treatment of malignancy, and lymphoma in particular, hold great promise.

Antibodies, Monoclonal↗
PubMedDate not supplied

Monoclonal antibody therapy with autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma.

BACKGROUND: With the introduction of novel monoclonal antibody products into the clinic, significant new strategies are being developed to improve upon existing treatment for non-Hodgkin's lymphoma. METHODS: Monoclonal antibodies are being used alone, in combination with chemotherapy, or as adjuncts to autologous bone marrow transplantation for the purpose of purging bone marrow of neoplastic cells. RESULTS: Monoclonal antibodies when used in vivo in conjunction with autologous bone marrow transplantation have been relatively well tolerated. Results from several trials seem to demonstrate a therapeutic benefit for the use of such combinations. CONCLUSIONS: Before these agents can be included in standard bone marrow transplantation regimen, long-term survival outcomes need to be obtained from randomized trials. We review the results from recent trials using monoclonal antibodies in conjunction with autologous stem cell transplantation for the treatment of non-Hodgkin's lymphoma.

Antibodies, Monoclonal↗