Biomedical subjects

Michael Crump

Publications and source records attributed to Michael Crump.

32 records · Page 2Linked to original sources

PubMed2003

Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis.

PURPOSE: To assess the safety and efficacy of intensive methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Twenty-eight patients received induction chemotherapy using high-dose systemic methotrexate (3.5 g/m2) and cytarabine (3 g/m2 daily for 2 days). Fourteen patients with chemosensitive disease evident on neuroimaging then received high-dose therapy using carmustine, etoposide, cytarabine, and melphalan with autologous stem-cell rescue. RESULTS: The objective response rate to the induction-phase chemotherapy was 57%, and median overall survival is not yet assessable, with a median follow-up time of 28 months. The overall median event-free survival time is 5.6 months for all patients and 9.3 months for 14 patients who underwent transplantation. Six of these 14 patients (43%) remained disease-free at last follow-up. Treatment was well tolerated; there was one transplantation-related death. Prospective neuropsychologic evaluations have revealed no evidence of treatment-related neurotoxicity. CONCLUSION: This treatment approach is feasible in patients with newly diagnosed PCNSL without evidence of significant related neurotoxicity. Although the transplantation results are similar to those achieved in patients with aggressive or poor-prognosis systemic lymphoma, the low response rate to induction chemotherapy and the significant number of patients who experienced relapse soon after HDT suggest that more aggressive induction chemotherapy may be warranted.

Adult↗

PubMed2003

Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome.

PURPOSE: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct lymphoma with unique clinicopathologic features. We report the clinical outcome of stage I and II MALT lymphoma treated with involved field radiation therapy (RT). PATIENTS AND METHODS: From 1989 to 2000, 103 patients with stage IE and IIE disease were referred. Their median age was 60 years, with a 2:1 female predominance. Presenting sites were stomach (17 patients), orbital adnexa (31 patients), salivary glands (24 patients), thyroid gland (13 patients), and other sites (18 patients). Ninety-three patients received RT--85 received RT alone, and eight received chemotherapy and RT--with a median dose of 30 Gy. The median follow-up time was 5.1 years. RESULTS: A complete response (CR) to RT alone was achieved in 84 of 85 patients. Among CR patients, 14 experienced relapse. Relapse sites were mostly contralateral paired-organ or distant MALT locations and, infrequently, lymph nodes. The crude local control rate with RT was 95.3% (81 of 85 patients). No relapses were observed in patients with stomach or thyroid lymphoma, whereas 14 of 63 patients (22%) experienced relapse in the other sites. The overall 5-year survival rate was 98%, and the disease-free survival rate was 77%. Transformed lymphoma was observed in 14% of patients (two of 14) experiencing relapse. CONCLUSION: Moderate-dose RT achieved excellent local control in localized MALT lymphomas and had curative potential for three fourths of the patients. Gastric and thyroid MALT lymphomas had better outcome, whereas distant failures were common for other sites. Despite relapse, the disease often maintained an indolent course.

Adult↗

PubMed2003

Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Cyclophosphamide, epirubicin, and fluorouracil (CEF), compared with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. has lead to an improvement in relapse-free and overall survival in premenopausal women with node-positive breast cancer. We undertook this analysis to more accurately define the estimate of risk of secondary acute leukemia (sAL) following epirubicin-containing chemotherapy regimens. PATIENTS AND METHODS: We assessed the conditional probability of sAL among 1,545 women who received adjuvant (n = 1,477) or neoadjuvant (n = 68) chemotherapy in four National Cancer Institute of Canada Clinical Trials Group trials from 1990 to 1999. The risks associated with epirubicin-containing regimens (CEF or epirubicin and cyclophosphamide [EC]) and other regimens (doxorubicin and cyclophosphamide [AC] or CMF) were determined. RESULTS: A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia, two acute lymphoblastic leukemia): seven among women treated with CEF, two who had received AC, and one following CMF. Using competing risk statistics, the conditional probability of sAL was 1.7% (95% confidence interval [CI], 0.5 to 3.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years, 0.4% (95% CI, 0% to 1.3%) among the 678 who received CMF, and 1.3% (95% CI, 0% to 4.7%) among the 231 treated with AC. The conditional probability of death from breast cancer at 8 years for the entire group of women treated with epirubicin-containing regimens in all four trials was approximately 34.9%. CONCLUSION: CEF chemotherapy for breast cancer carries a small increased risk of sAL compared with CMF. These estimates of acute leukemia risk are important in discussing treatment with women, especially patients with a lower risk of death from breast cancer, such as those with node-negative breast cancer.

Acute Disease↗

PubMed2003

Contamination of bone marrow products with an actinomycete resembling Microbacterium species and reinfusion into autologous stem cell and bone marrow transplant recipients.

Bacterial contamination of bone marrow or peripheral blood stem cell transplant products typically occurs with skin flora or, rarely, gram-negative organisms. We describe a clonal outbreak of contamination in transplant products caused by contamination with an aerobic actinomycete that occurred at our institution during the summer of 2001. From 1 July through 12 September 2001, 73 peripheral blood or bone marrow stem cell products were obtained from 39 patients, and 34 products were found to be contaminated with the outbreak strain. Fourteen patients were reinfused with contaminated cells, and the outbreak strain was isolated from the blood cultures for one patient. Investigation revealed multiple potential sources for contamination during the product cryopreservation process. The outbreak of contamination was aborted upon modification of the cryopreservation process.

Actinobacteria↗

PubMed2003

Treatment options for patients with acute myeloid leukemia with a matched sibling donor: a decision analysis.

BACKGROUND: The role of allogeneic bone marrow transplantation (BMT) in the consolidation of young adults with acute myeloid leukemia (AML) with matched sibling donors (MSD) is controversial. Although BMT is associated with increased event free survival compared with intensive chemotherapy (CT) consolidation, BMT also is associated with increased treatment-related mortality and likely decreased quality of life and life expectancy in patients who do not develop recurrent disease. METHODS: The authors used decision analysis to compare three strategies for maximizing quality-adjusted life years (QALYs) in patients with AML in first remission with an MSD: BMT All, BMT None (consolidation CT only), or BMT in high-risk patients, as defined by baseline cytogenetic testing (Test strategy). A second decision-analysis tree was then constructed that compared BMT with CT specifically for patients with intermediate cytogenetics. RESULTS: Using expected QALYs as the outcome measure, the Test, BMT All, and BMT None strategies were associated with 20.10 QALYs, 19.63 QALYs, and 18.38 QALYs, respectively. Thus, the Test strategy, with CT for low-risk patients and BMT for intermediate risk and high-risk patients, was expected to be the optimal strategy. In the intermediate cytogenetic decision analysis, although the expected QALY for BMT recipients was higher compared with CT recipients (19.78 QALYs vs. 18.75 QALYs), because of uncertainty in variable estimates, the optimal choice was less clear. CONCLUSIONS: CT consolidation is a reasonable option for patients with AML who have favorable cytogenetics, even if an MSD is available. This model provides a framework from which patients with AML and their physicians can make decisions about consolidation therapy.

Acute Disease↗

PubMed2003

Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC). PATIENTS AND METHODS: Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m(2) weekly for the first three administrations and was increased to 80 mg/m(2) for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. RESULTS: Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. CONCLUSION: Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.

Administration, Oral↗

PubMed2003

Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype.

The purpose of this study was to evaluate the outcome of high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplant (ASCT) for patients with relapsed T-cell non-Hodgkin's lymphoma. We reviewed 36 patients with peripheral T-cell lymphoma (PTL) who underwent ASCT between January 1987 and June 2001. Patients had chemosensitive disease, and received high-dose melphalan and etoposide with or without total body irradiation supported by unpurged autologous stem cells. Comparisons were made with 97 diffuse large B-cell lymphoma (DLBL) patients. PTL patients had a median age of 46 years (19-62 years). Twenty-nine had relapsed and seven had primary refractory disease. DLBL patients were statistically similar in baseline characteristics. Of patients with PTL, six (17%) died of treatment-related complications and 14 (39%) were in remission with a median follow-up of 42 months (range 6-116 months). Three-year overall survival and event-free survival (EFS) were 48% and 37%, respectively, for PTL, compared with 53% and 42% for DLBL (P = 0.41 and 0.29 respectively). There was no significant prognostic variable found by univariate analysis for the PTL cohort. Major PTL subtypes were analysed for outcomes. The 20 patients with PTL, not otherwise specified (PTL-NOS), had an inferior EFS compared with DLBL patients (23%, P = 0.028). In contrast, the nine patients with anaplastic large T/null cell lymphoma had a non-significant trend for improved EFS (67%, P = 0.41). While ASCT in patients with relapsed or primary refractory PTL results in long-term remission rates comparable to DLBL patients, those with PTL-NOS do significantly worse.

Adult↗

PubMed2002

Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death.

Activation enhanced cell death (AECD) involves stimulating cells with growth or activation signals while concurrently blocking calcium influx. In this study, we have evaluated the effect of AECD on human breast cancer cells. MCF-7 or MDA-MB-231 cells treated with Ca2+ influx blockers econazole or ketotifen for 24 h underwent a dose-dependent, irreversible loss of viability, and clonogenicity. Two-hour treatment of these cells with higher concentrations of the drugs also resulted in loss of clonogenicity, but morphological indicators of cell death were apparent only after longer incubation. Loss of clonogenicity could be enhanced almost 10-fold by co-stimulation of the cells with the agonists EGF or bombesin. Econazole was also effective in inducing cell death in multi-drug resistant MCF-7adr cells. Human hemopoietic progenitor cell sensitivity to econazole or ketotifen was evaluated by colony assay. Under conditions resulting in 2.5-3 logs of breast cancer cell loss, 60-70% of hemopoietic progenitors could be recovered. We further evaluated the effect of econazole on breast cancer cells present in mobilized hemopoietic cells obtained from patients undergoing high dose chemotherapy with autologous stem cell support. In six of eight samples evaluated, cytokeratin-positive breast cancer cells could be detected by immunofluorescence microscopy and colony formation. Breast cancer colonies were reduced 60-500-fold or more after exposure to econazole while hemopoietic colonies were typically reduced only 2-fold. In all cases, addition of EGF as an activator either had no evaluable effect or enhanced breast cancer cell loss. We conclude that Ca2+ influx blockade with concurrent EGF stimulation is a promising approach for purging breast cancer cells from hemopoietic progenitor cell preparations.

Bone Marrow Purging↗

PubMed2002

Pure red cell aplasia due to parvovirus following treatment with CHOP and rituximab for B-cell lymphoma.

A 26-year-old woman, diagnosed with diffuse large B-cell lymphoma, was treated with CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone), rituximab and radiotherapy. She developed transfusion-dependant anaemia, which persisted following chemotherapy. Bone marrow aspirate and biopsy were consistent with pure red cell aplasia and parvovirus infection. Serology was negative for previous or acute infection but parvovirus DNA was detected by polymerase chain reaction. Administration of intravenous immunoglobulin (1 g/kg) resulted in reticulocytosis and recovery of her haemoglobin. We hypothesize that rituximab caused depletion of her normal B cells, resulting in an inability to mount a primary immune response to parvovirus infection.

Acute Disease↗

PubMed2002

Phase II study of sequential topotecan and etoposide in patients with intermediate grade non-Hodgkin's lymphoma: a National Cancer Institute of Canada Clinical Trials Group study.

Preliminary results indicate that inhibitors of the nuclear enzyme topoisomerase (topo) I, such as topotecan, may be active in non-Hodgkin's lymphoma (NHL). Pre-clinical studies have shown sequential administration of a topo I and II inhibitor has supra-additive anti-tumor effects in some model systems, and that greater cytotoxicity occurs if the topo I inhibitor is given first. We enrolled, 22 eligible patients with relapsed or refractory intermediate grade NHL in a phase II study ofsequential administration of topotecan 1.25 mg/m2 days 1-5 and etoposide 50 mg po b.i.d. days 6-12, every 28 days without G-CSF. Most patients had diffuse large B-cell lymphoma and all had received only one prior regimen (CHOP, 20 patients, or equivalent, 2 patients). Patients with stable or responding disease were allowed to proceed to high-dose therapy and autologous stem-cell transplant after 2 cycles of therapy. The 22 patients received a total of 62 cycles of topotecan + etoposide (median 2, range 1-6), and 4/22 completed all six planned cycles. Hematologic toxicity was significant and resulted in incomplete etoposide dosing in half of all cycles in 16/22 patients. Nineteen of twenty-two patients had grade 3/4 neutropenia, 12 had grade 3/4 thrombocytopenia, and 6 grade 3/4 anemia. Eleven patients had at least one episode of febrile neutropenia or had documented infection. Non-hematologic toxicity was mild. Four patients had a partial response (PR) (18.2%), nine had stable disease and seven progressed; three patients with stable disease went on to ABMT. The combination of topotecan and etoposide as given in this study has modest activity in relapsed/refractory aggressive histology NHL, and produces marked myelosuppression. Other doses and schedules combining topo I and II inhibitors, or topo I inhibitors with alkylating agents, should be explored with the addition of hematopoietic growth factors in this patient population.

Adult↗

PubMed2002

Inhibition of raf kinase in the treatment of acute myeloid leukemia.

Adult acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) remain a formidable therapeutic challenge. Although 30-40% of young adults with AML may have prolonged remissions, following either intensive chemotherapy or bone marrow transplantation, the remainder relapse and ultimately die of their disease. Older adults, or those with leukemia following an antecedent hematologic disorder such as MDS, experience only brief remissions with modern chemotherapy, and in this population the rate of long-term disease-free survival is less than 10%. Treatment of MDS consists mainly of supportive care with antibiotics and transfusion therapy, and only a small minority of patients are cured with allogeneic stem cell transplantation. As the biology of the acute leukemias and MDS has unfolded, new potential targets for arresting malignant cell growth and restoring normal hematopoiesis have been identified. This article will discuss the relevance of the ras-raf signaling pathway in the pathogenesis of myeloid leukemia, and describes some early results in the use of novel small molecule inhibitors of farnysltransferase and raf protein kinase in leukemia therapy.

Acute Disease↗

PubMed2002

Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma.

Advanced-stage mantle cell lymphoma (MCL) is a disease for which no curative treatment strategy exists. Results with standard combination chemotherapy, with or without an anthracycline, are disappointing, and new and better therapies are needed. High-dose therapy and autologous stem-cell transplantation (ASCT) have been performed in patients with MCL both up front and at relapse with varying degrees of success. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) has shown moderate response rates in patients with MCL. It has also been used safely and effectively as an in vivo purge during ASCT for patients with lymphoma. We are currently investigating an aggressive protocol in patients with newly diagnosed, untreated MCL using a combination of two promising therapeutic modalities, high-dose therapy-ASCT and rituximab. Since 1999, 13 patients with newly diagnosed MCL have been enrolled in this phase II clinical trial. CHOP (cyclophosphamide/prednisone/vincristine/doxorubicin) is used as debulking chemotherapy. Stem cells are mobilized with 5 days of granulocyte colony-stimulating factor 10 microg/kg/d, with a single infusion of rituximab 375 mg/m(2) used as an in vivo purge before stem-cell collection by large-volume leukapheresis. The transplant conditioning regimen is cyclophosphamide/carmustine/etoposide. Post-transplant consolidative immunotherapy consists of rituximab 375 mg/m(2), administered as two 4-week cycles at 2 and 6 months post-transplant. So far, 12 patients (7 men/5 women) with a median age of 55 years (range, 41 to 65 years) have been transplanted. Patients were first assessed and then transplanted a median of 40 and 201 days, respectively, from diagnosis. International Prognostic Index at diagnosis was low (n = 3), low-intermediate (n = 8), and high-intermediate (n = 1). A median of six cycles of CHOP was required to debulk tumor sufficiently for transplant. Response to CHOP was 100% with six complete responses, one complete response unconfirmed, and five partial responses. Transplantation was well tolerated. Patients engrafted quickly, with a median of 11.5 days to neutrophil engraftment and 10 days to platelet independence. Patients had modest transfusion requirements, requiring a median of four units of packed red blood cells and two and a half platelet transfusions. Six to 8 weeks post-transplant, six patients were in complete response, four in complete response unconfirmed, and two in partial response. Eight patients have received all eight maintenance rituximab treatments, and four have received only their first cycle. Following rituximab, the two patients in partial response and two in complete response unconfirmed converted to complete response. With a median follow-up of 239 days from transplant (range, 61 to 727 days), all patients remain alive and well with no documented relapses. Samples for molecular monitoring have been drawn from the stem-cell graft, and serially from the peripheral blood and bone marrow of patients at baseline, preapheresis, pretransplant, and post-transplant at 3-month intervals. This data shows that ASCT followed by rituximab immunotherapy is feasible and safe in patients with MCL. Although patient numbers are low and follow-up time is short, preliminary results are encouraging. Rituximab may convert partial responders to complete responders. The durability of responses will be determined with longer follow-up.

Adult↗

PubMedDate not supplied

Hodgkin's lymphoma.

Explore the source record for details and available documents.

Clinical Trials as Topic↗

PubMedDate not supplied

Lymphoma.

Explore the source record for details and available documents.

Adult↗