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Biomedical subjects

H M Prince

Publications and source records attributed to H M Prince.

At least 37 records · Page 2Linked to original sources
PubMed2003

Successful mobilization of peripheral blood stem cells after addition of ancestim (stem cell factor) in patients who had failed a prior mobilization with filgrastim (granulocyte colony-stimulating factor) alone or with chemotherapy plus filgrastim.

This study assessed the ability of recombinant human stem cell factor (rHuSCF) to mobilize stem cells in 44 patients who had failed a prior mobilization (CD34(+) yield 0.5-1.9 x 10(6)/kg BW) with filgrastim-alone or chemotherapy-plus-filgrastim. The same mobilization regimen was used with the addition of rHuSCF. In the filgrastim-alone group (n=13), rHuSCF 20 microg/kg was started 3 days before filgrastim and continued for the duration of filgrastim. In the chemotherapy-plus-filgrastim group (n=31), rHuSCF 20 microg/kg/day plus filgrastim 5-10 microg/kg/day were administered concurrently. Leukaphereses were continued to a maximum of four procedures or a target of >or=3 x 10(6) CD34(+) cells/kg. In both groups, CD34(+) yield (x 10(6)/kg BW) of the study mobilization was higher than that of the prior mobilization (median: 2.42 vs 0.84 P=0.002 and 1.64 vs 0.99 P=<0.001, respectively). In all 54 and 45% of patients in the filgrastim-alone group and chemotherapy-plus-filgrastim group, respectively, reached the threshold yield of 2 x 10(6)/kg. The probability of a successful mobilization was the same in those with a CD34+ yield of 0.5-0.75 x 10(6)/kg BW in the prior mobilization as in those with 0.76-1.99 x 10(6)/kg BW. Downmodulation of c-kit expression and a lower percentage of Thy-1 positivity in the mobilized CD34(+) cells were noted in the successful mobilizers compared with those in the poor mobilizers. This study shows that rhuSCF is effective in approximately half the patients who had failed a prior mobilization and allows them to proceed to transplant. It also points to the likely role of the SCF/c-kit ligand pair in mobilization.

Adult↗
PubMed2003

Primary cutaneous B-cell lymphomas.

B-cell lymphomas comprise up to 25% of primary cutaneous non-Hodgkin lymphoma (NHL). Two main classification systems are used, namely the European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) classification of tumours. Indeed, there is much controversy surrounding which classification system to use, which in turn influences the interpretation of existing data and subsequently how we manage patients with these conditions.

Humans↗
PubMed2003

A case of clinical indolent natural killer cell lineage large granular lymphocytic leukemia in a patient with rheumatoid arthritis.

We report a case of natural killer (NK) cell leukemia with unusual biological features in a 65-year-old woman with a 20-year history of rheumatoid arthritis. She presented with neutropenia, thrombocytopenia, splenomegaly and bone marrow infiltration. Immunophenotyping (CD2+ CD3- CD4- CD5- CD8- CD16+ CD56-) confirmed NK cell leukemia. Her neutropenia and thrombocytopenia resolved following splenectomy and she has remained well with stable disease for 12 months on oral low-dose methotrexate. In contrast to all previous reports, in this instance the phenotype of large granular lymphocytic (LGL) leukemia occurring in the context of rheumatoid arthritis was NK-cell rather than T-cell. Furthermore, the clinical course was indolent, whereas, all prior literature reports have described a very aggressive clinical course for this disorder with a median survival of just 3.5 months. This case illustrates previously unrecognized heterogeneity in the natural history of this disorder.

Aged↗
PubMed2003

Regulation of cellular therapies: the Australian perspective.

The first step in the process of regulating cell-based products in Australia was taken in 1991, when the code of good manufacturing practice (cGMP) for 'Blood and Blood Components' was instituted. Paradoxically, it focused on the regulation of plasma fractionation, the non-cellular component of blood. Subsequently, Australia's regulatory body for medicinals, the Therapeutic Goods Administration (TGA), has clearly stated that all cell-based therapies utilizing components of blood and/or tissues will be regulated. The final landscape for the regulation of cellular therapies has yet to be defined, but is likely to be clarified within the next 12 months. The current cGMP for 'Blood and Tissues' is the regulatory document for all aspects of cell processing, including standard blood components (cellular and plasma), cord blood and allogeneic cells for storage. Currently, there are some exemptions to government regulation, and the most important of these is autologous hemopoietic stem cells (HSC). Indeed, no licensing is required for processing of HSC at the moment, although most centers subject themselves to a self-imposed auditing system through the National Association of Testing Authorities, Australia. However, it is anticipated that within 12 months this and the other exemptions within the Act will be removed. The TGA will become the formal regulator of all cell-based therapies, and laboratories will be required to apply for cGMP auditing and licensing. It is likely that the Foundation for the Accreditation of Cellular Therapy (FACT) guidelines or others of a similar nature, will form the basis of one of the regulatory standards for HSC processing. Of particular note is the inclusion of apheresis as an integral component of cGMP licensing.

Australia↗
PubMed2002

Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate-grade non-Hodgkin's lymphoma.

Central nervous system (CNS) relapse of non-Hodgkin's lymphoma (NHL) is usually fatal despite therapy and effective prophylaxis is desirable. Patients at high-risk usually receive intrathecal (i.t.) prophylaxis, although its efficacy is unproven. We therefore analyzed the outcome of all patients with newly diagnosed "intermediate-grade" NHL receiving i.t. prophylaxis from 1991 to 1999. Twenty-six patients were identified and analyzed. All were free of CNS involvement at diagnosis with negative cerebrospinal fluid (CSF) cytology. Disease stage was IE in 7, and IV in 19, with a median of two extranodal sites involved. Serum lactate dehydrogenase was elevated in 65%, and the median International Prognostic Factors Index score was 3 (range 0-5). Anthracycline-based chemotherapy was used in all cases and included high-dose methotrexate +/- ara-C in six patients. The median number of i.t. treatments was 5 (range 1-12) and comprised methotrexate +/- steroid in 15, together with ara-C in 11. The actuarial 3-year CNS-relapse rate was 26 +/- 10%. Six CNS-relapses were observed and involved the spinal cord or brain parenchyma in two cases each, and the leptomeninges in four patients. Treatment-related variables associated with higher CNS-relapse rates (34-50%) were: delay of > or = 14 days from diagnosis to first i.t. injection, < 5 i.t. treatments, delay of i.t. prophylaxis until after attaining CR and systemic treatment lacking high-dose methotrexate +/- ara-C (each P < or = 0.17). I.t. CNS prophylaxis, as used here, was inadequate. Alternative approaches should be pursued.

Adolescent↗
PubMed2002

Isolex 300i CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: We have previously reported that repeated cycles of high-dose therapy (HDT), can be supported by unmanipulated autologous PBPC. Here we investigate whether purified CD34+ cells, obtained by immunomagnetic separation using the Isolex 300i device, can support such therapy. METHODS: Twenty-nine consecutive patients with metastatic breast cancer had PBPC mobilized and harvested following chemotherapy and G-CSF (10 microg/kg per day). Patients with > 4.0 x 10(6)/kg CD34+ cells in the apheresis product underwent CD34-selection using the Isolex 300i (v2.0) device. All cells collected were equally divided into three aliquots and cryopreserved. Patients who did not achieve this threshold had unmanipulated cells collected and stored. Patients subsequently received three cycles of HDT with paclitaxel (175 mg/m2), thiotepa (300 mg/m2) and either ifosfamide (10 g/m2) or cyclophosphamide (4 g/m2). It was intended for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e 1/3 for each cycle) and to compare hemopoietic recovery between patients receiving CD34-selected cells or unmanipulated cells. RESULTS: Thirteen of the 29 patients (45%) did not mobilize sufficient CD34+ cells to undergo CD34-selection. The remaining 16 patients underwent CD34-selection with a median purity of 84.3% (range: 16.3-96.1%) and yield of 34% (range: 1-60%). Fifteen of these patients proceeded to HDT and 42 of the planned 45 cycles were administered. Nine patients had all three HDT cycles supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (range: 0.04-3.01). Three of the 15 patients required infusion of 'back-up' unmanipulated cells because of delayed neutrophil recovery. Of the 13 patients whose PBPCs did not undergo CD34+ cell selection, 11 proceeded to HDT with a median of 3.2 x 10(6)/kg (range: 2.0-4.4) unselected cells infused per cycle and 31 of 33 planned cycles were delivered. When hemopoietic recovery was compared between cycles of HDT supported by CD34-selected (n = 34) and unmanipulated cells (n = 31), there was a modest slowing in the patients receiving CD34-selected cells; time to ANC > 1.0 x 10(9)/L = 11 days versus 10 days (P = 0.0122) and platelets > 20 x 10(9)/L = 14 days versus 13 days (P = 0.0009). No difference in recovery to 50 x 10(9)/L was observed (P = 0.54). CONCLUSION: We have demonstrated that Isolex 300i CD34-selected cells are capable of supporting multiple cycles of HDT. However, we were unable to acquire sufficient CD34+ cells to perform this processing in 45% (13/29) of patients and further improvements in yield are required to overcome the modest delay in neutrophil and platelet recovery.

Adult↗
PubMed2002

CliniMACS CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: Traditionally, following high-dose therapy (HDT), unmanipulated autologous PBPC are infused. Alternatively, purified CD34+ cells can now be obtained by immunomagnetic separation using the CliniMACS device. Limited data currently exist examining hemopoietic recovery with such cells. METHODS: Ten patients with advanced breast cancer had PBPC mobilized with docetaxel (100 mg/m2) and G-CSF (10 microg/kg per day), harvested and processed using the CliniMACS CD34-selection device and equally divided into three aliquots for cryopreservation. Unmanipulated 'back-up' cells were also collected on a separate day of the same mobilization, divided into three and cryopreserved. Patients subsequently received three cycles of HDT with cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2). The intent was for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e., 1/3 for each cycle). If, however, hemopoietic recovery was delayed after Cycle 1, 1/3 of the unmanipulated cells were infused following Cycle 2 and the remaining CD34-selected cells (2/3) were used to support Cycle 3. RESULTS: PBPC from 10 patients underwent CD34-selection with a resulting median purity of 93% (range: 76-98%) and yield of 62% (range: 16-93%). Of the 10 patients, only two were able to be supported with CD34-selected cells for all three cycles of HDT. The remaining eight patients required unmanipulated 'back-up' cells to support Cycle 2. Three patients also required infusion of 'back-up' unmanipulated cells because of persistent neutropenia (n = 1) or thrombocytopenia (n = 2) following cycles initially supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (0.7-2.6) (n = 20) and unselected cells was 1.7 (1.4-2.8) (n = 10). Comparing hemopoietic recovery between cycles of HDT supported by CD34-selected (n = 20) and unmanipulated cells (n = 10) there was a significant slowing with the CD34-selected cells; time to ANC > 1.0 = 13 days versus 10 days, platelets > 20 = 17 days versus 13 days, > 50 = 25 versus 17 days (all P values < 0.001). There was no correlation between the dose of CD34-selected cells infused and neutrophil/platelet recovery. DISCUSSION: We have demonstrated that, although unmanipulated PBPC achieve rapid hemopoietic recovery (at modest CD34 doses of < or = 2.8 x 10(6)/kg), CliniMACS-selected CD34+ cells (in the doses utilized in this study of < or = 2.6 x 10(6)/kg) result in significantly prolonged recovery.

Adult↗
PubMed2001

Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph(+) metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P =.0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P =.057 and P =.034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials.

Adult↗
PubMed2001

Repetitive high-dose topotecan, carboplatin, and paclitaxel with peripheral blood progenitor cell support in previously untreated ovarian cancer: results of a Phase I study.

OBJECTIVE: In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. METHODS: Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC = 5 and 175 mg/m(2) of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily x5 schedule, paclitaxel (250 mg/m(2) over 24 h), and carboplatin (AUC = 12-16). RESULTS: Nineteen patients with a median age of 49 years (range 21-63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m(2)/day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m(2)/day), paclitaxel (250 mg/m(2)) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m(2)/day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pathological CR. With a median follow-up of 28 months (range 11-40 months), the median PFS is 36 months and OS has not been reached. CONCLUSION: When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m(2)), the recommended topotecan dose is 3.5 mg/m(2)/day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.

Adult↗
PubMed2001

Lack of efficacy of twice-weekly urokinase in the prevention of complications associated with Hickman catheters: a multicentre randomised comparison of urokinase versus heparin.

Hickman catheters (HC) are associated with complications, in particular infection, occlusion and thrombosis. We tested the hypothesis that regular flushing of catheters with urokinase would reduce the frequency of these complications. Patients who required a double-lumen HC for (1) bone marrow or peripheral blood progenitor cell transplantation or (2) intensive combination chemotherapy for haematological malignancies were randomised to receive twice-weekly flushes of either urokinase (5000 units) or heparin (50 units). HC-survival analysis was determined by Cox regression. 100 patients were enrolled (urokinase=52; heparin=48) and treated for a mean of 8.5 weeks. No significant difference was observed in the incidence of HC-associated septicaemic events, which occurred in 8/52 in the urokinase group and 9/48 in the heparin group (actuarial incidence 20% versus 25%, P=0.50). Similarly, there was no differences in the incidence of exit site infections (urokinase=27/52 and heparin=28/48, P=0.122); HC-septic thromboses (urokinase=2/52 and heparin=4/48, P=0.34); lumen occlusion (urokinase=30/52 and heparin=30/48, P=0.681); or venous thrombosis (urokinase=8/52 and heparin=6/48, P=0.726). Overall, a high incidence of HC-related complications was seen in both groups; 40/52 in the urokinase group and 40/48 in the heparin group (actuarial incidence 80% versus 90%, P=0.367). Despite this only 18% of HC required early removal due to complications (urokinase=8, heparin=10). There was no difference in the incidence of complications in patients undergoing transplantation (n=68) compared with chemotherapy alone (n=32). Patients with haematological malignancies were more likely to have HC-related infective complications (P=0.006), and patients with solid tumours more likely to have venous thrombosis (P=0.027). The cumulative incidence of HC-related complications in this prospective study was higher than in previously reported series. Urokinase did not appear effective in reducing the frequency of these complications.

Anticoagulants↗
PubMed2001

Severe interstitial pneumonitis following high-dose cyclophosphamide, thiotepa and docetaxel: two case reports and a review of the literature.

The use of high-dose chemotherapy for metastatic breast cancer has been an area of recent interest and the role of such treatment in the management of metastatic breast cancer is still to be defined. Multiple studies have suggested that such treatment can be given with minimal morbidity and mortality. We describe two cases of life-threatening interstitial pneumonitis, following high-dose chemotherapy (HDT) with cyclophosphamide, thiotepa and docetaxel with stem cell rescue given for metastatic breast cancer. The available relevant literature is reviewed.

Adult↗
PubMed2001

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation.

Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-alpha was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis.

Adult↗
PubMed2001

Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: results of the Australian patients treated on phase II trials.

Bexarotene (Targretin, LGD1069) is a novel synthetic retinoid analogue that binds selectively to retinoid X receptors. We describe eight previously treated patients who entered phase II international multicentre studies examining the role of bexarotene in cutaneous T-cell lymphoma. Patients received either the oral formulation (n = 7) or the topical gel (n = 1). Of the seven patients who received 300 mg/m2 per day capsules, five (71%) achieved a partial response, with mean time to onset of response of 27 days (range, 20-29) with responses persisting for a mean of 92 days (range, 57-115). The single patient receiving the topical preparation (stage IB) remains in partial response at 31 months. The major toxicity with oral administration was hypertriglyceridaemia requiring therapy. Bexarotene capsules and gel are active and generally well-tolerated agents in patients with cutaneous T-cell lymphoma and studies examining its role in previously untreated patients or as part of combination therapy are warranted.

Administration, Oral↗
PubMed2001

High-dose therapy and autologous transplantation for lymphoma: The Peter MacCallum Cancer Institute experience.

BACKGROUND: High-dose therapy (HDT) with autologous bone marrow or blood cell transplantation for the treatment of lymphoma commenced at Peter MacCallum Cancer Institute in 1986. AIM: To examine the patient characteristics and outcomes of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) treated with HDT and autologous transplantation at our Institute in the first 10 years of the service (1986-95). METHODS: A retrospective analysis was performed examining patient characteristics, prior chemotherapy regimens, pretransplant disease status, HDT regimen, source of stem cells, time for haematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and progression-free survival (PFS). RESULTS: Sixty-seven patients with NHL were treated with an estimated 5-year OS rate of 44% (95% confidence interval (CI) 32-56%) and PFS rate of 34% (95% CI 21-44%). Factors independently predictive of an unfavourable PFS on multivariate analyses were presence of constitutional symptoms at transplant (P < 0.002) and chemotherapy-resistant disease at transplant (P = 0.02). Twenty-three patients with HD were treated with a 5-year predicted OS rate of 74% (95% CI 56-92%) and PFS rate of 57% (95% CI 36-77%). There was no difference in PFS for HD patients who relapsed either within 12 months of completion of front-line therapy or after this time (P= 0.5). The transplant-related mortality for the entire cohort was 17%, with a progressive decrease over time. CONCLUSION: HDT with autologous transplantation achieves durable PFS and OS in patients with lymphoma. Improved patient selection, therapy modifications according to prognostic factors and ongoing improvements in supportive care should improve outcomes further.

Adolescent↗