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D Bunjes

Publications and source records attributed to D Bunjes.

At least 37 records · Page 2Linked to original sources

Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Patients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29. 9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs >/= 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs >/= 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.

Actuarial Analysis↗

Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND: There is increasing pressure for the recognition and replication of good clinical practice. We undertook a study to assess the variability in outcome of allogeneic bone-marrow transplantation among major European centres. METHODS: We studied 13 centres, including 522 patients (aged 16-55 years), which had undertaken more than 30 bone-marrow transplantations between Jan 1, 1987, and Dec 31, 1995, for acute myeloid leukaemia in first complete remission. We undertook a (global) multivariate analysis of all factors known previously to influence outcome and a stratified analysis that initially defined, by multivariate analysis, significant variables in this study and then used a proportional-hazard model including centres. FINDINGS: The overall results at 3 years were 57% (95% CI 53-61) for leukaemia-free survival (LFS), 23% (19-27) for relapse incidence (RI), and 26% (22-30) for treatment-related mortality (TRM) with a range for centres of 36-75%, 10-37%, and 8-54%, respectively. Both methods of analysis showed the centre effect to be highly significant for LFS and TRM, but not for RI. Variables associated with a significantly poor outcome were age over 43 years (p=0.01), time from diagnosis to first complete remission longer than 65 days (p=0.02), and centre (p=0.013) for LFS, and age over 43 years (p=0.023), time from first complete remission to transplantation of longer than 93 days (p=0.03), and centre (p=0.001) for TRM. Moreover, different centres had different prognostic criteria for good-risk or bad-risk patients indicating that risk factors do not have the same impact in each individual centre. INTERPRETATION: The outcome of bone-marrow transplantation for acute myeloid leukaemia in first complete remission is influenced by the centre in which the procedure is done, even with adjustment for known prognostic risk factors. Significant prognostic factors vary among centres, which means that the relative risk is not the same in each individual centre. However, centres may treat populations with different risks of as yet unidentified prognostic factors. Experience may partly account for the difference in outcome among centres.

Adolescent↗

CD34+ selected cells in mismatched stem cell transplantation: a single centre experience of haploidentical peripheral blood stem cell transplantation.

Over the past 3 years we have performed 10 haploidentical peripheral blood stem cell transplants in patients with incurable haematological malignancies and no prospect of a matched unrelated donor within an adequate time period. Conditioning consisted of ATG, TBI, thiotepa, cyclophosphamide and additional radioimmunotherapy in five patients. All patients received G-CSF mobilized peripheral blood stem cell grafts. GVHD prophylaxis consisted of T cell depletion by CD34+ selection; no post-transplant immunosuppression was given in nine patients. Stable engraftment was achieved in nine patients; one case of acute graft rejection was observed. Seven patients developed grade I acute GVHD, and six patients have developed chronic GVHD. Infections were the most significant clinical problem post transplant. Two patients have suffered a relapse of their disease and two further patients have died of transplant-related complications. After a median follow-up of 13 months (range 5-37 months) six patients are surviving in remission. We conclude that haploidentical PBSCT is a reasonable alternative to a MUD transplant.

Adult↗

Non-infectious lung complications are closely associated with chronic graft-versus-host disease: a single center study of incidence, risk factors and outcome.

Non-infectious lung complications (NILC) are frequent, influencing morbidity and mortality of patients after allogeneic BMT. Although the term NILC encompasses a number of different entities, an association with GVHD has been noted for almost all of them. Our study was directed towards assessing the incidence and risk factors for developing NILC, as well as the response to treatment and long-term outcome. Forty (14.7%) out of 272 patients surviving for more than 3 months after allogeneic BMT, developed lung complications fulfilling the criteria for NILC. The evaluation was based on clinical investigation, radiologic imaging, lung function tests, broncho-alveolar lavage and biopsies. Risk factors were assessed by univariate and multiple statistical regression models, where chronic GVHD proved to be the only significant risk factor for the development of NILC (P = 0.011). In three patients NILC developed in direct association with donor lymphocyte infusions. The majority of patients responded well to treatment with corticosteroids and immunosuppressive drugs. NILC had no adverse effect on survival. The frequency of NILC was low in autologous (5%) as compared with allogeneic transplants (14.7%) but this difference was not statistically significant. Bone Marrow Transplantation (2000) 25, 1263-1268.

Bone Marrow Transplantation↗

CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 microg/ml and 120 microg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection.

Alemtuzumab↗

Prospective screening by a panfungal polymerase chain reaction assay in patients at risk for fungal infections: implications for the management of febrile neutropenia.

Invasive fungal infections are a major cause of mortality in neutropenic cancer patients. To determine whether a polymerase chain reaction (PCR)-based assay enabled the identification of patients at risk for invasive fungal infections, a prospective monitoring once per week was performed during 92 neutropenic episodes in patients receiving chemotherapy for acute leukaemia or high-dose therapy followed by allogeneic or autologous stem cell transplantation, with the investigators blinded to clinical and microbiological data. PCR positivity was documented in 34 out of 92 risk episodes. All patients developing proven invasive fungal infection were found PCR positive, and PCR was found to be the earliest indicator of invasive fungal infection preceding clinical evidence by a mean of 5.75 d (range 0-14 d). In febrile neutropenic patients without a prior history of invasive fungal infection, a sensitivity of 100% and a specificity of 73% of the PCR assay for the development of proven or probable invasive fungal infection was documented. In conclusion, panfungal PCR performed prospectively once a week enabled the identification of patients at high risk for invasive fungal infections.

Acute Disease↗

Severe Chlamydia pneumoniae infection in patients with neutropenia: case reports and literature review.

Three cases of life-threatening C. pneumoniae infection in patients with acute leukemia and treatment-induced neutropenia are described. Diagnosis was made on the basis of the detection of C. pneumoniae-DNA, complemented by serology. The role of the widely distributed respiratory tract pathogen C. pneumoniae in febrile neutropenia is poorly understood, and studies are needed to estimate the frequency of severe pulmonary infection caused by this agent in patients with neutropenia.

Adolescent↗

Radioimmunotherapy for the intensification of conditioning before stem cell transplantation: differences in dosimetry and biokinetics of 188Re- and 99mTc-labeled anti-NCA-95 MAbs.

UNLABELLED: A new concept is the intensification of preparative regimens for patients with advanced leukemia using monoclonal antibodies (MAbs) with an affinity for beta emitter-labeled bone marrow. 188Re is a high-energy beta emitter that has therapeutic promise. Our first aim was to clarify whether the therapeutic application of 188Re-MAb against nonspecific cross-reacting antigen 95 (NCA-95) can be predicted from biokinetic data derived from 99mTc-labeled NCA-95. Our second aim was to show that a radiation absorbed dose of > or =12 Gy in the bone marrow can be achieved using 188Re-MAb. METHODS: Dosimetric data were obtained for both radiotracers from multiple planar whole-body scans (double-head gamma camera), blood samples, and urine measurements from 12 patients with advanced leukemia. Radiation absorbed doses were calculated using MIRDOSE 3 software. RESULTS: Radiation absorbed doses to bone marrow, liver, spleen, lung, and kidney were 2.24, 0.50, 1.93, 0.05, and 0.90 mGy/MBq, respectively, using 99mTc-MAb and 1.45, 0.43, 1.32, 0.07, and 0.71 mGy/MBq, respectively, using 188Re-MAb. These differences were statistically significant for bone marrow, spleen, and kidney. The main differences were less accumulation of 188Re-MAb in bone marrow (31%+/-13% compared with 52%+/-13%) and faster elimination through urine (25%+/-3% compared with 15%+/-5% after 24 h). On the basis of these data, a mean marrow dose of 14+/-7 Gy was achieved in 12 patients suffering from leukemia after application of approximately 10+/-2 GBq 188Re-MAb. CONCLUSION: Myeloablative radiation absorbed doses can easily be achieved using 188Re-MAb. 99mTc- and 188Re-MAb showed similar whole-body distributions. However, direct prediction of radiation absorbed doses from the 99mTc-MAb, assuming identical biokinetic behavior, is not valid for the 188Re-MAb in a single patient. Therefore, individual dosimetry using 188Re-MAb is needed to calculate therapeutic activity.

Adult↗

Preparation and evaluation of the rhenium-188-labelled anti-NCA antigen monoclonal antibody BW 250/183 for radioimmunotherapy of leukaemia.

Anti-NCA antigen antibody BW 250/183 (Anti-Granulocyte) localizes more than 50% of injected antibody dose to the bone marrow. Therefore, this antibody is promising for adjuvant conditioning radioimmunotherapy of bone marrow before bone marrow transplantation. To examine its potential use for radioimmunotherapy, we developed an efficient and reproducible technical protocol for labelling anti-NCA antigen antibody BW 250/183 with generator-produced rhenium-188, aiming at both high radiochemical yield and high specific activity. (188)Re-labelled BW 250/183 antibody was used in 12 patients with advanced leukaemia. Labelling of BW 250/183 with (188)Re was accomplished by the direct radiolabelling method using tris-(2-carboxyethyl) phosphine (TCEP) as the reducing agent. Twelve patients with recurrent acute or chronic leukaemia were treated with activities of 6.5-12.4 GBq of (188)Re-labelled BW 250/183. Standard gamma camera scintigraphy was used to evaluate the biodistribution, and a region of interest analysis together with the MIRDOSE 3.1 software was applied to determine the radiation doses to relevant tissues. The (188)Re-BW 250/183 antibody was labelled in high radiochemical yield, with high radiochemical purity (94%+/-3%) and specific activity (5.55-7.4 GBq/mg) within 1 h. The preliminary biodistribution studies showed persistent uptake of (188)Re-BW 250/183 in bone marrow. The radiation absorbed doses (mGy/MBq) delivered to the total body, red marrow, liver, spleen and kidneys were 0.13+/-0.02, 1.45+/-0.71, 0.43+/-0.21, 1.32+/-0.99 and 0.71+/-0. 17, respectively. TCEP reduction enabled the direct, fast and effective labelling of the monoclonal antibody BW 250/183 with (188)Re. Preliminary clinical results suggest delivery of a significant radiation dose to bone marrow and thus the potential for adjuvant conditioning therapy before BMT.

Adolescent↗

Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients.

AML1/MTG8 was quantified relative to the expression of the GAPDH housekeeping gene by real-time RT-PCR in 22 patients with t(8;21)-positive acute myeloblastic leukaemia (AML) at initial diagnosis and in seven of these patients also during/after chemotherapy and allogeneic bone marrow transplantation. Real-time PCR was able to specifically detect and quantify AML1/MTG8 over a 5 log range. The detection limit for t(8;21)-positive cells was a dilution of 1:105. The AML1/MTG8 expression varied considerably among the 22 AML patients at intial diagnosis with a ratio AML1/MTG8:GAPDH of 0.5135+/-0.536 (range 0.1-2.14, median 0.318). In six patients with t(8;21)-positive AML a marked decline of AML1/MTG8 could be induced by chemotherapy. These patients are in ongoing complete haematological remission (CR) with a constant low-level AML1/MTG8 expression. In another patient a rapid rise of AML1/MTG8 transcripts could be detected in CR after allogeneic bone marrow transplantation and the patient relapsed 10 weeks later. In conclusion, real-time RT-PCR is a suitable approach for the quantification of AML1/MTG8 transcripts in the monitoring of AML patients with t(8;21) during/after chemotherapy and can provide data of prognostic relevance.

Chromosomes, Human, Pair 21↗

Comparison of T-cell-depleted BMT and PBPCT with respect to chimerism, graft rejection, and leukemic relapse.

Chimerism analysis by DNA-based methods is a valuable diagnostic tool for monitoring engraftment and leukemic relapse after allogeneic BMT or PBPC transplantation (PBPCT). We investigated the chimerism after T-cell-depleted BMT (n = 32) in comparison with T-cell-depleted PBPCT (n = 39). BM grafts were T-cell depleted using the Campath-IgM antibody plus complement. For T-cell depletion of the PBPC grafts, a selection of CD34+ cells with or without a subsequent CD2/3 depletion was performed. In all patients, the T-cell dose of the transplant was < 10(6)/kg body weight. Between day 13 and day 120 after transplantation, chimerism analysis was done by RFLP or amplified fragment length polymorphism (PCR-AFLP), with a detection limit of 1%-5% recipient cells. In the BMT group, 8 of 32 (25%) patients showed a mixed chimerism, but only one graft rejection and no leukemic relapse occurred after a median follow-up of 41 (3-84) months. All patients with PBPCT revealed a complete chimerism of their granulocytes, and 38 of 39 patients showed complete chimerism of their lymphocytes. Follow-up time in these patients is 7 (2-21) months, with no graft rejection and two leukemic relapses. G-CSF-mobilized PBPC are superior to BM cells for full engraftment even after T-cell-depleted transplantation. The more relevant factor for developing complete chimerism seems to be the quantity and possibly the quality of the stem cells rather than the residual T-cell load of the graft. However, a mixed chimerism of the lymphocytes early after transplantation does not predict a higher rate of graft rejection or leukemic relapse.

Adult↗

Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P <.001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P <.001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P =.04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v 52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.

Alemtuzumab↗

Chemotherapy-induced mobilization of karyotypically normal PBSC for autografting in CML.

High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a new and interesting therapeutic option for CML patients not eligible for allogeneic transplantation. We investigated the feasibility and toxicity of this approach in 57 patients with Ph-positive CML. For mobilization of Ph-negative PBSC, patients were treated either with '5 + 2/7 + 3'- type chemotherapy or with 'mini-ICE/ICE' chemotherapy followed by administration of G-CSF. Fourteen patients were in early chronic phase, 30 patients in late chronic phase and 13 patients in accelerated phase (AP) or blast crisis (BC). Cytogenetic responses in the PBSC harvests were dependent on both disease stage and type of chemotherapy: in late chronic phase and AP/BC, a complete or major cytogenetic response could be obtained in nine out of 13 patients treated with 'mini-ICE/ICE' but only in three out of 23 patients treated with '5 + 2/7 + 3' chemotherapy. However, in early chronic phase a Ph-negative autograft could be obtained in three out of eight patients upon mobilization with '5 + 2' chemotherapy. Thirty-one patients underwent PBSC transplantation and all of them successfully engrafted. Post-transplant cytogenetic analysis was available on 21 cases, of whom seven achieved a complete or major cytogenetic response, with two minor cytogenetic remissions. One patient (1/57) in blast crisis died during mobilization therapy (1.8%). Transplantation related mortality was 0%. This study demonstrates that mobilization of Ph-negative PBSC after myelosuppressive chemotherapy is feasible in CML patients and is associated with acceptable toxicity. Autologous transplantation of in vivo purged PBSC is a safe procedure with rapid and complete hematopietic recovery.

Adult↗

Successful adoptive immunotherapy for relapse of AML 9 years after T-cell-depleted BMT.

Relapse is one of the main problems which can occur following allogeneic transplantation for haematological malignancies. In this situation the enhancement of the graft-versus-leukaemia effect by transfusion of donor buffy coats with or without cytokines may lead to complete remission especially in myeloid leukaemias. FISH (fluorescence in situ hybridization) is a sensitive method to monitor chimaerism in gender-different transplantation. We report a case of successful buffy coat transfer therapy > 9 years after bone marrow transplantation. This is the longest interval reported, to our knowledge, between transplantation to relapse, which was treated by adoptive immunotherapy. Complete donor chimaerism was confirmed by FISH.

Adult↗

Chronic myeloid leukemia in accelerated phase: treatment results with conventional chemotherapy and allogeneic bone marrow transplantation in 96 patients.

The treatment results of 96 patients with Philadelphia-positive chronic myeloid leukemia (CML) in accelerated phase (AP) were reviewed retrospectively. Treatment of AP consisted of allogeneic bone marrow transplantation in 20 (14 related and 6 unrelated donors) or conventional chemotherapy (CC) in 76 patients. Three main treatment strategies were followed in the CC group: continuation (group A) or dose escalation (group B) of chronic phase therapy or change of chronic phase therapy to hydroxyurea (group C). Median survival was 7.0 months in group A (range 1.8-110), in group B 8.3 months (range 0.9-40) and in group C 9.6 months (range 1.5-47.6), p=0.89. Survival in CC was dependent on response to therapy as the achievement of a second chronic phase was significantly associated (p<0.001) with a longer median survival (21 months) compared with stable accelerated phase disease (11 months) or treatment failure (5 months). Median survival in the BMT group was 16.7 months (range 5-77), the 5-yr probability of relapse was 25% and the 5-yr disease-free survival was 36%. For patients <55 yr median survival after BMT was significantly prolonged compared with median survival after CC (n=45, 8.3 months, p=0.008). After developing criteria of AP, median survival in our analysis has been less than 1 yr. The results of conventional chemotherapy in the treatment of accelerated phase CML are disappointing. If a suitable donor is available allogeneic BMT should be performed without delay in patients with AP.

Adolescent↗

Mobilization and collection of allogeneic peripheral blood progenitor cells for transplantation.

A median dose of 11 (6-17) microg G-CSF per kg and day was given to 96 (49 female, 47 male) healthy family donors in order to mobilize and to collect peripheral blood progenitor cells (PBPC) for allogeneic transplantation. Donor age was 36 (17-76) years. The leukocytes of the donors increased to 46 (12-115) x 10(9)/l on days 4-6 of G-CSF treatment with a median of 71 (2-657) CD34+ cells per microl, respectively. Female and older donors seem to have a lower response to G-CSF. About 32% of the donors suffered from side-effects of G-CSF requiring analgetics. A total of 197 stem cell aphereses were performed using the COBE Spectra cell separator. Median apheresis time was 225 (118-300) min processing 11.8 (5.7-20) l blood, collecting 5.3 (1.7-14.9) x 10(10) nucleated cells and containing 0.7 (0.1-3.7)% CD34+ cells. Severe citrate toxicity occurred in 5% of the donors. Retransfusion of autologous platelets post apheresis was necessary in 16% of the donors because of a platelet count <80 x 10(9)/l. An insufficient number of stem cells was collected in four female donors due to a very poor response to G-CSF. In conclusion, the collection of allogeneic G-CSF-mobilized PBPC is safe and effective. One or two aphereses were sufficient in 91% of the donors to achieve >4 x 10(6) CD34+ cells per kg. In 4% of the donors an additional bone marrow harvest or the use of an alternative donor was necessary because of a poor mobilization.

Adolescent↗

German consensus on immunogenetic donor search for transplantation of allogeneic bone marrow and peripheral blood stem cells.

In Germany allotransplantation of bone marrow or peripheral blood stem cells is presently performed by 34 different teams operating more or less independently. Thus, strategies of immunogenetic donor search, use of the various tissue typing techniques and policy on acceptable HLA mismatches in related and unrelated settings may vary considerably from one transplant centre to another. This paper summarises the results of the first German consensus meeting on immunogenetic donor search for bone marrow/peripheral blood stem cell grafting. The main goal of the participating transplant physicians and immunogeneticists was to define national standards for the above issues.

Bone Marrow Transplantation↗