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PubMed1984

[Transplant conditioning and transplant size in heterotopic autologous spleen transplantation].

In an experimental study we compared two methods of preparing transplants in rabbits (n = 66): 4-5 splenic fragments with a thickness of 1 mm and graduated weight (5-800 mg) were attached onto the peritoneal peritoneum. Splenic homogenates with increasing weight (5-800 mg) were placed in 4-5 preformed pockets in the parietal peritoneum. At different postoperative intervals (maximum 42 days), a relaparotomy was performed. The regenerated splenic tissue was dissected, weighted and histologically examined. We found a linear correlation between pre- and postoperative weight. However, this correlation applies only to the homogenates with a weight of maximal 200 mg and to the fragments with a weight of maximal 300 mg. We have come to the conclusion that homogenates regenerate better than fragments.

Animals↗
PubMed2002

Intracellular Ca2+ regulation in hepatocytes under experimental transplantation conditions.

Under transplant conditions excessive accumulation of intracellular calcium ([Ca2+](i)) is considered to be a mediator of cell injury during ischaemia and re-oxygenation. To clarify this consideration as well as the necessity of calcium-free preservation solutions, we used a well-known in-vitro model. Furthermore, a new application to mimic clinical situation was established, and we evaluated the correlation between [Ca2+](i) change and cell survival in monolayers of isolated rat hepatocytes undergoing cold hypoxia in defined solutions and during re-oxygenation. [Ca2+](i) was measured in single cells by ratio imaging of Fura-2 fluorescence after various periods of cold hypoxia (ischaemia phase) in different preservation solutions [UW, HTK, EC and Krebs-Henseleit buffer (KH)] and following warm normoxic reperfusion (re-oxygenation phase) with KH. Cell survival was measured simultaneously by trypan-blue exclusion. Cell survival decreased, depending on preservation solution and preservation time. The partially tremendous [Ca2+](i) change under cold hypoxia did not correlate with the change in cell survival. For example, UW-stored cells showed a [Ca2+](i) loss from 280 nM to 56 nM, compared with KH-stored cells with a [Ca2+](i) increase of up to 445 nM. Our results indicate that [Ca2+](i) plays only a minor role in the pathomechanisms of hypoxic and re-oxygenation hepatocellular injury.

Animals↗
PubMed2004

High-dose chemotherapy using BEAM for tumor debulking without stem cell support followed by early allogeneic reduced intensity conditioning transplantation to induce a graft-versus-lymphoma effect in patients with high risk or refractory lymphoma.

In patients with refractory lymphoma, we tested the hypothesis that high-dose chemotherapy (BEAM) without stem cell support followed by a reduced intensity (RIC) allogeneic transplant with fludarabine and 2 Gy TBI 28 days later results in tumor debulking and establishment of a graft vs lymphoma effect, with acceptable toxicity. In a pilot protocol we treated 10 patients, 22-62 (median 47) years of age with high-risk or refractory Hodgkin's or non-Hodgkin's lymphoma. Donors were HLA identical siblings (eight) or unrelated volunteers. None died during the neutropenic phase after BEAM which lasted up to the RIC HSCT. The duration of neutropenia was 31-43 (median 36) days. All patients engrafted and nine achieved CR. All developed acute GvHD (median grade III) and all patients at risk developed chronic GvHD. Three patients died of GvHD. One relapsed and six patients are in continuous CR 10-32 (median 15) months after HSCT. This approach appears feasible and results in a high response rate. Neutropenia duration is of concern. It remains to be tested whether separation of debulking chemotherapy and induction of allogeneic effects confers an advantage.

Adolescent↗
PubMed1996

A more immunosuppressive pre-transplant conditioning may be required for Chinese patients with thalassaemia.

Bone marrow transplantation was performed on 14 Chinese patients with transfusion dependent thalassaemia major (n = 13) and haemoglobin H disease (n = 1). The donors were HLA identical siblings. The source of haematopoietic stem cells were from bone marrow (n = 13) and umbilical cord blood (n = 1). The pre-transplant conditioning regimens were (1) busulphan 14 mg/kg and cyclophosphamide 200 mg/kg in two patients; (2) busulphan 16 mg/kg, cyclophosphamide 200 mg/kg and anti-thymocyte globulin 110 mg/kg in five patients; (3) busulphan 16 mg/kg, cyclophosphamide 150 mg/kg and anti-thymocyte globulin 110 mg/kg in seven patients. Graft-versus-host disease prophylaxis was cyclosporin A and methotrexate. All patients engrafted and achieved stable haematopoiesis except the one who underwent the umbilical cord blood transplant, who had autologous marrow recovery. One patient who had stable engraftment rejected the marrow graft and developed aplastic anaemia 4 months after BMT. This patient had a second BMT but rejection recurred again. She eventually died of septicaemia. The other 12 patients were transfusion independent and disease free. The majority have gone back to school or work. Disease-free and actuarial survival probability were 85 and 93%, respectively with a median follow-up time of 30 months (13 to 42 months). Our data suggest that BMT from HLA identical siblings for transfusion dependent thalassaemia gives a high chance of cure with acceptable mortality and morbidity, and that a more immunosuppressive pre-transplant conditioning schedule may be required to prevent rejection.

Adolescent↗
PubMed2004

Cytopenia and hematopoietic recovery after low intensity conditioning transplants.

AIM: To compare hematopoietic reconstitution after low intensity conditioning transplants and standard allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively analyzed the kinetics of cytopenia of 50 consecutive patients treated with HSCT during a 60 day posttransplant period. Twenty four patients were treated with a low intensity regimen (Fludarabine, 2 Gy total body irradiation) and 26 patients with the standard conditioning regimen. Patients who received the low intensity HSCT were analyzed in two groups, patients with engraftment of donor hematopoiesis and those who rejected the graft. RESULTS: Patients treated with low intensity conditioning, regardless of its outcome, experienced significantly less severe cytopenia than the patients from the control group. Except for reticulocytes, the development of cytopenia was significantly slower in these patients, and the duration of severe cytopenia was significantly shorter. However, full neutrophil recovery (absolute neutrophil count >1.0 x 10(9)/L) took longer in patients with low intensity HSCT. CONCLUSIONS: The kinetics of cytopenia and hematopoietic recovery after low intensity conditioning HSCT significantly differ from standard HSCT. There is no difference in the initial hematopoietic recovery between patients with or without engraftment after low intensity conditioning. This indicates that the onset, severity, and duration of the cytopenia are influenced primarily by the intensity of the conditioning and by the immunosuppressive regimen after transplantation. Effects are more pronounced for neutrophils than for platelets and reticulocytes.

Adult↗
PubMed1999

Use of idarubicin in pre-transplant conditioning in children with high-risk acute leukaemia.

The major cause of treatment failure following allogeneic bone marrow transplantation for acute leukaemia is disease relapse. In an attempt to reduce post- transplant relapse in 33 children with high-risk acute leukaemia who received a related or unrelated bone marrow transplant, the pre-transplant conditioning regimen was intensified by the addition of idarubicin. Its toxicity and effects on survival were evaluated over a 57-month period. Toxicity, largely gastrointestinal, was increased but acceptable, and there was no specific regimen-related toxicity. Relapse rates were low (24%) in this high risk group, but mortality was increased in those receiving unrelated donor grafts, largely due to sepsis. Idarubicin does appear to have a role to play in the conditioning regimen of patients with high-risk acute leukaemia undergoing BMT, and may reduce relapse rates without increasing transplant-related mortality.

Acute Disease↗
PubMed2006

[Alterations in coagulation in patients during transplant conditioning regimen before allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the alterations in coagulation in patients during conditioning with modified busulfan plus cyclophosphamide (BU/CY) +/- antithymocyte globulin (ATG) regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT), and to assess the effect of ATG on coagulation system. METHODS: Thirty-five patients with various hematological malignancies undergoing allo-HSCT were assessed. Of them, 19 patients with HLA-matched sibling donors (group A) were conditioned with modified BU/CY regimen, 16 with HLA-mismatched family members or HLA-matched unrelated donors (group B) were conditioned with modified BU/CY + ATG regimen. Blood samples were collected before the beginning of conditioning till d + 1 after allo-HSCT. The following parameters were measured: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fg), antithrombin (AT), D-Dimer, fibrin degradation product (FDP), platelet (BPC), liver enzymes and bilirubin. FVIII: C, FIX: C, FXI: C and FXII: C in prolonged APTT blood samples were also determined. Clinical hemorrhagic symptoms were monitored. RESULTS: During conditioning, temporary lengthening of APTT, persistent rising in Fg and declining of BPC were observed in the two groups. Alterations of Fg and BPC were more significant in group B than in group A. Transient D-Dimer increase occurred only in group B on administration of ATG. Among intrinsic pathway coagulation factors, FXII: C and FXI: C were commonly decreased while APTT prolonged. No difference between the two groups was found with regard to PT, FDP, AT and liver parameters which remained in normal ranges. Most of patients in the two groups did not have overt bleeding manifestations. CONCLUSIONS: Modified BU/CY +/- ATG conditioning regimen can induce subclinical alterations in coagulation. The regimen containing ATG has more significant effect on coagulation parameters.

Adolescent↗
PubMed1991

Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens.

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.

Animals↗
PubMed1981

[Effect of different transplant conditions on lipid peroxidation in the transplant and the recipient's tissues].

This work analyses the change of LPO intensity in transplanted skin and in recipient tissue: in blood and skin adjoining the transplants during 27 days after auto- and homotransplantation. A conclusion is made that primary LPO strengthening of autotransplants and skin, adjoining the transplant during 9-14 days after transplantation, growing lesser, reaches the level of intact skin. Under homotransplantation the primary LPO strengthening not only reaches the initial level 9-14 days of the transplantation, but continues to increase. It was shown that the first maximum of LPO strengthening in the transplants (2-5 days after transplantation) were caused by ischemic lesions and the second maximum - by immunologic shifts.

Animals↗
PubMed1984

Investigations on the instability of drug sensitivity in dependence on culture and transplantation conditions in case of a human lung carcinoma.

Changes of biological properties, DNA-distribution patterns and drug sensitivity testing in vivo and in vitro after different culture and transplantation conditions in case of a human lung carcinoma are described. While DNA-distribution patterns of cells before any culture (OSC, TC 0) showing two clearly different aneuploid cell populations (DNA-index DI: 3.9 and 4.9), cells after 8 passages (TC 8) in vitro demonstrate only one cell population. These cells do not differ from double value (4C) of diploid cells (2C). DNA-distribution patterns of cells of solid tumors grown in nude mice (nu/nu 2089-1) show a cell population with DI 6.3. In line with these results, cells and tissues after different culture and transplantation conditions exhibit variable drug sensitivities. The lung carcinoma (OSC) shows clear reactions measured either by 3H-thymidine or 3H-deoxyuridine in the presence of Cyclophosphamide and Methotrexate. Adriblastin and 5-Fluorouracil did not show any effects after 48 hours treatment. Cultivated cells (TC 8) were sensitive against all antineoplastic drugs tested. Tumor tissue grown in nude mice (nu/nu 2089-1) shows the strongest effect after 5-Fluorouracil treatment both in vitro and in vivo. Selection of different cell population were discussed with regard to these findings.

Adenocarcinoma↗
PubMed2000

Melphalan/TBI is not more carcinogeneic than cyclophosphamide/TBI for transplant conditioning: follow-up of 725 patients from a single centre over a period of 26 years.

As there is concern regarding the high carcinogenic potential of melphalan (Mel), 725 patients with haematological malignancies who received allogeneic (n = 714) or syngeneic (n = 11) transplants over the last 26 years were followed-up to evaluate if melphalan was more likely to result in secondary malignant neoplasms (SMNs) than cyclophosphamide (Cy). Three hundred and ninety-five were treated with Cy/TBI and 330 with Mel/TBI. Twelve patients developed non-haematological SMN. Median time to develop a SMN was 7 years (range 2-17 years). Age-adjusted rate was significantly higher than in the general population (observed 12 expected 1.2, risk 10; P < 0.0001). The cumulative overall risk of developing a SMN at 2, 5, 10 and 15 years post transplant was 0.4% (95% CI 0.1-2.6%), 1.7% (95% CI 0.6-4.4%), 6.4% (95% CI 2.8-10.8%) and 6.6% (95% CI 3.4-12.4%), respectively. Even though age-adjusted rates were higher than the general population melphalan/TBI was not associated with higher age-adjusted risk than Cy/TBI (increased risk 7.9 vs 11.4; P = NS). The cumulative overall risk of SMNs was not different with CY/TBI or Mel/TBI (8/393 vs 4/363; 10 year risk 4.4%, 95% CI 1.8-10.6 vs 8.4%, 95% CI 2.9-22.9; P = NS). The risk was significantly higher with use of additional cranial or cranio-spinal irradiation (17.5% vs 2.7% at 10 years; P = 0.0241). Transplants for acute lymphatic leukaemia resulted in a higher incidence of SMNs than did transplants for other diseases (ALL: 17.4%, 95% CI 6.3-42.6%; other diseases: 3.4% (95% 1.3-8.5%, P = 0.0469). The risk of SMN for patients with chronic GVHD was 8.4% (95% CI 3.7-18.7%) as compared to 3.5% (95% CI 1-11.1%) for patients without chronic GVHD (P = NS). No factor was associated with independently increased risk in multivariate analysis. Use of melphalan and TBI for transplant conditioning does not appear to be associated with higher risk of second malignant neoplasms than cyclophosphamide and TBI.

Adolescent↗
PubMed1995

TNF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD.

TNF alpha levels were determined by ELISA in serum from 112 BMT patients during pre-transplant conditioning. Patients who developed post-transplant complications had significantly higher TNF alpha levels than those without complications (mean 620 pg/ml vs 440 pg/ml, P = 0.04). In particular this effect is associated with patients who developed grade II-IV acute GVHD (mean 960 pg/ml, P < 0.001) and chronic GVHD (mean 724 pg/ml, P = 0.001). High TNF alpha levels were the only statistically significant risk factor for acute GVHD. IL-1 beta and IL-6 levels were not correlated with TNF alpha levels or posttransplantation complications. In multivariate analysis of chronic GVHD, patient age > 17 years and CMV disease were the only statistically significant risk factors. Relapse was associated with low levels of TNF alpha during conditioning (mean 318 pg/ml, P = 0.02). In multivariate analysis, high risk disease was the only factor that correlated with relapse. Low risk patients had significantly higher levels than high risk patients (551 vs 377, P= 0.04). CML and MDS patients had higher TNF alpha levels than acute leukemia patients. There was no difference in TNF alpha levels between patients conditioned with BU/CY and CY/TBI. We conclude that determination of TNF alpha levels during conditioning may be useful in the prediction of acute GVHD.

Acute Disease↗
PubMed1998

Allogeneic peripheral blood progenitor cell transplantation conditioned with anti-thymocyte globulin for treatment of graft failure after allogeneic bone marrow transplantation.

A 43-year-old female with AML-M1 developed late graft failure 4 months after her first allogeneic bone marrow transplant. The patient then underwent a second transplant with peripheral blood progenitor cells obtained from the same HLA-identical brother. The donor peripheral blood progenitor cells were mobilized with granulocyte colony-stimulating factor (10 micrograms/kg daily s.c. for 6 days). The patient received horse anti-thymocyte globulin alone (15 mg/kg per day for 5 days) as the conditioning regimen. Rapid hematopoietic recovery followed a sustained engraftment. The time to reach 0.5 x 10(9)/l neutrophils and 25 x 10(9)/l platelets was 10 and 12 days, respectively. Cytogenetic analysis of bone marrow performed on day +20 demonstrated a 46XY karyotype of donor origin. There was no acute graft-versus-host disease. The patient remains in complete remission with a karnofsky score of 90% 5 months after peripheral blood progenitor cell transplantation. To treat graft failure after allogeneic bone marrow transplantation, allogeneic peripheral blood progenitor cell transplantation conditioned with anti-thymocyte globulin alone should be considered as a feasible alternative to marrow transplant.

Adult↗
PubMed2001

Bone marrow transplant conditioning intensified with liposomal clodronate to eliminate residual host antigen presenting cells fails to ameliorate GVHD and increases PERI-BMT mortality.

BACKGROUND: Graft versus host disease (GVHD) mediated by allogeneic donor T cells may be initiated and/or exacerbated by residual host antigen presenting cells (APC) which survive the transplant conditioning regimen. We examined whether the depletion of hepatic and splenic APC could reduce the severity of hepatic GVHD after bone marrow transplantation (BMT). METHODS: Recipient mice were depleted for hepatic and splenic phagocytic APCs by i.v. injection of clodronate- (dichloromethylene diphosphonate) containing liposomes before fully allogeneic or MHC-matched, minor Ag-mismatched BMT. Severity of hepatic GVHD was scored on histological sections 2, 3, 4, or 9 weeks after BMT. RESULTS: No differences in the severity of GVHD were observed between APC-depleted mice and control mice. APC-depleted mice had increased peritransplant mortality due to sepsis. Bacterial clearance assays showed that APC-depleted mice were unable to efficiently clear bacteria, although nondepleted, transplanted mice were able to clear bacteria as quickly as naive control mice. CONCLUSIONS: Residual host phagocytic APC do not appear to play a role in the induction of GVHD after BMT. They are, however, essential for prevention of sepsis in the transplant host.

Animals↗
PubMed2002

Increasing use of reduced intensity conditioning transplants: report of the 2001 EBMT activity survey.

Since 1990, the EBMT has annually collected numbers of HSCT by disease indication, donor type and stem cell source. The 2001 survey concentrates on the use of reduced intensity conditioning (RIC) transplants and its dissemination in Europe. In 2001, there were 19576 HSCT for new patients, 6413 with allogeneic HSCT (33%), 13163 with autologous HSCT (67%) and 3256 additional re- or multiple transplants, 868 (667/201) allogeneic and 2658 (537/2121) autologous, collected from 596 centers in 35 European countries. The main indications in 2001 were leukemias (32%; 73% of them allogeneic); lymphomas (53%; 92% of them autologous); solid tumors (11%; 93% of them autologous) and non-malignant disorders (4%; 90% of them allogeneic). Compared to 2000, there was a drop in allogeneic HSCT of over 20% for chronic myeloid leukemia and an increase of 2% in autologous HSCT. A total of 1759 or 27% of allogeneic transplants were reported as RIC HSCT. These have risen in number in 3 years from <1% in 1998. There are wide variations from 0 to 71% RIC HSCT in European countries with no obvious explanation. These data document the current status of blood and marrow transplantation in Europe and indicate a marked change towards RIC HSCT in allogeneic transplantation.

Bone Marrow Transplantation↗
PubMed2004

Treatment of hematological malignancies with allogeneic nonmyeloablative stem cell transplantation: conditioning regimens with fludarabine.

Allogeneic stem cell transplantation (alloSCT) is an accepted therapeutic option for various hematological malignancies. For many years, alloSCT was based on the concept that a myeloablative dose of chemoradiotherapy was necessary to allow successful donor stem cell engraftment. These high-dose regimens cause considerable toxicity in graft recipients and even the most intensive conditioning regimens do not reliably eliminate all malignant cells. During the last decade, it became clear that the curative potential of alloSCT was not solely due to the conditioning regimen but also to an immune response of donor cells against the malignancy, termed the graft-versus-leukemia (GVL) effect. The increasing evidence that the GVL effect is essential for the eradication of host tumor cells has led to the development of a new concept in alloSCT: the use of reduced intensity, nonmyeloablative conditioning regimens that allow exploitation of the GVL effect without the toxicity of myeloablative therapy. The purine analog fludarabine is immunosuppressive and has activity against many hematological malignancies. The introduction of nonmyeloablative fludarabine-based conditioning regimens has facilitated alloSCT, while limiting regimen-related morbidity and mortality in patients with susceptible hematological malignancies. This potentially curative approach extends the use of alloSCT to older patients and to those with comorbidities that preclude high-dose chemoradiotherapy. The purpose of this review is to summarize the results obtained with fludarabine-based nonmyeloablative conditioning regimens and alloSCT in patients with malignant hematological disorders.

Hematologic Neoplasms↗
PubMed2001

CD34+-selected autologous peripheral blood stem cell transplantation conditioned with total body irradiation for malignant lymphoma: increased risk of infectious complications.

Although high-dose chemotherapy with autologous peripheral blood stem cell transplantation (autoPBSCT) has been shown or confirmed to be an effective treatment for high-risk and relapsed non-Hodgkin's lymphoma (NHL), relapse after autoPBSCT remains a serious problem. In a clinical trial to overcome relapse, we adopted a treatment plan in which PBSCs purified in vitro to CD34+ cells to deplete tumor cells (CD34+ autoPBSCT), total body irradiation (TBI) of 1200 cGy, and melphalan, 180 mg/m2, were used as a preconditioning regimen. Eighteen patients with relapsed or high-risk NHL participated in the study. This study compared the incidence of complications following CD34+ autoPBSCT preconditioned with the TBI regimen (n = 10): the TBI group; CD34+ autoPBSCT with the non-TBI regimen (n = 8): the non-TBI group; and unselected autoPBSCT with the non-TBI regimen (n = 19): the unselected autoPBSCT control group. After day 30 posttransplantation, 6 of 10 patients treated with the TBI regimen developed 11 infectious complications in total, compared with only 1 of 8 patients treated with the non-TBI regimen and 4 of 19 patients given unselected autoPBSCT. Two fatal complications occurred in the TBI group, but none occurred in the other 2 groups. The CD4+ lymphocyte count at 1 month posttransplantation was significantly lower in the TBI group than in the unselected autoPBSCT group. These findings suggest that the addition of TBI to the preconditioning regimen for CD34+ autoPBSCT is associated with an increased incidence of severe infectious complications after transplantation.

Adult↗
PubMed2006

Optimization of allogeneic transplant conditioning: not the time for dogma.

Numerous reduced-intensity conditioning regimens for allogeneic hematopoietic cell transplantation are currently being explored, primarily in older patients and in individuals with comorbid conditions who are not eligible for conventional myeloablative conditioning regimens. There is agreement that these approaches have reduced early transplant-related (non-relapse) toxicity and mortality. It is unclear, however, whether these strategies improve long-term survival. Furthermore, as most trials with reduced-intensity regimens have enrolled older patients and patients with comorbid conditions, it is not appropriate to compare the results of these trials to those obtained with more conventional approaches. It remains to be determined whether younger patients, and patients without comorbid conditions, will derive significant long-term benefits from reduced-intensity regimens when compared to conventional strategies. It may be that the different approaches are complementary and in the end will preferentially serve specific patient populations based on age, comorbid conditions and malignancy type. To determine the role of reduced-intensity approaches, controlled prospective trials are needed, with enrolled patients being stratified according to comorbid conditions, disease characteristics, pre-transplant therapy and source of stem cells, at a minimum.

Hematopoietic Stem Cell Transplantation↗