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PubMed2001

Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. I. The roles of individual components of a transplantation conditioning regimen and of pig peripheral blood progenitor cells.

BACKGROUND: The induction of tolerance to pig antigens in primates may facilitate the development of successful clinical xenotransplantation protocols. The infusion of mobilized porcine peripheral blood leukocytes (PBPCs, comprised of approximately 2% peripheral blood progenitor cells) into splenectomized preconditioned baboons, intended to induce mixed hematopoietic cell chimerism, however, results in a severe thrombotic microangiopathy (TM) that includes pronounced thrombocytopenia. Because the mechanisms responsible for this phenomenon are unclear, we have explored the effects of individual components of the conditioning regimen, of therapeutic adjuncts, and of PBPCs on platelet aggregation. METHODS: Groups of splenectomized baboons (n = at least 2 in each group) were treated with single components of the conditioning regimen--whole body irradiation (WBI), antithymocyte globulin (ATG), extracorporeal immunoadsorption (EI), mycophenolate mofetil (MMF), anti-CD40L monoclonal antibody (mAb), cobra venom factor (CVF), pig hematopoietic growth factors (interleukin-3 (pIL3) and stem cell factor (pSCF))--or with potential adjuncts, prostacyclin (PGI2), heparin, methylprednisolone, and eptifibatide (a GPIIb/IIIa antagonist). Blood samples were collected and platelet-rich plasma (PRP) was prepared. Using light transmission aggregometry, the extent of aggregation induced by platelet agonists (thrombin, adenosine diphosphate (ADP), collagen, ristocetin, and arachidonic acid) was determined in vitro. PRP was also prepared from untreated baboons, PBPCs were added, and platelet aggregation was measured in the absence of exogenous platelet agonists. RESULTS: WBI, ATG, MMF, anti-CD40L mAb, CVF, pIL3, pSCF, and PGI2 had no effect on purified baboon platelet aggregation profiles in vitro. Eptifibatide markedly inhibited platelet aggregation induced by all standard agonists. EI or heparin inhibited thrombin-induced platelet aggregation, and methylprednisolone inhibited ADP-induced aggregation to some extent. In vitro addition of PBPCs to PRP stimulated platelet aggregation in the absence of any agonists. Prior treatment of baboons with eptifibatide, however, inhibited this effect by 70% to 80%. CONCLUSIONS: Aggregation of baboon platelets and TM is directly induced by PBPCs, but not by individual components of the conditioning regimen. GPIIb/IIIa antagonists, such as eptifibatide, interfere directly with xenogeneic PBPC-platelet interactions and may further ameliorate TM in the pig-to-primate model.

Animals↗
PubMed2004

Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide.

Long-term data on lung function after bone marrow transplantation (BMT) are inconclusive. Previously, a persistent reduction in gas transfer 1 yr after allogeneic BMT with busulphan and cyclophosphamide conditioning was reported by the current authors. In the present study this reduction was examined to see if it was permanent, transient or progressive. Prospectively, 43 consecutive adult patients with malignant blood disorders undertook lung function measurements prior to BMT, at 3 month intervals during the 1st yr after BMT and finally after 5 yrs. Mean baseline lung function values were >90% predicted. Within the 1st yr after BMT a transient decline in lung volumes and a persistent reduction in gas transfer were observed. After 5 yrs, baseline values were restored for all variables, except in four patients who developed obliterative bronchiolitis. Acute leukaemia and smoking were independently associated with gas transfer reductions at baseline and during the 1st yr after BMT. Allogeneic bone marrow transplantation with busulphan and cyclophosphamide conditioning was associated with a reduction in gas transfer 1 yr after bone marrow transplantation but baseline values were usually restored after 5 yrs. Since recovery may be gradual and slow, an observation period >1 yr is required before drawing conclusions concerning the development of a permanent reduction in lung function after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide.

Adolescent↗
PubMed2000

Is there a best transplant conditioning regimen for acute myeloid leukemia?

The outcome of marrow transplantation is largely determined by the effectiveness of the transplant preparative regimen. Nonetheless, there have been startlingly few randomized trials attempting to identify optimal regimens for specific conditions and, at present, no single approach has emerged as superior for the treatment of acute myeloid leukemia (AML) in the few trials that have been performed. Newer approaches that appear encouraging in phase II studies include substituting etoposide for cyclophosphamide, adding thiotepa to the traditional cyclophosphamide plus total body irradiation combination in the setting of T cell depletion, and using antibody-based targeted radiotherapy as part of the transplant regimen. The ability to obtain allogeneic engraftment with nonablative regimens may open the door to additional innovative approaches, combining very specific antileukemia therapy with relatively nontoxic measures to ensure engraftment.

Acute Disease↗
PubMed2004

The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns over the use of total-body irradiation in systemic sclerosis.

Hematopoietic stem cell transplantation (HSCT) is becoming an increasingly recognized indication for treatment of autoimmune diseases and severe immune-mediated disorders. However, multicenter registry data have demonstrated higher than anticipated early toxicity, approximately 10% for autoimmune diseases in general, and 20-27% for diffuse systemic sclerosis (scleroderma). If uncorrected, this high treatment-related mortality will hinder development of stem cell therapy for immune-mediated diseases. In order to develop safer regimens, we address some pitfalls and concepts involved in design and selection of conditioning regimens for autoimmune diseases in general, and because it is associated with the highest regimen-related toxicity, scleroderma in specific.

Autoimmune Diseases↗
PubMed2005

The impact of donor factors on primary non-engraftment in recipients of reduced intensity conditioned transplants from unrelated donors.

BACKGROUND AND OBJECTIVES: Primary graft failure is a serious complication following hematopoietic cell transplants, particularly when using unrelated donors. We analyzed factors affecting primary graft failure in recipients of hematopoietic cell transplants from unrelated donors, which were performed using reduced intensity conditioning. DESIGN AND METHODS: This was a retrospective analysis of 144 patients whose transplants took place between March 1998 and October 2004. The data were analyzed in January 2005. RESULTS: The median age of the patients was 51 years. The diagnoses were varied. Conditioning regimens were fludarabine, melphalan, campath (n=80), fludarabine, busulphan, campath (n=38), fludarabine, BEAM, campath (n=9) and other (n=17). The donor was 10/10 allele matched in 95/144 (66%) cases; 94 donated bone marrow and 50 peripheral blood stem cells. The 3-year probability of overall survival was 43%. The median follow-up was 724 days (range: 91-1651 days). Of evaluable patients, 7/140 (5%) failed to achieve myeloid engraftment. Primary graft failure was significantly associated with the use of a mismatched donor (6/47,13% versus 1/93, 1%, p=0.006), as well as: bone marrow as the source of stem cells (p=0.046), chronic myeloid leukemia compared to other diagnoses (p=0.022), and a female rather than a male donor (p=0.019). In multivariate analysis chronic myeloid leukemia, HLA mismatched and/or female donors remained significantly associated with primary graft failure. Single HLA mismatches were tolerated, however in multiply mismatched grafts, overall survival was worse (p=0.005); transplanted-related mortality (p=0.005) and chronic graft-versus-host disease (p=0.025) were increased. INTERPRETATION AND CONCLUSIONS: These data have implications for the choice of donor and stem cell source in transplants performed using reduced intensity conditioning regimens, suggesting that the use of bone marrow, female donors and HLA-mismatched grafts increase the risk of primary graft failure, and should be avoided in certain situations.

Adolescent↗
PubMed2006

Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Adult↗
PubMed1996

Interstitial pneumonitis following autologous bone-marrow transplantation conditioned with cyclophosphamide and total-body irradiation.

PURPOSE: To assess the influence of different total-body irradiation (TBI) regimens on interstitial pneumonitis (IP), we retrospectively analyzed our clinical data concerning an homogeneous group of patients conditioned with cyclophosphamide (CY) alone and single-dose or fractionated TBI before autologous bone-marrow transplantation (ABMT). METHODS AND MATERIALS: One hundred eighty-six patients with acute nonlymphoblastic leukemia (n = 101), acute lymphoblastic leukemia (n = 62), chronic myeloid leukemia (n = 11), non-Hodgkin's lymphoma (n = 10), and multiple myeloma (n = 2) referred to our department between May 13, 1981 and September 16, 1992, underwent TBI before ABMT. The male-to-female ratio was 123:63 (1.95), and mean and median age was 33 +/- 12 (6-63 years) and 35 years, respectively. Cyclophosphamide alone (60 mg/kg/day on each of 2 successive days) was used as conditioning chemotherapy in all patients. Patients were irradiated according to two techniques: either with single-dose (STBI) (n = 124; 10 Gy administered to the midplane at the level of L4, and 8 Gy to the lungs) or with fractionated (FTBI) (n = 62; 12 Gy in 6 fractions over 3 consecutive days to the midplane at the level of L4, and 9 Gy to the lungs) TBI. The mean instantaneous dose rate was 0.057 +/- 0.0246 Gy/min (0.0264-0.1692 Gy/min). It was < or = 0.048 Gy/min in 48 patients (LOW group), > 0.048 and < or = 0.09 Gy/min in 129 patients (MEDIUM group), and > 0.09 Gy/min in 9 patients (HIGH group). The median follow-up period was 5 years (24-120 months). RESULTS: In January 1994, the 5-year overall (including all causes of death) and disease-free survival (DFS) rates were 50 and 48%, respectively. The 5-year DFS was 47.9% in the STBI group, and 47.8% in the FTBI group (p = 0.77). It was 44% in the HIGH group, 53% in the MEDIUM group, and 34% in the LOW group (LOW vs. MEDIUM, p = 0.009). The 5-year IP incidence was 17% in all patients, 16% in the STBI group and 18% in the FTBI group (p = 0.37), but it was significantly higher in patients receiving high instantaneous dose rate TBI (56% in the HIGH, 13% in the MEDIUM, 20% in the LOW groups; HIGH vs. MEDIUM, p = 0.002). However, sex (p = 0.37), age (18% for > 20 vs. 10% for < or = 20 years, p = 0.37), and body weight (> 60 kg vs. < or = 60 kg, p = 0.09) did not influence the IP incidence in univariate analyses. Multivariate analysis (Cox model) revealed that the instantaneous dose rate (p = 0.05), and the age (p = 0.04) were the two independent factors influencing the incidence of IP. CONCLUSION: This retrospective study including only the patients transplanted with ABMT conditioned with CY alone and STBI or FTBI concluded that instantaneous dose rate and age significantly influenced the incidence of IP, whereas sex, body weight, and fractionation did not.

Adolescent↗
PubMed2002

Temporary amelioration of bilirubin conjugation defect in Gunn rats by transplanting conditionally immortalized hepatocytes.

BACKGROUND: Conditionally immortalized hepatocytes (CIH) have been used in hepatocyte transplantation as an alternative to primary hepatocytes to cope with the shortage of donor organs. However, CIH are known to undergo apoptosis at body temperature and survive in vivo for a short period. In the present study, we investigated whether CIH function or not and how long their function is maintained in vivo. METHODS: Various CIH cell lines that were established with temperature-sensitive Simian virus 40 large T antigen were transplanted into the spleen of Gunn rats, which are defective in bilirubin uridine diphosphate glucuronoside transferase (BUGT). Then, we measured biological changes over 3 months. RESULTS: Serum bilirubin of the syngeneic CIH recipients decreased by 30%, which was maintained for 8 weeks. Thereafter, it began to rise to basal levels. The recipients of allogeneic CIH showed a minor reduction of bilirubin, although this was not statistically significant. However, there was no significant change in the bilirubin level in recipients of BUGT-defective congeneic CIH throughout the study period. Bilirubin monoglucuronides in the bile were not detected in the recipients of BUGT-defective CIH. However, they appeared in recipients of non-defective CIH and made up approximately 41% of total bile pigments. CONCLUSIONS: Conditionally immortalized hepatocytes expressed hepatocyte function in vivo as well as in vitro, but the function lasted for a couple of months. According to our previous study, the limited functional duration may be related to the inevitable occurrence of apoptosis of these cells at body temperature. These data suggest that CIH can be used in hepatocyte transplantation only for temporary hepatic support.

Animals↗
PubMed1997

[Effect of bone marrow transplantation conditioning regimen on thyroid and adrenocortical functions in patients with blood diseases].

OBJECTIVE: In order to investigate the life quality of patients with hematological diseases after bone marrow transplantation (BMT). METHODS: Pituitary-thyroid and adrenocortical function were de tected in 29 patients with hematological diseases before and after BMT. RESULTS: All patients had normal thyroid and adrenocortical functions before BMT. As compared with pre-BMT,the median serum TSH levels were significantly increased at 3, 6, 12 (P<0.01), 24-60 (P<0.05) months post-BMT. The adrenocortical function had no change in all patients, and thyroid dysfunction were found in 6 of 24 patients detected at a median time of 6 month post-BMT. Five of the 6 thyroid dysfuntion patients developed hypothyroidism, and one hyperthyroidism. CONCLUSION: There was little effect of conditioning regimen on adrenocortical function, while thyroid dysfunction was common after BMT. Long term follow up on thyroid function in patients after BMT is necessary.

Adolescent↗
PubMed1994

A successful pregnancy after bone marrow transplantation for severe aplastic anaemia with pre-transplant conditioning of total lymph-node irradiation and cyclophosphamide.

Pregnancy after bone marrow transplantation (BMT) for severe aplastic anaemia (SAA) is now an encouraging reality. We present a successful pregnancy, 4 years after BMT for SAA, in a woman being immunosuppressed before transplantation with cyclophosphamide and total lymph-node irradiation (TLI). No fetal complication was diagnosed.

Adolescent↗
PubMed1995

Decreased lung function in one year survivors of allogeneic bone marrow transplantation conditioned with high-dose busulphan and cyclophosphamide.

Conditioning with busulphan (BU) and cyclophosphamide (CY) prior to allogeneic bone marrow transplantation (BMT) is an alternative to regimens that include total body irradiation (TBI). The aim of the study was to assess the occurrence and degree of lung function impairment after this treatment. Prospectively, 43 consecutive patients, aged 17-51 (median 31) yrs, were examined by lung function measurements and clinical and radiographic evaluation, prior to BMT and at 3 month intervals up to 1 yr after BMT. All patients had normal chest radiographs before BMT and at the 12 month follow-up. Mean baseline values were above 100% of predicted normal for lung volumes and above 90% for gas transfer. Excluded from the lung function follow-up analyses were nine patients who had suffered infectious pneumonia and/or developed obliterative bronchiolitis. For the remaining patients (n = 34), mean alveolar volume (VA), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) had dropped by nearly 10% compared with baseline 3 months after BMT, but were restored within 1 yr. FEV1/FVC x 100 (FEV1%) was increased, reflecting the restrictive pattern. Hb-adjusted transfer factor of the lungs for carbon monoxide (TL,CO) had dropped by 20% after 3 months, and remained reduced by 15% after 1 year. Prior to BMT the smokers had significantly lower TL,CO than the nonsmokers, and after BMT the difference was accentuated. Reductions in lung function were independent of sex, age and type of haematological disorder. We conclude that BMT with BU/CY is associated with transient declines in lung volumes and a persistent reduction in gas transfer 1 yr after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗