The relevance of glycine and serine in poultry nutrition: a review.

1. Dietary glycine equivalents (Glyequi) for glycine and serine represent the first-limiting non-essential amino acid in poultry diets. Targeted adjustment of essential amino acids and Glyequi in diets can considerably decrease crude protein (CP) in poultry diets below the limit of CP reduction when only essential amino acids are adjusted. 2. The level to which CP can be reduced in diets adequate in Glyequi depends on the objective; which includes reducing dietary CP without affecting performance and increasing nitrogen utilisation efficiency. Dietary CP can be reduced to ~15-16% in diets for up to 21 d old broiler chicken without affecting growth performance compared to responses to diets with currently common CP concentrations by considering Glyequi in the diet formulation. Dietary CP can be further reduced to maximise nitrogen utilisation efficiency; however, this leads to reduced growth performance. 3. The dietary Glyequi requirement of poultry varies depending on other dietary constituents. In broiler chickens up to 21 days of age, the dietary Glyequi requirement is estimated to be between 11 and 20 g/kg. This estimate is influenced by the concentrations of Cys and the endogenous Glyequi precursors, threonine and choline. Urinary nitrogen excretion seems to be a major determinant of the response to dietary Glyequi, because it is needed for uric acid formation. 4. The variable requirement for dietary Glyequi means that its static recommendation in poultry diets would lead to high safety margins in Glyequi supply or the risk of Glyequi deficiency. Variable recommendations for dietary Glyequi concentrations would help to supply birds based on their specific requirements and could reduce nitrogen emissions originating from poultry farming.

Meta-analysis of the influence of dietary glycine and serine, with consideration of methionine and cysteine, on growth and feed conversion of broilers.

The existing literature is inconsistent with respect to optimal dietary concentrations of glycine (Gly) and serine (Ser) in broiler feed. Therefore, we conducted a meta-analysis to investigate the response of broilers to dietary levels of Gly using a full quadratic model based on mixed model methodology. Response was measured as ADG (g/d), ADFI (g/d), and G:F (g/g). In addition, the influence of other dietary constituents was evaluated. This meta-analysis was based on a data set comprising a total of 9,626 broilers in 10 peer-reviewed papers that investigated the response of broilers to different dietary concentrations of Gly, achieved by addition of free Gly. The fitted quadratic model, with either Gly+Ser or the calculated glycine equivalent (Glyequi) of both amino acids as the independent variable, revealed that all model terms were significant (P ≤ 0.05), and hence proved a curvilinear relationship between these independent variables and response traits. The R(2) value and root MS error confirmed a strong relationship between observed and predicted traits. A comparison of the influence of Gly+Ser and Glyequi on response traits revealed that both approaches produced similar results. Because Glyequi should meet the physiological values of a diet better than Gly+Ser, models with 2 independent variables were conducted using Glyequi. The second independent variables were methionine (Met):TSAA ratio and the concentrations of cysteine (Cys) and CP. In models with one or 2 independent variables, the impact of dietary Gly on ADFI was low. By contrast, G:F was markedly influenced by dietary Gly; this effect intensified at lower Met:TSAA ratios and higher Cys and CP levels. ADG was also a function of Glyequi and the second independent variables. For ADG, an optimal Met:TSAA ratio of 0.655 and Cys concentration of 0.302% was calculated. Following the nonlinear nature of relationship, generally applicable replacement values could not be calculated. However, it was concluded that consideration of dietary Cys can diminish the requirement for Glyequi, and therefore, enable a reduction in the CP of broiler diets without limiting growth performance.

Activity of thalidomide in patients with platinum-refractory germ-cell tumours.

The aim of this study was assess the activity of thalidomide in patients with progressive relapsed or platinum-refractory germ-cell tumours (GCT). Between April 2002 and January 2003, 15 patients with inoperable progressive GCT were treated with escalated daily doses of 200-600 mg thalidomide. All patients had failed first-line and salvage chemotherapy with a median of 6 (range 4-12) cisplatin-based treatment cycles, 13/15 (87%) patients had received high-dose chemotherapy (HDCT) and 8/15 (53%) patients were considered platinum-refractory or absolute refractory; 8/15 (53%) patients had previously received other palliative chemotherapy regimens. No patient achieved a complete remission (CR) or partial remission (PR). However, 5/15 (33%) patients achieved serological PR and 1 additional patient had stable disease for 3 months. The median duration of remissions was 3 months (range 2-12 months) including 2 patients with a progression-free survival of 9 and 12 months. Responses occurred mainly in patients with a low tumour burden, slow disease progression and alpha-foetoprotein (AFP) elevations. Responses to thalidomide were independent from platinum-sensitivity. Toxicity was mild, with lethargy and constipation in the majority of patients. Skin rash grade II developed in 2 patients and peripheral neurotoxicity grade II/III developed in 4 patients. One responding patient died suddenly from an unknown cause. It is concluded that thalidomide shows single-agent activity in patients with heavily pre-treated GCT, AFP elevations and slowly progressive disease.

A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.

BACKGROUND: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy. PATIENTS AND METHODS: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B). RESULTS: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P <0.04). CONCLUSIONS: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.

Second-line high-dose chemotherapy in patients with mediastinal and retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience.

BACKGROUND: Results of second-line chemotherapy in patients with extragonadal non-seminomatous germ cell tumor (NSGCT) appear inferior to results in testicular NSGCT. Patients with retroperitoneal NSGCT achieve a comparable long-term survival rate of 30%, but the salvage rates of patients with mediastinal primary are less than 10%. We conducted a retrospective analysis on patients with mediastinal and retroperitoneal NSGCT treated with second-line high-dose chemotherapy (HDCT) registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: Between 1987 and 1999, 59 registered patients with retroperitoneal (n=37) and mediastinal (n=22) primary NSGCT, median age 28 years (range 18-60), were treated with second-line HDCT. All had received cisplatin-containing chemotherapy as first-line treatment. RESULTS: Toxic death occurred in three cases (5%). With a median follow-up of 58 months (range 14-114), 18/59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one patient achieved a disease-free status with further chemotherapy and surgery. In total, 19 patients (32%) are currently disease-free. Sixteen of 37 patients (43%) with retroperitoneal NSGCT, and three of 22 patients (14%) with mediastinal NSGCT are currently alive and disease-free. CONCLUSIONS: Second-line HDCT might represent a possible option for patients with retroperitoneal primary NSGCT. New salvage strategies are needed for patients with mediastinal NSGCT.

Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer.

PURPOSE: To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). PATIENTS AND METHODS: Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. RESULTS: Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. CONCLUSION: Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.

The role of high-dose chemotherapy in relapsed germ cell tumors.

Overall, patients with relapsed or progressive germ cell tumors after cisplatin-based chemotherapy have a low chance of cure. Using conventional-dose chemotherapy (CDCT) as salvage treatment, only 15-30% of the patients will become long-term survivors. It is well known that the majority of these patients will ultimately die of their disease. Therefore, improvement of the standard treatment is clearly desirable. In the last years, high-dose chemotherapy (HDCT) has been established as an effective salvage modality. A matched-pair analysis showed an advantage for HDCT compared with CDCT with an improvement in event-free and overall survival. Furthermore, due to increasing clinical experience in the management of side-effects, the use of peripheral blood progenitor cells and the availability of hematopoietic growth factors, HDCT has become relatively safe. Therefore, HDCT should be administered in patients with first relapse and unfavorable prognostic factors, and as second or subsequent salvage treatment followed by complete resections of tumor residuals. Patients with relapse or progressive disease after HDCT who do not qualify for desperation surgery could be salvaged with palliative chemotherapy combinations using gemcitabine, oxaliplatin and paclitaxel. This report reviews the current treatment strategies and recent developments with respect to HDCT given as salvage treatment and discusses the role of prognostic factors in the management of such situations.

Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation--a retrospective analysis.

It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m2 FLU (n=45) or 8 mg/kg BU, 180 mg/m2 FLU and 40 mg/kg ATG (n=38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n=32) or a combination with either MTX or MMF (n=51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P=0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P=0.017), and less platelet (P<0.001) and red blood cell (P=0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ATG (54 vs 23%, P=0.02). The overall survival, non-relapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD.

[Quantitative determination of CMV-DNA in saliva of patients with bone marrow and stem cell transplantation using TaqMan-PCR]. / Quantitative Bestimmung humaner CMV-DNA im Speichel von Patienten mit Knochenmark- und Stammzelltransplantation mithilfe der TaqMan(R)-PCR.

BACKGROUND: Human cytomegalovirus (HCMV) infection is associated with severe and life-threatening diseases in immunocompromised patients, especially after bone marrow (BM) and stem cell (SC) transplantation. Prior to transplantation the potential risk of HCMV disease is therefore determined by HCMV-antibody blood testing of transplant donor (D) and recipient (R). Virus carriers are positive for anti-CMV-IgG. Virus patterns are distinguished as follows: group 1 (D+/R+), group 2 (D-/R+), group 3 (D+/R-), and group 4 (D-/R-). AIM: The aim of this study was qualitative and quantitative determination of the HCMV DNA load in saliva of BM and SC transplantation patients. PATIENTS AND METHOD: Unstimulated saliva was collected from 20 patients prior to BM and SC transplantation, during the time of conditioning, and after transplantation. DNA was isolated and analyzed for evidence of HCMV DNA with TaqMan PCR. RESULTS: HCMV DNA was isolated in seven cases. In all group 1 patients (D+/R+) HCMV DNA could be demonstrated. Only three of seven group 2 patients (D-/R+) were positive for HCMV DNA. The only group 3 patient (D+/R-) and all eight group 4 patients (D-/R-) were negative. CONCLUSION: TaqMan PCR is a reliable method for HCMV DNA quantification. In three patients (anti-HCMV-IgG positive) who received an anti-CMV-IgG negative transplant HCMV DNA was isolated. In contrast, no HCMV-DNA was evident in HCMV-negative patients who received an HCMV-negative transplant. Accordingly, the risk of HCMV reactivation is more probable than the risk of reinfection.

Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia.

Since the incidence of cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation (HSCT) may depend on the intensity of the pretreatment, we studied the incidence of CMV infections after reduced-intensity compared to myeloablative conditioning. A total of 82 patients with matched related or unrelated donors were prospectively monitored for CMV infections after HSCT by CMV-PCR techniques, CMV-antigenemia and clinical observation. A total of 45 patients received reduced-intensity conditioning consisting of fludarabine, busulfan and ATG and 37 patients received myeloablative conditioning. Leukocyte engraftment occurred after a median of 15 vs 18 days (P=0.012) and platelet engraftment after 12 days vs 20 days (P=0.001), respectively. Acute graft-versus-host disease (GVHD) grade II-IV was observed in 58 vs 54% patients (P=0.737), respectively. The onset and peak values of CMV-antigenemia and DNAemia and the incidence of CMV infections did not differ statistically significantly between the two treatment groups. Multivariate analysis confirmed CMV seropositivity of the recipient (P=0.035), acute GVHD II-IV (P=0.001) but not the type of conditioning as significant risk factors for CMV-antigenemia. In conclusion, the kinetics of CMV-antigenemia and DNAemia and the incidence of CMV infections were not statistically different in patients who received HSCT after reduced-intensity conditioning with fludarabine, busulfan and ATG compared to myeloablative conditioning.

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0-65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.

Individualised dosing strategy for high-dose carboplatin in patients with germ cell cancer.

In contrast to conventional chemotherapy, carboplatin is still dosed per unit of body surface area (BSA) in high-dose chemotherapy protocols in clinical practice. To individualise dosing, a population pharmacokinetic model for poor-risk germ cell tumour patients receiving 1500 mg m(-2) carboplatin was developed. The typical central volume of distribution (19.9 l) and typical clearance (110 ml min(-1)) corresponded approximately to the extracellular fluid space or glomerular filtration rate, respectively. The covariate analysis identified several patient-specific factors. Carboplatin clearance was significantly related to creatinine clearance and body height, explaining 73% of the interindividual variability. Thus, an equation to predict individual clearance prior to treatment was developed (CL=0.41 x creatinine clearance+1.05 x body height-124.4). The relative frequency of developing toxicity increased significantly with higher AUC values for different types of toxicity. In addition, overall nonhaematological toxicity correlated significantly with exposure of carboplatin, leading to the assessment of a target AUC. Based on the prediction of individual clearance and the definition of a target AUC associated with moderate toxicity, an individualised dosing equation is proposed. Retrospectively, the individualised dosing strategy would have led to a higher dose on average and a broader range to be administered, compared to empirical dosing per unit BSA in the high-dose setting.

Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group.

PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5-20% blasts (P=0.002) and 14% with >20% blasts (P

Influence of amifostine on reconstitution of lymphocyte subpopulations after conventional- and high-dose chemotherapy in patients with germ cell tumor.

We assessed the influence of amifostine on immune reconstitution after conventional-dose paclitaxel, ifosfamide, cisplatin and high-dose carboplatin, etoposide and thiotepa followed by autologous peripheral blood progenitor cell (PBPC) rescue in patients with germ cell tumor (GCT). A total of 40 patients were treated with one cycle of paclitaxel and ifosfamide (TI) followed by granulocyte-colony stimulating factor (G-CSF) to mobilize PBPC, three cycles of paclitaxel, ifosfamide and cisplatin (TIP) and one course of high-dose carboplatin, etoposide and thiotepa (CET) plus PBPC rescue. Patients were randomized to receive an absolute dose of 500 mg amifostine (group A, n=20) on each day of chemotherapy or no amifostine (group B, n=20). Prior to each cycle of chemotherapy, after hematologic engraftment from CET, 6 weeks and 3 months after transplantation the subpopulations of lymphocytes were phenotyped. Between the two study groups no statistically significant differences were observed concerning reconstitution of lymphocyte subpopulations. Throughout treatment with TIP or CET lymphocyte counts and their subpopulations remained low without severe clinical complications. Delayed reconstitution of the CD4(+) cell compartment after PBPC rescue was observed in both study groups, but did not result in any severe or atypical infections. Treatment with amifostine administered at this dose did not significantly influence the reconstitution of lymphocyte subpopulations. Low numbers of lymphocytes during chemotherapy and delayed reconstitution of CD4(+) cells and other lymphocyte subpopulations after PBPC rescue had no clinical relevance for patients with GCT.

High-dose chemotherapy as salvage treatment for seminoma.

Between October 1989 and February 1997, 13 patients with refractory or relapsed seminomas were treated with high-dose chemotherapy (HDCT) as part of consecutive phase I/II studies. Six patients had failed prior cisplatin-based first-line treatments and seven patients had also failed cisplatin-based salvage treatments. After HDCT 4/12 (33%) patients became disease-free, 4/12 (33%) patients achieved partial remissions and 4/12 (33%) patients suffered progressive disease despite HDCT. One patient developed multiorgan failure and died. With a median follow-up of 4.5 years (range 3.4 to 8 years) five patients (38%) are alive and eight patients (62%) have died. Patients with non-pulmonary visceral metastases, with short relapse-free intervals and with cisplatin-refractory tumors were more likely to fail. HDCT can be curative in seminoma patients even if offered as second salvage treatment.

High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analysis.

BACKGROUND: The purpose of this study was to compare high-dose chemotherapy (HDCT) with conventional-dose chemotherapy (CDCT) as first-salvage treatment in patients with relapsed or refractory non-seminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: One hundred and ninety-three patients with relapsed or refractory NSGCT, between 1981 and 1995, were identified from two large databases. In 74 of these, intensification of first-salvage treatment by HDCT was planned. Patients were matched based on primary tumor location, response to first-line treatment, duration of this response and serum levels of the tumor markers, human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP). Multivariate analyses were performed using event-free survival and overall survival as primary endpoints. RESULTS: Full matches on all five factors were found for 38 pairs of patients; for a further 17 pairs, matches on at least four factors could be identified. Hazard ratios in favor of HDCT were obtained between 0.72 and 0.84 [confidence interval (CI) 0.59-1.01] for event-free survival and between 0.77 and 0.83 (CI 0.60-0.99) for overall survival, depending on the type of analysis. CONCLUSIONS: The current analysis suggests a benefit from HDCT, with an estimated absolute improvement in event-free survival of between 6 and 12% and in overall survival of between 9 and 11% at 2 years. This benefit is lower than expected from previous phase I/II studies.

Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia.

We studied in 30 patients with progressive or relapsing chronic lymphocytic leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after conditioning with fludarabine, busulfan and ATG is effective and if treatment related mortality can be reduced compared to myeloablative conditioning regimens. Patients had 15 matched related and 15 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination with "short course" methotrexate or mycophenolate mofetil. The median follow-up is 24 months. At last follow up 11 patients were in complete and 13 in partial remission. Six patients had stable or progressive disease. Late complete remissions occurred up to one year after transplantation and the number of patients with CR is still increasing. Four patients died due to treatment related complications resulting in a probability of treatment-related mortality of 15% (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and progression free survival at two years was 79% and 61%, respectively. In conclusion, HSCT after reduced conditioning may lower the treatment-related toxicity and has the capacity to induce complete remissions.

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.