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A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients., (© 2024. The Author(s).)

Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification., Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II-IV aGvHD within 100 days post-HSCT., Results: Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II-IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II-IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II-IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios., Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials. The final population PK model was 2-compartmental with dosing in the central compartment, linear elimination, and inter-compartmental clearance. Inter-individual variability was included on clearance (CL), central volume (V1), peripheral volume (V2), and inter-compartmental clearance (Q). The final model described an effect of the body surface area (BSA) on CL, V1, V2, and Q. The final model resulted in a modified dose recommendation for children and advises treosulfan doses of 10 g/m 2 , 12 g/m 2 , and 14 g/m 2 for BSAs of <0.4 m 2 , ≥0.4 to <0.9 m 2 , and ≥0.9 m 2 , respectively. This simplified BSA-dependent dose recommendation was developed for children, ensuring a well comparable treosulfan exposure as a dose of 14 g/m 2 in adults - irrespective of their age and without applying individual therapeutic drug monitoring., Competing Interests: Declaration of competing interest XL, JK, AKM, and JB are employees of medac GmbH. All other authors declare no conflict of interest., (Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population., Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m 2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m 2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393)., Findings: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related., Interpretation: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population., Funding: medac GmbH., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R-AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R-AML during active disease has been equally disappointing. In this retrospective observational study, high-dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)-based or a treosulfan-based dose-adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17-74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen-mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high-dose melphalan-based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long-term remission to be achieved in a substantial proportion of patients with active R/R-AML., (© 2018 John Wiley & Sons Ltd.)

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation is a multifactorial process. Some of the predictors exhibit time-dependent effects. We present a systematic analysis and description of selected clinical predictors influencing outcome in a time-dependent manner based on an analysis of registry data from the German Registry for Stem Cell Transplantation. A total of 14,951 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome and non-Hodgkin lymphoma transplanted with peripheral blood stem cells or bone marrow grafts were included. Multivariate Cox regression models were tested for time-dependent effects within each diagnosis group. Predictors not satisfying the proportional hazards assumption were modeled in a time-dependent manner, extending the Cox regression models. Similar patterns occurred in all diagnosis groups. Patients with a poor Karnofsky performance score (<80) had a high risk for early mortality until day 139 following transplantation (HR 2.42, CI: 2.19-2.68; P<0.001) compared to patients with a good Karnofsky performance score (80-100). Afterwards the risk reduced to HR 1.43, CI: 1.25-1.63; P<0.001. A lower mortality risk was found for patients after conditioning treatment with reduced intensity until day 120 post transplant (HR: 0.81 CI: 0.75-0.88; P<0.001). After this, a slightly higher risk could be shown for these patients. Similarly, patients who had received a PBSC graft exhibited a significantly lower mortality risk until day 388 post transplantation (HR 0.79, CI: 0.73-0.85; P<0.001), reversing to a significantly higher risk afterwards (HR 1.23, CI: 1.08-1.40; P=0.002). Integrating time dependency in regression models allows a more accurate description and quantification of clinical predictors to be made, which may help in risk assessment and patient counseling., (Copyright© Ferrata Storti Foundation.)

Background: Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen., Methods: In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival., Findings: We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99 [95% CI 0·83-1·20]; p=0·95) or leukaemia-free survival (HR 0·97 [0·81-1·16]; p=0·71). Main causes of non-relapse mortality were graft-versus-host disease (49 [10%] in the intravenous busulfan plus cyclophosphamide group vs 25 [7%] in the cyclophosphamide plus TBI group) and infection (36 [7%] vs 18 [5%])., Interpretation: From a practical standpoint, the use of intravenous busulfan plus cyclophosphamide is likely to be a valid and efficient alternative to cyclophosphamide plus TBI conditioning regimen for patients with refractory acute myeloid leukaemia, especially for those transplant centres without access to radiation facilities., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission., Methods: Patients were aged 18-60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m(2) fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00150878., Findings: The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% [95% CI 6-21] vs 18% [10-26]; HR 0·62 [95% CI 0·30-1·31]). Relapse incidence (cumulative incidence 3 years 28% [95% CI 19-38] vs 26% [17-36]; HR 1·10 [95% CI 0·63-1·90]), disease-free survival (3 year disease-free survival 58% [95% CI 49-70] vs 56% [46-67]; HR 0·85 [95% CI 0·55-1·32]), and overall survival (3 year overall survival 61% [95% CI 50-74] vs 58% [47-70]; HR 0·77 [95% CI 0·48-1·25]) did not differ significantly between groups. Grade 3-4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups., Interpretation: Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3., Design and Methods: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (≥ 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 × 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 × 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 × 10(7) (range 0.00-37.3) CD56(+) cells/kg., Results: Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 × 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 × 10(9) (range 7-38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively., Conclusions: This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917).

An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m(2) treosulfan and 5 × 30 mg/m(2) fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III-IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II-IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.

Background: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome., Design and Methods: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival., Results: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively., Conclusions: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.

Myelodysplastic syndromes (MDSs) often occur in older adults with significant comorbidities. Therefore, a reduced-toxicity conditioning regimen may be more suitable than standard conditioning regimens before allogeneic blood stem cell transplantation. Here, we retrospectively compare the outcome of a treosulfan-based conditioning regimen with standard myeloablative TBI-based conditioning regimens in patients (pts) with MDS. A total of 48 pts with MDS were included in the study, of which 29 (60%) pts received TBI-based and 19 (40%) pts received a treosulfan-based conditioning regimen. A significantly lower relapse incidence (5% vs 34% at 3 years, P=0.019) resulting in a better, but not statistically significant relapse-free survival (RFS) (57% vs 31%, P=0.086) was observed after treosulfan-based conditioning. In pts with increased risk for significant side effects due to comorbidities (haematopoietic stem cell transplantation specific comorbidity index), the estimated 3-year RFS was significantly better in the treosulfan group: 54% (95% confidence interval (CI), 17-90%) compared with pts in the TBI group: 11% (95% CI, 0-44%; log-rank test P=0.0455). Treosulfan-based conditioning therapy is a feasible and effective regimen for pts with MDS, especially in pts with preexisting comorbidities.

Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150-200 mg/m(2)), thiotepa (10 mg/kg), melphalan (120 mg/m(2)) and OKT-3 (5 mg/day, day -5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age=42 (range, 21-59) years) have been transplanted with this regimen. Diagnosis were AML (n=16), ALL (n=7), NHL (n=3), MM (n=2) and CML (n=1). Patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6x10(6) (range, 3.4-17x10(6)) CD34+ cells/kg, 4.4x10(4) (range, 0.006-44x10(4)) CD3+ T cells/kg and 7.2x10(7) (range, 0.02-37.3x10(7)) CD56+ cells/kg. Donor-recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2-3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m(2) fludarabine, the dose was reduced to 150 mg/m(2). Engraftment was rapid with a median time to >500 granulocytes/microL of 12 (range, 10-21) days, >20,000 platelets/microL of 11 (range, 7-38) days and full donor chimerism after 2-4 weeks in all patients. Incidence of grade II-IV degrees GVHD was 48% with grade II degrees =10, III degrees =2 and IV degrees =2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n=1), mucormycosis (n=1), pneumonia (n=3) or GVHD (n=1). Overall survival is 9/29 patients (31%) with deaths due to infections (n=7), GVHD (n=1) and relapse (n=12) with a median follow-up of 241 days (range, 112-1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.

In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.

Bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) are late-onset non-infectious pulmonary complications (LONIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT). In the present study 10 of 197 conventionally prepared stem cell recipients developed BOOP after 365 days and 6 patients developed BO 333 days post-transplant. No BOOP or BO was diagnosed following T-cell depletion (p<0.05). Chronic GVHD was ascertained in all BOOP patients and appeared significantly (p<0,001) more frequent in the conventional transplant group. The data confirm a strong association between T-cell activity, chronic GVHD, BO and BOOP and point out the impact of T lymphocytes in the pathomechanism of BOOP.

Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 x 12 or 3 x 14 g/m2) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progression-free survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications.

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

The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immunosuppression or imatinib. Three of 11 patients (27%) are alive in CR 5 to 30 months after NST. Eight of 11 patients have died, 3/8 from leukemia and 5/8 from transplant-related causes. After salvage NST, 8/11 patients (73%) engrafted. Seven of nine patients with active disease reached CR. Only one of 11 patients transplanted, who was in CR before undergoing salvage NST is alive 19 months after NST. Five of 11 have died from leukemia, one of 11 after graft failure and four of 11 from transplant-related causes. Four of 22 patients (18%) are alive in CR 5, 14, 19 and 30 months after NST. NST is feasible in adults with high risk ALL. However, transplant-related mortality remains high and only patients transplanted in CR seem to have long-term disease-free survival.

Invasive fungal infections (IFI) are increasingly diagnosed in patients undergoing allogeneic BMT. We have previously shown that the addition of metronidazole to ciprofloxacin for gastrointestinal bacterial decontamination significantly reduces the incidence of grades II-IV aGVHD by reduction of the anaerobic intestinal bacterial flora. Here, we found that the combined use of ciprofloxacin, metronidazole and fluconazole as antifungal prophylaxis increased intestinal yeast colonization when compared to ciprofloxacin and fluconazole alone (P < 0.01). Based on the EORTC criteria, a total of 18 out of 134 study patients developed IFI: seven of 68 (10%) patients who received metronidazole compared to 11 of the 66 (17%) patients decontaminated without metronidazole developed IFI (log-rank P = 0.36). Lethal IFI occurred in two of seven patients receiving metronidazole and in four of 11 patients without anaerobic decontamination. In conclusion, bacterial intestinal decontamination using metronidazole as an antibiotic with activity against most anaerobic intestinal bacteria significantly increases the intestinal yeast burden without influencing the incidence of IFI in patients undergoing allogeneic BMT.