Time-dependent prediction of mortality and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation using machine learning.

Allogeneic hematopoietic cell transplantation (HCT) effectively treats high-risk hematologic diseases but can entail HCT-specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models that integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well-calibrated, time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both models were successfully validated in a prospective, non-interventional study and performed on par with expert hematologists in a pilot comparison.

External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails.

Several studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.

Optimizing anti-T-lymphocyte globulin dosing to improve long-term outcome after unrelated hematopoietic cell transplantation for hematologic malignancies.

Prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in-vivo T cell depletion using anti-T-lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte- and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N = 723, 48%) or with additional ATLG (N = 777, 52%). In the ATLG cohort, grades III-IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P < .0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event-free and overall survival estimates at 10 years were 44% and 51% with ATLG and 33% and 35% without ATLG (P < .002 and <.0001). A dose-dependent ATLG effect on lymphocyte- and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P = .001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD-HCT.

Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity.

Allogeneic haematopoietic cell transplantation offers the chance of cure for patients with transformed follicular lymphoma.

PURPOSE: In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL. METHODS: The database of the German Registry for Stem Cell Transplantation (DRST) was screened for patients who underwent allo-HCT for tFL 1998-2008. Confirmation of tFL-diagnosis by local and/or pathologists of the National NHL Board was mandatory for enrolment. Gaps in reported EBMT Minimum Essential Data datasets (MED-A) were filled by local DRST data managers. Relevant HCT outcome variables were evaluated by uni- and multivariate statistical analysis. RESULTS: Median age of enrolled 33 patients was 51 years with a post allo-HCT median follow-up of 7.1 years of surviving patients. At time of HCT 24/33 patients had chemosensitive disease. In 24/33 patients reduced intensity conditioning (RIC) was used. Estimated 1, 2, 5-year overall survival (OS) and event-free survival rates were 49/39/33, and 33/30/24%. Cumulative 100 days non-relapse mortality was 25%. Chemosensitive disease, RIC, and limited chronic GvHD were identified as independent prognostic factors for OS. CONCLUSIONS: Allo-HCT offers the chance of cure for tFL.

High-dose melphalan-based sequential conditioning chemotherapy followed by allogeneic haematopoietic stem cell transplantation in adult patients with relapsed or refractory acute myeloid leukaemia.

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.

Assessing the risk of CMV reactivation and reconstitution of antiviral immune response post bone marrow transplantation by the QuantiFERON-CMV-assay and real time PCR.

BACKGROUND: CMV reactivation is a major cause of severe complications in allogeneic hematopoietic stem cell transplant (HSCT) recipients. The risk of CMV reactivation depends on the serostatus (+/-) of the donor (D) and recipient (R). The reconstitution of CMV-specific T-cell responses after transplantation is crucial for the control of CMV reactivation. OBJECTIVES: The study aimed to determine the cellular immune status correlating with protection from high-level CMV viremia (>5000 copies/ml) and disease. STUDY DESIGN: We monitored CMV-specific cellular immune responses in 9 high-risk (D-/R+), 14 intermediate risk (D+/R+) and 3 low risk individuals (D+/R-), and 8 CMV negative controls (D-/R-). Interferon- γ (IFN-γ) levels as a marker for the CD8+ T-cell response were determined by the QuantiFERON-CMV-assay and compared to viral loads determined by PCR. RESULTS: Early CMV reactivation was detected in all high-risk and 13/14 intermediate risk individuals. High-level viremia was detected in 5/7 high and 7/14 intermediate risk patients. Reconstitution of the CMV-specific cellular immune response started from 3 months after transplantation and resulted in protection against CMV reactivation. Re-establishing of CMV-specific T-cell immune responses with IFN- γ levels >8.9 IU/ml is crucial for protection from high-level CMV viremia. CONCLUSIONS: Monitoring of HSCT-recipients with the QuantiFERON-CMV-assay might be of great benefit to optimize antiviral treatment.

Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial.

BACKGROUND: Previously, we demonstrated that the addition of anti-human-T-lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial. METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n=103, non-ATLG n=98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD-free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials.gov (NCT00655343), and EudraCT (2004-000232-91). FINDINGS: Median follow-up was 8·6 years (IQR 8·0-9·3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio [HR] 0·18, 95% CI 0·09-0·34; p<0·0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0·66, 95% CI 0·38-1·16; p=0·15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1·17, 95% CI 0·71-1·93; p=0·54), relapse mortality was 31% (95% CI 23-41) versus 29% (21-40; adjusted HR 1·03, 95% CI 0·61-1·76; p=0·90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0·91, 95% CI 0·63-1·31; p=0·60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0·82, 95% CI 0·56-1·20; p=0·31), and severe GvHD-free and relapse-free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0·55, 95% CI 0·39-0·76; p=0·0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years. INTERPRETATION: ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression. FUNDING: Neovii Biotech.

Treatment of graft failure with TNI-based reconditioning and haploidentical stem cells in paediatric patients.

Graft failure is a life-threatening complication after allogeneic haematopoietic stem cell transplantation (HSCT). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias (n = 14) and non-malignant diseases (n = 5) who experienced graft failure after previous HSCT from matched (n = 3) or haploidentical donors (n = 16) between 2003 and 2012. After total nodal irradiation (TNI)-based reconditioning combined with fludarabine, thiotepa and anti-T cell serotherapy, all patients received T cell-depleted peripheral blood stem cell grafts from a second, haploidentical donor. Median time between graft failure and retransplantation was 14 d (range 7-40). Sustained engraftment (median: 10 d, range 9-32) and complete donor chimerism was observed in all evaluable patients. 5 patients additionally received donor lymphocyte infusions. Graft-versus-host disease (GvHD) grade II and III occurred in 1 patient each (22%); no GvHD grade IV was observed. 2 patients had transient chronic GvHD. The regimen was well tolerated with transient interstitial pneumonitis in one patient. Treatment-related mortality after one year was 11%. Event-free survival and overall survival 3 years after retransplantation were 63% and 68%. Thus, a TNI-based reconditioning regimen followed by transplantation of haploidentical stem cells is an option to rescue patients with graft failure within a short time span and with low toxicity.

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT.

The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (ΔFD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 ΔFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for ΔFD >2.665, compared with ΔFD ≤2.665 (88% vs 25%, P < .0001). In multivariate analysis, ΔFD >2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with ΔFD ≤2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high ΔFD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on ΔFD compared with 5 others (P = .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of ΔFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT.

Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial.

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.

Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients.

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Advanced-stage III/IV follicular lymphoma: treatment strategies for individual patients.

BACKGROUND: In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient. METHODS: The literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank. RESULTS: In advanced-stage III/IV FL, median survival may approach 8-10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and - as an experimental approach so far - radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response. CONCLUSION: In case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab +/- single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes.

Nodal follicular lymphoma: the role of radiotherapy for stages I and II.

PURPOSE: To clarify the role of external-beam radiotherapy (RT) in patients with stage I and II nodal follicular lymphoma (FL). METHODS: The literature was reviewed with respect to different treatment strategies in patients with stage I and II nodal FL by screening the PubMed databank. RESULTS: In patients with stage I and II nodal FL, RT alone with different irradiation techniques (involved-field [IFI]/extended-field [EFI]/total nodal [TNI]/total lymphoid irradiation [TLI]) produces excellent local disease control (approximately 95%) resulting in disease-free survival and overall survival (OS) rates of 37-94% and 40-93% at 5-15 years, respectively. The main cause of failure is out-of-field recurrence. In nonrandomized trials, IFI led to higher relapse rates, but larger irradiation volumes failed to show an impact on OS and were associated with increased toxicity. Additional chemotherapy mostly failed to improve treatment results achieved with RT alone. CONCLUSION: Since there is no evidence so far that the prognosis of stage I and II nodal FL can be improved by the use of EFI/TNI/TLI, IFI is recommended internationally. Adequate irradiation doses range between 25-30 Gy to subclinical disease and 36-40 Gy to involved sites. To further improve the curative potential of RT in early-stage FL, novel combined approaches (e.g., RT + immunotherapy with rituximab) are under investigation.

Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.

BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. FINDINGS: The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. INTERPRETATION: The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. FUNDING: Fresenius Biotech GmbH.

The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia--a report from the German Registry covering the period from 1998 to 2004.

Due to the recent changes in the indication to allogeneic stem cell transplantation (SCT) in chronic myeloid leukemia (CML), we retrospectively analyzed 1,716 patients with different CML stages who received an allograft from related (n = 767) or unrelated donors (n = 938) within the German Registry of Stem Cell Transplantation (DRST) from 1998 to 2004. Myeloablative conditioning was performed in 724/871 cases (83%), dose-reduced conditioning in 147/871 (17%). Annual transplantations were decreasing from 357 to 98 (28%) in the period of study, but the proportion of advanced cases was increasing from 32% (112/346) to 53% (50/94) of all SCTs. Stage of disease, intervals from diagnosis, and patients' age were independent prognostic parameters, while peripheral stem cells and unrelated transplantation seemed equal to bone marrow/related transplantation. This study demonstrates that allo-SCT still has an important role in advanced CML, which emphasizes the need for optimized transplantation strategies for these high-risk patients.

Immunosuppressive total lymphoid irradiation-based reconditioning regimens enable engraftment after graft rejection or graft failure in patients treated with allogeneic hematopoietic stem cell transplantation.

PURPOSE: To retrospectively evaluate the efficacy of total lymphoid irradiation (TLI)-based reconditioning regimens in patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation. METHODS AND MATERIALS: The results of 14 patients (7 adults and 7 children) with a variety of hematologic malignant diseases treated with a TLI-based reconditioning regimen with 7-Gy single-dose application plus anti-T-lymphocyte antibody OKT3 (n = 11) and/or antithymocyte globulin (n = 7)/fludarabine (n = 9), followed by an infusion of peripheral blood stem cells (n = 13) or bone marrow stem cells (n = 1) from related or unrelated donors, were retrospectively analyzed. RESULTS: Of the 14 recipients, the data from 11 were evaluable for engraftment after TLI-based reconditioning because 3 adults died early (at Day 2, 5, and 15) after the second transplantation of infectious complications. Engraftment in 4 adults was seen after a median of 12 days (range, 10-18) and occurred after a median of 10 days (range, 9-32) in the 7 children. TLI-based reconditioning was well-tolerated with no severe toxicity. The median overall survival and disease-free survival for the whole cohort was 140 days (range, 5-1,268). After a median follow-up of 681 days, the disease-free survival and overall survival rate was 85.7% and 85.7%, respectively, in the children. Despite engraftment in the 4 remaining adults, 1 died of fatal graft-vs.-host disease, 1 of infectious complications, 1 of disease relapse, and 1 of acute respiratory distress syndrome. CONCLUSIONS: In patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation, TLI-based reconditioning regimens allow sustained engraftment, paralleled by a favorable toxicity profile, potentially leading to long-term survival.

Relevance of C1 and C2 epitopes for hemopoietic stem cell transplantation: role for sequential acquisition of HLA-C-specific inhibitory killer Ig-like receptor.

Killer Ig-like receptors (KIR) and HLA class I ligands were studied in unrelated hemopoietic stem cell transplantation for chronic myeloid leukemia (n = 108). Significantly improved overall survival was observed in patients, which were homozygous for HLA-C-encoded group 1 (C1) ligands compared with those with group 2 (C2) ligands. Favorable outcome in the former patient group was an early effect that was highly significant in patients transplanted with G-CSF-mobilized peripheral blood and patients with advanced disease stages. In contrast, presence of C1 ligands in the donor was associated with significantly reduced patient survival. The differential roles of the two HLA-C ligands are explained in the context of a biased NK cell reconstitution, which is generally dominated by the presence of C1- but absence of C2-specific NK cells. The clinical observations are corroborated by in vitro experiments showing that NK cells derived from hemopoietic progenitor cells generally acquire the C1-specific inhibitory KIR2DL2/3 at earlier time points and with higher frequency than the C2-specific KIR2DL1. These findings define a novel determinant for understanding the role of NK cells in clinical hemopoietic stem cell transplantation.