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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., (Copyright © 2018. Published by Elsevier Inc.)

Lung function deterioration contributes to treatment-related morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Better understanding of impaired lung function including bronchiolitis obliterans syndrome (BOS) as chronic manifestation of graft-versus-host disease (GVHD) might improve outcomes of patients after allo-HCT. To detect early pulmonary function test abnormalities associated with BOS incidence and outcome after allo-HCT, we performed a retrospective analysis of homogenous-treated 445 patients (median age, 61.9 years; range, 19 to 76 years) with a reduced intensity/toxicity conditioning protocol. The cumulative incidence of BOS was 4.1% (95% confidence interval [CI], 2.6 to 6.4) at 1 year and 8.6% (95% CI, 6.3 to 11.6) at 5 years after allo-HCT with a median follow-up of 43.2 months (range, 3.3 to 209 months). In multivariate analysis, pre-existence of moderate small airway disease reflected by decreased midexpiratory flows before allo-HCT was associated with increased risk for BOS development. In addition, severe small airway disease before allo-HCT and combined restrictive/obstructive lung disease at day +100 after allo-HCT were associated with higher risk for nonrelapse mortality (NRM) due mainly to pulmonary cause of death. In summary, we identified novel pulmonary function test abnormalities prior and after allo-HCT associated with BOS development and NRM. These findings might help to identify a risk population and result in personalized GVHD prophylaxis and preventive or early therapeutic interventions., (Copyright © 2018. Published by Elsevier Inc.)

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to -4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days -5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Molecular pathogenesis of relapse after allogeneic hematopoietic cell transplantation is poorly understood. Data regarding relapse mechanisms after transplantation is scarcely available. We investigated genomic aberrations (GAs) in 21 patients undergoing related and unrelated HLA-matched transplantation in leukemic blasts before transplant and at relapse after transplantation. We found a higher number of GAs after transplantation, suggesting increased genomic instability during relapse. Two of 21 patients showed a large homozygous region spanning the whole HLA-locus on chromosome 6p in the relapse sample. In both patients sequence-based HLA typing of the blasts revealed a loss of the patient-specific allele at the mismatched locus leading to homozygosity for the HLA haplotype shared by the patient and the donor. In addition, GAs were found in critical regions such as 12p13, 13q12.2, and 17p13. Our results suggest that escape from immunologic surveillance may be a relevant mechanism of relapse after transplantation in patients with GAs on chromosome 6p. A combination of continuous immunologic pressure mediated by donor T cells and clonal evolution of myeloid leukemia may result in acquired GAs after transplantation., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Animal and human studies have shown that after allogeneic hematopoietic cell transplantation, epithelial cells containing donor-derived genome emerge. The mechanisms underlying this phenomenon are still unclear. We hypothesized that horizontal transfer of the hematopoietic donor-DNA to the host epithelium confers a possible operating mechanism. In an in vitro model mimicking the lymphocyte-epithelial interaction, we cocultivated keratinocyte HaCaT cells (Y-chromosome negative) with nonapoptotic or apoptotic, CMFDA, or BrdU-labeled hematopoietic Jurkat cells (Y+) and looked for the emergence of HaCaT cells bearing Jurkat genome. We found that DNA can be horizontally transferred from hematopoietic to epithelial cell lines through phagocytosis of apoptotic bodies. The ingested genomic material was also found within the nuclear compartment and in isolated chromosomes obtained from HaCaT metaphases. Both lysosomal inhibition in HaCaT cells and repetitive load of HaCaT cells with apoptotic bodies increased the intercellular and intranuclear DNA delivery. Although recipient cells remained viable and showed to express the foreign DNA, this expression was transient. Taking into consideration these findings of horizontal DNA transfer between hematopoietic and epithelial cells, we evaluated by quantitative microsatellite analysis the amount of donor DNA in 176 buccal swabs obtained from 71 patients after allogeneic transplantation. We found a high amount of donor-DNA (mean 26.6%) in the majority (89.7%) of them, although no donor hematopoietic cells were evident in the samples by immunofluorescence. We propose that the incessant charge of the transplant recipient with donor-DNA and its "inappropriate" intranuclear delivery in host epithelium may explain the emergence of epithelial cells with donor-derived genome., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Toxicity-reduced conditioning is a curative treatment option for medically compromised or elderly patients ineligible for myeloablative hematopoietic cell transplantation (HCT). The aim of this study was to detect prognostic factors for overall survival (OS) and to evaluate quality of life (QOL) in a large homogeneous cohort of 160 consecutive patients aged > or =60 years treated with allogeneic HCT. We evaluated age, sex, performance status, comorbidities, pulmonary function, lactic dehydrogenase concentration, type of donor, disease status, CD34(+) cells transplanted, cytomegalovirus status, time from diagnosis to HCT, and the development of acute and chronic graft-versus-host disease (GVHD). All patients who survived for > or =6 months (n = 79) were asked to complete a QOL survey. All patients (median age, 64.7 years; range, 60.1-76 years) received pretransplantation conditioning with fludarabine, BCNU, and melphalan. With a median follow-up of 35 months, the 1-year OS was 62.4% and 3-year OS was 47.4%. Multivariate analysis revealed compromised performance status as the most significant negative prognostic parameter for OS (P < .003), whereas male donor (P = .008) and chronic GVHD (P = .024) were associated with better OS. The 89% of survivors who returned the QOL questionnaire rated their global QOL as good-to-excellent despite impaired functional capabilities and such symptoms as fatigue, dyspnea, and loss of appetite. The main prognostic factor was performance status, not age. Our data suggest that toxicity-reduced conditioning offers a chance for enhanced OS with an adequate QOL.

Prophylaxis of acute graft-versus-host disease (aGVHD), while maintaining the graft-versus-leukemia (GVL)/lymphoma effect and preventing severe infectious diseases, remains the main challenge in allogeneic hematopoetic cell transplantation (allo-HCT). To evaluate this, we examined the feasibility of deescalating the dose of alemtuzumab (MabCampath) in combination with cyclosporine (CsA) as the sole GVHD-prophylaxis in patients after fludarabine (Flu)-based reduced-intensity conditioning (RIC) in an observational cohort study. We included 127 consecutive patients (median age 63 years) with an unrelated (UD; n=69) or related donor (SIB; n=58) after their first transplantation, mostly presenting with advanced disease. The first 30 patients received 20 mg/day on day -2 and -1 (40 mg), the following 48 patients 10 mg/day on day -2 and -1 (20 mg), and the last 49 patients 10 mg on day -1 (10 mg) alemtuzumab intravenous (i.v.) prior to transplant. We observed no statistical differences comparing the 40 mg, 20 mg, or 10 mg dose groups, in terms of cumulative incidences of aGVHD grade III-IV 7% (confidence interval [CI] 95%; 1-51), 12% (1-40), 6% (1-40), extensive chronic GVHD (cGVHD) 24.4% (3.3-55.8), 17% (2.5-42), and 14.2% (1.5-41.5) and of aGVHD grade II-IV 7 % (0-51.5), 29% (11.9-49.1), 21% (15.3-43.1), respectively. The difference between the 20-mg and 40-mg groups was significant for aGVHD grade II-IV(P < .05). In conclusion, we demonstrate the feasibility of reducing the dose of alemtuzumab as GVHD-prophylaxis to 10 mg absolute in combination with CsA only for UD transplantation in particular.

Development of severe steroid-resistant acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with poor outcome. The humanized monoclonal antibody alemtuzumab was shown to be effective in GVHD prophylaxis in conditioning regimens before allogeneic HCT. We evaluated the efficacy and safety of alemtuzumab in 20 patients with histologically confirmed steroid refractory grade III and IV intestinal GVHD after related and unrelated HCT. Overall response rate was 70%, with complete response in 35%. Despite the severe grade of GVHD in our patients, the median survival of 280 days and 1-year overall survival (OS) of 50% were superior or comparable to those associated with other treatment options. Cytomegalovirus (CMV) reactivation, bacterial infection, and invasive aspergillosis were frequent complications; however, infection was not a significant predictor for survival. These data suggest that treatment with alemtuzumab has favorable activity in severe intestinal GVHD after allogeneic HCT, but emphasize the importance of careful monitoring and anti-infectious supportive care.

Buccal administration of budesonide (mouthwash) may be effective as a topical add-on therapy in patients with oral chronic graft-versus-host disease (cGVHD). Safety of approved oral budesonide is based on high intestinal and hepatic extraction by cytochrome P450 3A (CYP3A) enzymes. The purpose of this study was to evaluate the presystemic extraction and pharmacodynamic action of buccal budesonide. Oral budesonide (3 mg) was taken as reference to which various single and multiple dose regimens of buccal budesonide were compared. Budesonide and the 2 main CYP3A-dependent metabolites (6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone) were analyzed in blood and urine along with the drug's effect on endogenous cortisol in 12 healthy subjects and 7 patients with oral cGVHD. We assessed CYP3A-dependent metabolites in both healthy subjects and patients after buccal budesonide. Whereas systemic exposure to budesonide was markedly lower in healthy subjects after the mouthwash compared to oral dosing (mean relative bioavailability 18%-36%), the systemic concentrations thereafter in patients were as high as those after the identical dose of oral budesonide. Reduced buccal CYP3A activity (lower inactivation of budesonide) in patients contributed to this remarkable difference. Endogenous cortisol was suppressed in some patients during 1 week of continuous treatment with buccal budesonide (3 x 3 mg per day). We are the first to report the biotransformation of budesonide via CYP3A enzymes after buccal drug administration. Only 2% of a buccal dose of budesonide achieves systemic circulation in healthy individuals; that fraction is 10% in patients with oral cGVHD, probably because of alterations in drug uptake and metabolization.