Search

Chronic diarrhea, villous atrophy and/or increased intraepithelial T-lymphocytes (IEL) occur in many inflammatory disorders including celiac disease (CD). However, a definite diagnosis is difficult to make in some patients despite an extensive diagnostic work-up. Clinical outcomes and histological phenotypes of such patients we refer to as unclassifiable enteropathy (UEP) remain unclear. We performed a retrospective single-center analysis of patients with chronic diarrhea, weight loss and increased IEL. Patients with defined etiologies including infections, CD, drugs, immunodeficiencies or neoplasms were excluded. Clinical and histologic/immunophenotypic parameters were analyzed. Nine patients with UEP were identified. Small intestinal damage ranged from minor villous abnormalities to complete atrophy while all patients displayed high numbers of CD103+ CD8+ IELs. In contrast to CD, these CD8+ T cells were not confined to the surface epithelium, but also infiltrated the crypts. Additional histological features included apoptotic crypt epithelial cells and mixed inflammatory infiltrates in the tunica propria. Involvement of other segments of the gastrointestinal tract was observed in 7/9 patients. A clonal intestinal T-cell lymphoproliferative disorder developed in 2 patients, one of which had a fatal disease course. The majority of patients responded to corticosteroids, while response to immunosuppressive medications yielded heterogeneous results. We report a patient population with 'difficult-to-classify' enteropathies characterized by various degrees of villous atrophy and strongly increased intraepithelial CD103+ CD8+ T cells in the small intestine which harbor an increased risk for T-cell lymphoproliferative disorders. Clinical course, histology, and response to immunosuppressive therapy all suggest an autoimmune pathogenesis. [ABSTRACT FROM AUTHOR]

Rabbit anti-T-lymphocyte-globulin (ATG) is used for immunosuppression in organ and stem cell transplantation. The aim of this study was to investigate ATG-induced cell death compared to CD95-signaling of apoptosis. We measured features of cell death at the cell membrane, mitochondria, nuclei and caspase-3 cleavage. We used the following inhibitors: the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (O-Me)-fluoromethyl ketone (zVAD-fmk), the serine protease inhibitors 3,4 dichloroisocoumarin (DCI) and N-alpha-tosyl-L-lysinyl-chloromethylketone (TLCK) and the reducing agent N-acetycysteine (NAC). ATG-induced cellular changes were rapid, included mitochondrial membrane permeability (MMP) induction and annexin V/propidium iodide (PI) positivity but little caspase-3 activation and nuclear morphology changes. MMP was not sensitive to caspase inhibition, serine protease inhibition with DCI moderately reduced MMP. These findings were in contrast to CD95-signaling. Interestingly, TLCK massively augmented CD95-induced MMP which could be abrogated by NAC. In conclusion, ATG-signaling differs in features and kinetics from CD95-induced apoptosis with caspase-independent mechanisms involved in MMP. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 24-year-old female who was diagnosed with acute disseminated encephalomyelitis (ADEM) by repeated brain biopsy while presenting with isolated central nervous system manifestation. It mentions that her bone marrow aspiration revealed no diagnostic clue and so was administered with Prednisolone was administered. It notes that the patient underwent chemoimmunotherapy.

Background: Rabbit polyclonal anti-T-lymphocyte Globulin ( ATG-F®, Fresenius) is widely used for GvHD prophylaxis in allogeneic stem cell transplantation (SCT). ATG has a wide epitope spectrum and has been shown to react with all compartments of peripheral blood mononuclear cells (PBMNCs). ATG induces apoptosis in all cellular compartments. In this study we investigated the binding of ATG in sera from ten patients treated with rabbit ATG to PBMNCs and subcellular compartments after full hematopoetic regeneration on day 21 post SCT. Methods: Sera from ten patients treated with unrelated donor allogeneic SCT for hematologie malignancy were collected after full hematopoetic regeneration on day 21 post SCT and incubated with healthy donor PBMNCs. Rabbit ATG on PBMNCs was detected by staining with fluorochrome labeled anti-rabbit igG antibody. PBMNC compartments were investigated by counterstaining with lineage markers CD4, CD8, CD14 CD20 and CD56. Positive control was the fresh ATG preparation. Results: We found that patient's' sera retained activity towards PBMNCs in all patients, yet at reduced intensity. When cell compartments were analyzed we found a differential pattern of ATG reactivity within sera. The mean percentage of total cells reacting with serum ATG from ten patients compared to fresh ATG (100%) was 44% of CD4 positive and 58% of CD8 positive T-lymphocytes, 41% of CD56 positive NK-cells, 83% of CD20 positive B-lymphocytes and 98% of CD14 positive monocytes. However, inter-individual variations were high with a wide spread around the mean especially for T-lymphocytes. Conclusion: We conclude that upon PBMNC regeneration following SCT and immunosuppressive treatment with ATG subpopulations of T-lymphocytes (CD4, CD8) and NK cells (CD56) are selected that lose epitopes recognized by ATG while B-lymphocytes (CD20) and monocytes (CD14) maintain a homogeneity with respect to epitopes recognized by ATG. This may be due to loss of idiotypes reacting with subpopulations of high frequency and turnover. Further studies should investigate the subphenotype of these populations and functional effects of extremely high or low reactivity with one or more compartments in some patients on GvHD and disease outcome. [ABSTRACT FROM AUTHOR]

Immune surveillance against malignant cells is mediated by cytotoxic T-lymphocytes and NK-cells (CTL/NK) that induce apoptosis through the granzyme-B-dependent pathway. The serine protease inhibitor serpinB9/protease inhibitor-9 (PI-9) is a known inhibitor of granzyme B. Ectopic expression of PI-9 in tumour cells has been reported. However, the impact of PI-9 on granzyme-B-induced apoptosis in tumour cells remains unclear. The aim of this study was to investigate the influence of constitutive PI-9 expression in leukaemia cell lines on the activity of granzyme B and apoptosis induction. PI-9 negative (lymphoblastic Jurkat cells; myeloblastic U937 cells) and PI-9-expressing cell lines (myeloblastic K562 cells, EBV-transformed LCL-1 and LCL-2 B-cells, lymphoblastic Daudi cells, AML-R cells f leukaemia and the U937 subclone U937PI-9 +). For accurate granzyme B activity determination a quantitative substrate (Ac-IEPD-pNA) cleavage assay was established and caspase-3 activation measured for apoptosis assessment. Cells were treated with a cytotoxic granule isolate that has previously been shown to induce apoptosis through granzyme B signalling. We found a robust correlation between constitutive PI-9 expression levels and the suppression of granzyme B activity. Further, inhibition of granzyme B translated into reduced caspase-3 activation. We conclude, suppression of granzyme B initiated apoptosis in PI-9-expressing cells could contribute to immune evasion and the measurement of granzyme B activity with our assay might be a useful predictive marker in immune-therapeutic approaches against cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [Copyright &y& Elsevier]

Abstract: Allogeneic haematopoietic cell transplantation (allo-HCT) provides effective therapy for patients with various haematological malignancies. In multiple myeloma (MM) this approach can induce response rates in 35–75% of patients. However, the outcome is hampered by high rates of treatment-related mortality (TRM). Reduced intensity conditioning to lower TRM has been successfully applied. The fact that previous clinical reports have documented graft-versus-myeloma (GVM) activity without graft-versus-host disease (GVHD) suggests that at least two distinct immunocompetent cell populations mediating GVHD and/or GVM may exist. Further characterization of effectors after allo-HCT and their targets may help to clarify the immune response that mediates the GVM effect. This review considers the clinical results with myeloablative and reduced intensity conditioning prior to allo-HCT for MM, with emphasis on attempts to prevent GVHD while preserving the GVM effect. Strategies including donor lymphocyte infusions as part of the allogeneic protocol and antigenic targets for GVM effect are reviewed. [Copyright &y& Elsevier]

Biologics are used in solid organ allografting and hematopoietic stem cell transplantation (HSCT) for the induction and maintenance of immunosuppression. In solid organ transplantation, antibodies targeting T cells are part of induction protocols administered for initiation of immunosuppression during organ transfer and during sustained post transplant periods for prevention of graft rejection. Several clinical trials in renal allografting provide data for the efficacy and safety of biologics in this clinical setting. Application of biologics also allows the reduction of calcineurin inhibitors, thereby reducing toxicity and improving long-term graft function. In acute rejection periods, anti T cell antibodies are established in steroid-resistant cases. Strategies interfering with the activity of soluble cytokines are less frequently applied for solid organ transplantation. In HSCT, T cell directed antibodies as part of conditioning protocols improve engraftment and reduce the incidence of detrimental graft vs host disease (GvHD). In acute GvHD, both antibodies targeting T cells and cytokines like TNF-α are established therapeutics for remission induction. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is highly sensitive to chemo- and radiotherapy. However, cure can not be achieved with conventional chemotherapy. Results from several large clinical trials indicate that 50–60% of patients treated with high dose chemo-/radiotherapy (HDT) and autologous blood stem cell transplantation (SCT) for relapse after standard chemotherapy have a 3–5-year chance of disease-free survival (DFS). Overall as well as disease-free survival are improved in patients with negative results in sensitive PCR assays for the disease-specific t(14;18) translocation in bone marrow (BM) or peripheral blood samples taken after transplantation. These data compare favourably to historical results with standard dose chemotherapy. The role of high dose therapy and autologous stem cell transplantation in the primary treatment of follicular lymphoma is presently addressed in randomized trials. Patients with refractory disease or relapsing from standard as well as high dose therapy can achieve long term complete remissions (CR) with allogeneic blood stem transplantation mainly due to the graft-versus-lymphoma effect of the donor immune system. [Copyright &y& Elsevier]

Despite improvements in HLA typing, graft-versus-host disease (GVHD) continues to impair the results after volunteer unrelated donor bone marrow transplantation (VUD-BMT) in adult patients compared with matched sibling BMT. Here, the outcome after VUD-BMT using a specific regimen with high-dose anti-T-lymphocyte globulin (ATG) was analysed. Fifty-five adult patients, median age 34 years (range 17–55 years), with acute or chronic leukaemia or myelodysplastic syndrome (MDS) were transplanted in first complete remission (CR1)/first chronic phase (CP1) (early disease) (n = 21) or in advanced (CR2/CP2, no remission) disease (n = 34) from an unrelated marrow donor. GVHD prophylaxis consisted of ATG-S (Fresenius) 60–90 mg/kg b.w. prior to transplantation, in addition to cyclosporin A and short-course methotrexate. Graft failure did not occur and white blood cell count (WBC) > 1·0 × 109/l was reached at median day +16. The cumulative incidence of acute (a)GVHD grade II–IV was 15% [95% CI (8%, 28%)] and of chronic GVHD was 51% [95% CI (38%, 68%)]. The cumulative incidence of relapse within 1 year was 0% [95% CI (0%, 19%)] and 21% [95% CI (11%, 40%)] for patients with early and advanced disease respectively. With a median follow-up of 28 months (range 16–45 months), 2-year disease-free and overall survival for patients transplanted in CR1/CP1 was 81% and 81% [95% CI (64%, 98%)], respectively, and for patients with advanced disease was 33% [95% CI (17%, 50%)] and 40% [95% CI (23%, 57%)] respectively. Complete and persistent donor chimaerism was seen in 77·5% of 40 patients evaluated. All 14 chronic myeloid leukaemia (CML)-CP1 patients became bcr–abl negative within 250 d. High-dose ATG pretransplant results in a low incidence of severe aGVHD without compromising donor chimaerism or elimination of minimal residual disease. Our results are similar to data obtained after matched sibling donor transplantation. [ABSTRACT FROM AUTHOR]

Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto‐HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety‐six patients undergoing auto‐HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO‐diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto‐HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT‐CI score ≥ 4, and cardiac disease before auto‐HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto‐HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non‐relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto‐HSCT. [ABSTRACT FROM AUTHOR]

Antifungal prophylaxis/therapy (AP/AT) raises the cost of allogeneic haematopoietic cell transplantation (alloHCT). Its efficacy, different approaches for AP/AT, diagnostic measures and cost-effectiveness must still be evaluated. In 2010, we conducted a prospective study with 106 consecutive patients receiving an alloHCT analysing AP/AT, choice and costs of diagnostics applied including CT scans, galactomannan (Gal) and β-D-glucan (β-D) testing. Antifungal prophylaxis in 91 patients consisted of fluconazole (FLU) or L-AMB (AmBisome™ 1 or 3 mg/kg/day b.w.), and antifungal therapy had to be initiated in 38 % of the FLU/L-AMB-1-mg patients but in none with L-AMB 3 mg. Empirical AT consisted of L-AMB 1 mg/kg (n = 12) and preemptive AT of L-AMB 3 mg/kg (n = 17) and proved very efficacious with no further antifungal drug escalation in 89.6 %. Mean costs of diagnostic measures were 402 €/alloHCT; however, only 22 % of the CT scans, 4 % of β-D and 3 % of galactomannan testing were positive. We detected one proven, 17 probable and 14 possible fungal infections. Due to the German diagnosis-related group system with additional compensation, all our AP/AT strategies were adequately reimbursed. While clinical symptoms and CT scans are the most commonly used, inexpensive decision-making tools for starting AT, the expensive laboratory diagnostic procedures are ineffective; we have therefore discontinued regular GAL/β-D testing and changed our AP in patients at risk. [ABSTRACT FROM AUTHOR]

• Relapse- and immunosuppression-free survival were novel endpoints after transplant. • These endpoints were formulated and statistically analyzed by multistate methodology and resampling. • A randomized clinical trial was conducted on GVHD prophylaxis. • The difference between treatment groups was estimated as approximately 30% over 8 years. • An R code was provided to promote our methods to the transplant community. In most clinical oncology trials, time-to-first-event analyses are used for efficacy assessment, which often do not capture the entire disease process. Instead, the focus may be on more complex time-to-event endpoints, such as the course of disease after the first event or endpoints occurring after randomization. We propose "relapse- and immunosuppression-free survival" (RIFS) as an innovative and clinically relevant outcome measure for assessing treatment success after hematopoietic stem cell transplant (SCT). To capture the time-dynamic relationship of multiple episodes of immunosuppressive therapy during follow-up, relapse, and nonrelapse mortality, a multistate model was developed. The statistical complexity is that the probability of RIFS is nonmonotonic over time; thus, standard time-to-first-event methodology is inappropriate for formal treatment comparisons. Instead, a generalization of the Kaplan-Meier method was used for probability estimation, and simulation-based resampling was suggested as a strategy for statistical inference. We reanalyzed data from a recently published phase III trial in 201 leukemia patients after SCT. The study evaluated long-term treatment success of standard graft-versus-host disease prophylaxis plus a pretransplant antihuman T-lymphocyte immunoglobulin compared with standard prophylaxis alone. Results suggested that treatment increased the long-term probability of RIFS by approximately 30% during the entire follow-up period, which complements the original findings. This article highlights the importance of complex endpoints in oncology, which provide deeper insight into the treatment and disease process over time. Multistate models combined with resampling are highlighted as a promising tool to evaluate treatment success beyond standard endpoints. An example code is provided in the Supplementary Materials. [ABSTRACT FROM AUTHOR]

• Allotransplant for myelodysplastic syndrome is limited by high nonrelapse mortality. • Comorbidities assessed by the original Sorror score impact mortality negatively. • Chronological age also continues to play an independent prognostic role on mortality. • Both age and comorbidities should be integrated in the allotransplant decision process. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDSs) but is severely limited by nonrelapse mortality (NRM), especially in this mostly older population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years, the age at which transplants are made has been progressively increasing, and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study by the European Group for Blood and Marrow Transplantation registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDSs between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47%, respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio (HR) for NRM. In multivariate analysis, age band (HR, 1.13; 95% CI, 1.02 to 1.25; P =.016), HCT-CI ≥3 (HR, 1.34; 95% CI, 1.04 to 1.73; P =.022), and Karnofsky Performance Status ≤80 (HR, 2.03; 95% CI, 1.52 to 2.73; P <.0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDSs. [ABSTRACT FROM AUTHOR]

Background: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after ≥2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes.Methods: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after ≥2 courses of induction chemotherapy.Results: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively.Conclusions: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. Cancer 2017;123:1965-1970. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Despite improvements in DLBCL therapy and the availability of a range of new anti-lymphoma drugs and effective salvage strategy, it remains an urgent medical need to improve first-line treatment outcomes in patients with DLBCL or HGBL with high-risk features. Favourable outcomes of double-hit/double-expressor lymphoma and high-grade B-cell lymphoma, not otherwise specified after early dose-intensive treatment and up-front autologous stem cell transplantation: a single-centre retrospective experience Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and burkitt lymphoma: study of 39 cases. [Extracted from the article]

Simple Summary: The major cause of treatment failure after allogeneic stem cell transplantation (allo-HSCT) is due to relapse of the underlying disease. Novel methods and strategies are needed to detect early relapse after allo-HSCT. The present study reports the clinical utility of monitoring measurable residual disease (MRD) and mixed chimerism (MC) by droplet-digital PCR in circulating cell-free DNA (cfDNA) in 62 patients with myeloid malignancies undergoing allo-HSCT. MC in circulating cfDNA at an optimal threshold of 18% discriminated patients with hematological relapse from patients in complete remission after allo-HSCT. Most of the mutations identified using a targeted next-generation sequencing (NGS) panel were detected in cfDNA at relapse and were suitable for the monitoring of MRD. In several cases, mutations were detected earlier in cfDNA than in peripheral blood mononuclear cells. In conclusion, longitudinal analysis of cfDNA for MRD and MC can be used as a complementary tool for early detection of relapse in patients after allo-HSCT and could be used to guide clinical interventions. Relapse of the underlying disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe the clinical utility of measurable residual disease (MRD) and mixed chimerism (MC) assessment in circulating cell-free DNA (cfDNA) analysis to detect earlier relapse in patients with hematological malignancies after allo-HSCT. A total of 326 plasma and peripheral blood mononuclear cell (PBMCs) samples obtained from 62 patients with myeloid malignancies were analyzed by droplet-digital PCR (median follow-up: 827 days). Comparison of MC in patients at relapse and in complete remission identified an optimal discriminating threshold of 18% of recipient-derived cfDNA. After performing a targeted next-generation sequencing (NGS) panel, 136 mutations in 58 patients were detected. In a total of 119 paired samples, the putative mutations were detected in both cfDNA and PBMCs in 73 samples (61.3%). In 45 samples (37.8%) they were detected only in cfDNA, and in only one patient (0.9%) were they detected solely in DNA from PBMCs. Hence, in 6 out of 23 patients (26%) with relapse after allo-HSCT, MRD positivity was detected earlier in cfDNA (mean 397 days) than in DNA derived from PBMCs (mean 451 days). In summary, monitoring of MRD and MC in cfDNA might be useful for earlier relapse detection in patients with myeloid malignancies after allo-HSCT. [ABSTRACT FROM AUTHOR]

Background aims. The anti-CD52 monoclonal antibody alemtuzumab is employed in allogeneic hematopoietic cell transplantation (alloHCT) for the prevention of graft-versus-host disease (GVHD). However, its optimal dosing in this setting has not been determined yet. We compared three different alemtuzumab dose levels in reduced intensity conditioning (RIC) alloHCT with respect to lymphocyte recovery and outcome. Methods. In 127 consecutive patients with predominantly advanced stage hematologic malignancies, a first alloHCT after RIC was performed, applying a fludarabine-based protocol (in 93% FBM: fludarabine, bis-chloroethyl-nitrosourea [BCNU], and melphalan). For GVHD prophylaxis, cyclosporine and alemtuzumab at three different dose levels (40 mg, 20 mg, 10 mg) were administered. Recovery of the peripheral blood (PB) lymphocyte sub-populations and clinical outcome were determined with regard to the alemtuzumab dose. Results. Natural killer (NK) cell concentrations in PB around day +30 correlated inversely with the alemtuzumab dose, whereas other PB lymphocyte subtypes remained essentially unaffected by dosing of alemtuzumab. Lower alemtuzumab doses were associated with a tendency toward improved overall survival mainly during the early post-transplantation months. With regard to the PB NK cell concentration around day +30, "early intense NK cell reconstituters" tended to show an overall survival benefit. Conclusions. An alemtuzumab dose reduction to only 10-20 mg provides sufficient GVHD prophylaxis and supports improved NK cell regeneration early after alloHCT in PB ("NK cell saving effect"), which may have a positive effect on overall survival. [ABSTRACT FROM AUTHOR]

In our patient, s.c.-daratumumab administration was safe and resulted in a long-term remission, leading us in two recent severely refractory ITP patients to conventional ITP treatment to treat them likewise. Dear Editor, Idiopathic immune thrombocytopenia (ITP) is a common acquired autoimmune-mediated thrombocytopenia. Of note, one patient responded like our first patient, but the other patient unfortunately did not respond to daratumumab treatment. [Extracted from the article]

Simple Summary: Due to its graft-versus-myeloma effect, allogeneic hematopoietic stem cell transplantation (allo-SCT) can enable long-term survival or even cure in carefully selected patients with multiple myeloma (MM), but remains controversial due to its relevant treatment-related toxicity. Current data suggest that allo-SCT should be considered in young MM-patients without relevant comorbidities in case of a high-risk constellation according to cytogenetics or stage, primarily as part of a tandem approach with autologous-SCT followed by allo-SCT and early in the course of the disease. Prospective studies are warranted, due to a suspected synergism especially those including new immunotherapeutic approaches for induction, conditioning and maintenance therapy. The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches. [ABSTRACT FROM AUTHOR]

Induction of tumor-antigen-specific T cells in active cancer immunotherapy is generally difficult due to the very low anti-tumoral precursor cytotoxic T cells. By improving tumor-antigen uptake and presentation by dendritic cells (DCs), this problem can be overcome. Focusing on MAGE-A3 protein, frequently expressed in many types of tumors, we analyzed different DC-uptake routes after additional coating the recombinant MAGE-A3 protein with either a specific monoclonal antibody or an immune complex formulation. Opsonization of the protein with antibody resulted in increased DC-uptake compared to the uncoated rhMAGE-A3 protein. This was partly due to Fcγ receptor-dependent internalization. However, unspecific antigen internalization via macropinocytosis also played a role. When analyzing DC-uptake of MAGE-A3 antigen expressed in multiple myeloma cell line U266, pretreatment with proteasome inhibitor bortezomib resulted in increased apoptosis compared to γ-irradiation. Bortezomib-mediated immunogenic apoptosis, characterized by elevated surface expression of hsp90, triggered higher phagocytosis of U266 cells by DCs involving specific DC-derived receptors. We further investigated the impact of antigen delivery on T-cell priming. Induction of CD8 T-cell response was favored by stimulating naïve T cells with either antibody-opsonized MAGE-A3 protein or with the bortezomib-pretreated U266 cells, indicating that receptor-mediated uptake favors cross-presentation of antigens. In contrast, CD4 T cells were preferentially induced after stimulation with the uncoated protein or protein in the immune complex, both antigen formulations were preferentially internalized by DCs via macropinocytosis. In summary, receptor-mediated DC-uptake mechanisms favored the induction of CD8 T cells, relevant for clinical anti-tumor response. [ABSTRACT FROM AUTHOR]

Standard first-line therapy for older patients with high-risk myelodysplastic syndrome (MDS) includes hypomethylating agents, such as azacitidine (AZA). However, the only approach with curative potential remains allogeneic hematopoietic cell transplantation (HCT). To date, no direct comparison of both strategies has been reported. The outcomes of 2 well-balanced cohorts of patients with high-risk MDS defined by age (60-70 years), performance status (Eastern Cooperative Oncology Group score ≤2), and donor availability (yes/no) were compared, including 103 patients undergoing HCT and 75 patients without this option who received AZA. The estimated 2-year overall survival after the start of treatment was 39% (95% confidence interval, 30%-50%) for the patients undergoing HCT and 23% (95% confidence interval, 14%-40%) for the patients receiving AZA therapy. In a multivariate Cox regression analysis of all patients (n = 178), Eastern Cooperative Oncology Group score (0 versus 1 versus 2; hazard ratio [HR], 2.9/3.9; P <  .001), cytogenetics (good versus intermediate versus poor; HR, 1.2/1.7; P = .026), and treatment (HCT versus AZA; HR, 0.3; P = .007) were associated with overall survival. This retrospective cohort analysis suggests a survival advantage for allogeneic HCT compared with AZA therapy in medically fit patients with high-risk MDS age 60-70 years. Prospective controlled studies are warranted. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) frequently involves oral tissues. Although the mucosal changes may be painful and impair oral function, there is currently no topical therapy available for oral cGVHD that has been proven to work in an evidence-based manner. The aims of this study were to (1) assess the response of patients with oral cGVHD to various doses of a new topical budesonide formulation; (2) evaluate the efficacy and safety of the new topical budesonide formulation in these patients. An open, randomized, multicenter phase II pilot study with 4 treatment arms differing in application frequency and duration was performed. Response to treatment was scored by the clinician and patient using several scales. Oral cGVHD improved in all patients, with a median reduction of 70%. Pain reduction was similar in all study arms. The rate of objective improvement (defined as ≥50%) was not significantly different among the 4 study arms. The safety profile was satisfactory. Topical budesonide mouthwash (3 mg/10 mL) improved oral cGVHD in all patients when applied for 5 or 10 minutes, 2 or 3 times daily. The response was similar in all treatment arms. Safety analysis supported a dosing schedule of 3 mg of budesonide 3 times a day for 10 minutes. [ABSTRACT FROM AUTHOR]

Abstract: Polyclonal anti-T-lymphocyte globulins (ATG) are used in allogeneic stem cell transplantation (SCT) for the prophylaxis of graft versus host disease (GVHD) by in vivo T cell depletion. In this study we investigated the complement independent induction of apoptosis by rabbit ATG in peripheral blood mononuclear cell (PBMNC) compartments and hematopoetic stem cells (HSC). We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells. We found ATG to induce apoptosis in T-lymphocytes (CD4+, CD8+), B-lymphocytes (CD20+), natural killer (NK)-cells (CD56+), and monocytes (CD14+). HSC, in contrast, were apoptosis resistant and could be growth stimulated by low-dose ATG in the presence of bystander cells. The human leukemia cell lines Jurkat, Daudi, DG-75 (lymphoblastic), and K562, HL-60, KG1, and U937 (myeloblastic) underwent ATG-induced apoptosis, whereas the NK-cell line YT was resistant. Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia, 9 of 10 patients with chronic lymphocytic leukemia, and 4 of 8 patients with acute myeloblastic leukemia underwent ATG-induced apoptosis. We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis. ATG might support engraftment. Finally, antileukemic activity of ATG could positively influence the transplantation outcome. [Copyright &y& Elsevier]

Cytotoxic T lymphocytes and natural killer cells (CTL/NK) induce cell death in leukemia cells by the granzyme B (grB)-dependent granule cytotoxin (GC) pathway. Resistance to GC may be involved in immune evasion of leukemia cells. The delivery of active grB into the cytoplasma is dependent on the presence of perforin (PFN) and grB complexes. We developed a rapid method for the isolation of GC to investigate GC-mediated cell death in primary leukemia cells. We isolated GC containing grB, grB complexes and PFN by detergent free hypotonic lysis of the human NK cell leukemia line YT. The GC induce grB-mediated, caspase-dependent apoptosis in live cells. The human leukemia cell lines KG-1, U937, K562 (myeloid leukemia), Jurkat, Daudi, and BV173 (lymphoblastic leukemia) treated with GC internalized grB and underwent cell death. In primary leukemia cells analyzed ex vivo, we found GC-resistant leukemia cells in three out of seven patients with acute myeloid leukemia and one out of six patients with acute lymphoblastic leukemia. We conclude that our method is fast (approximately 1 h) and yields active GC that induce grB-dependent cell death. Furthermore, resistance to GC can be observed in acute leukemias and may be an important mechanism contributing to leukemia cell immune evasion. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI "preemptively," in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML. [ABSTRACT FROM AUTHOR]

We report a single-center phase I/II trial exploring the combination of everolimus (EVE) and mycophenolate mofetil (MMF) as calcineurin inhibitor (CNI)-free GVHD prophylaxis for 24 patients with hematologic malignancies and indication for allogeneic HCT after a high dose or reduced-intensity ablative conditioning. The study was registered as EudraCT-2007-001892-12 and Clinicaltrials.gov as NCT00856505. All patients received PBSC grafts and no graft failure occurred. 7/24 patients (29%) developed acute grades III and IV GVHD (aGVHD), 16/19 evaluable patients (84%) developed chronic GVHD (cGVHD) of all grades, and 6/19 (31.6%) of higher grades. No severe toxicities related to study medication were observed. The median follow-up of all surviving patients is 2177 days. The 3-year OS was 45.2% (95% CI: 27.4–61.4%), and the 3-year PFS was 38.7% (95% CI: 22.0–55.1%). The cumulative incidence of relapse at 1 year and 3 year was 25% (95% CI: 12.5–50.0%), and 33.3% (95% CI: 18.9–58.7%), the cumulative incidence of NRM at 1 year and 3 years was 20.8% (95%CI: 9.6–45.5%), and 29.2% (95%CI: 15.6–54.4%), respectively. The utilization of CNI-free GVHD prophylaxis with EVE+MMF resulted in high rates of acute and chronic GVHD. Therefore, we do not recommend a CNI-free combination of mTOR inhibitor EVE with MMF as the sole GVHD prophylaxis. In subsequent studies, this combination should be modified, e.g., with further components like post-transplant cyclophosphamide (PTCy) or anti-thymocyte globulin (ATG). [ABSTRACT FROM AUTHOR]

Summary: Optimal donor choice for a second allogeneic haematopoietic cell transplant (allo‐HCT) in relapsed acute myeloid leukaemia (AML) remains unknown. We compared overall survival (OS) using registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) involving 455 adults who received a second allo‐HCT from a human leucocyte antigen (HLA)‐matched unrelated (MUD) (n = 320) or a haploidentical (n = 135) donor. Eligibility criteria required adults aged ≥18 years who received a second allo‐HCT for treating AML relapse between 2005 and 2019. The primary end‐point was OS. There was no statistically significant difference in the median (interquartile range) age between the groups, MUD 46 (35–58) versus haploidentical 44 (33–53) years (P = 0·07). The median OS was not different between the MUD and the haploidentical groups (10 vs. 11 months, P = 0·57). Similarly, the 2‐year OS was 31% for the MUD and 29% for the haploidentical donor groups. The OS was worse if the procedure was performed with active AML [hazard ratio (HR) 1·42, 95% confidence interval (CI) 1·07–1·89; P = 0·02]. Conversely, a longer time from first allo‐HCT to relapse (>13·2 months) was associated with better OS (HR 0·50, 95% CI 0·37–0·69; P < 0·0001). The results of the present analysis limit the ability to recommend one donor type over another when considering a second allo‐HCT for relapsed AML. Our findings highlight that best OS is achieved when receiving the second allo‐HCT in complete remission. [ABSTRACT FROM AUTHOR]

• FLAMSA (fludarabine, Ara-C, and amsacrine) sequential chemotherapy followed by total body irradiation (TBI)-based reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) led to similar transplantation outcomes in relapsed/refractory active acute myeloid leukemia. • FLAMSA sequential chemotherapy followed by TBI-free RIC was associated with lower nonrelapse mortality resulting in increased overall survival. • There were no significant differences in relapse incidence between FLAMSA sequential chemotherapy followed by RIC and MAC. The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P =.04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P =.03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM:.40, P =.01; HR for OS:.65, P =.01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting. [ABSTRACT FROM AUTHOR]

Ibrutinib in patients with relapsed/refractory central nervous system lymphoma: A retrospective single-centre analysis Keywords: BTK inhibition; central nervous system lymphoma; Ibrutinib; real-world analysis; relapsed/refractory disease EN BTK inhibition central nervous system lymphoma Ibrutinib real-world analysis relapsed/refractory disease e110 e114 5 07/20/20 20200715 NES 200715 Central nervous system lymphomas (CNSL) including primary CNSL (PCNSL) and isolated secondary CNSL (iSCNSL) are rare diseases predominantly classified as diffuse large B-cell lymphomas (DLBCL). Two patients deceased immediately after disease progression following ibrutinib treatment and one patient was lost to follow-up after PD (Table SI, Figure S1). [Extracted from the article]

Treosulfan conditioning for allogeneic transplantation in multiple myeloma - improved overall survival in first line haematopoietic stem cell transplantation - a large retrospective study by the Chronic Malignancies Working Party of the EBMT Keywords: multiple myeloma; allogeneic stem cell transplantation; treosulfan; reduced intensity conditioning; myeloablative conditioning EN multiple myeloma allogeneic stem cell transplantation treosulfan reduced intensity conditioning myeloablative conditioning e213 e217 5 06/08/20 20200601 NES 200601 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of multiple myeloma (MM) is controversial mainly due to the high non-relapse mortality (NRM) with myeloablative conditioning (MAC). Our study shows that Treo-conditioning in upfront-treated patients is superior to other RIC- or MAC-conditioning regimens for reducing NRM without hampering long-term survival, despite a slightly increased relapse rate. Treosulfan, treosulfan included in a conditioning regime; RIC, non-treosulfan-reduced intensity conditioning; MAC, non-treosulfan myeloablative conditioning. [Extracted from the article]

Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing-based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/- mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-β-activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor-based approach against GVHD-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

• In this largest cohort of myelofibrosis transplants analyzed to date, no significant difference in 5-year probabilities of overall survival (OS) was noted between those undergoing myeloablative conditioning (MAC) (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and reduced-intensity conditioning (RIC) (51.0%; 95% CI, 48.3% to 53.7%); P =.78. • Graft failure rates appeared higher in those undergoing RIC protocols compared with MAC protocols. • MAC platforms demonstrated a trend toward less relapse and significantly improved graft-versus-host disease-free/relapse-free survival, although this requires validation. This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P =.10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P =.08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P =.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P =.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required. [ABSTRACT FROM AUTHOR]

• Marked improvement has been achieved in recent years in stem cell transplantation (SCT) from unrelated donors. • Long-term outcome is equivalent after SCT from unrelated and sibling donors. • Patients who are leukemia-free 2 years after SCT can expect a favorable outcome. Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDs) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P =.005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P <.001). Sixty-one percent of siblings and 62% of MUDs had reduced-intensity conditioning (P =.78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P =.30). Multivariate analysis identified active leukemia at SCT (hazard ratio [HR], 1.86; P =.0001) or CR2 (HR, 1.51; P =.02) compared with CR1, female recipients (HR, 0.71; P =.006), adverse cytogenetics (HR, 2.52; P =.01), and prior graft-versus-host disease (HR, 1.31; P =.04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence was 15% and 17% (P =.97) for late relapse mortality and 13% and 21% for late nonrelapse mortality, respectively (P =.15). In conclusion, long-term LFS is similar, and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types. [ABSTRACT FROM AUTHOR]

Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p =.02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p =.04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation. [ABSTRACT FROM AUTHOR]

• Overall outcomes of patients allografted for BC CML remain poor in the TKI era. • Survival after alloSCT for BC CML depends on the pretransplant remission status. • Conventional prognostic factors remain outcome determinants for BC CML in remission. • UD transplant is associated with better LFS in patients with active BC at alloSCT. The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry-based study of adult patients allografted for BC CML, focusing on patients with active disease at transplant and pretransplant prognostic factors. One hundred seventy patients allografted for BC CML after tyrosine kinase inhibitor pretreatment between 2004 and 2016 were analyzed. Before transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (hazrd ratio, 1.87; P =.010) and shorter leukemia-free survival (LFS; hazard ratio, 1.69; P =.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended toward improved overall survival. In summary, survival of patients allografted for BC CML was strongly dependent on pretransplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplant was associated with prolonged LFS in our study. [ABSTRACT FROM AUTHOR]

Introduction Recurrent disease is the major cause of treatment failure after allogeneic stem cell transplantation (SCT) in patients with AML. Second SCT (SCT2) is a valid treatment option in this setting but outcome is relatively poor. Haplo-identical (haplo) SCT is increasingly used over the last decade due to the introduction of non T-depleted methods. Prior studies have shown similar outcome when using the same or different HLA-matched donor for SCT2. However, there is relatively limited data on the use of haplo-donors in this setting. Methods and Results The study included 556 patients with AML relapsing after a first allogeneic SCT (SCT1) given in CR1 from sibling (sib, n= 294) or unrelated donor (UD, n=262) and given SCT2 during the years 2006-2016. The median age at SCT2 was 46 years (20-73). 247 patients were in CR2 (45%) and 309 had active leukemia (55%) at SCT2. The conditioning regimen for SCT1 was myeloablative (MAC, 66%) or reduced-intensity (RIC, 34%), and 41% and 59%, respectively for SCT2. Patients were divided into 3 groups based on the donor selected for SCT2; 1) same donor (n=163, sib/sib-112, UD/UD-51), 2) different matched donor (n=305, sib/different sib-44, sib/UD-93, UD/ different UD- 168), 3) haplo-donor (n=88, sib/haplo-45, UD/haplo-43). All haploSCT were non T-depleted. The 2-year leukemia-free survival (LFS) after SCT2 was 23.5%, 23.7% and 21.8%, respectively (unadjusted P=0.30). Multivariate analysis showed no effect of second donor type on subsequent relapse, hazard ratio (HR) 0.96 (P=0.83) and 1.20 (P=0.47) for different donor and haplo-donor compared to same donor, respectively. UD in SCT1, CR2 at SCT2 and chronic GVHD after SCT1 were associated with reduced relapse risk after SCT2, HR 0.70 (P=0.02), 0.60 (P=0.001) and 0.66 (P=0.03), respectively. Second donor type did predict for non-relapse mortality (NRM) after SCT2; HR 1.26 (P=0.41) and 2.18 (P=0.02) for different donor and haplo-donor compared to same donor, respectively. Advanced age and MAC in SCT1 also predicted for NRM, HR 1.40 (P<0.001) and 0.61 (P=0.04), respectively. The second donor predicted for LFS after SCT2; HR 1.05 (P=0.77) and 1.55 (P=0.03), respectively. Advanced age and SCT2 in CR2 predicted for LFS; HR 1.11 (P=0.06) and 0.66 (P=0.002), respectively. In all, there were no differences between same or different matched donors in SCT2 outcomes, but haploSCT2 was associated with higher NRM and lower LFS. The inferior outcome after SCT2 with haplo-donor was limited to patients given MAC in SCT1 and not observed in patients given RIC in SCT1. Conclusions Second SCT with the same donor or different matched donor is associated with similar outcomes in patients with relapsed AML after a first SCT. However, SCT2 with a haplo-donor is associated with higher NRM and lower LFS, mostly in patients given MAC in SCT1. Second haplo donor does not provide better GVL effect in this setting. [ABSTRACT FROM AUTHOR]

Summary: Although second allogeneic haematopoietic cell transplantation (allo‐HCT2) is a therapeutic option for patients relapsing after first HCT (allo‐HCT1), there is limited data on allo‐HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo‐HCT2 as a salvage treatment for relapse following allo‐HCT1 between the 2000 and 2017. The median age at allo‐HCT2 was 34·6 years (range: 18–74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo‐HCT2. Acute graft‐versus‐host disease (GVHD) grade II–IV and III–IV occurred in 33% and 17% of the patients, respectively. The incidence of 2‐year total and extensive chronic GVHD was 38% and 19%, respectively. The 2‐ and 5‐year cumulative incidence of non‐relapse mortality, relapse incidence, leukaemia‐free survival, overall survival and GVHD‐free, relapse‐free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo‐HCT1 to relapse, conditioning for allo‐HCT1, Karnofsky score at allo‐HCT2 and donor type for allo‐HCT2. In conclusion, outcomes of allo‐HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence. [ABSTRACT FROM AUTHOR]

• The DIPSS was not predictive of survival in myelofibrosis secondary to essential thrombocythemia or polycythemia vera after stem cell transplantation. • The MYSEC-PM predicted survival and showed improved prognostic ability. • Although performance of the MYSEC-PM was still moderate, risk stratification may be improved by incorporating clinical, mutational, and transplant-related factors. We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P =.78). Overall, the DIPSS was not significantly predictive of outcome (P =.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P =.05), whereas groups with intermediate 2 and high risk showed no significant difference (P =.44). Assessment of prognostic utility yielded a C-index of.575 (95% CI,.502 to.648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of.636 (95% CI,.563 to.708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P =.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P =.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification. [ABSTRACT FROM AUTHOR]

Summary: Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo‐HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)‐identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3‐year progression‐free (PFS) and overall survival (OS) for the entire group was 36% (34–37%) and 41% (40–43%), respectively. The cumulative incidence of relapse and non‐relapse mortality (NRM) was 37% (35–39%) and 27% (26–29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo‐HSCT. [ABSTRACT FROM AUTHOR]

Background: Minimal residual disease (MRD) and hematopoietic chimerism testing influences clinical decision and therapeutic intervention in patients after allogeneic stem cell transplantation (HSCT). However, treatment approaches to induce complete donor chimerism and MRD negativity can lead to complications such as graft-versus-host disease (GvHD) and marrow aplasia. Therefore, there is a need for comprehensive characterization of the molecular remission status after transplantation. Methods: We analyzed 764 samples from 70 patients after HSCT for the simultaneous measurement of chimerism and molecular targets used for MRD testing with a digital PCR (dPCR) platform. Results: Mixed chimerism (MC) was detected in 219 samples from 37 patients. The mean percentage of host derived DNA in these clinical samples was 4.3%. Molecular relapse with a positive MRD marker and/or increased WT1 expression was observed in 15 patients. In addition to WT1 overexpression, other MRD positive markers were: NPM1 (Type A, B, K), DNMT3A (R882H), MLL-PTD, IDH1 (R132H) and KRAS (G12S). Increasing MC was observed in 15 patients. This group of patients showed either a positive MRD marker, increased WT1 expression or both. Next, we analyzed whether MC or the molecular target for MRD was first detected. MC and MRD marker positivity in this group was first detected in six and two patients, respectively. In the remaining seven patients MC and MRD positivity was detected simultaneously. Conclusions: The combination of MRD and chimerism markers in a dPCR platform represents a practical, sensitive and accurate diagnostic tool for the comprehensive assessment of the molecular remission status of patients undergoing HSCT. [ABSTRACT FROM AUTHOR]

Highlights • Major mechanisms of relapse include HLA loss, HLA down-regulation, and expression of coinhibitory ligands. • Combination of donor lymphocyte infusion with immunomodulating agents and tyrosine kinase inhibitors may enhance the graft-versus-leukemia (GVL) effect. • Immune checkpoint inhibitors can induce a significant GVL effect, but toxicity is high. ABSTRACT The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs. [ABSTRACT FROM AUTHOR]

Highlights • Overall survival, progression-free survival, and nonrelapse mortality were better in haploidentical than in cord blood donors. • Nonrelapse mortality was not significantly different between haploidentical and mismatched unrelated donor. • Relapse risk was not influenced by the type of donor. • Acute graft-versus-host disease risk was lower with haploidentical or cord blood donors than with mismatched unrelated donors. • Chronic graft-versus-host disease was not influenced by the type of donor. Abstract Recently, haploidentical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood (CB) donor, and a haploidentical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haploidentical donor using PTCy, an HLA-mismatched unrelated donor (marrow or peripheral blood stem cells), or an unrelated mismatched CB donor. A total of 833 MDS patients from the European Group for Blood and Marrow Transplantation (EBMT) registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared with mismatched unrelated and CB donors in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute graft-versus-host disease (GVHD) than mismatched unrelated donor (P =.010) but at similar risk than CB. Progression-free survival was better after haplo (versus mismatched unrelated, P =.056; versus CB, P =.003) and overall survival tended to be superior after haplo (versus mismatched unrelated, P =.082; versus CB, P =.002). Nonrelapse mortality was not significantly different between haplo and mismatched unrelated donors. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving hematopoietic stem cell transplantation from a haplo donor have significantly better outcome than those receiving hematopoietic stem cell transplantation from a CB donor and at least similar or better outcome than with a mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption. [ABSTRACT FROM AUTHOR]

Highlights • The impact of donor age and sex but not CMV matching is comparable with that of single HLA disparity on survival after HSCT. • Similar survival after matched unrelated and related donor HSCT for AML or MDS reflects lower NRM but higher relapse risks in the latter. Abstract 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. [ABSTRACT FROM AUTHOR]

Background: Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD.Methods: The RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers.Discussion: This randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur.Trial Registration: NCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015). [ABSTRACT FROM AUTHOR]

Highlights • Incidence of BOS after reduced-intensity conditioning. • Mild small airway disease before transplantation predicts bronchiolitis obliterans. • Pulmonary cause of death is linked to pretransplantation severe small airway disease. • Mixed lung disease after transplantation is associated with non-relapse mortality Abstract 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. [ABSTRACT FROM AUTHOR]