Allogeneic Hematologic Stem Cell Transplantation Research Articles

Impact of bone marrow fibrosis on outcomes of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Bone marrow fibrosis (BMF) of unknown etiology was common in hematological malignancies, but its prognostic value for acute myeloid leukemia (AML) is unclear. We interrogated data from 532 newly diagnosed subjects with AML receiving allogeneic hematological stem cell transplantation to evaluate the prognostic impact of BMF on transplant outcomes. Using the European consensus on the grading of BMF at diagnosis, 255 (48%) subjects were BMF-0, 209 (39%), BMF-1 and 68 (13%), BMF-2-3. Subjects with BMF-2-3 had poor overall survival (P < 0.001), disease-free survival (P < 0.001) and a higher incidence of relapse (CIR, P < 0.001). Multi-variable analyses in subjects achieving pre-transplant complete remission showed BMF-2-3 was an independent risk factor for CIR (Hazard Ratio [HR] = 2.17, (95% CI, 1.11, 4,24); P = 0.02). Furthermore, BMF-2-3 group showed delayed neutrophil and platelet engraftment and delayed B cell recovery post-transplantation. These findings demonstrate the significance of BMF in transplant outcomes and attract more attention to AML with BMF.

Virtual Reality-Assisted Exercise Therapy during Inpatient Treatment after Intensive Chemotherapy for Acute Myeloid Leukemia (AML) and after Autologous or Allogeneic Stem Cell Transplantation

Background and Objectives Medical advances in treatment of hematologic malignancies have led to improved survival. However, aggressive treatments come with the potential of significant side effects that can affect quality-adjusted life years. During treatment, physical activities are markedly reduced and immobility and psychologic burden, especially during long isolation processes, result in fatigue and decline of quality of life as well as loss of cognitive function. Physiotherapy and exercise therapy positively impact muscle strength, quality of life, cognitive functioning and fatigue, but sufficient implementation of training in the inpatient setting is often limited by shortage in human resources. The aim of this study was to assess the feasibility of a virtual reality (VR) based exercise program during inpatient stay of patients undergoing intensive treatment for hematologic malignancies, including autologous and allogeneic hematologic stem cell transplantation (HSCT). Method Patients aged 18 or above, admitted to the hematology ward for HSCT or intensive chemotherapy for acute leukemia were included. As this was a feasibility trial, there was no randomization. After consent, patients were asked to use the VR training device on a daily basis for the length of their stay, accompanied by medical personal. The training program consisted of customized VR-applications addressing movement, concentration and alertness as well as relaxation. An individual program was developed for every patient at the beginning of treatment and continuously readjusted according to individual needs and preferences. Patients who did not want to or were not able to use the VR device were asked to participate in the control group and received the standard-of-care treatment consisting of once daily physiotherapy. As objectives, quality of life, fatigue, strength and cognitive function were assessed once weekly until discharge as well as two weeks post discharge in both groups. The time of usage was recorded by the VR device. A structured interview was conducted after discharge to evaluate the patients' perspective on the intervention. Results Over a three-months period, a total of 10 patients were enrolled in the study, seven patients with intervention, three patients in the control group. The usage was feasible and well tolerated. No unpleasant side effects such as dizziness, nausea or fatigue were reported. Mean time of usage varied between patients (132.6±68.6 minutes, min 12.4, max 463.5 minutes) on 31±28.2% of hospitalization days. Patients in the intervention group achieved a higher overall score in EORTC QLQ-C30 after discharge (s). Moreover, the use of VR was associated with a trend towards improved mean symptom burden (60 vs 43.3 pts), cognitive function (83.3 vs. 16.7pts) and physical strength (63.3 vs 26.7pts) post discharge (significance was not calculated due to the small number of cases). VR occupation time was markedly affected by age and general condition during treatment. The patients perception of the intervention was positive. Conclusions The results show that the use of a VR based exercise program during inpatient stay of patients receiving intensive treatment for hematologic malignancies is feasible and safe, and can improve QoL. Because of the small number of subjects and distinctive differences in time of usage we can only recognize a trend towards positive effects so far. In view of these promising results a larger prospective, randomized trial has been designed.

Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.

e19032 Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.

One fits all: a highly sensitive combined ddPCR/pyrosequencing system for the quantification of microchimerism after hematopoietic and solid organ transplantation.

A combined digital droplet PCR (ddPCR)/pyrosequencing assay system was developed that demonstrated advantages applicable to multiple qualitative and quantitative molecular genetic diagnostic applications. Data for characterizing this combined approach for hematologic stem cell transplantation (HSCT) and allele quantification from graft-derived cell-free (cf) DNA in solid organ transplantation (SOT) is presented. ddPCR and pyrosequencing assays targeting 32 SNPs/markers were established. ddPCR results from 72 gDNAs of 55 patients after allogeneic HSCT and 107 plasma-cfDNAs of 25 liver transplant recipients were compared with established methods/markers, i.e.short-tandem-repeat PCR and ALT, respectively. The ddPCR results were in good agreement with the established marker. The limit of detection was 0.02 % minor allele fraction. The relationship between ddPCR andSTR-PCR was linear with R2=0.98 allowing to transfer previously established clinical STR-PCR cut-offs to ddPCR; 50-fold higher sensitivity and a variation coefficient of <2 % enable the use of low DNA concentrations (e.g. pre-sorted cells). ddPCR detected liver allograft injury at least as sensitive as ALT suggesting that ddPCR is a reliable method to monitor the transplant integrity, especially when other biomarkers are lacking (e.g. kidney). Combining pyrosequencing for genotyping and ddPCR for minor allele quantification enhances sensitivity and precision for the patient after HSCT and SOT. Theassay is designed for maximum flexibility. It is expected to be suitable for other applications (sample tracking, prenatal diagnostics, etc.).

Outcome and Molecular Measurable Residual Disease Monitoring in Adult B-Cell Acute Lymphoblastic Leukemia Patients with MEF2D Fusions

Oncogenic gene fusions caused by chromosomal rearrangements are the major hallmarks of B-cell acute lymphoblastic leukemia (B-ALL). With the application of next-generation sequencing technologies, several non-scarce recurrent fusion genes have been identified in B-ALL, and MEF2D fusions is the one. More clinical data is needed to clarify the incidence and prognosis. Furthermore, the prognostic significance of measurable residual disease (MRD) monitored by the quantitative detection of MEF2D fusions remains absent to date. A total of 357 adult Ph-negative B-ALL cases who were consecutively diagnosed and received treatment in our institute from 2009 to 2021, and have available bone marrow cDNA samples at diagnosis were retrospectively screened MEF2D fusions. All patients have been tested common fusion transcripts at the time of diagnosis. MEF2D fusions were tested by the multiplex TaqMan-based real time quantitative polymerase chain reaction technology. A total of 7 fusion partners were included. The split-out real time PCR was performed to identify the partner. Totally 16 patients were identified MEF2D fusions with the incidence of 4.5% in Ph-negative BCP-ALL. The distributions were as follows: 7 MEF2D-BCL9, 7 MEF2D-HNRNPUL1, 1 MEF2D-DAZAP1 and 1 MEF2D-FOXJ2. Their median transcript levels were 65.0% (range, 20.9%-335.5%) at diagnosis. The median age of these 16 patients were 30 (range, 17-60) years and 10 of them were male (63%). The median follow-up time of 16 patients with MEF2D fusions was 26 months (range, 8-156 months). 9 (61.1%) patients were alive at the last follow-up. 14 and 2 patients individually achieved complete remission (CR) after 1 and 2 courses of CODP ± L regimen for induction. Thereafter, 8 patients received hyper-CVAD-based chemotherapy alone and all of them relapsed after 1-6 cycles of consolidation, then 2 relapsed patients received allogeneic hematologic stem cell transplantation (allo-HSCT) as salvage treatment after achieving the 2nd CR (CR2); the remaining 8 patients received chemotherapy followed by allo-HSCT (matched sibling donor, n = 3; haploidentical related donor, n = 5) in CR1. The median follow-up time after HSCT was 19 (6-148) months, and 5 patients (4 CR1, 1 CR2) relapsed at a median of 9 (range 6-15) months post-HSCT. The 3-year relapse free survival [RFS] and overall survival (OS) rates of all 16 patients were 30.0% (95% confidence interval [CI]: 10.2%-53.0%) and 54.6% (95% CI: 23.9%-77.5%) (Fig 1). Bone marrow samples serially collected after treatment were retrospectively tested MEF2D fusion transcript for MRD monitoring. 58.3% (7/12) and 50.0% (6/12) of patients were PCR-negative at the time of achieving CR1 and after one cycle of consolidation, respectively. PCR-negative at the above both time-points was not related to relapse (P=1.0 and 0.45). For patients receiving allo-HSCT, the scheduled monitoring time-points were 0, 1, 2, 3, 4.5, 6, 9, 12, 18, 24 months post-HSCT then every 12 months thereafter. There was a tendency that PCR-negative at the time of receiving HSCT was related to a lower relapse rate (post-HSCT 2-year RFS rate, 75.0% [95% CI, 12.8%-96.1%] vs 20.0% [95% CI, 0.8%-58.2%], P=0.13). 5 patients who were in continuous CR were tested MEF2D fusion transcript at a median of 9 (range, 3-11) time-points after HSCT, 38 (97.4%) samples were PCR-negative. 5 patients who relapsed post-HSCT were tested MEF2D fusions at a median of 5 (range, 4-7) time-points before relapse, they all were in continuous PCR-negative from 1 to 2-6 months post-HSCT, then all became PCR-positive before the occurrence of relapse. Their intervals between the 1st PCR-positive and relapse were 1.5-6 months. As a result, occurrence of PCR-positive post-HSCT was significantly related to relapse (post-HSCT 2-year RFS rate, 100.0% (95% CI, 100%-100%) vs 33.0% (95% CI, 4.3%-67.2%), P=0.039, Fig 2). In conclusion, MEF2D fusions confer adverse prognostic significance to adult B-ALL, and relapse is a treatment challenge. PCR-negative of MEF2D fusion transcript at the time of achieving CR and after the 1st consolidation could not predict long-term CR, whereas PCR-positive after HSCT predict relapse. The benefit of urgent allo-HSCT after achieving CR and MEF2D fusion transcript levels directed intervention post-HSCT remains to be investigated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mixed chimerism after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia

ABSTRACT Background: Mixed chimerism (MC) frequently occurs in patients with severe aplastic anemia (SAA) after allogeneic hematological stem cell transplantation (allo-HSCT). Methods A retrospective study on 287 patients with SAA who underwent allo-HSCT between October 2012 and January 2020 was conducted to explore the outcomes, risk factors and treatment options for MC. Among 287 AA patients who excluded Fanconi anemia (FA), Congenital dyskeratosis (DKC), Paroxysmal nocturnal hemoglobinuria (PNH), etc.112 underwent matched sibling donor (MSD)-HSCT, 91 matched unrelated donor-HSCT and 84 haploidentical-HSCT. Patients were divided into the following 4 groups: group 1: Donor chimerism (DC); group 2: MC without cytopenia; group 3: MC with cytopenia; group 4: secondary graft failure (SGF). Results Compared with the other three groups, SGF predicted a poor prognosis of SAA (P< 0.001). In addition, SGF was associated with the early (within 3 months after transplantation) presence of MC and the high levels of MC. Uni- and multivariate logistic regression analysis showed that donor/recipient sex-mismatching and CTX + ATG regimen were high-risk factors for MC. Of note, in MC patients with cytopenia (group 3), the effective response rate reached 55% (6/11) following enhanced immunosuppression combined with cellular therapy, while only one of the four was effective who received enhanced immunosuppression alone. Conclusion SGF was associated with poor prognosis, early presence of MC and increased levels of recipient chimerism. The donor/recipient sex-mismatching and CTX + ATG regimen based MSD-HSCT were risk factors for MC. Cellular therapy could improve the effective response rate of patients with progressive MC.

A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation

AbstractThe importance of HLA-DPB1 matching for the outcome of allogeneic hematologic stem cell (HSC) transplantation is controversial. We have previously identified HLA-DPB1*0901 as a target of cytotoxic T cells mediating in vivo rejection of an HSC allograft. Here we show that HLA-DPB1*0901 encodes a T-cell epitope shared by a subset of DPB1 alleles that determines nonpermissive mismatches for HSC transplantation. Several T-cell clones obtained from the patient at the time of rejection showed HLA-DP restricted recognition of allogeneic targets expressing HLA-DPB1*0901, *1001, *1701, *0301, *1401, and *4501, but not other alleles. Based on these findings, we developed an algorithm for prediction of nonpermissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplantations showed that the presence of nonpermissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II to IV graft-versus-host disease (HR = 1.87, P = .046) and transplantation-related mortality (HR = 2.69, P = .027) but not relapse (HR = 0.98, P = .939), as compared with the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR = 1.64, P = .1). These data suggest that biologic characterization of in vivo alloreactivity can be a tool for definition of clinically relevant nonpermissive HLA mismatches for unrelated HSC transplantation.

Disruption of the Oral Microbiota Predicts Poor Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

Background: The intestinal microbiota (IM) has been shown to play a vital role in regulating host immunity. In allogeneic hematologic stem cell transplantation (allo- HSCT), IM disruption also seems to affect the incidence of graft versus host disease (GVHD), overall survival (OS), and underlying disease relapse. The oral microbiota (OM) directly influences human health. Changes in the OM in patients undergoing allo- HSCT are known to be associated with respiratory signs and symptoms and oral mucositis; however, no correlation between OM and allo-HSCT outcomes have been reported to date. Objectives: The study aims to evaluate whether the OM modulated the host systemic immune response and outcomes in patients who underwent allo-HSCT. Patients and Methods: We collected samples from the oral mucosa of patients who underwent allo-HSCT between January 2016 and April 2018. Samples were collected at three time points: before the conditioning regimen, at aplasia, and at engraftment. DNA extraction: Bacterial cells were recovered from oral mucosa swabs through vortexing in TE buffer supplemented with 6 μL PureLink RNAse A. DNA was extracted using a QIAamp DNA Blood Mini Kit and stored at -80°C. 16S rRNA amplicon sequencing: 16S rRNA amplicon sequencing, 12.5ng DNA and prevalidated primers were used to amplify 16S rRNA hypervariable regions V3-V4. Amplicons were sequenced as described elsewhere on an Illumina MiSeq platform. Results: We analyzed 30 patients. The most common diagnosis was acute leukemia (60%), most patients received reduced-intensity conditioning (60%). Donors were haploidentical in 33%, matched sibling in 30%, matched unrelated in 30%, and mismatched unrelated in 7%. Peripheral blood was the most common stem cell source (67%). We stratified patients into low or high diversity at each collection time. A swimmer plot was used to illustrate these correlations at preconditioning (Fig. 1). High OM diversity at preconditioning was associated with a lower risk of relapse at 3 years when compared with low diversity (33% versus 68%, respectively, P = 0.04; Fig. 2). The presence of dominance by any genus at preconditioning was also associated with an increased risk of relapse at 3 years when compared with the absence of dominance (63% versus 36%, respectively, P = 0.03; Fig. 3). The presence of dominance by any genus at preconditioning was also associated with inferior PFS (19% versus 55%, respectively, P = 0.01; Fig. 4) and OS (38% versus 81%, respectively, P = 0.02; Fig. 5). After adjusting analyses for the DRI, there was a trend toward a higher risk of relapse/progression in those with low OM diversity (HR = 0.30, 95% CI: 0.08-1.09, P = 0.07), and bacterial dominance of any genus remained significantly associated with the risk of relapse (HR = 4.19, 95% CI: 1.25-14.1, P = 0.02) and worse PFS (HR = 4.14, 95% CI: 1.15-14.89, P = 0.03); there was a tendency for bacterial dominance of any genus to also be related to worse OS (HR = 4.12, 95% CI: 0.89-19.13, P = 0.07). To further evaluate the association between preconditioning OM and transplant outcomes, we analyzed whether non-core genera were associated with a higher risk of relapse. Of the 18 genera that matched the selection criteria tested in univariate analysis for relapse (Fig. 6), only Solobacterium was significantly associated with lower relapse risk (9% versus 56%, respectively, P = 0.04; Fig. 7), and this association remained significant after adjusting for DRI (HR = 0.20, 95% CI: 0.06-0.67, P = 0.01). Conclusion: High OM diversity and presence of dominance by any genus (more importantly Solobacterium)at preconditioning was associated with a lower risk of relapse. Prospective trials and validation cohorts are needed to confirm these findings and to test whether early interventions to correct OM dysbiosis or more aggressive strategies to prevent relapse in OM dysbiotic patients, such as early immunosuppression withdrawal, maintenance therapy, or prophylactic donor lymphocyte infusions, could improve allo-HSCT outcomes. Disclosures No relevant conflicts of interest to declare.

Effect of Salvage Chemotherapy Before Donor Lymphocyte Infusion in Patients With Relapse After Allogeneic Hematologic Stem Cell Transplantation

ObjectivesAllogeneic hematopoietic stem cell transplantation (AHSCT) is an important treatment option in hematologic malignancies. Relapse after AHSCT is an indicator of poor prognosis. These patients may be treated with donor lymphocyte infusion (DLI). The chemotherapy given before DLI increases the success of the treatment by reducing the burden of disease. The aim of this study is to investigate post-DLI graft vs host disease (GvHD) and survival based on the course of chemotherapy given before DLI. MethodsA total of 23 patients who received DLI because of relapsed disease after AHSCT were enrolled. All of the patients received 1 or more courses of cytoreductive chemotherapy before DLI. ResultsComplete remission (CR) after DLI remained in 78.2% of all patients. There is no difference between 1 or multiple courses of chemotherapy in terms of CR (55.6% vs 44.4%; P = .21). During follow-up after DLI, although it did not reach statistical significance (P = .09), the patients receiving single-course chemotherapy tended to have longer survival (36.1 vs 4.3 months, respectively). Four patients who received multiple courses of chemotherapy were lost because of infection-related disease (pneumonia, sepsis) while they were in CR. GvHD development was more frequent in patients receiving multiple courses of chemotherapies (60% of all GvHD patients). ConclusionIt has been demonstrated that reducing the tumor burden by multiple-cycle chemotherapy does not have any advantage in terms of CR and does not improve the overall survival.

Evaluation of clinical outcomes of allogeneic hematopoietic stem cell transplantation for relapsed/refractory peripheral T-cell lymphoma with chemoresistance

Objective: To evaluate the clinical outcomes in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who had undergone allogeneic hematological stem cell transplantation (allo-HSCT). Methods: From June 2007 to June 2017, the clinical data of PTCL patients who underwent HSCT from eight hospitals were assessed retrospectively. Results: There were 23 patients diagnosed as relapsed or refractory PTCL with chemoresistance who underwent allo-HSCT. Among these patients, 18 were identified as progressive disease (PD) status and 5 patients as stable disease (SD) status before allo-HSCT. Seventeen patients received allo-HSCT from matched sibling donor (MSD),2 patients from matched unrelated donor and 4 patients from related haplo-identical donor (HD). After a median follow-up of 29 months, 21 patients survived longer than 28 days after allo-HSCT. Hematopoietic reconstitution was achieved in 20 of the 21 patients. The median time of myeloid and platelet engraftment were+13 (9-22) d and+16(10-38) d, respectively. The 100-d treatment-related mortality rate was 13.1%. Acute GVHD occurred in 11(47.8%) patients at a median time of 22(6-82) d after transplantation. Grade Ⅱ~Ⅳ aGVHD occurred in 6 patients. Chronic GVHD occurred in 10 patients at a median of 7.9 (3.5-27) months. After a median follow-up of 29 months, 13 patients died after HSCT. Four of them died of complications associated with allo-HSCT, and other 9 patients died of the primary lymphoma. The 3-years cumulative overall survival (OS) and progress-free survival (PFS) were 43.03% (95%CI: 29.79-69.16) and 39.13% (95%CI: 23.50-65.14), respectively. No significant difference was found in the 3-year PFS between patients with PD status and SD status before allo-HSCT (P=0.133). Conclusion: Allo-HSCT can be a promising treatment for relapsed or refractory PTCL with chemoresistance.

Subgroup Analysis Can Optimize the Relapse-Prediction Cutoff Value for WT1 Expression After Allogeneic Hematologic Stem Cell Transplantation in Acute Myeloid Leukemia

High WT1 expression after allogeneic hematologic stem cell transplantation (allo-HSCT) can strongly predict relapse in acute myeloid leukemia (AML). However, the cutoff values obtained have been inconsistent. Precise cutoff values may be optimized through subtype analysis; the RUNX1-RUNX1T1 fusion transcript provides an ideal reference. RUNX1-RUNX1T1 and WT1 transcript levels were simultaneously measured in 1299 bone marrow samples serially collected from 176 t(8;21) AML patients after allo-HSCT. The upper limit of the normal bone marrow WT1 level was 0.6%, which we previously reported to be the cutoff value for significant relapse prediction in AML as a whole. WT1 cutoff values of 0.6%, 1.2%, and 1.8% significantly differentiated patients in relapse after allo-HSCT. Nonetheless, patients with WT1 levels of 0.6% to 1.2% and those with levels of >1.2% and 1.8% after HSCT had rates of cumulative incidence of relapse similar to those with a continuous WT1 level of ≤0.6%, and both were significantly lower than that in patients with a WT1 level of >1.8%. WT1 expression was significantly related to RUNX1-RUNX1T1 transcript levels at WT1 levels of >1.8% but not at levels of 0.6% to 1.2% or >1.2% to 1.8%. Therefore, subgroup analysis can optimize the relapse-prediction cutoff value of WT1 expression. A cutoff level of 1.8% more accurately differentiates t(8;21) AML patients in relapse after allo-HSCT than does a cutoff level of 0.6%.

Classical Monocyte Deficiency Calculated By the Mono-Index Can Predict Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Patients

Background: Most studies in immune reconstitution after allogeneic hematologic stem cell transplantation (alloHSCT) focus on adaptive immunity, particularly in lymphocyte recovery. Classical monocytes (cMo) are part of the innate immunity, playing an important role in the defense against fungal and bacterial infections. The innate and adaptive immunity are closely related, and non-classical monocytes (ncMo) participate in this connection, regulating T cell response. However, the role of these cells in the graft versus tumor effect and graft versus host disease (GVHD) is still unclear. Objectives: The aim of the study was to investigate cMo and ncMo reconstitution after alloHSCT and a possible impact of these cells subsets on acute and chronic GVHD, relapse, non-relapse related mortality (NRM) and overall survival (OS). Patients and Methods: This is a retrospective analysis of 77 patients who underwent alloHSCT in 4 different transplant centers in Brazil. Peripheral blood samples were collected from patients at neutrophil engraftment (NE) and 3, 7, 14, 21, and 42 days after NE. The cMo (DR+, CD11c+, CD14+, CD16-) and ncMo (DR+, CD11c+, CD14-, CD16+) were classified and analyzed by 8-color multiparametric flow cytometry (FACSCanto II). In order to analyze the possible impact of duration and severity of monocytopenia after transplant, we calculated then the 'mono-index' and the 'ncMo-index', based on the area over the curve (AOC) of absolute cMO counts (AMC) and absolute ncMo counts, respectively, considering a horizontal line of AMC 0.5x10e9/L as cut-off value for both subpopulations. Results: The medium follow up was 82 months. Out of 77 patients, 46 (60%) were male, and the median age was 17 years (range: 1-74). The stem cell source was bone marrow in 36 (47%), cord blood in 23 (30%), and peripheral blood in 18 (23%); and donors were matched unrelated in 61 (79%), and matched related in 16 (21%) cases. Most patients received myeloablative conditioning (n=47, 61%); and acute leukemia was the most common diagnosis (72%). A total of 40 (52%) patients received total body irradiation (TBI), and 27 (35%) patients received antithymocyte globulin (ATG). We calculated the possible impact of cMo at all timepoints and found no differences in the main outcomes between patients with lower or higher counts. We then analyzed the AOC of all cMo counts (the mono-index). A higher index represents a more severe deficiency of cMo. We then used the receiver operating characteristic (ROC) curve to define the cut-off value of 14234.4 cells/days x mm3 to discriminate patients as cMo deficient (n=31, 40%) or non-deficient (n=46, 60%). Non relapse mortality (NRM) at 6 years was higher in cMo deficient patients calculated by the mono-index (40% vs. 16% for non-deficient, p=0.02, Figure 1). Deficient patients also had worse OS at 6 years (58% vs. 37% for non-deficient, p=0.03, Figure 2). In multivariate analyses, cMo deficiency calculated by the mono-index remained significantly associated with NRM (hazard ratio 3.07, 95% confidence interval) and OS (HR 2.05, 95%CI 1.20-7.85). We observed no impact of mono-index on acute or chronic GVHD or relapse. We observed no impact of the ncMo counts at all timepoints or the ncMo-index in any of the analyzed outcomes. Conclusion: cMo deficiency calculated by the mono-index can predict mortality in alloHSCT. Mono-Index is an inexpensive, accessible and easy to perform tool that might help clinicians in predicting unfavorable outcomes. Further studies are needed to confirm these findings and to test how different transplant strategies or therapeutic changes might interfere with monocytes recovery in alloHSCT. Disclosures No relevant conflicts of interest to declare.

Optimization of nutrition during allogeneic hematologic stem cell transplantation.

Malnutrition before and during hematopoietic stem cell transplantation (HSCT) is an independent risk factor for mortality in patients undergoing hematopoietic stem cell transplantation. Yet, optimal use of nutritional support to improve outcomes remains controversial. Our aim was to do an up-to-date literature review regarding nutritional therapy in allogeneic HSCT, the neutropenic diet and the use of immunonutrients. Several observational studies find malnutrition to be associated with poor outcome, increased complications and lower overall survival. There are, however, few interventional trials proving the benefits of nutritional therapy in this population compared with no nutritional treatment. Regarding routes of treatment, studies suggested that parenteral nutrition is associated with higher risk for complications compared with enteral nutrition. Whether the use of specific formulas, such as immunonutrition, has a beneficial effect on clinical outcome is not established yet. Strict use of neutropenic diets did not show a reduction in infection risk and clinical outcome, and can no longer be recommended. Our updated search confirms that malnutrition is a strong negative predictor for outcome, yet optimal use of nutritional interventions to prevent or treat malnutrition remains ill-defined. There is need for larger randomized trials to better address these issues in the future.

Emergence of linezolid- and vancomycin-resistant Enterococcus faecium in a department for hematologic stem cell transplantation

BackgroundPrevalence of vancomycin-resistant enterococci has increased in Germany. Here, we report the cluster of linezolid- and vancomycin-resistant Enterococcus faecium (LVRE) in a German department for hematologic stem cell transplantation (HSCT).MethodsIn this retrospective analysis we included all patients with LVRE in a university-based department for HSCT in 2014 and 2015. Patients chart reviews were used to investigate the epidemiology and clinical outcome. Available LVRE isolates underwent detailed microbiological characterization and genotyping by pulsed-field gel electrophoresis (PFGE).ResultsIn total, 20 patients with LVRE were identified within the observed time period. All except two patients underwent allogeneic HSCT. Surveillance culture results from incoming patients and chart review revealed that 10 of 20 patients were colonized at hospital admission. Eight of 10 patients with in-hospital acquired LVRE had previous linezolid treatment. Analysis of spatio-temporal patterns showed no evidence for LVRE patient-to-patient or environment-to-patient transmission within the HSCT department. In five cases (25 %) LVRE bloodstream infection occurred. Nine LVRE isolates could be saved for characterization. Eight isolates carried vanA, one isolate vanB. PFGE analysis showed that four different LVRE clones were responsible for the cluster. One single genotype was present in six LVRE isolates whereupon the corresponding patients were all referred from the same hospital to the HSCT department.ConclusionsThis is the first report demonstrating the emergence of LVRE in a German HSCT department. (L)VRE screening at patients’ admission and appropriate infection control strategies were sufficient to prevent any transmission. Further studies in this predisposed patient collective are warranted.

Changes in serum uric acid levels after allogeneic hematologic stem cell transplantation: A retrospective cohort study.

BackgroundSince cell turnover in the hematopoietic system constitutes a major source of uric acid (UA) production, we investigated whether hematopoietic stem cell transplantation (HSCT) is associated with significant changes in serum UA levels in patients with hematological disorders.MethodsPatients who underwent HSCT at our institution between 2001 and 2012 were retrospectively enrolled. Serum UA levels at 3 months before, 1 week before, and 3 months and 1 year after HSCT were examined.ResultsComplete clinical and laboratory information including data regarding UA levels was available for 93 patients. At baseline, the mean UA level was 4.9±2.1 mg/dL, with an overall prevalence of hyperuricemia of 15% (defined as serum UA>6.8 mg/dL). Mean UA levels tended to be higher in patients with acute myeloid leukemia (4.8±2.0 mg/dL) and non-Hodgkin lymphoma (5.1±2.3 mg/dL) and lower in patients with aplastic anemia (mean, 4.2±1.8 mg/dL). UA levels dropped during myeloablative conditioning, reaching a nadir on the day of HSCT (3.27±1.4 mg/dL). Over the 3 months following HSCT, UA levels rose sharply (5.0±2.1 mg/dL) and remained stable up to 1 year after HSCT (5.5±1.6 mg/dL). UA levels in HSCT recipients at 12 months correlated with those of their respective graft donors (Pearson r=0.406, P=0.001).ConclusionHSCT is associated with significant changes in uric acid levels in patients with hematologic disorders.

An Evaluation of Molecular Response in a Phase 2 Open-Label, Multicenter Confirmatory Study in Patients (pts) with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Receiving Treatment with the BiTE® Antibody Construct Blinatumomab

An Evaluation of Molecular Response in a Phase 2 Open-Label, Multicenter Confirmatory Study in Patients (pts) with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Receiving Treatment with the BiTE® Antibody Construct Blinatumomab

Tear osmolarity in ocular graft-versus-host disease.

The aim of this study was to evaluate tear osmolarity in patients with chronic graft-versus-host disease (cGVHD) with ocular involvement. In this observational cross-sectional study of 56 patients with ocular cGVHD referred to the tertiary-care Ocular Immunology and Uveitis Service at the San Raffaele Scientific Institute, Milan, from May 2010 to November 2013, we evaluated the following clinical parameters: Ocular Surface Disease Index (OSDI) symptoms questionnaire, tear osmolarity, Schirmer test, tear film break-up time (TBUT), corneal and conjunctival staining. All patients developed systemic GVHD after undergoing allogeneic hematologic stem cell transplantation. Mean osmolarity was 314.0 ± 22.1 mOsm/L, mean OSDI score was 26.4 ± 21.2, mean TBUT was 6.50 ± 4.75 seconds, and mean Schirmer test value was 3.8 ± 3.3 mm. Tear osmolarity significantly inversely correlated with TBUT (r = 0.681; P < 0.001). Statistically significant inverse correlation was present with the Schirmer test (r = 0.203; P < 0.001), and positive correlation with the OSDI score (r = 0.188; P < 0.001), but both with low correlation strength. Osmolarity was statistically different in the subgroups according to the Oxford corneal staining scale (P = 0.0006) and to the van Bijsterveld conjunctival staining score (P = 0.006). Tear osmolarity increased in patients with ocular cGVHD, significantly correlated with TBUT and, to a lesser extent, with the Schirmer test value and OSDI. These results emphasize the role of aqueous-deficient and evaporative dry eye disease in patients with cGVHD after undergoing allogeneic hematologic stem cell transplantation. Tear osmolarity may be considered a useful test in diagnostic assessment of dry eye disease associated with cGVHD.

Geriatric assessment before reduced intensity conditioning allogeneic hematologic stem cell transplantation in elderly patients

Introduction: A growing number of patients with hematological malignancies over the age of 65 years are considered for more intensive treatment. Elderly patients represent a heterogeneous population in which the decision to proceed to a reduced intensity conditioning allogeneic hematologic stem cell transplantation (RIC-AHSCT) is often difficult to assess because of more comorbidities and frailty. Objectives: The present studydescribes a population of patients older than 65 years who received a geriatric assessment before a RIC-AHSCT. Methods: During 2013 we have systematically carried out geriatric consultations, usingwell-validated international scales for elderly patients whowere considered for RIC-AHSCT by the transplant physician. Patients were evaluated before the start of the conditioning regimen by functional ability (ADL, IADL), nutritional status (weight loss, Mini Nutritional Assessment, albuminemia), socio environmental circumstances, cognition and mental health (minCOG and/or Mini Mental State Examination), mobility and pain. Comorbidities were also listed for each patient. Results: From February to December 2013, 28 patients over the age of 65 years (19 men, 9 women) with a median age of 68.5 years (range 65– 73 years) were considered for RIC-AHSCT. All patients had hematological malignancieswithmostly diagnoses of acute leukemiamyeloproliferative and myelodysplastic syndromes and were evaluated by a geriatric physician. The geriatric assessment resulted in functional disability in 28.6%of patients,malnutrition in 46%of patients anda risk ofmalnutrition in 25% of patients, a socio environmental risk in 18% of patients, cognitive impairment in 3.6% of patients and suspicion of cognitive impairment in 14% of patients, mobility impairment in 35% of patients, pain in 25% of patients, and thymic disorders in 35.7% of patients. Conclusion: In our knowledge, this is the first study that evaluates elderly patients who pretend to RIC-AHSCT. In this descriptive study 75% of patients with hematological malignancies considered for RIC-AHSCT were fit, 18% were vulnerable and 7% were frail. Up to now, for our knowledge the geriatric assessment has no impact on the decision of the transplant physician. With regard to the growing age of patients, the advances in treatment and supportive care will need a better collaboration between geriatrician and hematologist to optimize patient care. Further studies are necessary to assess the impact of geriatric assessment before RIC-AHSCT. Disclosure of interest: None declared.

Donor Haplotype B of NK KIR Receptor Reduces the Relapse Risk in HLA-Identical Sibling Hematopoietic Stem Cell Transplantation of AML Patients.

Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.

Multidisciplinary team diagnosis and therapy for a myeloid sarcoma/AML patient with adrenal mass after allogeneic hematological stem cell transplantation

Myeloid sarcoma is a rare hematological neoplasm that may develop de novo or concurrently with acute myeloid leukemia (AML), or represent the initial manifestation of relapse in a previously treated AML in remission. A 44-year-old man was diagnosed with testis MS in his local hospital. A month later, November 2010, our department confirmed the clinical diagnosis of AML through his bone marrow biopsy and aspirate. The patient underwent allogeneic hematological stem cell transplantation from his sister and achieved complete remission. Five months later, however, a mass in his adrenal was revealed by Positron Emission Tomography-Computer Tomography (PET-CT). After a multidisciplinary team diagnosis, radiotherapy for this lesion was performed. As of the follow up conducted until March 2013, the patient remains healthy and shows no evidence of recurrent MS or leukemia.