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Background: Memory T cells are a heterogeneous population of immune cells that provide adaptive immunity. Its full recovery seems essential for graft-versus-tumor reactions that provide an opportunity for biological cure in patients with acute leukemia. The use of mismatched or haploidentical donors has increased, which has become possible because of modifications in graft versus host disease (GVHD) prophylaxis. Materials and Methods: Sixty-five leukemia patients (acute myeloid leukemia - 40, acute lymphoblastic leukemia - 25), median age 33 (17-61) years, underwent allo-HSCT from 2016 to 2019 in the National Research Centre for Hematology. Patients were divided into three groups based on the impact of GVHD prophylaxis on T cell recovery: horse antithymocyte globulin (ATG)-based regimen (n=32), horse ATG combined with posttransplant cyclophosphamide (PT-Cy) (n=18), and ex vivo T cell depletion (n=15). Results: The early period after transplantation (before day +100) was characterized by significantly lower absolute numbers of T naïve, memory stem and T central memory cells in peripheral blood in patients after ATG+PT-Cy-regimen or ex vivo T cell depletion than after ATG-based prophylaxis (p<0.05). Moreover, strong depletion of naïve T and memory stem cells prevents the development of GVHD, and determining the absolute number of CD8+ naïve T and memory stem cells with a cutoff of 1.31 cells per microliter seems to be a perspective in assessing the risks of developing acute GVHD (p=0.008). The dynamics of T cell recovery showed the involvement of either circulating or bone marrow resident T effector cells shortly after allogeneic transplantation in all patients, but the use of manipulated grafts with ex vivo T cell depletion requires the involvement of naïve and memory stem cells. There was no significant effect of T cell recovery on leukemia relapse after allogeneic transplantation. Conclusion: These experimental outcomes contribute to providing the best understanding of immunological events that occur early after transplantation and help in the rational choice of GVHD prophylaxis in patients who will undergo allogeneic transplantation. Our study demonstrated the comparable immunological effects of posttransplant cyclophosphamide and ex vivo T cell depletion and immunological inefficiency of horse ATG for GVHD prevention.

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Fluoroquinolones (FQ) has been used after allogeneic hematopoietic stem cell transplantation (allo-HCT) for decades. This study on 284 allo-HCT recipients aimed to analyze the impact of FQ on pre-engraftment BSI. A total of 154 patients were colonized with resistant gram-negative bacteria, and 130 patients were not. Colonized patients did not receive FQ (n = 147) except 7 who received FQ as sequential therapy; 98 non-colonized patients received FQ, whereas 32 did not. Gram-negative (p < 0.0001), and ESBL-E BSI (p < 0.0001) were higher in colonized patients receiving FQ. No difference was found in gram-positive BSI (p = 0.452). In multivariate analysis colonized patients with (p < 0.0001) or without FQ (p = 0.007), omission of FQ in non-colonized patients (p = 0.038), and active disease (p = 0.042) were associated with gram-negative BSI, whereas mismatched unrelated donor transplantations - with gram-positive BSI (p = 0.009). Colonized patients with FQ have a higher risk of gram-negative BSI. In non-colonized patients, FQ prophylaxis is effective approach significantly reducing gram-negative BSI risk.

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BACKGROUND: Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSI in allo-HCT recipients. MATERIALS AND METHODS: The retrospective study included 261 patients with documented engraftment after first allo-HCT performed from January 2018 till September 2021. RESULTS: Of 261 patients 29 (11.1%) developed at least one post-engraftment BSIs episode with a median time to post-engraftment BSI of 49 days (range, 1 - 158 days from the engraftment). A total of 45 pathogens were isolated from blood - 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) - by Gram-positive bacteria. Secondary graft failure (hazard ratio [HR]: 39.93; 95% confidence interval [CI]: 7.64-208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut graft-versus-host-disease (GvHD) grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) were associated with the higher risk of Gram-negative post-engraftment BSIs. Overall 30-day survival after post-engraftment BSIs was 71.4%. By multivariate analysis post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 - 7.38; P = 0.011), and acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001) were associated with the higher 180-day non-relapse mortality risk. CONCLUSION: Gram-negative bacteria prevailed in the etiology of post-engraftment BSIs with secondary graft failure. secondary poor graft function. and acute gut GvHD being the main predisposing factors for their development. Post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.

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INTRODUCTION: With an increasing number of allogeneic hematopoietic cell transplantations (allo-HCT) bloodstream infections (BSI) are still among the most common and serious complications. This study aimed to analyze the incidence, etiology, risk factors, and outcomes of pre-engraftment BSI after the first and the second allo-HCT. MATERIALS AND METHODS: This is a retrospective study of 284 patients who underwent the first allo-HCT and 37 patients after the second allo-HCT at the National Research Center for Hematology in Moscow, Russia, from January 2018 till September 2021. RESULTS: Cumulative incidence of pre-engraftment BSI was 29.9% after the first allo-HCT and 35.1% after the second (p = .805). The median time to the first BSI was 9 days (range 0-61 days) after the first and 16 days (range 1-28 days) after the second allo-HCT (p = .014). A total of 113 pathogens were isolated during 94 BSI episodes after the first allo-HCT (gram-negative bacteria 52.2%; gram-positive bacteria 47.7%). Fourteen pathogens were isolated during 14 BSI episodes after the second allo-HCT (gram-negative bacteria 50.0%; gram-positive bacteria 50.0%). The only significant difference was found in the rate of carbapenem-resistant gram-negative bacteria, which was higher after the second allo-HCT compared to the first (57.1% vs. 13.6%; p = .048). Mismatched unrelated donor (hazards ratio [HR] 3.01; 95% confidence interval [CI]: 1.62-5.60; p < .0001) and haploidentical donor transplantations (HR 1.84; 95% CI: 1.02-3.33; p = .042) were the only independent risk factors associated with the higher risk of pre-engraftment BSI. Overall 30-day survival after all BSI episodes was 94.4%. Survival was lower after BSI during the second allo-HCT compared to the first (71.4% vs. 97.9%; p < .0001), particularly after BSI was caused by carbapenem-resistant gram-negative bacteria (25.0% vs. 100.0%; p = .0023). The non-relapse mortality rate at day +60 was 4.0%, and the risk was highly associated with primary graft failure (HR 9.62; 95% CI: 1.33-71.43), second allo-HCT (HR 6.80; 95% CI: 1.36-34.48), and pre-engraftment BSI caused by carbapenem-resistant gram-negative bacteria (HR 32.11; 95% CI: 4.91-210.15). CONCLUSIONS: Pre-engraftment BSI is still a common complication after allo-HCT, particularly after mismatched unrelated and haploidentical donor transplantations. BSI incidence was slightly higher after the second allo-HCT with a significantly higher rate of carbapenem-resistant BSI. Although pre-engraftment BSI would generally follow a benign clinical course, survival was dramatically lower during the second allo-HCT, especially after carbapenem-resistant BSI.

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OBJECTIVE: Acute graft-versus-host-disease (aGVHD) develops in 10-80% of allo-HSCT patients. More than half of all aGVHD cases are refractory to first-line therapy with steroids. We hypothesized that bowel wall thickness at the time of aGVHD diagnosis could be an early sign of steroid-refractory aGVHD with gut involvement. METHOD: Our prospective study included 85 patients with hematological malignancies who had undergone allo-HSCT. We used an inexpensive, widespread and simple method of transabdominal ultrasonography to examine bowel wall thickness in patients suspected to have gut aGVHD. RESULTS: Descending colon wall thickness was significantly greater in patients with gut aGVHD later found to be steroid-refractory than in patients with steroid-sensitive gut aGVHD, with AUC-0.73 (95% CI 0.58-0.87, p = 0.013). We showed that bowel wall thickness could predict the steroid-refractoriness of aGVHD. CONCLUSION: Transabdominal ultrasonography could be used as a marker of steroid-refractory aGVHD with gut involvement after allo-HSCT.

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Granzyme B is known to be a serine protease contained in granules of cytotoxic T cells. We have previously reported an influence of granzyme B expression in T regulatory cells (Tregs) on the risk of acute graft versus host disease (GVHD) onset. However, it is still unknown if conventional T cells (Tcon) use the granzyme B pathway as a mechanism of alloimmunity. We hypothesized that granzyme B in Tcon may affect recurrence within the first 6 months after allogeneic transplantation (allo-HSCT). A total of 65 patients with different hematological malignancies were included in this study. Blood samples were collected on day +30 after allo-HSCT. The percentage of granzyme B positive conventional T cells in patients who developed relapse in the first 6 months after allo-HSCT was 11.3 (4.5-35.3) compared to the others in continuous complete remission-1.3 (3.65-9.7), р = 0.011. The risk of relapse after allo-HSCT was in 3.9 times higher in patients with an increased percentage of granzyme B positive conventional T cells. The findings demonstrated that the percentage of granzyme B positive conventional T cells on day +30 after allo-HSCT could be a predictable marker of relapse within the first 6 months after allo-HSCT.

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.

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Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to-perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft-versus-host disease after day +30 after allo-HSCT.

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