Increased co-expression of ICOS and PD-1 predicts poor overall survival in patients with acute myeloid leukemia.

BACKGROUND: Inducible co-stimulatory factor (ICOS) has a dual role: activating cytotoxic T cells against tumors or exacerbating immunosuppression of regulatory T cells (Tregs) to participate in immune evasion. However, the correlation between ICOS and its co-expression with inhibitory immune checkpoints (IICs) and prognosis in acute myeloid leukemia (AML) is little known. METHODS: The prognostic importance of ICOS and IICs in 62 bone marrow (BM) samples of de novo AML patients from our clinical center (GZFPH) was explored and then the RNA sequencing data of 155 AML patients from the Cancer Genome Atlas (TCGA) database was used for validation. RESULTS: In both GZFPH and TCGA cohorts, high expression of ICOS was significantly associated with poor overall survival (OS) in patients with AML (P < 0.05). Importantly, co-expression of ICOS and PD-1, PD-L1, PD-L2, CTLA-4, and LAG-3 predicted poor OS in AML; among them, ICOS/PD-1 was the optimal combination of immune checkpoints (ICs). The co-expression of ICOS and PD-1 was correlated with poor OS in non-acute promyelocytic leukemia (non-APL) patients following chemotherapy. Additionally, ICOS/PD-1 was an independent OS-predicting factor (P < 0.05). Notably, a nomogram model was constructed by combining ICOS/PD-1, age, European Leukemia Net (ELN) risk stratification, and therapy to visually and personalized predict the 1-, 3-, and 5-year OS of patients with non-APL. CONCLUSION: Increased expression of ICOS predicted poor outcomes, and ICOS/PD-1 was the optimal combination of ICs to predict outcomes in patients with AML, which might be a potential immune biomarker for designing novel AML therapy.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.

The evolution and impact of sarcopenia in severe aplastic anaemia survivors following allogeneic haematopoietic cell transplantation.

BACKGROUND: Sarcopenia is a potential risk factor for adverse outcomes in haematopoietic cell transplantation (HSCT) recipients. We aimed to explore longitudinal body changes in muscle and adipose mass and their prognostic value in allogeneic HSCT-treated severe aplastic anaemia (SAA) patients. METHODS: We retrospectively analysed consecutive SAA patients who underwent allogeneic HSCT between January 2017 and March 2022. Measurements of pectoral muscle and corresponding subcutaneous fat mass were obtained via chest computed tomography at baseline and at 1 month, 3 months, 6 months, and 12 months following HSCT. Sarcopenia was defined as pectoral muscle index (PMI) lower than the sex-specific median at baseline. Changes in body composition over time were evaluated by generalized estimating equations. Cox regression models were used to investigate prognostic factors affecting overall survival (OS) and failure-free survival (FFS). A nomogram was constructed from the Cox regression model for OS. RESULTS: We included 298 adult SAA patients (including 129 females and 169 males) with a median age of 31 years [interquartile range (IQR), 24-39 years] at baseline. Sarcopenia was present in 148 (148/298, 50%) patients at baseline, 218 (218/285, 76%) patients post-1 month, 209 (209/262, 80%) patients post-3 month, 169 (169/218, 78%) patients post-6 month, and 129 (129/181, 71%) patients post-12 month. A significant decrease in pectoral muscle mass was observed in SAA patients from the time of transplant to 1 year after HSCT, and the greatest reduction occurred in post 1-3 months (P < 0.001). The sarcopenia group exhibited significantly lower 5-year OS (90.6% vs. 100%, log-rank P = 0.039) and 5-year FFS (89.2% vs. 100%, log-rank P = 0.021) than the nonsarcopenia group at baseline. Sarcopenia at baseline (hazard ratio, HR, 6.344; 95% confidence interval, CI: 1.570-25.538; P = 0.01; and HR, 3.275; 95% CI: 1.159-9.252; P = 0.025, respectively) and the delta value of the PMI at 6 months post-transplantation (ΔPMI6) (HR, 0.531; 95% CI: 0.374-0.756; P < 0.001; and HR, 0.666; 95% CI: 0.505-0.879; P = 0.004, respectively) were demonstrated to be independent prognostic factors for OS and FFS in SAA patients undergoing HSCT, and were used to construct the nomogram. The C-index of the nomogram was 0.75, and the calibration plot showed good agreement between the predictions made by the nomogram and actual observations. CONCLUSIONS: Sarcopenia persists in SAA patients from the time of transplant to the 1-year follow-up after HSCT. Both sarcopenia at baseline and at 6 months following HSCT are associated with poor clinical outcomes, especially in patients with persistent muscle mass loss up to 6 months after transplantation.

Letermovir Effectively Prevents Cytomegalovirus Infection in Patients with Aplastic Anemia After Hematopoietic Stem Cell Transplantation: A Real-World Retrospective Cohort Study.

INTRODUCTION: In this single-center retrospective cohort study, we investigated the efficacy of letermovir in preventing Cytomegalovirus (CMV) infection in patients with aplastic anemia (AA) who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Based on whether or not letermovir was used for preventing CMV infection, the patients were categorized into two groups: letermovir and control groups. The overall survival (OS) rate and cumulative incidence of CMV infection during the first 100 days after allo-HSCT were evaluated. The study included 21 matched pairs of patients, identified through propensity score matching analysis, to compare CMV infection rates, treatment efficacy, and regression. RESULTS: The incidence of CMV infection within 100 days after transplantation was significantly lower in the letermovir group than in the control group (26.5 vs. 77.4%, respectively; P < 0.001), among a total of 87 patients who underwent the transplant. In the matched cohort of 21 patients with AA, the letermovir group also showed a significantly reduced cumulative incidence of CMV infection (14.3 vs. 90.5% in the control group; P < 0.001). Compared to the control group, patients with CMV infection in the letermovir group had lower CMV-DNA load and a shorter clearance time. However, there was no significant difference in OS between both groups (P = 0.34). CONCLUSIONS: Letermovir effectively prevents CMV infection in allo-HSCT recipients with AA and demonstrates a high safety profile.

High-dimensional immune profiling using mass cytometry reveals IL-17A-producing γδ T cells as biomarkers in patients with T-cell-activated idiopathic severe aplastic anemia.

Severe aplastic anemia (SAA) is a bone marrow failure syndrome characterized by activated T cells. Features of T-cell activation in the pathophysiology of SAA remain unknown. To understand T cell activation states, we investigated the atlas of peripheral immune cells and the secreted cytokine network with single cell mass cytometry analysis. We found decreased γδ T-cell frequencies in all patients with SAA, together with a significantly increased proportion of interleukin (IL)-17A-producing cell subsets. Cytokine network analysis of immune cells showed significant positive relationship between IL and 17A production from immune cells and disease severity of severe aplastic anemia. On separating SAA into two distinct subgroups based on T-cell activation stage, the proportion of γδ T cells tended to decrease in the T-cell-activated SAA group compared with non-T-cell-activated group. And the proportion of IL-17A-producing γδ T cells (γδT17) within γδ T cells was newly found to be significantly higher in the T-cell-activated SAA group, implying that IL-17A production by γδ T cells was associated with T-cell activation. Overall, our study revealed a role of γδT17 cells in mediating autoreactive T-cell activation in SAA and provided a novel diagnostic indicator for monitoring autoreactive T-cell activation status during the progression of aplastic anemia in the clinic.

Prospective Study of a Modified Post-Transplantation Cyclophosphamide Regimen for Severe Aplastic Anemia Patients with HLA-Haploidentical Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality for severe aplastic anemia (SAA). The availability of haploidentical donors has expanded valid options for SAA; however, previous post-transplantation cyclophosphamide (PTCy)-based protocols for HLA-haploidentical HSCT in SAA patients are associated with relatively delayed neutrophil and platelet engraftment. We prospectively studied HLA-haploidentical HSCT using bone marrow (BM) combined with peripheral blood stem cells (PBSC) as grafts and a modified PTCy regimen for treating SAA. We evaluated the efficacy and safety of this regimen, which had an increased dose (from 4.5 mg/kg to 6.0 mg/kg) and backward-adjusted timing (from day -9 to -7 to days -5 to -3) of antithymocyte globulin (ATG) compared with previous PTCy protocols. Seventy-one eligible patients were included in this prospective study between July 2019 and June 2022. The median time to neutrophil and platelet engraftment was 13 days (range, 11 to 19 days) and 12 days (range, 7 to 62 days), respectively, and the cumulative incidence (CuI) of neutrophil and platelet engraftment was 97.2 ± 2.2% and 94.4 ± 2.9%, respectively. Five patients experienced graft failure (GF), including 2 with primary GF and 3 with secondary GF. The CuI of GF was 7.0 ± 3.1%. A ≥1-year interval between diagnosis and transplantation was a risk factor for the development of GF (HR, 8.40; 95% confidence interval [CI], 1.40 to 50.47; P = .02). No patients developed grade IV acute graft-versus-host disease (aGVHD) or severe chronic graft-versus-host disease (cGVHD). The 100-day CuI of grade II-IV aGVHD was 13.4 ± 4.2%, and the 2-year CuI of cGVHD was 5.9 ± 2.9%. With a median follow-up of 580 days (range, 108 to 1014 days) for 63 survivors, the estimated 2-year overall survival (OS) and 2-year GVHD-free and failure-free survival (GFFS) were 87.3% (95% CI, 79.4% to 96.0%) and 83.8% (95% CI, 74.9% to 93.7%), respectively. In conclusion, the PTCy regimen with an increased dose and backward-adjusted timing of ATG is an effective and feasible choice for treatment with HLA-haploidentical HSCT using BM combined with PBSC as grafts, with a high rate of and faster engraftment, low rate and intensity of aGVHD and cGVHD, and prolonged OS and GFFS.

Optimal combination of immune checkpoint and senescence molecule predicts adverse outcomes in patients with acute myeloid leukemia.

BACKGROUND: High expression of immune checkpoints (ICs) and senescence molecules (SMs) contributes to T cell dysfunction, tumor escape, and progression, but systematic evaluation of them in co-expression patterns and prognosis in acute myeloid leukemia (AML) was lacking. METHODS: Three publicly available datasets (TCGA, Beat-AML, and GSE71014) were first used to explore the effect of IC and SM combinations on prognosis and the immune microenvironment in AML, and bone marrow samples from 68 AML patients from our clinical center (GZFPH) was further used to validate the findings. RESULTS: High expression of CD276, Bcl2-associated athanogene 3 (BAG3), and SRC was associated with poor overall survival (OS) of AML patients. CD276/BAG3/SRC combination, standard European Leukemia Net (ELN) risk stratification, age, and French-American-British (FAB) subtype were used to construct a nomogram model. Interestingly, the new risk stratification derived from the nomogram was better than the standard ELN risk stratification in predicting the prognosis for AML. A weighted combination of CD276 and BAG3/SRC positively corrected with TP53 mutation, p53 pathway, CD8+ T cells, activated memory CD4+ T cells, T-cell senescence score, and Tumor Immune Dysfunction and Exclusion (TIDE) score estimated by T-cell dysfunction. CONCLUSION: High expression of ICs and SMs was associated with poor OS of AML patients. The co-expression patterns of CD276 and BAG3/SRC might be potential biomarkers for risk stratification and designing combinational immuno-targeted therapy in AML.Key MessagesHigh expression of CD276, BAG3, and SRC was associated with poor overall survival of AML patients.The co-expression patterns of CD276 and BAG3/SRC might be potential biomarkers for risk stratification and designing combinational immuno-targeted therapy in AML.

Feasibility of thoracic CT in assessing anemia for aplastic anemia patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Anemia is an important clinical symptom for aplastic anemia (AA) patients who are suffered with peripheral pancytopenia. OBJECTIVE: To evaluate the accuracy of diagnosing anemia with non-invasive chest computed tomography (CT) for AA patients. METHODS: The CT attenuation of left ventricular (LV) cavity and interventricular septum (IVS) on unenhanced thoracic CT images of AA patients are retrospectively analyzed, including 84 AA patients in pre-transplant and 1-month (n = 82), 2-month (n = 72), 3-month (n = 75), 6-month (n = 74) and 12-month (n = 70) followed patients in post-transplant. The difference (IVS-LV) and ratio (LV/IVS) of the CT attenuation between LV cavity and interventricular septum are calculated. Serum hemoglobin is estimated within 24 hours of CT imaging. The CT attenuations of IVS-LV and LV/IVS are correlated with hemoglobin, and their variation tendency is analyzed during the treatment of a-HSCT. A receiver operating characteristic (ROC) curve analysis is then performed for the diagnosis of anemia. RESULTS: The CT attenuations of IVS-LV and LV/IVS well correlate with hemoglobin (r = -0.618 and 0.628, respectively, P <  0.001). The variation tendency of IVS-LV and LV/IVS is similar to that of hemoglobin with opposite directions during one-year follow-up of a-HSCT. When a threshold of CT attenuation of IVS-LV and LV/IVS is set at 11.5HU and 0.77, respectively, both the sensitivity and specificity in diagnosing anemia are good (74.7% and 73.8% in CT attenuation of IVS-LV; 77.4% and 70.4% in LV/LVS, respectively). CONCLUSIONS: Both CT attenuation of LV/IVS and IVS-LV had similar accuracy in diagnosing anemia for AA patients. The non-invasive chest CT can offer a new possibility to complementarily evaluate anemia for AA patients in the diagnostic radiology reports.

Prognostic Impact of Quantifying Sarcopenia and Adipopenia by Chest CT in Severe Aplastic Anemia Patients Treated With Allogeneic Hematopoietic Stem Cell Transplantation.

RATIONALE AND OBJECTIVES: To investigate the prognostic role of chest CT-defined sarcopenia and adipopenia in severe aplastic anemia (SAA) patients treated with hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: This was a retrospective study of 123 consecutive SAA patients treated with HSCT. CT imaging was performed to quantify the pectoralis muscle (including major and minor) index (PMI) and the corresponding subcutaneous adipose tissue index (SAI). Sarcopenia and adipopenia were defined as PMI and SAI lower than the respective sex-specific medians. Correlations of the PMI and SAI with anthropometric indexes were calculated. Transplant-related outcomes were compared between the sarcopenia and adipopenia groups. Prognostic factors for overall survival (OS) and fail-free survival (FFS) were identified by Cox regression and were used to create a nomogram. The accuracy of the nomogram was evaluated by ROC curves. RESULTS: PMI showed good correlation with BMI and fat-free mass index (p < 0.001). SAI correlated with BMI and fat mass index (p < 0.001). The sarcopenia group (47.2%) had a significantly worse 3-year OS (90.8% vs. 77.6%, p = 0.045) and 3-year FFS (89.2% vs. 74.1%, p = 0.035) than the nonsarcopenia group. Sarcopenia status and diagnostic category were used to construct the nomogram of OS, as these were independent prognostic factors in the multivariate analysis for OS and FFS (p < 0.05). The area under the curve of the nomogram at one year and three years was 0.801 and 0.721, respectively. CONCLUSION: Sarcopenia indicates a poor prognosis in SAA patients undergoing HSCT. Intensive supportive care is suggested for SAA patients with sarcopenia before transplantation.

Mild blurry vision as the initial presentation of central nervous system relapses of acute lymphoblastic leukemia: a case report.

BACKGROUND: Leukemia relapses after hematopoietic stem cell transplantation can sometimes occur from the central nervous system prior to relapse from the bone marrow, and manifestations varied. CASE REPORT: We present a case of mild blurry vision as the initial symptom of central nervous system relapse of adult acute lymphoblastic leukemia. A 30-year-old man presented with a 1 week history of painless visual loss in both eyes. At that time there were no headaches or other systemic features. The neurological examination was without positive findings except bilateral optic nerve edema. He had a history of acute lymphoblastic leukemia and hematopoietic stem cell transplantation, which had been in clinical remission post-transplant for 1 year. Lumbar puncture revealed relapsed disease within the central nervous system, confirmed with cerebrospinal fluid leukemic blasts. CONCLUSIONS: It highlights the need for ophthalmologists to be aware of the possibility of central nervous system involvement in patients with the setting of leukemia when visual symptoms as the initial manifestation.

The establishment of a cytomegalovirus -specific CD8+ T-cell threshold by kinetic modeling for the prediction of post-hemopoietic stem cell transplant reactivation.

The dynamic interaction between the CMV virus and host immune response remains obscure, thus hindering the diagnosis and therapeutic management of patients with HSCT. The current diagnosis of CMV viremia depends on viral load estimation. Medical intervention based on viral load, can be unnecessary or poorly timed for many patients. Here we examined the clinical features and blood samples of patients with HSCT and assessed the CMV reactivation kinetics and corresponding CMV antigen-specific T-cell response in individual patients based on a peptide pool stimulation T-cell assay, which showed that CMV-specific CD8+ T cells were more suitable to be a diagnosis indicator for suppressing CMV reactivation. Using ROC analysis, we defined and verified a CMV-specific CD8+ T-cell counts threshold (925 cells/106 PBMCs) as an indicator of CMV reactivation post-HSCT, and suggested that use of this threshold would provide more accurate guidance for prompt medication and better management of CMV infection post-HSCT.

Prevention of acute graft-vs.-host disease by targeting glycolysis and mTOR pathways in activated T cells.

Graft-versus-host disease (GvHD) is a common life-threatening complication that can occur following allogeneic hematopoietic stem cell transplantation. This occurs if donor T cells recognize the host as foreign. During acute GvHD (aGVHD), activated T cells utilize glycolysis as the main source of energy generation. Therefore, inhibition of T cell glycolysis is a potential treatment strategy for aGVHD. In the present study, the effects of the combination of the glycolysis inhibitor 3-bromopyruvate (3-BrPA) and the mTOR inhibitor rapamycin (RAPA) on a mode of aGVHD were explored. In vitro mixed lymphocyte culture model was established by using splenocytes from C57BL/6 (H-2b) mice as responder and inactivated splenocytes from BALB/c (H-2d) mice as stimulator. In this model, 3-BrPA treatment (0-100 µmol/l) was found to suppress cell viability, increase cell apoptosis and reduce IFN-γ secretion, in a concentration-dependent manner. 3-BrPA treatment (0-100 µmol/l) was found to suppress cell viability, increase cell apoptosis and reduce IFN-γ secretion, in a concentration-dependent manner. In addition, combined treatment with 3-BrPA (0-100 µmol/l) alongside RAPA (20 µmol/l) exhibited synergistic effects on inhibiting cell viability and IFN-γ production, compared with those following either treatment alone. An aGVHD model was established by injection of bone marrow cells and spleen cells from the donor-C57BL/6(H-2b) mice to the receptor-BALB/c(H-2d) mice which were underwent total body irradiation first. In the aGVHD model, 3-BrPA (10 mg/kg/day), RAPA (2.5 and 5 mg/kg/day) and both in combination (5 and 2.5 mg/kg/day for 3-BrPA and RAPA, respectively) were all found to alleviate the damage caused by aGVHD, in addition to prolonging the survival time of mice with acute GvHD. In particular, the combined 3-BrPA and RAPA treatment resulted in the highest median survival time among all groups tested. In addition, the effects induced by combined 3-BrPA and RAPA treatment were found to be comparable to those in the 5 mg/kg/day RAPA group but superior to the 3-BrPA group with regards to the cumulative survival profile, GvHD score and lung histological score. The 3-BrPA and RAPA combination group also exhibited the lowest IFN-γ levels among all groups. Therefore, the combination of inhibiting both glycolysis and mTOR activity is a promising strategy for acute GvHD prevention.

The Potential Association of Delayed T Lymphocyte Reconstitution Within Six Months Post-Transplantation With the Risk of Cytomegalovirus Retinitis in Severe Aplastic Anemia Recipients.

Background: Delayed immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) is significantly associated with cytomegalovirus (CMV) infection. The aim of this study was to observe the recovery trend of peripheral lymphocyte subsets and immunoglobulins in HSCT recipients who developed CMV retinitis (CMVR). Methods: We identified 37 CMVR cases and 303 non-CMVR controls in this case-control study from a database of 404 consecutive severe aplastic anemia patients who received allogeneic HSCT at a single center between 2015 and 2020. We analyzed the transplant outcomes and immune reconstitution principles with a focus on lymphocyte CD series and immunoglobulin series within the first year post-HSCT. Results: Thirty-seven patients (55 eyes) were diagnosed with CMVR, with a mean onset time of 155 days post-HSCT. Among the 37 patients, one never had CMV detected in his blood but had a high CMV load in his intraocular fluid at the time of CMVR diagnosis. In the controls, 195 had CMV viremia and 108 did not. Compared with controls, CMVR cases had a longer duration of CMV viremia and a higher peak number of CMV load. T lymphocyte subsets including CD3, CD4 and CD8 were significantly lower in CMVR cases within six months after HSCT (all p < 0.05). Immunoglobulins also showed a slower recovery trend in CMVR cases. The recovery of B lymphocytes and natural killer cells exhibited no significant differences between the two groups. Conclusions: It is not enough to develop fundus screening strategies by merely relying on the CMV serostatus of recipients. Dynamic and continuous monitoring of T lymphocyte subsets, especially within six months post-HSCT, as well as serum immunoglobulin levels, can provide assistance with screening program of CMVR in HSCT recipients with severe aplastic anemia.

Pre-Transplant Platelet Refractoriness and Alternative Donors Are Associated With Cytomegalovirus Retinitis in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia.

Background: Cytomegalovirus retinitis is a severe, vision-threatening opportunistic infection in an immunodeficient population. Reports on cytomegalovirus retinitis in hematopoietic stem cell transplant recipients due to severe aplastic anemia have been scant. This study assessed the risk of cytomegalovirus retinitis in relation to the pre-transplant status of severe aplastic anemia patients. Methods: We conducted a retrospective nested case-control study of cytomegalovirus retinitis among severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplants in a tertiary care institution that attends severe aplastic anemia patients from southern China from January 1, 2013 to December 31, 2018. Each cytomegalovirus retinitis case was matched with four controls without cytomegalovirus retinitis by age and gender. Thirteen pre-transplant parameters were chosen to compare the risk factor levels between the cases and controls. Multivariable logistic regressions were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 361 severe aplastic anemia patients received hematopoietic stem cell transplants in the study period 2013-2018 in our medical institution, and 31 (8.58%) developed cytomegalovirus retinitis. Cytomegalovirus retinitis was diagnosed in the median of 148 days after transplantation. We confirmed platelet refractoriness more frequently in cases than in controls (p = 0.0005). Compared with human leukocyte antigen-matched sibling donors, alternative donors were significantly more prone to cytomegalovirus retinitis (p = 0.0009). After stepwise selection in multivariate logistic regression, platelet refractoriness (OR 5.41, 95% CI 1.98-15.39), haploidentical donor (OR 7.46, 95% CI 2.19-34.87), and unrelated donor (OR 8.38, 95% CI 2.30-41.34) were associated with an increased risk of cytomegalovirus retinitis. Conclusions: Pre-transplant platelet refractoriness and alternative donors were significant predictors of cytomegalovirus retinitis in severe aplastic anemia recipients. These results highlight the importance of accounting for existing risks while developing prevention strategies and preemptive treatment for severe aplastic anemia recipients. We recommend that the platelet count be closely monitored and thrombopoietin be properly applied during the period when cytomegalovirus retinitis is prone to occur.

Basiliximab for steroid-refractory acute graft-versus-host disease: A real-world analysis.

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD.

A Simplified CMV-specific T Cell Transfer Targeting Drug-resistant CMV Retinitis.

BACKGROUND: Among severely immunosuppressed patients resistant or refractory cytomegalovirus (CMV) retinitis is not uncommon, and is potentially blinding in the affected eye. Immunotherapy using CMV-specific cytotoxic T lymphocytes (CTLs) is an emerging and promising alternative for the control of resistant or refractory CMV retinitis. However, highly purified CMV-CTLs are still not available in the majority of medical institutions in China because the generation of CMV-CTLs is labor intensive, time-consuming and expensive. PURPOSE: This letter describes the clinical responses to a simplified CMV-CTL immunotherapy aimed at controlling drug-resistant CMV retinitis in two immunodeficient patients. CONCLUSIONS: Our cases suggest that the simplified CMV-CTL immunotherapy offers a highly efficient and low-cost solution to drug-resistant CMV retinitis. This immunotherapy strategy targeting drug-resistant CMV retinitis is likely to be cost-effective in the context of a specific patient population.

[Relationship between Muscle Mass of Limbs and aGVHD in Patients with Allogeneic Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To explore the correlation of limb muscle mass and acute graft-versus-host disease. METHODS: Clinical data from 144 patients treated by allo-HSCT in Guangzhou First People's Hospital were collected and analyzed retrospectively. The age, sex, diagnosis, donor age, sex of the donors, preparative regimen, ATG dose, HLA match, graft source, and number of infused stem cells of the patients were collected as baseline information. Meanwhile, bioelectrical impedance principle (BIA) was used to measure the limb muscle mass, body weight, body mass index (BMI), waist-to-hip ratio, upper arm muscle circumference, triceps skinfold thickness, and body fat rate of the patients before and after transplantation, so as to compare the changes of limb muscle mass and investigate its correlation with aGVHD. RESULTS: It was found that 61.11% of allo-HSCT patients showed muscle mass loss, and the proportion of male and female was 35.42% and 25.69%, respectively. There were reduction in the body weight, BMI, upper arm muscle circumference and muscle mass of limbs after transplantation as compared with those before transplantation (P<0.05). By comparing with the cumulative incidence of aGVHD between the patients in low muscle mass group and normal muscle mass group, it was found that the cumulative incidence of Ⅱ-Ⅳdegree aGVHD in patients with low muscle mass (30.38%) was higher than those with normal muscle mass (8.93%), which showed statistical difference (P<0.05). Univariate analysis showed that muscle mass, the sex of the donors, and preparative regimen were the influencing factors of aGVHD (P<0.05). Binary logistic regression showed that low muscle mass was the independent risk factor affecting aGVHD (P<0.05). CONCLUSION: Patients treated by allo-HSCT shows a decline in muscle mass after transplantation, and the incidence of aGVHD is high in patients with low muscle mass. Therefore, the assessment of muscle quality in early stage in patients with HSCT can facilitate earlier detection of aGVHD.

Predicting mortality from intracranial hemorrhage in patients who undergo allogeneic hematopoietic stem cell transplantation.

Intracranial hemorrhage (ICH) is a rare but fatal central nervous system complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, factors that are predictive of early mortality in patients who develop ICH after undergoing allo-HSCT have not been systemically investigated. From January 2008 to June 2020, a total of 70 allo-HSCT patients with an ICH diagnosis formed the derivation cohort. Forty-one allo-HSCT patients with an ICH diagnosis were collected from 12 other medical centers during the same period, and they comprised the external validation cohort. These 2 cohorts were used to develop and validate a grading scale that enables the prediction of 30-day mortality from ICH in all-HSCT patients. Four predictors (lactate dehydrogenase level, albumin level, white blood cell count, and disease status) were retained in the multivariable logistic regression model, and a simplified grading scale (termed the LAWS score) was developed. The LAWS score was adequately calibrated (Hosmer-Lemeshow test, P > .05) in both cohorts. It had good discrimination power in both the derivation cohort (C-statistic, 0.859; 95% confidence interval, 0.776-0.945) and the external validation cohort (C-statistic, 0.795; 95% confidence interval, 0.645-0.945). The LAWS score is the first scoring system capable of predicting 30-day mortality from ICH in allo-HSCT patients. It showed good performance in identifying allo-HSCT patients at increased risk of early mortality after ICH diagnosis. We anticipate that it would help risk stratify allo-HSCT patients with ICH and facilitate future studies on developing individualized and novel interventions for patients within different LAWS risk groups.

[Clinical Analysis of CMV Infection after Allogeneic Hematopoietic Stem Cell Transplantation in Severe Aplastic Anemia].

OBJECTIVE: To investigate the clinical characteristics and risk factors of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). METHODS: Clinical data from 270 SAA patients with allo-HSCT were retrospectively analyzed, including 108 sib congruence patients and 162 substitute donors (68 unrelated donor congruence patients and 94 related haploid patients). Different pretreatment schemes were selected for different transplantation modes. The HLA-identical sibling and haploid grafts were all bone marrow and peripheral blood stem cells, and the grafts from unrelated donors were peripheral blood stem cells. After granulocyte implantation, blood CMV-DNA was regularly monitored. Flow cytometry was also used to determine the absolute number of CD3+, CD4+T lymphocytes and CD19+B lymphocytes at 1, 2, 3, 6 and 12 months after transplantation. RESULTS: CMV infection occurred in 229 of 270 patients with an incidence of 84.8%. Among them, 18 patients developed giant cell disease. Univariate analysis showed that alternative donors (unrelated total and haploid donors), mycophenolate mofetil and acute graft-versus-host disease were statistically significantly associated with CMV infection (P<0.05). Multivariate analysis showed that alternative donors were associated with CMV infection. The recovery of CD3+ and CD4+ in 6 months in the substitute donors was delayed in comparison with that in the full sib group. CONCLUSION: After allo-HSCT, substitute donors are more easily to develop CMV infection than full-sibling donors, and the reconstruction of immune function is delayed after transplantation.