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A 24-year-old man with central nervous system (CNS) involvement of T-cell lineage acute lymphoblastic leukemia received sibling allogeneic stem cell transplantation (allo-SCT). He developed isolated CNS relapse early post-SCT, while high-dose systemic chemotherapy, intrathecal (IT) triple infusion and IT donor lymphocytes infusion (DLI) all demonstrated effectiveness. We performed IT umbilical cord blood-derived CAR-NK (target CD7) cells infusion, which was not previously reported. After infusion, detection of cytokines revealed that interferon-γ, interleukin-6 and interleukin-8 increased in CSF. He developed high fever, headache, nausea, vomiting and a spinal cord transection with incontinence in a short time, whereas the ptosis and blurred vision improved completely. The bone marrow remained encouragingly complete remission and complete donor chimerism over 9 months after IT CAR-NK cells infusion. In conclusion, IT CAR-NK cells infusion is a potentially feasible and effective option for patients with CNS relapse, with limited neurological toxicity.

Background Lymphocyte trafficking via chemokine receptors such as CCR5 and CXCR3 plays a critical role in the pathogenesis of aGVHD. Our previous studies showed that addition of CCR5 or CXCR3 antagonist could only slightly alleviate the development of aGVHD. Given the specificity of T lymphocytes bearing CXCR3 and CCR5, we investigated whether combined CCR5 and CXCR3 blockade could further attenuate murine aGVHD. Methods A mouse model of aGVHD was established to assess the efficacy of CCR5 or/and CXCR3 blockade on the development of aGVHD. The distribution of lymphocytes was calculated by quantification of immunostaining cells. The immunomodulatory effect on T cells were assessed by evaluating T- cell proliferation, viability, and differentiation. Results Using murine allo-HSCT model, we demonstrated that blockade of both CCR5 and CXCR3 could efficiently alleviate the development of aGVHD. Further investigation on the immune mechanisms for this prophylactic effect showed that more T cells were detained into secondary lymphoid organs (SLOs), which may lead to reduced infiltration of T cells into GVHD target organs. Our study also showed that T cells detained into SLOs dampened the activation, suppressed the polarization toward Th1 and Tc1, and induced the production of Treg cells. Conclusion These data suggest that concurrent blockade of CCR5 and CXCR3 attenuates murine aGVHD through modulating donor-derived T cell distribution and function, and this might be applicable for aGVHD prophylaxis in clinical settings.

Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the tissue deposition of misfolded amyloid fibrils, leading to progressive organs dysfunction. We retrospectively analyzed 335 patients with AL amyloidosis in the First Hospital of Peking University from January 2011 to December 2021 to describe the real-world clinical characteristics and prognosis of the patients with AL amyloidosis in China. Patients (median age, 60 years) were diagnosed with multi-organ involvement of kidney (92.8%), heart (57.9%), liver (12.8%). 55.8% of patients were treated with chemotherapy, 63.4% of whom achieved hematologic response (≥ very good partial response). Only 18.2% of the patients received autologous stem cell transplant (ASCT), who were younger and less likely to have cardiac involvement. The median overall survival of patients with AL amyloidosis was 77.5 months. The level of brain natriuretic peptide, percentage of bone marrow plasma cell and total bilirubin were identified as independent prognostic factors for survival. Albeit the younger age and high ratio of renal involvement might contribute to the favorable prognosis of this cohort, the role of novel agents and ASCT is also discernible. This real-world research will provide a panoramic impression on the progress of AL amyloidosis in China.

Fibroblastic reticular cells (FRCs) are a type of stromal cells located in the T zone in secondary lymphoid organs. Previous studies showed that FRCs possess the potential to promote myeloid differentiation. We aim to investigate whether FRCs in lymph nodes (LNs) could induce tolerogenic macrophage generation and further influence T-cell immunity at an early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT).LNs were assayed to confirm the existence of proliferating macrophages after allo-HSCT. Ex vivo-expanded FRCs and bone marrow cells were cocultured to verify the generation of macrophages. Real-time quantitative PCR and ELISA assays were performed to observe the cytokines expressed by FRC. Transcriptome sequencing was performed to compare the difference between FRC-induced macrophages (FMs) and conventional macrophages. Mixed lymphocyte reaction and the utilization of FMs in acute graft-versus-host disease (aGVHD) mice were used to test the inhibitory function of FMs in T-cell immunity in vitro and in vivo.We found a large number of proliferating macrophages near FRCs in LNs with tolerogenic phenotype under allo-HSCT conditions. Neutralizing anti-macrophage colony-stimulating factor receptor antibody abolished FMs generation in vitro. Phenotypic analysis and transcriptome sequencing suggested FMs possessed immunoinhibitory function. Mixed lymphocyte reaction proved that FMs could inhibit T-cell activation and differentiation toward Th1/Tc1 cells. Injection of FMs in aGVHD mice effectively attenuated aGVHD severity and mortality.This study has revealed a novel mechanism of immune regulation through the generation of FRC-induced tolerogenic macrophages in LNs at an early stage of allo-HSCT.

Castleman disease(CD) is a rare lymphoid tissue proliferative disease with an increasing focus on etiology and treatment in recent years. The consensus on CD diagnosis and treatment has been published by several organizations, playing an important role in promoting cooperation on CD managements and investigations among different teams. Based on the last 15-years retrospective real-world data from Peking University First Hospital (PKUFH), we re-classified and re-evaluated the clinical and pathological information of patients with pathologically suspected diagnosis of CD. A total of 203 patients were included in our study, in which the diagnosis of CD was confirmed in 189 cases, including 118 patients with unicentric CD (UCD, n = 118, 62.4%) and 71 patients with multicentric CD (MCD, n = 71, 37.6%). 44.1% (n = 52) of UCDs in our cohort were complicated with Paraneoplastic Pemphigus (PNP). The treatment of UCD is mostly surgical resection, with a 5-year overall survival(OS) 88.1%. Patients with PNP had a poorer prognosis than those without PNP [82.9% (95% CI 123–178) vs 92.8% (95% CI 168–196), log-rank P = 0.041). The rate of concurrent systemic symptoms was 74.6% (n = 53), and renal involvement occurred in 49.3% (n = 35) MCD patients. The MCD treatments were mainly chemotherapy regimens, with a 5-year OS of 77.6% (95% CI, 143–213). In conclusion, UCDs have a better overall prognosis than MCDs. But the prognosis of those complicated with PNP was poor. Differential diagnosis of MCD is difficult. MCD treatment in China is heterogeneous. The inaccessibility of anti-IL-6-targeted drugs in China may contribute to the poor prognosis of MCD.

Multiple myeloma (MM) is a malignant plasma cell disorder affecting mainly the elderly population. Revolutionary progress in immunotherapy has been made recently, including monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapies; however, the high relapse rate remains problematic. Therefore, combination therapies against different targets would be a reasonable strategy. In this study, we present a new X-chromosome encoded testis-cancer antigen (CTA) AKAP4 as a potential target for MM. AKAP4 is expressed in MM cell lines and MM primary malignant plasma cells. HLA-A*0201-restricted cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) transduced with an adenovirus vector encoding the full-length

Zheng-Yang Song, Han-Yun Ren, Yu-Jun Dong, Yuan Li, Yue Yin, Yu-Hua Sun, Qian Wang, Wei-Lin Xu, Wei Liu, Jin-Ping Ou, Ze-Yin Liang Department of Hematology, Peking University First Hospital, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Han-Yun Ren; Ze-Yin LiangDepartment of Hematology, Peking University First Hospital, No. 8 Xi Shi Ku Street, Xi Cheng District, Beijing 100034, People’s Republic of ChinaTel/Fax +86 10-83575082Email renhy0813@163.com; walzyaw@163.comPurpose: To explore the efficacy of low-dose rabbit antithymocyte globulin (rATG) in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) for patients with acute leukemia or myelodysplastic syndrome.Patients and Methods: We performed a retrospective study of 79 patients with hematologic malignancies who received MSD-HSCT. All patients received standard graft-versus-host disease (GVHD) prophylaxis comprising cyclosporine, mycophenolate mofetil and short-term methotrexate. Among them, 38 were administered 5 mg/kg rATG as part of GVHD prophylaxis. Clinical outcomes including overall survival (OS), GVHD and relapse were analyzed.Results: No graft failure occurred in the antithymocyte globulin (ATG) or non-ATG group. The cumulative incidences of grade 2– 4 and 3– 4 acute GVHD at day +100 were 13.3% versus 19.5% (p=0.507) and 5.7% versus 15.2% (p=0.196), respectively. The 2-year cumulative incidences of chronic GVHD (cGVHD) were 35.4% and 60.4% (p=0.039), and those of extensive cGVHD were 12.9% and 40.0% (p=0.015), respectively. In a multivariate analysis, the use of low-dose rATG was an independent protective factor for extensive cGVHD (hazard ratio [HR] 0.256; 95% confidence interval [CI], 0.080 to 0.822, p=0.022). The 2-year OS was 88.1% and 68.4% (p=0.038), respectively, and the use of low-dose rATG was the only protective factor in the multivariate analysis (HR 0.216; 95% CI, 0.059 to 0.792, p=0.021). There was no significant difference between the two groups in terms of the 2-year cumulative incidence of relapse, leukemia-free survival or GVHD-free and relapse-free survival.Conclusion: Low-dose rATG used in MSD-HSCT as part of the conditioning regimen results in a reduced incidence of cGVHD and improves survival outcomes.Keywords: low-dose rATG, hematopoietic stem cell transplantation, matched sibling donor, graft-versus-host disease

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy arising from plasmacytoid dendritic cell precursors. The disease typically manifests in the skin, but it also evolves into a leukemic phase or can be complicated by other myeloid malignancies, especially myelomonocytic tumors. The association between these neoplasms is not fully elucidated. We report a case of BPDCN with a history of cytopenia that was supposed to be chronic myelomonocytic leukemia. The patient received intensive chemotherapy and achieved complete remission, but soon relapsed. The successive occurrence of myelomonocytic neoplasm and BPDCN is in accordance with the fact that they evolve from a common cell origin with a multilineage potential for myelomonocytic and plasmacytoid dendritic cell differentiation. This case may shed further light on the mystery of biology and the histogenesis of BPDCN.

Background Universal gene targets are in persistent demand by real‐time quantitative polymerase chain reaction (RT‐qPCR)‐based methods in acute leukemia (AL) diagnosis and monitoring. Human Krüppel‐like factor 3 (hKLF3), a newly cloned human transcription factor, has proved to be a regulator of hematopoiesis. Methods Sanger sequencing was performed in bone marrow (BM) samples from 17 AL patients for mutations in hKLF3 coding exons. hKLF3 expression in peripheral blood (PB) and BM samples from 45 AL patients was dynamically detected by RT‐qPCR. PB samples from 31 healthy donors were tested as normal controls. Results No mutation was sequenced in hKLF3 coding exons. hKLF3 expression in PB of AL was significantly lower than that in healthy donors [0.30 (0.02‐1.07) vs 1.18 (0.62‐3.37), P, In the present study, we investigated the expression of hKLF3 in acute leukemia patients by both Sanger sequencing and RT‐qPCR. ROC analyses indicated excellent efficacy of hKLF3 expression in PB samples for the diagnosis of AML. In addition, a significantly converse correlation between inhibition of hKLF3 expression in peripheral blood and increased leukemic burden was observed.

Clinical data of patients with severe aplastic anemia (SAA) were retrospectively analyzed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched related sibling hematopoietic stem cell transplantation (MSD-HSCT) in complications and survivals. Thirty consecutive patients were enrolled in the study with a median follow-up of 50 months (range 4, 141), and the median age of the patients was 21 years (range 3, 49). All the patients achieved myeloid engraftment in the two cohorts. The cumulative incidences of platelet engraftment were 95.5 and 100% in HID cohort and MSD cohort, respectively. The median time for neutrophil and platelet recovery was 11 (range 9, 19) and 15 (range 10, 25) days in HID cohort, and 12 (range 10, 19) and 14 (range 8, 25) days in MSD cohort. The cumulative incidences of grade II–IV and grade III–IV acute graft vs. host disease (aGvHD) in HID cohort and in MSD cohort were 18.9 vs. 14.3% (p = 0.77) and 10.5 vs. 0% (p = 0.42), respectively. The cumulative incidences of chronic graft vs. host disease (cGvHD) was 22.7% in HID cohort and 25.5% in MSD cohort (p = 0.868). The 5-year overall survival (OS) rates and 5-year failure-free survival (FFS) rates in HID cohort and MSD cohort were 85.1 vs. 87.5% (p = 0.858), 80.3 vs. 87.5% (p = 0.635), respectively. The median time to achieve engraftment, cumulative incidence of aGvHD and cGvHD, and the 5-year OS and FFS rates were not significantly different between the two cohorts. We suggest that HID-HSCT might be a safety and effective option for SAA patients without a matched donor.

The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.

Background Idiopathic pneumonia syndrome (IPS) is a non-infectious fatal complication characterized by a massive infiltration of leukocytes in lungs and diffuse pulmonary injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conventional immunosuppressive treatments for IPS have poor therapeutic effects. Safe and effective treatments are not yet available and under explorations. Our previous study demonstrated that mesenchymal stem cells (MSCs) can alleviate IPS, but the mechanisms remain unclear. Methods Co-cultured pre-activated T cells and MSCs in vitro to observe the changes in the CCR2-CCL2 axis. By establishing an IPS mouse model and administering MSCs to further verify the results of in vitro experiments. Results Co-culture of pre-activated T cells with MSCs in vitro modulated the CCR2-CCL2 axis, resulting in quiescent T cells and polarization toward CCR2+CD4+ T cell subsets. Blocking CCR2-CCL2 interaction abolished the immunoregulatory effect of MSCs, leading to re-activation of T cells and partial reversion of polarizing toward CCR2+CD4+ T cells. In IPS mouse model, application of MSCs prolonged the survival and reduced the pathological damage and T cell infiltration into lung tissue. Activation of CCR2-CCL2 axis and production of CCR2+CD4+ T cells were observed in the lungs treated with MSCs. The prophylactic effect of MSCs on IPS was significantly attenuated by the administration of CCR2 or CCL2 antagonist in MSC-treated mice. Conclusions We demonstrated an important role of CCR2-CCL2 axis in modulating T cell function which is one of the mechanisms of the prophylactic effect of MSCs on IPS.

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.

Voriconazole is widely recommended for the prevention and treatment of invasive fungal infections in hematopoietic stem cell transplantation patients. However, its use is limited by a narrow therapeutic range and large inter-individual variability. This study aimed to characterize the pharmacokinetics of voriconazole in Chinese hematopoietic stem cell transplantation patients, to explore factors affecting its pharmacokinetic parameters, and to provide recommendations for its optimal dosing regimens. A total of 121 serum concentration samples from 23 patients were retrospectively included. Voriconazole concentrations were detected, and patient clinical data were recorded. Population pharmacokinetic analysis was performed by a non-linear, mixed-effect modeling approach. Goodness-of-fit plots, bootstrap method, prediction-corrected visual predictive check and external validation by an independent group of seven patients were performed to evaluate the final model. A one-compartment model with first-order elimination successfully described the data. The absorption rate constant was fixed at 1.1 h−1 and bioavailability was fixed at 0.895. The typical values for voriconazole clearance and distribution volume were 9.52 L/h and 155 L, respectively. CYP2C19*2 genotype and mycophenolate mofetil combination presented a significant impact on the clearance. Compared with CYP2C19*2 carriers, voriconazole clearance was proven to be higher in CYP2C19*1/*1 patients. A population pharmacokinetic model of voriconazole was successfully established in Chinese hematopoietic stem cell transplantation patients. Based on the final model, CYP2C19*2 genotyping coupled with therapeutic drug monitoring seems to be useful to guide voriconazole dosing and to explain subtherapeutic concentrations in clinical practice.

Acute graft-versus-host disease (aGVHD) remains a significant and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to the occurrence of aGVHD, allo-HSCT significantly increases the mortality rate compared with autologous hematopoietic stem cell transplantation (auto-HSCT). In this study, auto-HSCT and allo-HSCT aGVHD mouse models were built to detect the difference in CD4+ lymphocyte in different tissues based on ribonucleic acid sequencing (RNA-Seq) analysis. Clustering analysis, functional annotation, and pathway enrichment analysis were performed on differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was used to find hub genes. CD4+T cells were activated by MLR and cytokine stimulation. Cells were sorted out by a flow cell sorter. The selected genes were verified by qRT-PCR, histology, and immunofluorescence staining. The GSE126518 GEO dataset was used to verify the hub genes. Enrichment analysis revealed four immune-related pathways that play an important role in aGVHD, including immunoregulatory interactions between a lymphoid and a nonlymphoid cell, chemokine receptors binding chemokines, cytokine and cytokine receptor interaction, and the chemokine signaling pathway. At the same time, with the PPI network, 11 novel hub genes that were most likely to participate in immunoregulation in aGVHD were identified, which were further validated by qRT-PCR and the GSE126518 dataset. Besides, the protein expression level of Cxcl7 was consistent with the sequencing results. In summary, this study revealed that immunoregulation-related DEGs and pathways played a vital role in the onset of aGVHD. These findings may provide some new clues for probing the pathogenesis and treatment of aGVHD.

Acute graft-versus-host disease (aGVHD) remains a significant and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to the occurrence of aGVHD, allo-HSCT significantly increases the mortality rate compared with autologous hematopoietic stem cell transplantation (auto-HSCT). In this study, auto-HSCT and allo-HSCT aGVHD mouse models were built to detect the difference in CD4+ lymphocyte in different tissues based on ribonucleic acid sequencing (RNA-Seq) analysis. Clustering analysis, functional annotation, and pathway enrichment analysis were performed on differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was used to find hub genes. CD4+T cells were activated by MLR and cytokine stimulation. Cells were sorted out by a flow cell sorter. The selected genes were verified by qRT-PCR, histology, and immunofluorescence staining. The GSE126518 GEO dataset was used to verify the hub genes. Enrichment analysis revealed four immune-related pathways that play an important role in aGVHD, including immunoregulatory interactions between a lymphoid and a nonlymphoid cell, chemokine receptors binding chemokines, cytokine and cytokine receptor interaction, and the chemokine signaling pathway. At the same time, with the PPI network, 11 novel hub genes that were most likely to participate in immunoregulation in aGVHD were identified, which were further validated by qRT-PCR and the GSE126518 dataset. Besides, the protein expression level of Cxcl7 was consistent with the sequencing results. In summary, this study revealed that immunoregulation-related DEGs and pathways played a vital role in the onset of aGVHD. These findings may provide some new clues for probing the pathogenesis and treatment of aGVHD.

Background The Epstein-Barr Virus (EBV) is tumorigenic, and can be detected in many kinds of lymphomas. Some studies have shown a worse prognosis for patients with EBV-associated lymphoma. However, the mechanism is not fully understood. This study aimed to investigate the T cell signatures in patients with EBV-associated lymphoma. Methods Peripheral blood was collected from 17 patients with EBV-associated lymphoma and 19 healthy donors. We first examined the proportions of the lymphocyte subpopulations in peripheral blood mononuclear cells in patients with both groups by flow cytometry. Then we employed the enzyme-linked immunospot assay to evaluate the EBV antigen-specific response of the cytotoxic T cells in the two groups. Finally, to explore the mechanism of T cells dysfunction in EBV-associated lymphoma, we examined the expression of multiple inhibitory receptors representing T cell exhaustion and biomarkers representing T cell senescence on the surfaces of CD4+ T cells and CD8+ T cells. Results The ratio of peripheral CD4+ T cells and the absolute cell counts of CD4+ T cells and CD8+ T cells were significantly decreased in patients with EBV-associated lymphoma compared with those of healthy donors. The IFN-γ production upon stimulation of EBV mixed peptides were remarkably reduced in the patients. Higher expression levels of T cell exhaustion markers, PD1, LAG3, TIM3 and CTLA4 on T cells were found in the patients. The two subsects of exhausted T cells (T-bethiPD1mid and EOMEShiPD1hi) were higher in the patients. More importantly, CXCR5+CD8+T cells controlling viral replication decreased significantly in the patients. The fractions of senescent T cells increased in the patients. Conclusions In summary, our study demonstrated that the reduced EBV-specific T cells, the exhaustion and senescence of T cells together contributed to the T cell dysfunction in the patients with EBV-associated lymphoma.

AMG 487 is the targeted blocker of chemokine receptor CXCR3 and improves inflammatory symptoms by blocking the inflammatory cycle. Here we investigated whether AMG 487 affects dendritic cell (DC) biology and function. The expression of co-stimulatory markers on DCs was reduced, indicating the semi-mature state of DC when AMG 487 was added throughout the in vitro differentiation period. Additionally, when added solely during the final lipopolysaccharide-induced activation step, AMG 487 inhibited DC activation, as demonstrated by a decreased expression of activation markers. AMG487 also promoted the expression of PD-L2 and impaired the ability to induce antigen-specific T cell responses. Our results demonstrated that AMG 487 significantly affects DC maturity in vitro and function leading to impaired T cell activation, inducing DCs to have characteristics similar to tolerogenic DCs. AMG 487 may directly play an immunomodulatory role during DC development and functional shaping.

Objective Serum free light chain (FLC) level is closely associated with the functional state of B lymphocytes, and many studies have shown that delayed reconstitution of B lymphocytes contributed to chronic graft-versus-host disease (cGVHD). This study assessed the predictive value of FLC levels in serum collected early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for cGVHD. Methods Sixty-two patients who had undergone allo-HSCT were retrospectively reviewed. The correlations between the FLC levels and the development of cGVHD were explored. Results Of the 62 patients, 33 cases developed cGVHD, with the prevalence of 53.2%. With Seattle classification, 19 cases had limited cGVHD while 14 cases contracted extensive cGVHD. While with NIH classification, 17 cases had mild cGVHD, 6 cases moderate cGVHD, and 10 cases severe cGVHD. Multivariant statistical analysis showed that the FLC levels were not associated with all severities of cGVHD but were correlated with the development of extensive or moderate to severe cGVHD (P = .01 and .038, respectively). Conclusions Serum FLC levels early after HSCT may reflect the functional state of B-cell reconstitution. Patients with low serum FLC Level early post-allo-HSCT tend to develop extensive cGVHD or moderate to severe cGVHD.

To date, there is no consensus on choosing autologous hematopoietic stem cell transplantation (auto-HSCT) or allogenic HSCT (allo-HSCT) for peripheral T-cell lymphomas (PTCLs). This study aimed to compare the relative efficacy of auto-HSCT versus allo-HSCT for patients with PTCLs. We conducted a multicenter retrospective study about 128 patients who underwent auto-HSCT (n=72) or allo-HSCT (n=56) at 8 medical centers across China between July, 2007 and June, 2017. With a median follow-up of 30 (2-143) months, outcomes of patients receiving auto-HSCT were better than those in allo-HSCT (3-year OS: 70% versus 46%, P = 0.003; 3-year PFS: 59% versus 44%, P = 0.002). Three-year non relapse rate (NRM) in auto-HSCT recipients was 6%, compared with 27% for allo-HSCT recipients ( P =0.004). There was no difference in relapse rate between these two groups (34% in auto-HSCT versus 29% in allo-HSCT, P =0.84). Specifically, patients with low PIT score who received auto-HSCT group in upfront setting had better outcome than patients with high PIT score (3-year OS: 85% versus 40%, P = 0.003). Regarding remission status before transplantation, patients with CR undergoing auto-HSCT had the best outcome (3-year OS: 88% versus 48% in allo-HSCT; P =0.008). For patients less than CR, the outcome of patients undergoing auto-HSCT was similar to that in allo-HSCT (3-year OS:51% versus 46%; P =0.30). When further checking patients in PD or SD, the survival curve of patients in the allo-HSCT group was better than that in the auto-HSCT group. It is plausible to choose auto-HSCT versus allo-HSCT according PIT score and remission status before transplantation.

The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2–4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ). The clinical trial was registered retrospectively.

Summary Background Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 10 9 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. Methods We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18–70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m 2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m 2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of −10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. Findings Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27–36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, −5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the −10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3–4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3–4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). Interpretation Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. Funding Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China.

To investigate the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on chemokine receptors and explore the potential mechanism of rhG-CSF inducing immune tolerance, ninety-seven donor and recipient pairs undergoing family-donor allogeneic hematopoietic stem cell transplantation were studied. The results indicated that different donors showed great disparities in expression changes after mobilization. Multivariate analysis revealed that both HLA mismatching and CCR7 downregulation on donors' CD4+ T cells after mobilization were independent risk factors for acute graft-versus-host disease (GVHD). In contrast, CCR5 downregulation on CD4+ T cells was associated with reduced incidence of acute GVHD. In conclusion, rhG-CSF mobilization could lead to differential regulation of chemokine receptors expression on T cell subsets in different donors. Downregulation of CCR5 and upregulation of CCR7 expression on donor CD4+ T cells might protect recipients from acute GVHD. This finding may provide a promising new strategy for the prevention and treatment of acute GVHD.

Human herpes virus type 8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disease often involving constitutional symptoms, cytopenias, and multiple organ system dysfunction. In China, the majority of MCD cases are HHV-8 negative. Given that siltuximab, the only FDA-approved treatment for iMCD is not available in China; rituximab- and cyclophosphamide-containing regimens are often used in the treatment of Chinese iMCD patients. To evaluate the efficacy of rituximab in this rare and heterogeneous disease, clinical and pathological data from 27 cases of iMCD were retrospectively analyzed from two large medical centers in China. The novel diagnostic criteria for iMCD were applied, and POEMS syndrome, IgG4-related diseases, and follicular dendritic cell sarcomas cases were excluded from analyses. Total response rate of rituximab- and cyclophosphamide-containing regimens was 55.5%, with 33.3% (9/27) of the cases reaching CR and 22.2% (6/27) PR. In the 14 cases of R-R iMCD, total response rate was only 42.9% (CR 14.3% [2/14], PR 28.6% [4/14]). The 5-year OS of these 27 iMCD cases was 81% (95% CI 64-98; 27 total patients, 4 events, 23 censored) after receiving these regimens, but the 5-year PFS was 43% (95% CI 19-66; 25 total patients, 11 events, 14 censored). Thus, rituximab-based regimens should be considered for the treatment of iMCD patients when siltuximab is not available and potentially in siltuximab-refractory cases.

In the Asia‐Pacific region, treatment options are limited for patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Rituximab is widely used in this setting when purine analog‐based therapies are not appropriate. We evaluated the efficacy and safety of ibrutinib compared with rituximab in a randomized, open‐label phase 3 study in predominantly Asian patients with relapsed/refractory CLL/SLL. Patients (N = 160) were randomly assigned 2:1 to receive 420 mg ibrutinib (n = 106) until disease progression (PD) or unacceptable toxicity or up to six cycles of rituximab (n = 54). The primary endpoint was investigator‐assessed progression‐free survival (PFS); key secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. Rituximab‐treated patients could crossover to receive ibrutinib after confirmed PD. At data cutoff, median treatment duration was 16.4 months for ibrutinib and 4.6 months for rituximab. Ibrutinib significantly improved PFS (hazard ratio [HR] = 0.180, 95% confidence interval [CI]: 0.105–0.308). ORR was significantly higher (P

BACKGROUND This Phase 3 randomized, double-blind study evaluated the efficacy and safety of plerixafor plus granulocyte-colony-stimulating factor for the mobilization of hematopoietic stem cells in Chinese patients with non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS Adults (ages 18-75 years) with non-Hodgkin's lymphoma in first or second complete or partial remission, without previous hematopoietic stem cell mobilization or autologous transplant, were included. Patients received granulocyte-colony-stimulating factor 10 µg/kg/day from Days 1 through 4 before they were randomized (1:1) to receive either plerixafor 0.24 mg/kg/day or placebo subcutaneously on Days 4 through 7 plus continued granulocyte-colony-stimulating factor on Days 5 through 8. Apheresis began on Day 5 and continued for no more than 4 days. The primary endpoint was collection of 5 × 106 CD34+ cells/kg or greater over no more than 4 days of apheresis. Other endpoints included the collection of 2 × 106 CD34+ cells/kg or greater and safety. RESULTS Overall, 101 patients were enrolled, and 50 were randomized to each group. More patients in the plerixafor group achieved 5 × 106 CD34+ cells/kg or greater (62 vs. 20%; p

Background： CT103A, a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product showed excellent safety and promising efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM) patients in our previous report [Blood. 2021; 137 (21): 2890-2901]. The unique CAR structure containing fully human single-chain variable fragments (scFvs) may bypass the potential host anti-CAR immunogenicity and retain antitumor activity. Here we reported the safety and efficacy results of 71 patients in 1.0×10 6 CAR+ T cells/kg cohort from the ongoing phase1/2 study (ChiCTR1800018137/ ChiCTR2000033946). Notably, it was the first time that prior BCMA CAR-T exposed patients were eligible to participate in an anti-BCMA CAR-T cell trial. Methods： This phase 1/2 study of CT103A is single-arm designed and is conducted in 13 centers in China. The study enrolled RRMM patients who had received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. 1.0 × 10 6 CAR+ T cells/Kg was previously identified as recommended phase 2 dose (RP2D). Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, patients received CT103A. The primary objectives of this study were to assess the safety and efficacy of CT103A at RP2D. The cellular pharmacokinetic profile of CT103A in peripheral blood was investigated by measuring CAR transgene levels using droplet digital polymerase chain reaction (ddPCR) and CAR-T cells by flow cytometry. Minimal residual disease (MRD) negativity was evaluated in bone marrow aspirate by standardized Euroflow 8-color flow cytometry with a minimum sensitivity of 10 -5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay. Results: As of the July 15, 2021, 71 patients [59.2% male; median age 58.0 years (range 41-71)] with RRMM received CT103A (9 in phase 1a; 17 in phase 1b; 45 in phase 2). The median follow-up time was 147 days (range 31 to 1029). The treated patients had received a median of 4 (range 3-13) lines of prior therapy. 28.2% and 18.3% were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 18.3% had previously received CAR-T therapy. What's more, 7% of the patients had the extramedullary disease at baseline, and 76.1% had high-risk cytogenetics. The most common ≥ grade 3 treatment-related AEs were hematological toxicities. 93.0% of the patients experienced CRS, among which only 2.8% were grade 3. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was 6 days (range 1-12) with a median duration of 4 days (range 1-27). Only one (1.4%) patient experienced grade 2 ICANS which manifested as a transiently decreased level of consciousness and soon recovered without intervention. All 71 patients were evaluable for at least one month of efficacy assessment. The median time to first response was 15 days (range 11-124). A 94.4% ORR was observed, with 50.7% ≥ CR, 26.8% VGPR, and 16.9% PR. Among them, 50 patients who have completed follow-up of 3 months achieved 96.0% ORR, with 54.0% ≥ CR, 28% VGPR, and 14% PR. For 13 patients who have previously been treated with CAR-T therapy, ORR was 76.9%, with ≥ CR rate of 38.5%，VGPR of 15.4%, and PR of 23.1%. Of the 69 patients with evaluable bone marrow aspirate, 92.8% achieved MRD-negativity with a median time to MRD-negative of 17 days (range 13-180), and among them, 75.0% (95%CI 53.1-87.6%) achieved sustained MRD negativity over six months. The expansion of CT103A reached the peak at a median of 12 days (range 5 to 29). CT103A was still detectable in 88.5% (23/26) patients at 6 months and 87.5% (14/16) patients at 12 months after infusion. The first enrolled patient remains in sCR for 34 months with significant persistence of CT103A transgene. In addition, only 2 of 71 patients were detected positive for anti-drug antibody, which was reported to be a high-risk factor for disease relapse/progression after CAR-T therapy. Conclusion: The impressive efficacy of CT103A, including time to response, overall response rate, and durability, was corroborated by robust expansion and prolonged persistence of CT103A. The expansion and clinical benefits of CT103A did not seem to be influenced by prior murine BCMA CAR-T. Disclosures No relevant conflicts of interest to declare.

Objective Although L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL), hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL). In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL. Methods Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China. Results All the 30 patients, including 19 males and 11 females with a median age of 30 (range: 18-62) years, completed 128 times of the PEG-ASP, with the median of 4 (range: 2-6) times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7% (26/30), with 50.0% (15/30) complete response and 36.7% (11/30) partial response. The 3-year overall survival was 46.0% [95% confidence interval (95% CI), 28.2%-64.8%], and the 3-year progression-free survival was 43.0% (95% CI, 25.7%-62.0%). Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. Conclusions Our clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3-4 neutropenia for adult LBL, and no therapy-related deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2-3 weeks of action duration, and convenience for patients and physicians.

Immortalized cell lines are useful for deciphering the pathogenesis of acute leukemia and developing novel therapeutic agents against this malignancy. In this study, a new human myeloid leukemia cell line YBT-5 was established. After more than 1-year cultivation from the bone marrow of a patient with acute monocytic leukemia, YBT cell line was established. Then a subclone, YBT-5, was isolated from YBT using single cell sorting. Morphological and cytogenetical characterizations of the YBT-5 cell line were determined by cytochemical staining, flow cytometry analysis, and karyotype analysis. Molecular features were identified by transcriptomic analysis and reverse transcription-polymerase chain reaction. To establish a tumor model, 5 × 106 YBT-5 cells were injected subcutaneously in nonobese diabetic/severe combined immune-deficiency (NOD/SCID) mice. DOT1L has been proposed as a potential therapeutic target for KMT2A-related leukemia; therefore, to explore the potential application of this new cell line, its sensitivity to a specific DOT1L inhibitor, EPZ004777 was measured ex vivo. The growth of YBT-5 does not depend on granulocyte-macrophage colony-stimulating factor. Cytochemical staining showed that α-naphthyl acetate esterase staining was positive and partially inhibited by sodium fluoride, while peroxidase staining was negative. Flow cytometry analysis of YBT-5 cells showed positive myeloid and monocytic markers. Karyotype analysis of YBT-5 showed 48,XY,+8,+8. The breakpoints between KMT2A exon 10 and exon 11 (KMT2A exon 10/11) and MLLT3 exon 5 and exon 6 (MLLT3 exon 5/6) were identified, which was different from all known breakpoint locations, and a novel fusion transcript KMT2A exon 10/MLLT3 exon 6 was formed. A tumor model was established successfully in NOD/SCID mice. EPZ004777 could inhibit the proliferation and induce the differentiation of YBT-5 cells. Therefore, a new acute monocytic leukemia cell line with clear biological and molecular features was established and may be used in the research and development of new agents targeting KMT2A-associated leukemia.

Objective The aim was to identify the change in gene expression between mesenchymal stem cells (MSCs) and induced endothelial cells (ECs) and to investigate the potential mechanism of endothelial differentiation based on ribonucleic acid sequencing (RNA-Seq) analysis. Methods MSCs were isolated from bone marrow and exposed to inducing medium. The dynamic transcription profiles of MSCs were identified and ECs were induced through RNA-seq. Differentially expressed genes (DEGs) were identified. Enrichment of functions and signalling pathways analysis were performed based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Quantitative real time polymerase chain reaction (qRT-PCR) was used to validate the genes selected from RNA-Seq. Results In total, 2769 DEGs were identified, of which 1117 genes were upregulated and 1652 genes were downregulated. GO and KEGG pathway analyses identified significantly enriched pathways in DEGs, including extracellular matrix organisation, blood vessel morphogenesis, angiogenesis, extracellular matrix binding, growth factor binding and glycosaminoglycan binding extracellular matrix–receptor interaction pathway, cytokine–receptor interaction pathway and transforming growth factor (TGF)-β signalling pathway. All genes found to be associated with the TGF-β pathway were significantly downregulated. Eleven novel genes were also identified that most likely are involved in endothelial differentiation and were upregulated with more than 10 fold change, which were further validated by qRT-PCR. Conclusion The GO and KEGG analysis revealed that extracellular matrix, cytokines and the TGF-β pathway play an important role in the process of endothelial differentiation. Furthermore, 11 genes were found that may be involved in the differentiation of MSCs into ECs and contribute to current understanding of the differentiation mechanism.

Rationale: Myeloid sarcomas (MS) are defined as rare extramedullary masses composed of immature myeloid cells. MS mostly develops in patients with acute myeloid leukemia (AML), and involves primarily the skin, soft tissues, bones, and lymph nodes. Pleura and pericardium involvement of MS are extremely uncommon. Polyserositis is also a very rare extramedullary presentation of acute myeloid leukemia (AML). Patient concerns: A 30-year-old woman with a complaint of right neck mass combined with coughing for 2 months as well as fever and systemic edema for the last 10 days, was admitted to our center on July 11, 2019. Initial positron emission tomography (PET) scan indicated systemic lymphadenopathy, bilateral pleural effusion, and pericardial effusion. Diagnosis: The initial pathological diagnosis of lymph nodes was MS. Subsequent bone marrow analysis confirmed AML. Interventions: Conventional IA induction regimen followed by high-dose cytarabine (HiDAC) regimen. Outcomes: Complete absorption of pericardial and pleural effusion after the first cycle of IA induction chemotherapy. Lessons: Polyserositis can be an extramedullary presentation of AML. Patients with polyserositis should undergo routine flow cytometric analysis. For AML with extamedullary infiltration, systemic chemotherapy should be administered in all confirmed cases.

Background: Acute myeloid leukemia (AML),which is the most common type of acute leukemia, is a clonal malignant hematological disease originated from hematopoietic stem cells, characterized with blocked differentiation, excessive proliferation, organs infiltration. "3+7" regimen [anthracyclines + cytarabine (Ara-c)] is the first choice of induction chemotherapy in young adult de novo AML, and cytarabine is always given by continuous intravenous infusion. It has been reported the concentration of Ara-CTP (active metabolite with anti-leukemia effect) was higher after subcutaneous injection than during continuous intravenous infusion for about 5 hours [Liliemark JO, Semin Oncol], and the subcutaneous injection is much more convenient and inexpensive for patients comparing to continuous intravenous infusion. However, no prospective, multicenter clinical evidenceto evaluate the efficacy and safety of subcutaneous injection administration compared with intravenous infusion of cytarabine. Objective: To evaluated whether subcutaneous injection of cytarabine is noninferior to intravenous infusion of cytarabine in "3+7" induction regimen for young adult patients with de novo AML. Design, setting and participants: Open-label, prospective, multicenter, noninferior, randomized clinical trial conducted in 10 hematological centers in China. Eligible patients (n=240) with de novo AML (exclude acute promyelocytic leukemia) has been enrolled. Patients were recruited between March 2015 and August 2017, with final follow-up in June 2020. Interventions: Patients were randomized to receive idarubicin 10 mg/m2 for 3 days and cytarabine 100 mg/m2/d by continuous intravenous infusion daily for 7 days (n=120) or idarubicin 10 mg/m2 for 3 days and cytarabine 100mg/m2/d subcutaneous injection every 12 hours for 7 days (n=120). Main outcomes and measures: The primary end point was the percentage of patients who achieved complete remission (CR). The noninferiority margin for the difference in CR was -15%. Secondary end points included overall survival (OS), event-free survival (EFS) and adverse events. Results: Among 240 randomized patients, the baseline characteristics including sex, age, ECOG, white blood cell, blasts percentage, FAB subtype, karyotype and NPM1, FLTS-ITD, c-kit, CEBPA, DNMT3A, IDH1 and IDH2 mutations were similar between two groups. CR was achieved by 86 of 120 (71.7%) patients in subcutaneous injection group vs 85/120(70.8%) in intravenous injection (difference, 0.9%[1-sided 95% CI, -8.8% to ∞]); p value for noninferiority=0.003) after first cycle of induction therapy. CR was achieved by 93 of 120 (77.5%) patients in subcutaneous injection group vs 91/120(75.8%) in intravenous injection group (difference, 1.7% [1-sided 95% CI, -7.3% to ∞]); p value for noninferiority=0.001) after first two cycles of induction therapy. 3-year OS were 60% [95% CI:50%-69%]in subcutaneous injection group vs 58% [95% CI:49%-67%] in intravenous injection group (Figure 1A). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the adjusted hazard ratio (AHR) of OS for subcutaneous vs intravenous was 0.95 [95% CI:0.62-1.47]. 3-year EFS were 49% [95% CI:39%-58%]in subcutaneous injection group vs 44% [95% CI:35%-53%] in intravenous injection group (Figure 1B). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the HAR of EFS for subcutaneous vs intravenous was 0.84[95% CI:0.58-1.22]. No differences of hematologic toxicity, non-hematologic toxicity and early death rate were observed between two groups. Conclusions: The efficacy of subcutaneous injection of cytarabine was non inferior to continuous intravenous infusion of cytarabine for the standard induction therapy in young adult de novo AML. The toxicity is equivalent between two groups. Subcutaneous injection of cytarabine offers a convenient and inexpensive alternative therapy to young adult de novo AML. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR-IPR-17012643. Figure 1 Disclosures No relevant conflicts of interest to declare.

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). As a complex immunopathology, aGVHD depends on the recognition of host antigens by donor T cells and induces augmented response of alloreactive T cells. Despite considerable achievements in the treatment of aGVHD, it remains a major clinical problem for the patients undergoing allo-HSCT. Therefore, it is necessary to further illustrate new mechanisms and develop novel therapeutic strategies of aGVHD. Previously we reported LYG1 (Lysozyme G-like 1) as a novel classical secretory protein promoted antitumor function of T cell. In this study, the role of LYG1 in aGVHD was investigated. Firstly, we examined whether LYG1 affected the alloreactivity of CD4+ T cells in vitro by MLR assay and discovered that LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio. Then we confirmed these observations using a major MHC mismatched aGVHD model by transferring T cells sorting from WT B6 or Lyg1-/- mice with bone marrow cells from WT B6 mice into lethally irradiated BALB/c mice. The alloreactive CD4+ T cells and the proportions of Th1 cells decreased whereas the proportions of Treg cells increased in spleens and livers in mice receiving Lyg1-/- T cells. LYG1-deficient T cells attenuated aGVHD severity, inhibited the expression of CXCL9 and CXCL10 and restrained CD4+ T cells infiltrating in livers. Furthermore, administration of recombinant LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production. More importantly, LYG1 deficiency did not affect GVT (graft-versus-tumor) effects. In summary, we demonstrate LYG1 regulates aGVHD via modulating the alloreactivity of CD4+ T cells and differentiation of Th1/Treg cells. Our study indicates that LYG1 may be a novel target in aGVHD by mitigating aGVHD without impairing GVT function. The therapeutic effect of targeting LYG1 is required in future investigations. Funding This study was supported by grant from The National Natural Science Foundation of China (NSFC) (Grant Number 81600144) and grant from Research Foundation of Peking University First Hospital. Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for patients with leukemia. However, relapse remains the leading cause of death after transplantation. In recent years, substantial progress has been made by Chinese physicians in the field of establishment of novel transplant modality, patient selection, minimal residual disease (MRD) monitoring, and immunological therapies, such as modified donor lymphocyte infusion (DLI) and chimeric antigen receptor T (CART) cells, as well as MRD-directed intervention for relapse. Most of these unique systems are distinct from those in the Western world. In this consensus, we reviewed the efficacy of post-HSCT relapse management practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association, and compared these studies withthe consensus or guidelines outside China. We summarized the consensus on routine practices of post-HSCT relapse management in China and focused on the recommendations of MRD monitoring, risk stratification directed strategies, and modified DLI system. This consensus will likely contribute to the standardization of post-HSCT relapse management in China and become an inspiration for further international cooperation to refine global practices.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB-DLBCL patients. We retrospectively reviewed data on 108 PB-DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow-up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5-year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5-year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10-year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB-DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB-DLBCL patients.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat malignant hematological neoplasms and non-malignant hematological disorders. Approximately, 5000 allo-HSCT procedures are performed in China annually. Substantial progress has been made in haploidentical HSCT (HID-HSCT), pre-transplantation risk stratification, and donor selection in allo-HSCT, especially after the establishment of the “Beijing Protocol” HID-HSCT system. Transplant indications for selected subgroups in low-risk leukemia or severe aplastic anemia (SAA) differ from those in the Western world. These unique systems developed by Chinese doctors may inspire the refining of global clinical practice. We reviewed the efficacy of allo-HSCT practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association and compared these studies to the consensus or guideline outside China. We summarized the consensus on routine practices of all-HSCT in China and focused on the recommendations of indications, conditioning regimen, and donor selection.

The China Assessment of Antifungal Therapy in Hematological Disease study, the first large-scale observational study of invasive fungal disease (IFD) in China, enrolled 1401 patients undergoing hematopoietic stem cell transplantation (HSCT) (75.2% allogeneic and 24.8% autologous) at 31 hospitals across China. The overall incidence of proven or probable IFD was 7.7% (108 of 1401); another 266 cases (19.0%) were possible IFD. After allogeneic or autologous HSCT, the incidence of proven/probable IFD was 8.9% (94 of 1053) and 4.0% (14 of 348), respectively. Some cases (14 of 108) developed during conditioning before transplantation. The cumulative incidence of proven/probable IFD increased steeply in the first month after transplantation and after 6 months, the incidence was significantly higher in allogeneic than it was in autologous transplant recipients (9.2% versus 3.5%; P = .001) and when stem cells were derived from cord blood or bone marrow and peripheral blood (P = .02 versus other sources). Independent risk factors for proven/probable IFD in allogeneic HSCT were diabetes, HLA-matched unrelated donor, prolonged severe neutropenia (absolute neutrophil count > 500/mm3 for >14 days), and immunosuppressants (odds ratio, 2.0 to 3.4 for all). Antifungal prophylaxis was independently protective (P = .01). Previous IFD and prolonged severe neutropenia were significant independent risk factors among autologous transplantation patients (P < .01, P = .04, respectively). In total, 1175 (83.9%) patients received antifungal prophylaxis (91.6% triazoles) and 514 (36.7%) were treated in the hospital with therapeutic antifungals (89.1% triazoles; median 27 days). Empirical, pre-emptive, and targeted antifungals were used in 82.3%, 13.6%, and 4.1% of cases, respectively. Overall mortality (13.4%; 188 deaths) was markedly higher in patients with proven (5 of 16; 31.3%), probable (20 of 92; 21.7%), or possible (61 of 266; 22.9%) IFD; allogeneic (171 of 1053; 16.2%) rather than autologous (17 of 348; 4.9%) HSCT and was significantly higher in patients receiving pre-emptive (18.6%) rather than empirical (6.1%) or targeted (9.5%) antifungal therapy (P = .002). Improvements in the selection and timing of prophylactic antifungals would be welcome. Health care providers should remain alert to the increased risk of IFD and associated mortality in allogeneic HSCT recipients and the ongoing risk of IFD even after discharge from the hospital.

One characteristic feature of graft-versus-host disease (GVHD) is lymphocytes' trafficking and recruitment to target tissues, and CCR5 plays a key role in the process. Thus, blockade of lymphocytes' chemotaxis may attenuate GVHD.We tested the effects of CCR5 blockade using an established murine model. The mean survival time, body weight change, and clinical GVHD scores were assessed. Concentrations of cytokines and chemokines, the CCR5, CXCR3, and CCR7 expressions on T lymphocytes, and histological changes of visceral organs were also evaluated. Additionally, we assessed the immunophenotype of infiltration cells in liver and intestine.Mice undergoing total body irradiation and allogenic hematopoietic stem cell transplantation (allo-HSCT) developed typical GVHD. MVC increased CCR5 expression whereas CCR7 and CXCR3 expression were unaffected. MVC also increased plasma levels of the ligands of CCR5. A combination of MVC with CsA significantly alleviated the degree of visceral injuries and prolonged survival time.MVC has a synergistic effect with CsA. It can attenuate the severity of GVHD and increase survival rate of mice in our murine model. This may offer a novel therapeutic perspective for clinical GVHD after allo-HSCT.

Background: Lenalidomide has emerged as an important treatment for patients with multiple myeloma (MM). However, its role in the management of MM is still controversial and requires further clarification. The aim of this study was to evaluate efficacy and safety of lenalidomide for MM using a meta-analysis. Methods: We searched the electronic databases including: PubMed, EMBASE and the Cochrane Center Register of Controlled Trials. Seven randomized clinical trials were identified, which included a total of 2357 patients with MM who received lenalidomide-containing, noncontaining lenalidomide regimens or placebo as induction therapy or maintenance therapy. The outcomes included overall response (OR) rate, complete response (CR) rate, 3-year progression-free survival (PFS) rate, 3-year overall survival (OS) rate, and different types of treatment-related adverse events. We calculated the risk ratios ( RR s) as well as their 95% confidence intervals of these outcomes and pooled the results using RevMan 5.2 software. Results: For patients with previously untreated MM, OR rate and CR rate was significantly higher in lenalidomide-containing group than the control group. For relapsed or refractory MM patients, lenalidomide-containing regimens significantly improved the OR rate, CR rate, 3-year PFS rate and 3-year OS rate. With regard to MM patients after autologous stem cell transplantation, lenalidomide maintenance therapy significantly improved 3-year PFS rate but did not result in improved 3-year OS rate. In terms of toxicities, lenalidomide therapy has a higher rate of Grade 3-4 grade cytopenias, infection, deep-vein thrombosis, and diarrhea. Furthermore, the incidence of second primary malignancies was significantly higher in the lenalidomide group. Conclusions: The lenalidomide-containing regimens as induction therapy clearly increased response rates and improved intervals of survival with acceptable toxicity rates for patients with MM. However, when physicians choose to use the lenalidomide as maintenance therapy, whether the benefits outweigh the risks should be taken into account.

Chemotaxis of T cells to acute graft-versus-host disease (aGvHD) target tissues directed by chemokines and their receptors plays a key role in the pathogenesis of aGvHD. Blockade of lymphocyte migration by targeting chemokine receptors may be a viable strategy for the prevention and treatment of aGvHD, which is quite distinguishable from typical efforts to use immunosuppressive medications that have been associated with some side effects. CXCR3 and its ligands have been reported to be correlated with aGvHD pathogenesis. Using the small-molecule CXCR3 antagonist AMG487, we demonstrated that AMG487 combined with cyclosporine A (CsA) effectively alleviated aGvHD with a prolonged mean survival time and significantly inhibited the infiltration of inflammatory cells in aGvHD target tissues in a murine aGvHD model. In addition, AMG487 combined with CsA inhibited the activation, proliferation and differentiation of donor-derived T cells in the spleens. Further results showed that the concentrations of Th1 cells associated with pro-inflammatory cytokines such as IFN-γ and TNFα in serum were decreased. In addition, AMG487 treatment did not alter CXCR3 and CCR5 expression in donor-derived T cells but elevated the serum CXCL9 and CXCL10 levels. This novel and effective approach has the potential to develop a new clinical method to prevent and treat aGvHD.

This Phase 3 randomized, double-blind study evaluated the efficacy and safety of plerixafor plus granulocyte-colony-stimulating factor for the mobilization of hematopoietic stem cells in Chinese patients with non-Hodgkin's lymphoma.Adults (ages 18-75 years) with non-Hodgkin's lymphoma in first or second complete or partial remission, without previous hematopoietic stem cell mobilization or autologous transplant, were included. Patients received granulocyte-colony-stimulating factor 10 µg/kg/day from Days 1 through 4 before they were randomized (1:1) to receive either plerixafor 0.24 mg/kg/day or placebo subcutaneously on Days 4 through 7 plus continued granulocyte-colony-stimulating factor on Days 5 through 8. Apheresis began on Day 5 and continued for no more than 4 days. The primary endpoint was collection of 5 × 10Overall, 101 patients were enrolled, and 50 were randomized to each group. More patients in the plerixafor group achieved 5 × 10Plerixafor plus granulocyte-colony-stimulating factor is superior to placebo plus granulocyte-colony-stimulating factor for the mobilization of CD34+ cells for autologous transplantation and is generally well tolerated in Chinese patients with non-Hodgkin's lymphoma.

Blockade of CC chemokine receptor 5 (CCR5) by maraviroc may induce immunological changes independent of its antiviral effects and may have immunoregulation properties. This study was designed to determine the effects of blocking CCR5 on human activated T cells in vitro and investigate the potential immunological mechanisms. Human CD3+ T cells were purified from peripheral blood mononuclear cells and then activated by cytokines. We tested the surface expressions and relative messenger RNA (mRNA) levels of CCR2, CCR5, CCR6, CCR7, and CXCR3, chemotaxis toward their cognate ligands, internalization of chemokine receptors, and production of cytokines. In conclusion, blocking CCR5 by maraviroc not only can block CCR5 and CCR2 internalization processes induced by CCL5 and CCL2, but also inhibit T cell chemotactic activities toward their cognate ligands, respectively. Moreover, blocking CCR5 with maraviroc at high doses tends to decrease the production of TNF-α and IFN-γ. In addition, there might be a form of cross talk between CCR5 and CCR2, and this may offer a novel immunological effect for blockade of CCR5.