The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety.

Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study.

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5 years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295 days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266 days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes.

A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation.

Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.

The MAGIC algorithm probability (MAP)-guided preemptive therapy of acute graft versus host disease with methylprednisolone: A randomized controlled trial.

Acute graft versus host disease (aGvHD) is a severe complication that arises in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remains the primary cause of nonrelapse mortality (NRM). The MAGIC algorithm probability (MAP) has been proposed to identify patients at intermediate and high risk of developing aGvHD. The levels of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (Reg3α) were assessed, and MAP was calculated on days 7, 14, 21, and 28 after allo-HSCT. Based on the MAP results, patients were classified into low-, intermediate-, or high-risk groups for the development of aGvHD. Random assignment was performed to allocate intermediate- or high-risk patients to receive preemptive therapy with methylprednisolone or not. The 100-day cumulative incidences of grade 2 or higher (35.5% ± 8.6%) and grade 3 or higher (12.9% ± 6.0%) aGvHD in the methylprednisolone group were significantly lower than those in the control group (66.7% ± 7.9%, p = .01; 42.9% ± 8.4%, p = .01), and similar to those observed in the low-risk group (31.7% ± 7.3%, p = .75; 2.4% ± 2.4%, p = .08). The 6-month cumulative incidences of NRM were 14.1% ± 6.6%, 22.7% ± 7.1%, and 2.4% ± 2.4% in the methylprednisolone, control, and low-risk groups, respectively, with no significant difference between the methylprednisolone and control groups (p = .29). Methylprednisolone did not increase infections (p = .34). The 100-day cumulative incidences of cytomegalovirus (CMV) reactivation were 67.7% ± 8.4%, 65.6% ± 8.4%, and 46.3% ± 7.8% (p = .08), and those of grade 2 or higher hemorrhagic cystitis were 29.0% ± 8.2%, 45.2% ± 8.9% and 22.0% ± 6.5% (p = .11) in the methylprednisolone, control, and low-risk groups, respectively. MAP-guided preemptive therapy for aGvHD is promising. The long-term efficacy and safety remain to be investigated.

Camrelizumab for relapsed or refractory classical Hodgkin lymphoma: Extended follow-up of the multicenter, single-arm, Phase 2 study.

Camrelizumab (a humanized high-affinity IgG4 mAb against programmed death-l) showed potent antitumor activity, well tolerance and controllable safety in patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL), based on the primary analysis of a Phase 2 study. Here, we present the extended follow-up outcomes. Seventy-five patients who had failed to achieve a remission or experienced progression after autologous stem cell transplantation or had received at least two lines of systemic chemotherapies were enrolled to receive camrelizumab 200 mg every 2 weeks. With a median follow-up of 36.2 months (range, 7.2-38.1), objective response rate per independent central review was 76.0% (95% confidence interval [CI], 64.7-85.1). Among the 57 responders, 31 (54.4%) had ongoing responses. Median duration of response was 31.7 months (95% CI, 16.7-not reached). Median progression-free survival was 22.5 months (95% CI, 14.7-not reached). Thirty-six-month overall survival rate was 82.7% (95% CI, 72.0-89.5). Reactive capillary endothelial proliferation (RCEP) occurred in 97.3% of patients (73/75), but all RCEP were Grade 1 or 2 in severity and 67.1% of these patients (49/73) achieved complete resolution. Occurrence of new RCEP lesions was rare (8/42 [19.0%] at 12 months; 2/32 [6.3%] at 24 months). No treatment-related deaths occurred, and no new toxicities were reported. With extended follow-up, camrelizumab monotherapy continues to provide a robust and durable response, long survival and manageable safety in r/r cHL patients.

A new conditioning regimen with chidamide, cladribine, gemcitabine and busulfan significantly improve the outcome of high-risk or relapsed/refractory non-Hodgkin's lymphomas.

Previous studies highlight the need for a more active conditioning therapy in high-risk or refractory and relapsed lymphomas. Our preclinical research shows that histone deacetylase inhibitors, such as either vorinostat or chidamide, sensitize lymphoma cells to the cytotoxic combination of cladribine, gemcitabine and busulfan, leading to cell apoptosis. To evaluate the efficacy of this chidamide-cladribine-gemcitabine-busulfan (ChiCGB) combination as a new conditioning therapy, we conducted a Phase II trial, as described here. Patients with high-risk, relapsed/refractory lymphomas received ChiCGB as conditioning therapy, after transplantation with autologous peripheral stem cells. The sample comprised 105 patients in total: 60 with B-cell non-Hodgkin lymphomas (B-NHL) and 45 with T-cell or natural killer/T-cell lymphoma (NK/T). All patients eventually achieved full hematopoietic recovery. Neutrophils and platelets were engrafted at a median of 10 days (8-14) and 13 days (8-38), respectively. There was no transplant-related mortality within 100 days of transplant. Neutropenic fever, mucositis and atopic dermatitis were the observed nonhematologic toxicities. At a median follow-up of 35.4 months, 80.6% of the patients presented with no tumor progression, and the overall survival (OS) reached as high as 86.1%. Concerning the OS rate, 94.5% of patients with B-NHL and 75.4% of patients with T-cell or NK/T lymphomas survived. These findings demonstrate the safety and validity of the proposed combined therapy for high-risk and refractory/relapsed lymphomas. Our study was registered on the Clinical Trial Registry (clinicaltrials.gov, NCT03151876).

[Intravascular Large B-cell Lymphoma: a Clinical Analysis of 17 Cases].

OBJECTIVE: To analyze the clinical features,response to therapy and prognosis of intravascular large B-cell lymphoma (IVLBCL). METHODS: The clinical data of 17 cases with IVLBCL were retrospectively reviewed,and survival analysis was conducted. RESULTS: The study involved 10 males and 7 females of IVLBCL with a mean age of 53 years old. The most common symptom of the disease was recurrent fever (76.5%). The lymphoma was mainly observed in bone marrow (64.7%) and was clinically determined as stage ⅣB (70.6%). Many of the patients were also diagnosed with the hemophagocytic syndrome (29.4%). R-CHOP (rituximab,cyclophosphamide,epirubicin,vindesine,prednisone) or CHOP regimen chemotherapy significantly improved the survival of the patients (P=0.000 2). Unfortunately,those patients with bone marrow involvement were prone to relapse after treatment. CONCLUSION: IVLBCL is highly invasive and associated with poor prognosis. R-CHOP chemotherapy can significantly improve the prognosis.

First Report of OXA-181-Producing Escherichia coli in China and Characterization of the Isolate Using Whole-Genome Sequencing.

We report the first OXA-181-producing strain in China. blaOXA-181 was found in sequence type 410 (ST410) Escherichia coli strain WCHEC14828 from a Chinese patient without recent travel history. Genome sequencing and conjugation experiments were performed. blaOXA-181 was carried on a 51-kb self-transmissible IncX3 plasmid and was linked with qnrS1, a quinolone resistance gene. blaOXA-181 was introduced onto the IncX3 plasmid from a ColE2-type plasmid, and IncX3 plasmids have the potential to mediate the dissemination of blaOXA-181.

[Comparing BFA with BuCyA as a myeloablative conditioning regimen for allogeneic stem cell transplantation in acute leukemias].

OBJECTIVE: To compare BFA (busulfan, fludarabine plus cytarabine) with BuCyA (busulfan, cyclophoshpamide plus cytarabine) as the conditioning regimens in allogeneic stem cell transplantation for acute leukemias. METHODS: 83 patients with acute leukemia were allocated to BFA group (busulfan 3.2 mg/(kg x d), -9 d-6 d; fludarabine 30 mg/(m2 x d), -5 d(-) -1 d; cytarabine, 1 g/(m2 x d), -5 d(-) - 1 d) or BuCyA group (busulfan, 3.2 mg/(kg x d), -8 d(-) - 5 d; cyclophoshpamide 60 mg/(kg x d),-2 d(-) - 1 d; cytarabine, 3 g/(m2 x d), -4 d(-) - 3 d). Their three-year disease-free survival (DFS) rate, complete remission (CR) rate and incidences of acute graft versus host disease (aGVHD) and hemorrhagic cystitis were monitored. RESULTS: BuCyA group had lower DFS (40.0% vs 61.9%, P = 0.039 9) and lower CR (44.0% vs 71.6%, P = 0.031 0) than BFA group. About 20% of patients treated with BuCyA were not in remission, compared with 51.6% of those treated with BFA. aGVHD occurred in 46.7% patients in the BuCyA group and 50.9% patients in the BFA group, which were 23.3% and 9.4%, respectively, for those graded III - IV. Severe infection occurred in 23.3% patients in the BuCyA group and 22.9% patients in the BFA group. Severe bleeding occurred in 26.7% patients in the BuCyA group and 11.4% patients in the BFA group. The incidence of hemorrhagic cystitis in the BuCyA group and BFA group was 16.7% and 5.7%, respectively. CONCLUSION: BFA is a safer and more effective conditioning regimen compared with BuCyA.

68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study.

INTRODUCTION: Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly diagnosed by diagnostic laparoscopy and peritoneal lavage evaluation. However, diagnostic laparoscopy is invasive and less cost-effective. It is urgent to develop a safe, fast and non-invasive functional imaging method to verify the peritoneal metastasis of gastric cancer. The aim of our study was to evaluate the proportion of patients in whom 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) led to a change in treatment strategy and to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of occult peritoneal metastasis compared with laparoscopic exploration. METHODS AND ANALYSIS: In this single-centre, prospective diagnostic test accuracy study, a total of 48 patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma (cT4a-b, N0-3, M0, based on CT images) who are considering radical tumour surgery will be recruited. All participants will undergo 68Ga-FAPI-04 PET/CT before the initiation of laparoscopic exploration. The primary outcome is the proportion of patients with occult peritoneal metastatic lesions detected by 68Ga-FAPI-04 PET/CT, leading to a change in therapy strategy. The secondary outcomes include the diagnostic performance of 68Ga-FAPI-04 PET/CT for occult peritoneal metastasis, including sensitivity, specificity, accuracy, positive predictive value and negative predictive value. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (2022-1484). Study results will be presented at public and scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300067591.

Fisetin nanoparticles based on cells cycle and apoptosis intervention for the treatment of lymphoma and leukemia.

Lymphoma and leukemia are both hematological system tumors with complex etiology, and mainly treated with chemotherapeutic drugs. However, therapeutic drugs can interrupt curative effect due to different side effects. Therefore, it is worthwhile to develop a novel therapeutic for providing insights for clinical tumor treatment. In this study, we developed a fisetin nanoparticles (Fisetin NPs) through a self-assembled method, and investigated the activity and potential mechanism of Fisetin NPs against lymphoma and leukemia. The spherical and uniformly distributed Fisetin NPs effectively inhibited both tumor cells proliferation, arrested EL4 cells G0/G1 phase and K562 cells G2/M phase, and induced apoptosis in vitro. In vivo, Fisetin NPs exhibited excellent tumor growth inhibition, effective inhibition of cell proliferation and angiogenesis, significant induction of apoptosis and ideal safety. Mechanically, fisetin upregulated genes (Fas, Pidd, Puma, Apaf1, and p21) in the p53 signaling pathway and bound to N-acetyltransferase 10 (NAT10), ribosomal protein L34 (RPL34) and GTP binding protein 4 (GTPBP4). Collectively, Fisetin NPs have promising therapeutic effects on lymphoma and leukemia, which are of great significant for clinical implications.

Prognostic characteristics of gastrointestinal tract NK/T-cell lymphoma: an analysis of 47 patients in China.

BACKGROUND: The gastrointestinal tract is the most common primary site of extranodal lymphomas, whereas gastrointestinal natural killer/T-cell (GINKT) lymphomas are relatively rare. To date, neither the prognostic characteristics nor the clinical features or optimal therapeutic approach for GINKT has yet been defined. PATIENTS AND METHODS: In this study, a retrospective analysis was carried out on clinical data obtained from 47 patients diagnosed with GINKT lymphoma between May 1999 and August 2011 at West China Hospital. RESULTS: Patients had a median age of 37 years. Thirty-five of the patients were men (74.5%). The common clinical manifestations included fever (78.7%) and abdominal pain (76.6%). Seventeen patients had intestinal perforation (36.2%). All patients showed ulcerative lesions; the most common site of involvement was the colon (27/47; 57.4%), followed by the jejunoileum and ileocecum (14/47; 29.8%). The median survival period was 2.83 (95% confidence interval, 0.27-29) months. Age, perforation, B syndrome, staging according to Lugano system, and surgery were independent prognostic risk factors for GINKT lymphoma. CONCLUSIONS: This study concluded that GINKT lymphoma is prone to perforation, hemorrhage, and other complications; moreover, the prognosis is very poor. The Lugano staging is a relatively suitable staging system. Surgery before perforation is a key therapy factor that affected prognosis. Although the roles played by chemotherapy and radiotherapy are unclear, combination therapy is necessary.

Efficacy and safety of leflunomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation. So far, no specific antiviral drug with proven efficacy has been approved for treating BKV-HC. Leflunomide is an immunosuppressive drug with antiviral activity and has been used in treating BKV-associated nephropathy after renal transplantation. This is the first report on the efficacy and safety of leflunomide in the treatment of BKV-HC. From January 2006 to January 2009, 89 patients received allogeneic hematopoietic stem cell transplantation, and among them, 18 patients were identified as having BKV-HC, with a 20% cumulative incidence. Fourteen patients were treated with oral leflunomide. Three days of 100 mg/day leflunomide was used as loading doses and followed by maintenance doses of 20 mg/day. The urinary BKV-DNA load was monitored weekly by real-time quantitative PCR. The efficacy was evaluated on day 20 after leflunomide treatment. Seven patients (50%) achieved complete remission, 5 patients (35.7%) achieved partial remission, and 2 patients (14.3%) had more than a 1-log reduction in urinary BKV-DNA loads after treatment. During the leflunomide treatment, the graft-versus-host disease of the patients did not progress, and the dosages of the immunosuppressant were reduced simultaneously. One patient discontinued treatment because of intolerable gastrointestinal symptoms. Neutropenia occurred in 2 cases. These preliminary data suggest that leflunomide may be a potentially effective medication for treating BKV-HC without significant toxicity, but evidence supporting its use requires randomized controlled trials.

A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.

The clinical features and prognostic implications of PTPN11 mutation in adult patients with acute myeloid leukemia in China.

BACKGROUND: The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11mut ) in acute myeloid leukemia (AML) is underestimated. METHODS: We collected the data of AML patients with mutated PTPN11 and wild-type PTPN11 (PTPN11wt ) treated at our hospital and analyzed their clinical characteristics and prognosis. RESULTS: Fifty-nine PTPN11mut and 124 PTPN11wt AML patients were included. PTPN11mut was more common in myelomonocytic and monocytic leukemia, and was more likely to co-mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11wt . The overall survival for AML patients with PTPN11mut was significantly shorter than that for those with PTPN11wt (p = 0.03). The negative impact of PTPN11mut on overall survival was pronounced in the "favorable" and "intermediate" groups of ELN2017 risk stratification, as well as in the wild-type NPM1 group (p = 0.01, p = 0.01, and p = 0.04). CONCLUSION: PTPN11mut is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

Comparison of netupitant/palonosetron with 5-hydroxytryptamine-3 receptor antagonist in preventing of chemotherapy-induced nausea and vomiting in patients undergoing hematopoietic stem cell transplantation.

Background: The use of 5-hydroxytryptamine-3 receptor antagonists (5HT3RA) has long been considered the standard regimen for preventing chemotherapy-induced nausea and vomiting (CINV) prior to hematopoietic stem cell transplantation (HSCT). However, their therapeutic outcomes have been unsatisfactory. NEPA, an oral formulation combining the neurokinin-1 receptor antagonist netupitant and the 5HT3RA palonosetron, has received regulatory approval for the management of highly and moderately emetogenic chemotherapy. This study aims to compare the efficacy of NEPA with that of 5HT3RA alone in preventing CINV among patients undergoing multiday conditioning chemotherapy prior to HSCT. Patients and methods: We conducted a retrospective analysis of patients who underwent HSCT between September 2019 and September 2022. Efficacy outcomes were assessed based on the rates of patients achieving complete response (CR: no emesis and no use of rescue medication), complete control (CC: CR without significant nausea), no vomiting, and no significant nausea. Results: The NEPA group consisted of 106 patients, while the 5HT3RA group included 107 patients. The NEPA group exhibited significantly higher rates of CR compared to the 5HT3RA group during the overall phase (71.7% vs. 32.7%, P<0.001), acute phase (78.3% vs. 43.0%, P<0.001), and delayed phase (84.9% vs. 58.9%, P<0.001). Similarly, rates of CC, no vomiting, and no significant nausea were significantly better in the NEPA group across all phases (P<0.001). Conclusion: NEPA demonstrated superior efficacy compared to 5HT3RA in preventing CINV during all phases of multiday conditioning regimens among patients undergoing HSCT.

SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies.

CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.

A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma.

Background: The prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT). Methods: Patients with PTCL or T-LBL were enrolled to receive ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess the patient outcome, and adverse events were used to assess the regimen's safety. The survival curve was estimated via the Kaplan-Meier method. Results: Twenty-five PTCL and 11 T-LBL patients were recruited. The median time to neutrophile and platelet engraftments was 10 days (8-13 days) and 13 days (9-31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR) but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable. Conclusions: ChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to assess ChiCGB as a conditioning regimen for ASCT.

Chimeric Antigen Receptor T Cells Targeting Cell Surface GRP78 to Eradicate Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a serious, life-threatening hematological malignancy. The treatment outcome of relapsed or refractory AML patients remains dismal, and new treatment options are needed. Chimeric antigen receptor (CAR) T cells have been successful in improving the prognosis for B-lineage acute lymphoblastic leukemia and lymphoma by targeting CD19. However, CAR T-cell therapy for AML is still elusive, owing to the lack of a tumor-specific cell surface antigen and spare hematopoietic stem cells (HSCs). This study generated a novel CAR construction that targets the cell surface protein glucose-regulated protein 78 (GRP78) (csGRP78). We confirmed that GRP78-CAR T cells demonstrate an anti-tumor effect against human AML cells in vitro. In xenograft models, GRP78-CAR T cells effectively eliminate AML cells and protect mice against systemic leukemia, in the meanwhile, prolonging survival. In addition, GRP78-CAR T cells also specifically eradicate the primary AML patient-derived blast. In particular, GRP78-CAR T cells spare normal HSCs, highlighting that GRP78-CAR is a promising approach for the therapy of AML.

Donor peritoneal-derived cells can attenuate graft-versus-host disease after MHC-incompatible bone marrow transplantation in mice.

BACKGROUND: Graft-versus-host disease (GVHD) remains one of the most important barriers to bone marrow transplantation (BMT) and quality of life. Peritoneal-derived cells (PCs) can regulate immune function. METHODS: The GVHD mouse model, which was established by injection with T-cell depleted bone marrow cells and spleen cells, was treated with donor PCs. The survival time, weight, GVHD score, and pathological organ damage were used to assess the efficacy of PCs. Various cytokines (e.g., TNF-α, IFN-γ, IL-2, IL-17, IL-15, IL-4, IL-10, and TGF-ß) and immunocytes (e.g., CD4+, CD8+, Treg, and NK cells) were employed to investigate the preliminary mechanism. The cytokine levels were tested via Luminex liquid chips, real-time PCR, and Western blotting, and the proportion of each T-cell subpopulation was detected via flow cytometry. One-way Analysis of Variance (ANOVA) followed by Tukey's post-test was employed to perform multiple comparisons, and Kaplan-Meier method was used to perform survival analysis. RESULTS: Compared to the saline group, the PC group harbored a significant reduction in pathological damage to the colon and small intestine, a longer survival time, and a lower GVHD score. The mice in the PC group had significantly higher levels of TGF-ß, IL-10, and IL-4 and lower levels of IFN-γ, TNF-α, and IL-15 than those in the saline group. In the PC group, CD8+ and Th1 ratios decreased, while CD4+, Th2, NK, and Treg ratios increased. CONCLUSIONS: Donor PCs can attenuate GVHD caused by MHC-incompatible BMT by regulating cytokine levels and immunocyte ratios.