Thrombopoietin receptor agonists for refractory thrombocytopenia in patients after autologous hematopoietic stem cell transplantation.

OBJECTIVE: Autologous hematopoietic stem cell (ASC) transplantation (ASCT) is an effective treatment method for patients with hematological disorders and malignant diseases. The patient's ASCs are harvested prior to radiotherapy/chemotherapy, cryopreserved and then transfused back after the high-dose radiotherapy/chemotherapy conditioning treatment. Since some patients develop thrombocytopenia after receiving ASCT, it is difficult for them to bear simultaneously the management of their original disease and thrombocytopenia. The present study aimed to evaluate the efficacy and safety of thrombocytopenia therapy with thrombopoietin receptor agonists (TPORAs) after ASCT. METHODS: We retrospectively analyzed the clinical safety and efficacy of TPORA treatment for the enrolled 20 patients who developed thrombocytopenia after ASCT. The measured parameters were prolonged isolated thrombocytopenia (PIT), secondary failure of platelet recovery (SFPR) and other calculated response index. Patients with platelet count (PC) ≤ 50×109/L were treated with TPORA, namely with either eltrombopag (Elt), hetrombopag (Het), or avatrobopag (Ava). RESULTS: The group of 20 patients, who received TPORA administration for their thrombocytopenia after ASCT, had a median age of 50 years (ranging between 17 and 60 years). The median administration time of TPORA application was 48 days (ranging from 7 to 451 days); an overall response rate (ORR) was 85% with no response in 15% of patients, while with complete response (CR) in 70% of patients and partial response (PR) in 15% of patients. The median platelet count was 19 × 109/L before TPORA treatment and increased to 87×109)/L after the treatment. The TPORA treatment was safe as only 4 patients (20%) displayed a mild transaminase elevation. No other reported side effects occurred, such as thrombosis, joint pain, diarrhea, and myelofibrosis. It was demonstrated that the short response time to TPORA treatment correlated to the fast platelet recovery, when the number of megakaryocytes in the bone marrow smear exceeded 35/4.5 cm2 under a low magnification of 100 times (p = 0.015). CONCLUSION: TPORA therapy for thrombocytopenia occurring after the radiotherapy/ chemotherapy-conditioned ASCT was well tolerated and effective for platelets recovery.

Facing challenges with hope: universal immune cells for hematologic malignancies.

Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation (allo-HSCT) has been widely implemented to treat hematologic malignancies. However, graft-versus-host disease (GVHD) and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life. In addition, GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions (DLIs) and chimeric antigen receptor (CAR) T-cell therapy. Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells, universal immune cell therapy may strongly reduce GVHD, while simultaneously reducing tumor burden. Nevertheless, widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy. Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy, including the use of universal cell lines, signaling regulation and CAR technology. In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.

Reverse effect of Semaphorin-3F on rituximab resistance in diffuse large B-cell lymphoma via the Hippo pathway.

BACKGROUND: Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL. METHODS: The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens. RESULTS: We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo . CONCLUSION: Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.

Recent advances and research progress in biomarkers for chronic graft versus host disease.

Chronic graft-versus host disease (cGVHD) is a major risk for patients undergoing allogeneic hematopoietic stem cell transplantation. With the emergence of novel therapies and the increased understanding of the mechanisms underlying cGVHD, there are more options for cGVHD treatment. Regardless of improvements in treatment, diagnosis mainly depends on identification of symptoms, which makes precise treatment a challenge. Numerous biomarkers for cGVHD have been validated and have demonstrated strong associations with prognosis and response to treatment. The most common biomarkers mainly include critical types of immune cells, chemokines, cytokines, microRNAs, and autoantibodies, all of which play important roles in the development of cGVHD. Compared to traditional tools, biomarkers have several advantages, for example, they can be applied for early diagnosis, to identify cGVHD risk before onset, and predict which therapy is most likely to benefit patients. In this review, we summarize biomarkers with potential clinical value and discuss future applications.

Amplifying STING activation by bioinspired nanomedicine for targeted chemo- and immunotherapy of acute myeloid leukemia.

Chemotherapy resistance and the tumor immune microenvironment are dual reasons for the poor therapeutic efficacy of treating acute myeloid leukemia (AML), causing suboptimal clinical outcomes and high relapse rates. Activation of the stimulator of interferon genes (STING) pathway based on innate immunity can effectively improve antitumor immunity. However, traditional STING agonists are limited due to their easy degradation and difficult membrane transport. Here, a bioinspired nanomedicine synergizing chemo- and immunotherapy was developed by activating the STING pathway for targeted and systemic AML cell damage. We show that a leukemia cell membrane (LCM)-camouflaged hollow MnO2 nanocarrier (HM) with encapsulated doxorubicin (DOX) (denoted LHMD) could bind specifically to AML cells with a homologous targeting effect. Then, MnO2 was decomposed into Mn2+ in response to endosomal acid and glutathione (GSH), which improved the magnetic resonance imaging (MRI) signal for AML detection and activated the STING pathway. In mouse models, LHMD was confirmed to eradicate established AML and prevent the engraftment of AML cells. The percentages of T-helper 1 (Th1) and T-helper 17 (Th17) cells and the concentrations of type I interferon (IFN-Ⅰ) and proinflammatory cytokines increased, while the percentage of T-helper 2 (Th2) cells decreased, reflecting the anti-AML immune response induced by Mn2+ after treatment with LHMD. This nanotechnology-based therapeutic regimen may represent a generalizable strategy for generating an anti-leukemia immune response. STATEMENT OF SIGNIFICANCE: Relapse and chemotherapy refractoriness are main causes for the dismal prognosis of AML, making it urgent to develop more effective anti-AML therapies. This study proposes an innovative strategy to combat this issue by designing a biomimetic BM-targeted nanomedicine based on a MnO2 nano-carrier to rationally deliver chemotherapeutic agents and to trigger Mn2+ mediated STING pathway activation for potent immune- and chemotherapy against AML cells. Hence, the nanomedicine design addresses the challenges associated with AML therapy and proposes a promising strategy to improve the therapeutic efficacy against AML.

Strategies to enhance CAR-T persistence.

Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development.

High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma.

The role of autologous hematopoietic stem cell transplantation (auto-HSCT) following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, its clinical efficacy as frontline therapy remains to be elucidated. This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients. We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone (year 2008-2014) from four hospitals. The median follow-up time was 29.4 months. Between the two treatment arms among the intermediate/high-risk DLBCL patients, the 3-year overall survival (OS) and progression-free survival (PFS) rates of patients given frontline auto-HSCT were 87.6% and 81.9%, respectively, and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9% and 59.59%, respectively. Compared with the chemotherapy-alone group, the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell (GCB) type. In addition, in the frontline auto-HSCT group, patients who achieved complete response (CR) at auto-HSCT had a longer survival time than those who did not achieve CR. Our results suggested that frontline auto-HSCT could improve the prognosis of intermediate/high-risk DLBCL patients.

Plasmacytoid Dendritic Cell Infiltration in Acute Myeloid Leukemia.

INTRODUCTION: Increasing evidence has demonstrated that plasmacytoid dendritic cells (PDCs) in the tumor microenvironment (TME) play an important role in tumorigenesis and progression. PDC infiltration has been found in certain malignancies such as classic Hodgkin's lymphoma and chronic myelomonocytic leukemia. Our previous work reported that PDC infiltration could occur in acute myeloid leukemia (AML), but the clinical significance of PDC in AML has not been thoroughly investigated. PATIENTS AND METHODS: Here, we evaluated the clinical significance of PDC to AML transition in a leukemia microenvironment. The frequency of PDCs in 80 acute myelomonocytic leukemia (AML-M4) and 83 acute monocytic leukemia (AML-M5) patients was determined by flow cytometry. RESULTS: We found 62 cases with PDC infiltration. These patients showed higher numbers of bone marrow blasts, higher mean Hb concentration, and required more cycles of chemotherapy before achieving complete remission (CR), but had lower white blood cell and platelet counts compared to patients without PDC infiltration. Drug sensitivity analysis showed that patients with PDC infiltration had lower sensitivity to standard chemotherapy regimens. Kaplan-Meier survival curves demonstrated that patients with PDC infiltration had a shorter overall survival (OS) time and progression-free survival time. DISCUSSION: These results suggested that PDC infiltration can be used for risk stratification of AML-M4/M5, and PDCs may transdifferentiate into leukemia in an AML microenvironment.

Plasma circulating tumor DNA assessment reveals KMT2D as a potential poor prognostic factor in extranodal NK/T-cell lymphoma.

BACKGROUND: The early detection of tumors upon initial diagnosis or during routine surveillance is important for improving survival outcomes. Here, we investigated the feasibility and clinical significance of circulating tumor DNA (ctDNA) detection for Extranodal NK/T-cell lymphoma, nasal type (ENTKL). METHODS: The plasma ctDNA assessment was based on blood specimens collected from 65 newly diagnosed patients with ENKTL in the hematology medical center of Xinqiao Hospital. Longitudinal samples collected under chemotherapy were also included. The gene mutation spectrum of ENKTL was analyzed via next generation sequencing. RESULTS: We found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%) and NOTCH1 (7.7%). The mutation allele frequencies of ATM and JAK3 were significantly correlated with the disease stage, and mutated KMT2D, ASXL3 and JAK3 were positively correlated with the metabolic tumor burden of the patients. Compared with the tumor tissue, ctDNA profiling showed good concordance (93.75%). Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequencies of the genes. Compared with PET/CT, ctDNA has more advantages in tracking residual disease in patients. In addition, patients with mutated KMT2D had higher expression compared with those with wild type, and mutated KMT2D predicted poor prognosis. CONCLUSION: Our results unveil the mutation spectrum of ENKTL patients' plasma, which can be used to monitor the disease status of the patients exactly, and KMT2D is the most frequently mutated gene with prognosis prediction value. The application of ctDNA sequencing can provide precision treatment strategies for patients. TRIAL REGISTRATION: This study is registered with chictr.org (ChiCTR1800014813, registered 7 February, 2018-Retrospectively registered).

Treatment Selection for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors.

With the advent of tyrosine kinase inhibitors (TKIs), the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has entered a new era. The efficacy of TKIs compared with other ALL treatment options is emphasized by a rapid increase in the number of TKI clinical trials. Subsequently, the use of traditional approaches, such as combined chemotherapy and even allogeneic hematopoietic stem cell transplantation (allo-HSCT), for the treatment of ALL is being challenged in the clinic. In light of the increased use of TKIs in the clinic, several questions have been raised. First, is it necessary to use intensive chemotherapy during the induction course of therapy to achieve a minimal residual disease (MRD)-negative status? Must a patient reach a complete molecular response/major molecular response before receiving allo-HSCT? Does MRD status affect long-term survival after allo-HSCT? Is auto-HSCT an appropriate alternative for allo-HSCT in those Ph+ ALL patients who lack suitable donors? Here, we review the recent literature in an attempt to summarize the current status of TKI usage in the clinic, including several new therapeutic approaches, provide answers for the above questions, and speculate on the future direction of TKI utilization for the treatment of Ph+ ALL patients.