Early granulocyte colony stimulating factor administration increases the risk of cytokine release syndrome in acute lymphoblastic leukemia patients receiving anti-CD19 chimeric antigen receptor T-cell therapy.

Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and neutropenia are common toxicities associated with chimeric antigen receptor T (CAR-T) cell therapy. The role of granulocyte colony stimulating factor (G-CSF) in CAR-T-cell-treated patients remains unclear. To explore the efficacy and safety of early G-CSF administration in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) who were receiving autologous anti-CD19 CAR-T cells, we retrospectively collected and summarized clinical data to compare patients receiving G-CSF within 14 days (early G-CSF group) to patients receiving later or no G-CSF (control group) after their CART infusion. The results showed that there was no significant difference in the incidence and duration of neutropenia between the early G-CSF group and the control group (77% vs. 63%, p = 0.65; 8 vs. 4 days, p = 0.37, respectively). However, the incidence and duration of CRS were significantly higher in the early G-CSF group than in the control group (81% vs. 38%, p = 0.03; 3 vs. 0 days, p = 0.004, respectively). Moreover, early G-CSF application had no significant effect on the expansion and efficacy of CAR-T cells. In conclusion, our study suggested that early G-CSF administration did not reduce the incidence and duration of neutropenia but rather increased the incidence and duration of CRS.

Effect of sorafenib maintenance on Epstein-Barr virus and cytomegalovirus infections in patients with FLT3-ITD AML undergoing allogeneic hematopoietic stem cell transplantation: a secondary analysis of a randomized clinical trial.

BACKGROUND: Use of kinase inhibitors such as dasatinib and imatinib might increase the risk of opportunistic infections, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. However, the effect of sorafenib on EBV and CMV infections remains unclear. The aim of this study was to investigate the effect of sorafenib maintenance post-transplantation on the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia. METHODS: This was a follow-up of our randomized controlled trial undertaken at seven hospitals in China. The primary endpoint was EBV and CMV infections within 3 years post-transplantation. Secondary endpoints included the cumulative incidences of relapse, non-relapse mortality (NRM), overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) at 3 years. RESULTS: Two hundred two patients were assigned to sorafenib maintenance (n=100) or non-maintenance (control, n=102). Median extended follow-up post-transplantation was 36.8 (range, 2.5-67.1) months. The 3-year cumulative incidences of EBV-DNAemia and EBV-associated diseases were 24.0% (95% CI: 16.1-32.8%) and 5.0% (1.8-10.6%) in the sorafenib group, and 24.5% (16.6-33.2%) and 5.9% (2.4-11.6%) in the control group (P=0.937; P=0.771). The 3-year cumulative incidences of CMV-DNAemia and CMV-associated diseases were 56.0% (45.6-65.1%) and 8.0% (3.7-14.4%) in the sorafenib group, and 52.9% (42.7-62.1%) and 8.8% (4.3-15.3%) in the control group (P=0.997; P=0.826). The 3-year cumulative mortality of EBV- and CMV-associated diseases was 0.0% (0.0-0.0%) and 2.0% (0.4-6.4%) in the sorafenib group, and 1.0% (0.1-4.8%) and 2.0% (0.4-6.3%) in the control group (P=0.322, P=0.980). The 3-year cumulative incidences of relapse, NRM, OS, LFS, and GRFS were 13.0%, 11.1%, 79.0%, 75.9%, and 65.8% in the sorafenib group and 34.8%, 12.7%, 61.4%, 52.5%, and 46.6% in the control group, respectively (P<0.001, P=0.656, P=0.005, P<0.001, P=0.003). The reconstitution of T lymphocyte subsets, B lymphocytes, and natural killer cells was similar between the two groups (all P>0.05). CONCLUSIONS: Sorafenib maintenance post-transplantation does not increase the incidence and mortality of EBV and CMV infections, demonstrating a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02474290 . Registered on June 14, 2015.

Preclinical and clinical advances in dual-target chimeric antigen receptor therapy for hematological malignancies.

In recent years, the excellent curative effect of CD19-specific chimeric antigen receptor (CAR) T-cell therapy has brought hope to patients with relapsing or refractory B-cell hematological malignancies, however relapse after CAR T-cell infusion has hindered the widespread clinical application of this immunotherapy and targeted antigen-negative relapse has caused widespread concern. Consequently, strategies for increasing targeted antigens have been created. In addition to the most widely applied target, namely CD19, researchers have further explored the possibility of other targets, such as CD20, CD22, CD33, and CD123, and have tested a series of combination antigen CAR T-cell therapies. Here, we summarize the current preclinical and clinical studies of dual-target CAR T cells.

Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial.

BACKGROUND: Findings of retrospective studies suggest that sorafenib maintenance post-transplantation might reduce relapse in patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. We investigated the efficacy and tolerability of sorafenib maintenance post-transplantation in this population. METHODS: We did an open-label, randomised phase 3 trial at seven hospitals in China. Eligible patients (aged 18-60 years) had FLT3-ITD acute myeloid leukaemia, were undergoing allogeneic haematopoietic stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days post-transplantation. Patients were randomly assigned (1:1) to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days post-transplantation. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 1-year cumulative incidence of relapse in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02474290; the trial is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were enrolled and randomly assigned to sorafenib maintenance (n=100) or control (n=102). Median follow-up post-transplantation was 21·3 months (IQR 15·0-37·0). The 1-year cumulative incidence of relapse was 7·0% (95% CI 3·1-13·1) in the sorafenib group and 24·5% (16·6-33·2) in the control group (hazard ratio 0·25, 95% CI 0·11-0·57; p=0·0010). Within 210 days post-transplantation, the most common grade 3 and 4 adverse events were infections (25 [25%] of 100 patients in the sorafenib group vs 24 [24%] of 102 in the control group), acute graft-versus-host-disease (GVHD; 23 [23%] of 100 vs 21 [21%] of 102), chronic GVHD (18 [18%] of 99 vs 17 [17%] of 99), and haematological toxicity (15 [15%] of 100 vs seven [7%] of 102). There were no treatment-related deaths. INTERPRETATION: Sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. This strategy could be a suitable therapeutic option for patients with FLT3-ITD acute myeloid leukaemia. FUNDING: None.

CD19 chimeric antigen receptor-redirected T cells combined with epidermal growth factor receptor pathway substrate 8 peptide-derived dendritic cell vaccine in leukemia.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy opens a new era for cancer treatment. However, in prolonged follow-up, relapse has emerged as one of the major obstacles. Dendritic cell (DC) vaccination is a promising treatment to eradicate tumor cells and prevent relapse. The epidermal growth factor receptor (EGFR) pathway substrate 8 (Eps8) gene is involved in regulating cancer progression and is considered an attractive target for specific cancer immunotherapy. The purpose of this study was to explore a combinatorial therapy using CAR-T cells and a DC vaccine such as Eps8-DCs to increase leukemia treatment efficacy. METHODS: We pulsed DCs with Eps8-derived peptides to generate Eps8-DCs, engineered T cells to express a second-generation CAR specific for CD19, and analyzed the effects of the Eps8-DCs on the in vitro expansion, phenotype and effector functions of the CD19 CAR-T cells. RESULTS: The Eps8-DCs significantly reduced the activation-induced cell death and enhanced the proliferative potential of CAR-T cells during in vitro expansion. In addition, the expanded T cells co-cultured with the Eps8-DCs exhibited an increased percentage of central memory T cells (Tcms) and a decreased percentage of effector memory T cells (Tems). The Eps8-DCs enhanced CD19 CAR-T cell immune functions, including cytokine production, CD107a degranulation activity and cytotoxicity. DISCUSSION: This study demonstrates that Eps8-DCs exert synergistic effect on CD19 targeting CAR-T cells and paves the way for clinical trials using the combination of DC vaccination and engineered T cells in relapsed leukemia.

Role of Toll-Like Receptor Signaling in the Pathogenesis of Graft-versus-Host Diseases.

Graft-versus-host disease (GVHD) and infection are major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the leading causes of morbidity and mortality in HSCT patients. Recent work has demonstrated that the two complications are interdependent. GVHD occurs when allo-reactive donor T lymphocytes are activated by major histocompatibility antigens or minor histocompatibility antigens on host antigen-presenting cells (APCs), with the eventual attack of recipient tissues or organs. Activation of APCs is important for the priming of GVHD and is mediated by innate immune signaling pathways. Current evidence indicates that intestinal microbes and innate pattern-recognition receptors (PRRs) on host APCs, including both Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), are involved in the pathogenesis of GVHD. Patients undergoing chemotherapy and/or total body irradiation before allo-HSCT are susceptible to aggravated gastrointestinal epithelial cell damage and the subsequent translocation of bacterial components, followed by the release of endogenous dangerous molecules, termed pathogen-associated molecular patterns (PAMPs), which then activate the PRRs on host APCs to trigger local or systemic inflammatory responses that modulate T cell allo-reactivity against host tissues, which is equivalent to GVHD. In other words, infection can, to some extent, accelerate the progression of GVHD. Therefore, the intestinal flora's PAMPs can interact with TLRs to activate and mature APCs, subsequently activate donor T cells with the release of pro-inflammatory cytokines, and eventually, induce GVHD. In the present article, we summarize the current perspectives on the understanding of different TLR signaling pathways and their involvement in the occurrence of GVHD.

G-A variant in miR-200c binding site of EFNA1 alters susceptibility to gastric cancer.

MicroRNAs (miRNAs) post-transcriptionally modulate gene expression by binding to complementary sites at 3'-untranslated regions (3'UTRs) of their target messenger RNAs (mRNAs). Genetic variations in miRNA binding sites may alter individual susceptibilities to many cancers. However, whether miRNA binding site single nucleotide polymorphisms (SNPs) interfere with gastric cancer (GC) susceptibility has not been reported. In this case-control study including 525 GC patients and 501 controls, we selected three miRNA binding site SNPs located in 3'UTRs of genes involved in GC to investigated their associations with GC susceptibility. We identified that rs12904 in ephrin-A1 (EFNA1) gene was significantly associated with risk of GC, with the OR for carrying AG or GG genotype being 0.65 (P = 0.002, OR 0.65; 95% CI, 0.50-0.85) compared with AA genotype. Specifically, we found that rs12904 is in strong linkage disequilibrium (LD) with rs4072037, a susceptibility variant reported by previous genome-wide association study (GWAS). No significant associations were observed for the other two SNPs (rs699517 in TYMS and rs1042542 in BIRC5). Furthermore, luciferase assays indicated EFNA1 as the target of hsa-miR-200c and rs12904 G > A change resulted in altered regulation of luciferase expression. In addition, rs12904 AA genotype was associated with increased expression of EFNA1 mRNA compared with AG or GG genotype in the cancer tissues from 48 patients. Taken together, these findings indicate that the miR-200c binding site SNP (rs12904 G > A) in the 3'UTR of EFNA1 can modulate EFNA1 expression and is associated with GC susceptibility. Larger replication studies are needed to confirm our findings.

[The outcome of thirteen patients with nonmalignant hematologic diseases treated with HLA haploidentical stem cell transplantation].

OBJECTIVE: To evaluate the clinical efficacy and safety of human leukocyte antigen (HLA) haploidentical stem cell transplantation in nonmalignant hematologic diseases. METHOD: To analyze the outcome of 13 patients with nonmalignant hematologic diseases who underwent HLA haploidentical stem cell transplantation from September 2001 to October 2013. RESULTS: Thirteen patients including 9 of severe aplastic anemia, 3 of severe ß thalassemia, 1 of congenital pure red cell aplastic anemia underwent HLA haploidentical stem cell transplantation. Three HLA loci mismatched in 4 cases, two HLA loci mismatched in 8 cases and one HLA locus mismatched in 1 case. The conditioning regime consisted of Fludarabine (30 mg×m(-2)×d(-1)×5 d ), Busulfan(0.8 mg×kg(-1)×6h(-1)×4 d), Cyclophosphamide (60 mg×kg(-1)×d(-1)×2 d ), rabbit anti-human lymphocyte globulin ( 2.5 mg×kg(-1)×d(-1)×5 d ). To prevent from graft-versus-host disease (GVHD), cyclosporin A and short term methotrexate (MTX) were used. All patients were successfully engrafted. The incidence of grade 1-2 acute graft-versus-host disease (aGVHD) was 3/13, and that of grade 3-4 was 1/13. The cumulative incidence of total chronic GVHD (cGVHD) was 3/13. Eleven patients survived free of disease at a median follow-up period of 13 months (2-145). CONCLUSION: HLA haploidentical stem cell transplantation is an effective and safe therapy for nonmalignant hematologic diseases.

Donor-derived CAR-T therapy improves the survival of relapsed B-ALL after allogeneic transplantation compared with donor lymphocyte infusion.

Chimeric antigen receptor (CAR)-T cell therapy revolutionized treatment for various hematologic malignances. However, limited studies were reported to compare the efficacy and safety of CAR-T and donor lymphocyte infusion (DLI) for patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) after hematopoietic stem cell transplantation (HSCT) comprehensively. We conducted a single-center, retrospective comparative study that consisted of 12 patients who were treated with DLI (control group) and 12 patients treated with donor-derived CD19 CAR-T cells (experimental group, 6 patients also received CD22 or CD123 CAR-T cells sequentially) with 3 overlaps. The event-free survival (EFS) of patients in experimental group was superior to that of the control group: 516 days versus 98 days (p = 0.0415). Compared with 7 of 12 patients treated with DLI suffered grades III-IV acute graft versus host disease (aGVHD), one grade III aGVHD developed in patients treated with CAR-T therapy. No significant difference in the incidence of infection was identified between these two groups. Most patients in the experimental group had only mild cytokine release syndrome and none developed neurotoxicity. The univariate analysis of patients in the experiment group revealed that earlier CAR-T therapy for post-transplantation relapse was associated with better EFS. There was no significant difference in EFS between patients treated with dual-target CAR-T with those with single CD19 CAR-T. In this study, our data supported that donor-derived CAR-T therapy is a safe and potentially effective treatment for relapsed B-ALL after HSCT and may be superior to DLI.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study.

Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2-44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%-84.6%) and 65.2% (95% CI 60.3%-70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37-0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14-0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33-0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, "activated signaling" and "DNA methylation" genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, "tumor suppressors" and "myeloid transcription factors" genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Donor-derived and off-the-shelf allogeneic anti-CD19 CAR T-cell therapy for R/R ALL and NHL: A systematic review and meta-analysis.

Allogeneic anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has the potential for extensive clinical applications. This study aimed to evaluate its efficacy and safety in treating relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Four databases were searched for relevant studies. Among patients treated with donor-derived CAR T-cell therapy, ALL patients had a complete remission (CR) rate of 80 % and a 1-year overall survival rate of 51 %. The graft-versus-host disease (GvHD) rate was 4 %, cytokine release syndrome was 69 %, and immune effector cell-associated neurotoxicity syndrome was 8 %. For off-the-shelf CAR T-cell therapy, the CR rate for ALL was 70 %, and for NHL, it was 52 %. The objective response rate for NHL was 72 %. The pooled GvHD of off-the-shelf CAR T-cell therapy for ALL and NHL combined was 0 %. Allogeneic anti-CD19 CAR T-cell therapy are effective and safe for treating R/R ALL and NHL. AVAILABILITY OF DATA AND MATERIALS: All datasets generated in this study are included in the article/Supplementary Material.

Current state of CAR-T therapy for T-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for relapsed/refractory B-cell lymphomas and greatly improves disease outcomes. The impressive success has inspired the application of this approach to other types of tumors. The relapsed/refractory T-cell malignancies are characteristic of high heterogeneity and poor prognoses. The efficacy of current treatments for this group of diseases is limited. CAR-T therapy is a promising solution to ameliorate the current therapeutic situation. One of the major challenges is that normal T-cells typically share mutual antigens with malignant cells, which causes fratricide and serious T-cell aplasia. Moreover, T-cells collected for CAR transduction could be contaminated by malignant T-cells. The selection of suitable target antigens is of vital importance to mitigate fratricide and T-cell aplasia. Using nanobody-derived or naturally selected CAR-T is the latest method to overcome fratricide. Allogeneic CAR-T products and CAR-NK-cells are expected to avoid tumor contamination. Herein, we review the advances in promising target antigens, the current results of CAR-T therapy clinical trials in T-cell malignancies, the obstacles of CAR-T therapy in T-cell malignancies, and the solutions to these issues.

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the therapeutic landscape of haematological malignancies. However, resistance and relapse remain prominent limitations, and they are related to the limited persistence and efficacy of CAR T cells, downregulation or loss of tumour antigens, intrinsic resistance of tumours to death signalling, and immune suppressive microenvironment. Rational combined modality treatments are regarded as a promising strategy to further unlock the antitumor potential of CAR T cell therapy, which can be applied before CAR T cell infusion as a conditioning regimen or in ex vivo culture settings as well as concomitant with or after CAR T cell infusion. In this review, we summarize the combinatorial strategies, including chemotherapy, radiotherapy, haematopoietic stem cell transplantation, targeted therapies and other immunotherapies, in an effort to further enhance the effectiveness of this impressive therapy and benefit more patients.

[Efficacy and Safety of Cladribine-based Intensified Conditioning Regimen in Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen. METHODS: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed. RESULTS: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD- high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients. CONCLUSION: The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD- high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.

Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation.

Bcr-Abl threonine 315 to isoleucine 315 (T315I) gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia (CML). Chemical degradation of Bcr-AblT315I protein has become a potential strategy to overcome drug resistance. Herein, we first described the design, synthesis, and evaluation of a new class of selective Bcr-AblT315I proteolysis-targeting chimeric (PROTAC) degraders based on GZD824 (reported as Bcr-AblT315I inhibitor by our group). One of the degrader 7o with 6-member carbon chain linkage with pomalidomide exhibits the most potent degradation efficacy with DR of 69.89% and 94.23% at 100 and 300 nmol/L, respectively, and has an IC50 value of 26.8 ± 9.7 nmol/L against Ba/F3T315I cells. Further, 7o also displays substantial tumor regression against Ba/F3-Bcr-AblT315I xenograft model in vivo.

Consolidative Hematopoietic Stem Cell Transplantation After CD19 CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis.

BACKGROUND: This study aimed to systematically evaluate and compare the efficacy and safety of consolidative hematopoietic stem cell transplantation (HSCT) after CD19 chimeric antigen receptor T (CAR-T) therapy with non-HSCT in the treatment of acute lymphoblastic leukemia (ALL). METHODS: The PubMed, Embase, Cochrane Library and Web of Science databases were searched for clinical trials. Pooled hazard ratios (HRs) for overall survival (OS), relapse rate, and leukemia-free survival (LFS) as well as overall incidence rates for transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and infections were calculated using Stata software. RESULTS: We screened 3,441 studies and identified 19 eligible studies with 690 patients. Among the patients who achieved complete remission (CR) after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (HR = 0.34, 95% CI, 0.170.68, P = 0.003), the relapse rate (HR = 0.16, 95% CI, 0.100.25, P < 0.001), and LFS (HR = 0.15, 95% CI, 0.080.28, P < 0.001). For patients who achieved MRD-negative (neg) CR after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (0.57, 95% CI, 0.330.99, P = 0.045), the relapse rate (0.14, 95% CI, 0.060.31, P < 0.001), and LFS (0.21, 95% CI, 0.120.35, P < 0.001). Regarding safety, we calculated pooled incidence rates for TRM (8%, 95% CI, 0.020.15), aGVHD (44%, 95% CI, 0.230.67), cGVHD (36%, 95% CI, 0.170.56), and infections (39%, 95% CI, 0.030.83). CONCLUSIONS: Compared with non-HSCT treatment, consolidative HSCT after CD19 CAR-T therapy for R/R B-ALL patients can prolong OS and LFS and reduce the risk of relapse. The incidence rates for adverse events are acceptable. More high-quality randomized controlled trials are required to avoid bias and further determine the efficacy of HSCT.