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Introduction: Despite the promising clinical trial data regarding programmed death 1 (PD-1) inhibitors in relapsed/ refractory classical Hodgkin lymphoma (R/R cHL), there remains a paucity of studies describing the outcomes of patients in a real-world setting, especially for Asian cohort. Methods: We present a multicenter retrospective analysis of patients with R/R cHL who had failed ≥2 prior lines of therapies and received Sintilimab or Tislelizumab developed in China (sintilimab or tislelizumab) monotherapy at 3 medical centers from January 2019 to September 2021. Efficacy was evaluated with progression-free survival (PFS), overall survival (OS), duration of response (DOR), best overall response (BOR) including objective response rate (ORR), complete response rate (CRR). Safety data were also recorded. Results: 74 patients were reviewed. The median age was 38 years (range, 14-85 years). The ORR, CRR and disease control rate (DCR) were 78.3%, 52.7% and 91.9%, respectively. The median duration of follow-up was 22 (4–36) months. Four patients (5.4%) died of disease progression. The median PFS and DOR was 22.1 and 23.5 months. BOR as a new emergent endpoint, was found to be the only independent prognostic factor for PFS in our study (HR=6.234, p=0.005), suggesting this endpoint carries stronger prognostic value over traditional endpoints in the immunotherapy era. 66 (89.2%) patients reported adverse event (AE) with any grade, with the majority of AEs being grade 1 or 2. Discussion/Conclusion: We presented an unique real-life experience and conducted a relatively long follow up of PD-1 antibodies developed in China for R/R HL patients which confirmed their promising effectiveness and manageable side effects given in real world in an Asian cohort. Even for those who would usually be excluded in most of clinical trials such as elderly or minor patients, anti-PD-1 monotherapy also showed a significant improvement of outcomes. Furthermore, the depth of response seemed to be a more powerful predictive tool in new era, which might serve as a basis for future immune risk-adapted strategies.

Background Abnormal alternative splicing is frequently associated with carcinogenesis. In B-cell acute lymphoblastic leukemia (B-ALL), double homeobox 4 fused with immunoglobulin heavy chain (DUX4/IGH) can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript (ERGalt ) and other splicing variants. However, the molecular mechanism underpinning this process remains elusive. Here, we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia. Methods The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients. X-ray crystallography, small angle X-ray scattering (SAXS), and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element (DRE)-DRE sites. The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity. To check whether recombination-activating gene 1/2 (RAG1/2) was required for DUX4/IGH-driven splicing, the proximity ligation assay, co-immunoprecipitation, mammalian two hybrid characterizations, in vitro RAG1/2 cleavage, and shRNA knock-down assays were performed. Results We reported previously unrecognized intron retention events in C-type lectin domain family 12, member A abnormal transcript (CLEC12Aalt ) and chromosome 6 open reading frame 89 abnormal transcript (C6orf89alt ), where also harbored repetitive DRE-DRE sites. Supportively, X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain (HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites. Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt , CLEC12Aalt , and C6orf89alt biogenesis, resulting in marked alleviation of its inhibitory effect on B-cell differentiation. Furthermore, we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes. Supportively, shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt , CLEC12Aalt , and C6orf89alt . Conclusions All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites, catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.

Platelet-targeted FVIII gene therapy can efficiently recover bleeding phenotype for hemophilia A (HA), yet characteristics of thrombus formation with this ectopic expression of factor VIII (FVIII) in platelets remain unclear. Here, we generated 2bF8trans mice restrictively expressing human B-domain–deleted FVIII (hBDD FVIII) in platelets on a hemophilic (FVIIInull) mice background. The results showed no statistical difference in clot strength and stability between wild-type (WT) and 2bF8trans mice, but with a prolonged reaction time (R-time), by thromboelastography. Fluid dynamics analysis showed that at the shear rates of 500 to 1,500 s−1, where physiological hemostasis often develops, the thrombi formed in 2bF8trans mice were more stable than those in FVIIInull mice, while at high pathological shear rates (2,500 s−1), mimicking atherosclerosis, thrombus size and fibrin deposition in 2bF8trans mice were less than those in WT mice. Thrombus morphology analysis showed that there was a locally concentrated deposition of fibrin in thrombus at the injured site and fibrin co-localized with activated platelets in 2bF8trans mice. Moreover, a higher ratio of fibrin to platelets was found in thrombus from 2bF8trans mice following laser-induced injury in cremaster arterioles, which might be the underlying mechanism of thrombus stability in 2bF8trans mice at physiological arterial circumstance. These observations suggest that specific morphological features of the thrombi might contribute to the efficacy and safety of platelet-targeted FVIII gene therapy for HA.

PURPOSE CARTIFAN-1 aimed to evaluate the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen–targeting chimeric antigen receptor T-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (RRMM). METHODS This pivotal phase II, open-label study (ClinicalTrials.gov identifier: NCT03758417 ), conducted across eight sites in China, enrolled adult patients with RRMM who had received ≥ 3 lines of prior therapy, including a proteasome inhibitor and immunomodulatory drug. Patients received a single infusion of cilta-cel (target dose 0.75 × 106 chimeric antigen receptor–positive viable T cells/kg). The primary end point was overall response rate. Secondary end points included progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). RESULTS As of the clinical cutoff of July 19, 2021, 48 patients received a cilta-cel infusion. At an 18-month median follow-up, the overall response rate was 89.6% (95% CI, 77.3 to 96.5), with a median time to first response of approximately 1 month; 77.1% of patients (95% CI, 62.7 to 88.0) achieved complete response or better. Medians for duration of response, PFS, and OS were not reached. The 18-month PFS and OS rates were 66.8% (95% CI, 49.4 to 79.4) and 78.7% (95% CI, 64.0 to 88.0), respectively. Hematologic AEs were common, including anemia (100%), neutropenia (97.9%), lymphopenia (95.8%), and thrombocytopenia (87.5%). Cytokine release syndrome occurred in 97.9% of patients (35.4% grade 3/4); the median time to onset was 7 days, and the median duration was 5 days. Infections occurred in 85.4% of patients (37.5% grade 3/4). Ten deaths occurred after cilta-cel infusion, eight of which were due to treatment-related AEs. CONCLUSION These data demonstrate a favorable risk-benefit profile for a single infusion of cilta-cel, resulting in early, deep, and durable responses in heavily pretreated patients with RRMM in China.

BACKGROUND: Central nervous system (CNS) mucormycosis is insidious and difficult to diagnose. It progresses rapidly and causes high mortality. Rare cases have been reported during ibrutinib use, which have poor prognosis. Through this case, we share the experience of successful diagnosis and treatment. We also emphasize the importance of focusing on high-risk groups, early diagnosis and prompt management. CASE DESCRIPTION: In this case, a 52-year-old patient was diagnosed with chronic lymphocytic leukemia (CLL) for more than 5 years. He was in remission after rituximab plus fludarabine and cyclophosphamide (RFC) regimen, and relapsed in the fourth year. During the ibrutinib monotherapy, the patient presented with sudden headache. Cranial imaging examination revealed a definite right occipitoparietal lobe mass with extensive edema. A rapid diagnosis of mucormycosis infection was made using metagenomic next-generation sequencing (mNGS). The patient at that time didn’t have neutropenia, but he had hypogammaglobulinemia. The infection was treated with amphotericin B cholesteryl sulfate complex, posaconazole, and interventional surgery, and the treatment was successful. At the same time, we considered the control of disease progression in this relapsed patient with, as well as to the drug interaction with posaconazole. We chose the next generation Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib as the treatment, whose safety has been identified. As of the submission date, the patient has been followed up for nearly 1 year, and his disease is stable. CONCLUSIONS: When new clinical problems arise in recurrent CLL patients, it is important to identify multiple factors, especially the insidious fungal infections. In particular, the immunocompromised patients should be concerned. CNS mucormycosis is extremely deadly, the early diagnosis will improve the prognosis. In clinical practice, the gold standard diagnosis of mucormycosis is difficult to obtain through pathology. In this case, mNGS was applied to quickly diagnose mucormycosis, enabling earlier treatment and ameliorating the prognosis. Thus, it will help us to early detect this group of people who may be potentially infected. Current guidelines do not recommend the prophylactic use of antifungal agents in treated CLL patients. However, in patients with prior severe infection or hypogammaglobulinemia, intravenous immunoglobulin is recommended to reduce the associated infection rate.

BackgroundImmunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored.MethodsThe efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging.ResultsWe report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2highMM cells in vitro and in vivo.ConclusionThis study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1–G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7–G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

International audience; Background: Early biomarkers allowing effective treatment stratification in adult T-cell acute lymphoblastic leukemia (T-ALL) patients remain elusive.Materials and methods: The mutation spectrum of 116T-ALL adult patients enrolled in the Shanghai Institute of Hematology (SIH)-based hospital network or Multicenter Hematology-Oncology Protocols Evaluation System (M-HOPES) in China were studied by using RNA-sequencing or targeted next generation sequencing. A comprehensive survival analysis based on clinical characteristics, immunophenotype and oncogenetic classifier was performed.Results: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has higher mutation rates of N/K-RAS and lower mutation rates of FBXW7 compared to non-ETP ALL, but the survival probability of ETP-ALL patients is similar to that of non-ETP ALL patients. T-ALLs with a NOTCH1/FBXW7 (N/F) mutation in the absence of RAS or PTEN abnormalities (NFRP class I) show a more favorable outcome compared to T-ALLs with no N/F mutation and/or with the presence of RAS/PTEN alterations (NFRP class II). A survival analysis of TALL , taking into account both the ETP-ALL/non-ETP TALL groups and the NFRP oncogenetic classifier, demonstrates that, within the non-ETP TALL subtype, NFRP class II identifies a group with poor prognosis and significant decreases of both OS (14.8% versus 50.9%, P = 0.019) and EFS (11.4% versus 42.4%, P = 0.001). In contrast, no survival difference is observed within ETP-ALL between the NFRP class I or class II (OS: 37.9% versus 33%, P = 0.876; EFS: 39.8% versus 33.7%, P = 0.969).Conclusion: In summary, the oncogenetic classifier based on the NFRP classes is particularly useful to improve the stratification of non-ETP ALL.

Background T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. Results The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. Conclusion Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.

Objectives T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment.Methods A specific pipeline designed to discover aberrantly active genes was applied here on the RNA-sequencing data of 109 T-ALL patients from our multicenter clinical study. A prognostic classifying test, based on the detection of the combined expression of a subset of these genes was designed and further validated in an additional cohort of 32 adult T-ALL patients by using RT-qPCR. Results The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients.Conclusion Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.

The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

Patients with multiple myeloma (MM), an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions. In this study, glycosphingolipids were essential in promoting autophagic degradation of the signaling molecule TRAF3, a key step in bone-resorbing osteoclast differentiation. Specifically altering the glycosphingolipid composition with eliglustat, an FDA approved glucosylceramide synthase inhibitor, arrested osteoclast differentiation; this could be rescued by exogenous addition of the missing glycosphingolipids. Eliglustat significantly reduced bone disease in several preclinical models of MM by inhibiting osteoclastogenesis and, due to its unique mode of action, it was able to act in combination with existing bone protective drugs. Furthermore, eliglustat arrested osteoclast differentiation from the bone marrow of MM patients in a glycosphingolipid-dependent way. This work identifies both the mechanism by which glucosylceramide synthase inhibition blocks autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the translational potential of eliglustat to be combined with current treatments.

International audience; T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of TALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on TALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of TALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

The morbidity and mortality of myeloproliferative neoplasms (MPNs) are primarily caused by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. However, identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge. We have previously shown that interferon regulatory factor-8 (IRF8) and IRF4 serve as tumor suppressors in myeloid cells. In this study, we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs. Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis (MF) and secondary AML (sAML) transformed from MPNs versus essential thrombocythemia (ET). Negative correlations between the JAK2V617F allele burden and the expression of IRF8 (P < 0.05) and IRF4 (P < 0.001) and between white blood cell (WBC) count and IRF4 expression (P < 0.05) were found in ET patients. IRF8 expression was negatively correlated with the JAK2V617F allele burden (P < 0.05) in polycythemia vera patients. Complete response (CR), partial response (PR), and no response (NR) were observed in 67.5%,10%, and 22.5% of ET patients treated with hydroxyurea (HU), respectively, in 12 months. At 3 months, patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups. In the 12-month therapy period, low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count. Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype, which may serve as biomarkers for the response to HU in ET.

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

Rationale and Objectives This study aimed to measure apparent diffusion coefficient (ADC) in Chinese patients with newly diagnosed multiple myeloma by whole-body diffusion-weighted magnetic resonance imaging (WB-DWI MRI) and assess the diagnostic accuracy of ADC in the discrimination of deep response to induction chemotherapy. Materials and Methods Seventeen patients underwent WB-DWI MRI before and after induction chemotherapy (week 20). DWI images and ADC maps were produced and 89 regions of interest were chosen. ADC percent changes were compared between deep (complete response or very good partial response) and non–deep responders (partial response, minimal response, stable disease, or progressive disease) as International Myeloma Working Group criteria. Diagnostic accuracy of ADC was calculated using specific cut offs. Predictive positive value of ADC was calculated to predict deep response to consolidation therapy. Results Lesions reduced in size and number and signal intensity decreased in follow-up DWI, which did not differ between deep and non–deep responders. ADC percent changes were significantly higher in deep responders (36.79%) than in non–deep responders (11.50%) after induction therapy (P = .02) in per lesion analysis. ADC percent increases by 46.96%, 78.0% yielded specificity at 81.4%, 90.7% in discriminating deep response to induction therapy. Predictive positive value predicting deep response to consolidation therapy was 60.5% by using ADC cutoff >1.00 × 10−3 mm2/s at week 20. Conclusions ADC from WB-DWI MRI increased remarkably in patients who achieved deep response at the end of induction chemotherapy, which represented a confirmatory diagnostic tool to discriminate deep response to induction therapy for patients with multiple myeloma. ADC may have a potential to predict deep response to consolidation therapy.

Background Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated. Methods The anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay. Cell cycle distribution and apoptosis were examined by flow cytometry. Transmission electron microscopy was used to visualized autophagosomes. Activation of AMPK and inhibition of mTORC1/C2 pathways was assessed by Western blot analysis. RPMI8226 cells and U266 cell lines with AMPK knockdown were generated by transfection with small interfering RNA targeting the AMPK-α1 and α2 subunits using Lipofectamine 2000 reagent. Results Metformin effectively inhibited the proliferation of MM cell lines, an effect that was associated with the induction of autophagy and G0/G1 cell cycle arrest, but not apoptosis. Metformin activated AMPK and repressed both mTORC1 and mTORC2 signaling pathways in myeloma cells as well as downstream molecular signaling pathways, such as p-4EBP1 and p-AKT. AMPK activation resulted in direct phosphorylation and activation of tuberous sclerosis complex 2 (TSC2), leading to inhibition of the mammalian target of rapamycin (mTOR). In addition, metformin inhibited myeloma cell growth in an AMPK-dependent manner. The xenograft mouse model further confirmed that metformin inhibited tumor growth by upregulation of AMPK and downregulation of mTOR. Conclusions Metformin inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. Our results suggest that the molecular mechanism involves dual repression of mTORC1 and mTORC2 pathways via AMPK activation. Our study provides a theoretical basis for the development of novel strategies for the treatment of MM using metformin as an already approved and safe drug.

Significance DNMT3A is a critical epigenetic modifier and tumor suppressor in the hematopoietic system. This gene is frequently mutated in hematopoietic malignancies, including acute myeloid leukemia (AML), with Dnmt3a R878H being the most common mutant. By using a conditional knockin approach, this study shows that Dnmt3a R878H is sufficient to initiate AML and recapitulate human leukemic features in mice. The leukemia-initiating cells are enriched in hematopoietic stem/progenitor cells. Through gene expression profiling, DNA methylation and histone modification analysis, and functional tests on important regulators for cell proliferation and differentiation in an animal model, this study has not only discovered mTOR pathway activation as a key player in the disease mechanism but also revealed the potential therapeutic effects of mTOR inhibition on DNMT3A mutation-related leukemia.

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

The value of clearance of peripheral blood blasts (PBB) as a predictor of outcomes in acute myeloid leukemia (AML) is controversial. To investigate the prognostic significance of the time to clearance of PBB after induction in Chinese patients with AML, a retrospective analysis of 146 patients with newly diagnosed AML at Shanghai Ruijin Hospital was performed. Patients were categorized into early blast clearance (EBC; ≤5 days) and delayed blast clearance (DBC; >5 days) groups based on a receiver operating characteristic analysis. Complete remission (CR) after induction chemotherapy was related to the time to clearance of PBB (p < 0.001). Relapse-free survival (RFS; p = 0.003) and overall survival (p < 0.001) were longer in the EBC group. Multivariate analysis demonstrated that the time to clearance of PBB and cytogenetic risk independently predicted CR and RFS. Early clearance of PBB after induction chemotherapy can be a significant predictor of survival outcomes in AML patients.