Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Several clinical trials have established DARA-based treatment as a standard of care globally for patients with newly diagnosed or relapsed/refractory multiple myeloma (MM). However, clinical trials do not always reflect routine clinical practice, and real-world (RW) studies thus provide an important complement to conventional clinical trials. Herein, we report results from an observational study that described RW treatment patterns and outcomes in routine clinical practice among patients with MM who were treated with DARA in China. This is possibly the first study to enroll a large population of Chinese patients with MM who were treated with DARA in the RW setting. Methods: This ongoing, multicenter, noninterventional, observational registry study is enrolling Chinese patients who have been diagnosed with symptomatic newly diagnosed or relapsed/refractory MM and either (1) started DARA treatment after August 1, 2019, and were expected to continue ongoing DARA at the time of study initiation (November 3, 2021) or (2) started DARA treatment after study initiation. Patients were excluded from the study if they had received ≥4 prior lines of MM therapy before starting DARA-based treatment or had a diagnosis of other cancers prior to their MM diagnosis. The decision to treat with DARA must have been made prior to and independently of the patient's inclusion in the study, and treatment was administered in accordance with local clinical practice. For patients who started DARA after August 1, 2019, but before study initiation, data were collected both retrospectively through medical chart review and prospectively after enrollment. RW baseline disease characteristics, treatment patterns, response rates, measurable residual disease (MRD), and safety are presented. Outcome and safety analyses were based on the DARA treatment period. Results: As of the cutoff date (April 30, 2023) for this analysis, 210 patients who received ≥1 dose of DARA have been enrolled in the study from 13 participating sites in China. At baseline (last status prior to the first DARA dose), patients had a median age of 64 y (range, 29-89) and a median time since MM diagnosis of 1 y (range, 0-12); the majority of patients had an ECOG performance status of 0 or 1 (82.4%) and a Durie-Salmon MM stage of III (74.4%). Most (83.8%) patients had received ≥1 prior line of therapy before initiating DARA, including 82.4% who had received prior protease inhibitors (PIs) and 58.1% who had received prior immunomodulatory drugs (IMiDs). A summary of prior therapies is provided in Table 1. DARA-based therapy included DARA monotherapy (n = 22) or combination with dexamethasone only (n = 21), PIs ± dexamethasone (n = 57), IMiDs ± dexamethasone (n = 71), PIs and IMiDs ± dexamethasone (n = 29), and other combinations (n = 10). The median DARA exposure time was 5.39 mo (interquartile range [IQR], 2.56-9.69), and the median follow-up time was 10.48 mo (IQR, 7.23-15.31). Of the 179 patients evaluable for response, a best overall response of partial response (PR) or better was achieved by 130 (72.6%) patients and a best response of very good partial response (VGPR) or better was achieved by 93 (52.0%) patients, with responses observed across DARA treatment regimens ( Table 2). MRD results were available for 53/179 (29.6%) patients, with 31/53 (58.5%) patients achieving MRD negativity. Adverse drug reactions were reported for 40 (19.0%) patients overall; events reported in ≥5% of patients included leukopenia (6.2%), thrombocytopenia (5.7%), and neutropenia (5.2%). Serious treatment-emergent adverse events were reported for 29 (13.8%) patients, with pneumonia (n = 10, 4.8%) the only serious event reported in ≥5 patients. Twenty-five patients died as of the cut-off date, regardless of timing (with/without DARA treatment period). Conclusions: This noninterventional, observational study provides RW insights into physician treatment decisions for patients with MM in China and the characteristics of patients who are selected for DARA-based treatment. In addition, the RW effectiveness, duration of therapy, and safety results support the use of DARA-based treatment as a standard of care in Chinese patients with newly diagnosed or relapsed/refractory MM. This study is ongoing, with a total planned enrollment of ~220 patients.

The prognostic significance of soluble immune checkpoint molecule TIM-3 and its ligands in the plasma has been illustrated in various solid tumors, but such study in newly diagnosed acute myeloid leukemia (AML) remains absent. Soluble TIM-3, Gal-9, and CEACAM1 levels in bone marrow plasma samples collected from 90 adult AML patients at diagnosis and 12 healthy donors were measured by enzyme-linked immunosorbent assays, and 16 AML patients were simultaneously tested cell membrane TIM-3 expression by multicolor flow cytometry. AML patients had significantly elevated soluble TIM-3 levels and similar soluble Gal-9 and CEACAM1 levels compared with healthy donors (P = 0.0003, 0.26, and 0.96, respectively). In the whole cohort, a high soluble TIM-3 level was the sole independent adverse prognostic factor for relapse-free survival (RFS) (P = 0.0060), and together with adverse European LeukemiaNet genetic risk they were independent poor prognostic factors for event-free survival (P = 0.0030 and 0.0040, respectively). A high soluble CEACAM1 level was significantly related to lower RFS (P = 0.028). In addition, a high soluble Gal-9 level had a significant association with lower RFS in patients receiving allogeneic hematopoietic stem cell transplantation at the first complete remission (P = 0.037). Furthermore, soluble TIM-3 level tended to have positive correlation with the percentage of nonblast myeloid TIM-3+ cells in nucleated cells in AML (r = 0.48, P = 0.073). Therefore, the high soluble TIM-3 level in the diagnostic BM plasma predicted poor outcome in adult AML patients, and a high sGal-9 level was associated with relapse after allogeneic hematopoietic stem cell transplantation.

Background: Jaktinib, a novel Janus kinase (JAK) and ACVR1 inhibitor, demonstrated promising clinical benefit with good tolerability, not only efficiently shrinking the spleen and reducing symptom burdens, but also improving anemia, in JAK-inhibitor naïve, ruxolitinib-intolerant or -resistant MF patients. We conducted a phase 2 study (the ZGJAK002 trial) to evaluate the effectiveness and safety of jaktinib at doses of 100 mg BID and 200 mg QD in JAK-inhibitor naïve patients with intermediate or high risk MF. Herein we present long-term data with a median follow-up time of 30.7 months. Methods: Patients who completed the 24 weeks of study treatment, tolerated the drug well, and had evidence of clinically significant improvement were allowed to enter an extension phase. Dose modifications were permitted according to the platelet count and neutrophil count. Duration of spleen response (from the first spleen volume reduction of ≥35% [SVR35] to an increase of 25% or more from the nadir), overall survival (OS), and leukemia-free survival (LFS) were evaluated in an intent-to-treat analysis using a Cox proportional hazard model that estimated the treatment effect. Results: A total of 118 patients were enrolled and treated with either jaktinib 100 mg BID (n=66) or 200 mg QD (n=52). The majority of patients remained on treatment after 48 weeks (100 mg BID group: 74.2%; 200 mg QD group: 65.4%). At the data cutoff of June 30, 2022, treatment was continued in 35 (29.7%) patients (30.3% in BID; 28.8% in QD). The best spleen response, defined as SVR35 at any time, was achieved by 59.3% (95% confidence interval [CI]: 49.9%-68.3%) of patients. The 100 mg BID group demonstrated a greater best spleen response (69.7% [95% CI: 57.1%-80.4%]) compared to the 200 mg QD group (46.2% [95% CI: 32.2%-60.5%]). The median maximum reduction from baseline in spleen volume was 49.7%. The median duration of spleen response was not reached, with 51.9% (95% CI: 36.0%-65.7%) of patients from 100 mg BID and 66.5% (95% CI: 41.4%-82.8%) from 200 mg QD maintaining a spleen response for over 108 weeks (Figure 1). The proportion of patients who achieved an improvement of ≥50% in the TSS (TSS50) was 69.6% (95% CI: 55.9%-81.2%) at week 24 and 74.2% (95% CI: 55.4%-88.1%) at week 108 in the 100 mg BID group. The proportion of patients who achieved TSS50 was 57.5% (95% CI: 40.9%-73.0%) at week 24 and 66.7% (95% CI: 44.7%-84.4%) at week 108 in the 200 mg QD group. As of the data cutoff, 25 (21.2%) deaths were reported (12 [18.2%] of 66 in the 100 mg BID group and 13 [25.0%] of 52 patients in the 200 mg QD group). Median OS was not reached, with 12, 24, and 36-month survival rates of 92.3%, 85.8%, and 78.2% in the 100 mg BID and 92.3%, 78.0%, and 73.6% in 200 mg QD groups. Median LFS was not reached, with 12, 24, and 36-month LFS rates of 94.8%, 90.6%, and 84.1% in the 100 mg BID and 95.5%, 85.7%, and 85.7% in 200 mg QD groups. The 100 mg BID induced more increase from baseline in hemoglobin concentration over 144 weeks with a range of 2.18-10.17 g/L compared to -1.74-1.96 g/L with 200 mg QD. The median (range) duration of jaktinib exposure was 672.0 (14-1262) days in the 100 mg BID group and 588.5 (42-1175) days in the 200 mg QD group. The median relative dose intensity for jaktinib was 97.5% (98.1% in BID; 96.3% in QD). There was no unexpected increased incidence of adverse events (AEs) with longer exposure. The most common grade ≥3 adverse drug reactions were anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in the 100 mg BID and 200 mg QD groups, respectively. Notably, infectious pneumonia (10.6%), thrombocytopenia (4.5%), and peripheral neuropathy (3.0%) were the most common drug-related serious AEs. AEs leading to treatment discontinuation occurred in 14 patients (11.9%), with higher rate in the 100 mg BID group compared to the 200 mg QD group (15.2% vs. 7.7%). AEs resulted in death in seven (5.9%) patients, with similar rates in both groups (6.1% in BID; 5.8% in QD). Conclusions: With over 30-month follow-up, jaktinib at doses of 100 mg BID and 200 mg QD demonstrated durable high effective rates and improved survival rates without new safety issue. The long-term data further supports the recommendation of 100 mg BID over 200 mg QD administration. It also concluded that jaktinib remains the treatment strategy that offers excellent chances for improving survival in MF patients.

Introduction: Immunosuppressive therapy (IST) combined with the thrombopoietin receptor agonist (TPO-RA) is the first-line recommendation for patients with severe aplastic anemia (SAA) who are not eligible for hematopoietic stem cell transplantation (HSCT). Hetrombopag, a novel small molecule TPO-RA, has demonstrated promising efficacy in IST-refractory SAA in our previous single-arm phase 2 study (NCT03557099). To further evaluate the efficacy and safety of hetrombopag in combination with standard IST as first-line treatment for untreated SAA patients, we conducted this randomized, double-blind, placebo-controlled phase 3 study (NCT03825744) and reported the results. Methods: Eligible patients aged 15-75 years with untreated SAA according to the Camitta criteria and ineligible for HSCT were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either hetrombopag plus IST (antithymocyte globulin [ATG] and cyclosporine [CsA]) or placebo plus IST. Randomization was stratified based on the source of ATG (rabbit or pig-derived). Hetrombopag or placebo was administered orally on an empty stomach at a daily dose of 15 mg for 6 months. ATG was administered intravenously for 5 consecutive days, and CsA was given orally for 6 months. The primary endpoint was hematologic complete response (CR) rate at 6 months. Results: A total of 240 patients were randomized, with 160 patients in the hetrombopag group and 80 in the placebo group. At 6 months, the CR rate was 28.1% (95% CI 21.2-35.1) in the hetrombopag group and 13.8% (95% CI 6.2-21.3) in the placebo group, indicating a significant between-group difference of 14.4% (95% CI 4.1-24.6, 2-sided p=0.0129). The OR rate at 6 months was 63.8% in the hetrombopag group and 42.5% in the placebo group. At 3 months, the CR rate was 8.8% and 5.0%, and the OR rate was 50.6% and 25.0% in the hetrombopag and placebo group, respectively. The median time to a first hematologic response was 87.0 days (95% CI 86.0-111.0) in the hetrombopag group and 141.0 days (95% CI 113.0-NA) in the placebo group. At 6 months, the proportion of patients who were red-cell transfusion independent was 69.0% in the hetrombopag group and 48.7% in the placebo group, respectively. Platelet transfusion independence was achieved in 69.0% and 50.6% of patients, respectively. At 3 months, the proportions were 56.8% in the hetrombopag group and 27.6% in the placebo group for red-cell transfusion independence, and 54.4% vs 31.2% for platelet transfusion independence, respectively. The incidence of adverse events was comparable between the two groups, with no unexpected safety signals observed for hetrombopag. Grade ≥3 treatment-related adverse events (TRAE) were reported in 15.6% of patients in the hetrombopag group and 19.2% in the placebo group, with serious TRAE reported in 2.5% and 2.6% of patients, respectively. There were no treatment-related deaths reported. The incidence of abnormal hepatic function was 41.9% in the hetrombopag group and 48.7% in the placebo group; 35.0% and 34.6% in each group were considered treatment-related. Additionally, myelodysplastic syndromes were observed in one (0.6%) patient in the hetrombopag group and not reported in the placebo group, while myelofibrosis was reported in 0.6% of patients in the hetrombopag group and 2.6% of patients in the placebo group, respectively. Conclusions: The addition of hetrombopag to IST as first-line treatment for SAA patients led to a significantly higher hematologic response rate. These findings support hetrombopag as an effective and safe therapy for SAA patients ineligible for HSCT. Further studies are necessary to assess the long-term efficacy and safety of this treatment approach.

Background: The effect of the expression of the newly identified immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) on NK cells in core binding factor-acute myeloid leukemia (CBF-AML) remains to be investigated. Methods: Fresh bone marrow samples from a total of 39 newly diagnosed CBF-AML patients and 25 healthy donors (HDs) were collected for testing the phenotype and function state of total NK, CD56bright, and CD56dim NK cell subsets after in vitro stimulation. Results: The frequencies of TIGIT+ cells in total NK, CD56bright, and CD56dim NK cell subsets had no significant difference between patients and HDs. TNF-α and INF-γ levels were uniformly lower in TIGIT+ cells than the corresponding TIGIT− cells in all HDs, whereas those for TIGIT+ to TIGIT− cells in patients were highly heterogenous; TIGIT expression was not related to PFP and GZMB expression in HDs, whereas it was related to higher intracellular PFP and GZMB levels in patients. Patients’ TIGIT+ NK cells displayed lower K562 cell-killing activity than their TIGIT− NK cells. In addition, high frequencies of TIGIT+ cells in total NK and CD56dim NK cells were associated with poor RFS. Conclusions: TIGIT expression affected the diagnostic bone marrow-sited NK cell function and had prognostic significance in CBF-AML patients.

Background: Ruxolitinib and hydroxyurea are recommended by Chinese myelofibrosis guideline for splenomegaly. There is an unmet need for new treatments. Jaktinib, a novel JAK and AVCR1 inhibitor, showed promising activity on splenomegaly, anemia, and myelofibrosis symptoms in a phase 2 study (NCT03886415). Aims: This randomized double-blind phase 3 study was aimed to assess the efficacy and safety of jaktinib compared to hydroxyurea in patients with intermediate-2 or high risk myelofibrosis. Methods: Patients aged ≥18 with primary, post-polycythemia vera or post-essential thrombocythemia myelofibrosis, dynamic international prognostic scoring system (DIPSS) Int-2 or high risk, and no prior or ≤10 days' treatment with a JAK inhibitor were enrolled and randomly assigned (2:1) to receive jaktinib 100 mg bid plus hydroxyurea placebo or hydroxyurea 0.5 g bid plus jaktinib placebo, stratified by DIPSS risk status (Int-2 or high risk). One interim analysis was pre-specified to be conducted when the 70 patients completed the 24-week treatment or met the criteria for the treatment termination before week 24. The primary endpoint was the proportion of patients with a spleen volume reduction of ≥35% from baseline (SVR35) at week 24, measured by MRI/CT images and assessed by Independent Review Committee. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of patients with a ≥50% reduction in Total Symptom Score (TSS50), improvement of anemia, safety, etc. Results: This interim analysis (data cut-off: April 8, 2022) included 47 patients receiving jaktinib and 23 receiving hydroxyurea. 66.0% (jaktinib) and 69.6% (hydroxyurea) had a baseline hemoglobin <100 g/L. 59.6% (jaktinib) and 69.6% (hydroxyurea) were JAK2V617F positive. Patient baseline characteristics were well balanced between the two arms (Table 1). The SVR35 rates at week 24 were 72.3% for jaktinib vs. 17.4% for hydroxyurea (p≤0.0001). Jaktinib showed a consistent spleen response benefit over hydroxyurea across all subgroups analyzed (Figure 1). The best spleen response rates were 80.9% of jaktinib-treat patients vs. 26.1% of hydroxyurea-treated patients (p≤0.0001). The median maximum percentage change from baseline in spleen volume were -46.59% vs. -18.50%. The TSS50 rates at week 24 were 63.8% for jaktinib vs. 43.5% for hydroxyurea (p=0.1163). 5 of 7 jaktinib-treated and two of 5 hydroxyurea-treated patients who required red blood cell transfusion at baseline achieved a ≥50% decrease in red blood cell transfusion by week 24. One of four jaktinib-treated and 0 of three hydroxyurea-treated patients who were transfusion-dependent at baseline changed to transfusion-independent. In transfusion-independent patients with baseline hemoglobin ≤100 g/L, 39.3% for jaktinib and 15.4% for hydroxyurea had a ≥20 g/L hemoglobin increase. The most common grade ≥3 hematological treatment-emergent adverse events (TEAEs) were anemia (25.5% [jaktinib] vs. 43.5% [hydroxyurea]), thrombocytopenia (17.0% vs. 39.1%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). Most common non-hematological TEAEs were upper respiratory tract infection (21.3% vs. 21.7%), elevated bilirubin (12.8% vs. 26.1%), fever (12.8% vs. 21.7%) and diarrhea (10.6% vs. 21.7%), predominantly of grade 1 or 2. TEAEs leading to treatment discontinuation occurred in 8.5% of jaktinib and 17.4% of hydroxyurea.Summary/Conclusion: Jaktinib demonstrated significant clinical benefits over hydroxyurea in myelofibrosis patients for spleen response with improved symptom response and less cytopenias. Jaktinib may be a new treatment option for myelofibrosis patients, especially for those with anemia. Keywords: Myeloproliferative disorder, Myelofibrosis, Janus Kinase inhibitor, Phase III

7015 Background: Ruxolitinib and HU are recommended by Chinese MF guideline for splenomegaly. There is an unmet need for new treatments. Jaktinib, a novel JAK and AVCR1 inhibitor, showed promising activity on splenomegaly, anemia, and MF symptoms in a phase 2 study (NCT03886415). Here we present the interim results of a phase 3 study, which assessed the efficacy and safety of jaktinib compared to HU. Methods: Pts aged ≥ 18 with primary or post-ET/PV MF, DIPSS Int-2 or high risk, and no prior or ≤10 days’ treatment with a JAK inhibitor were enrolled and randomly assigned (2:1) to receive jaktinib 100 mg bid plus HU placebo or HU 0.5g bid plus jaktinib placebo, stratified by DIPSS risk status (Int-2 or high risk). One interim analysis was pre-specified to be conducted when 70 pts completed the week (wk) 24 visit or met the criteria for treatment termination before wk 24. The primary endpoint was the proportion of pts with a spleen volume reduction of ≥ 35% from baseline (SVR35) at wk 24, measured by MRI/CT images and assessed centrally. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with a ≥ 50% reduction in Total Symptom Score (TSS50), improvement of anemia, safety, etc. Results: This interim analysis (cut-off: April 8, 2022) included 47 pts receiving jaktinib and 23 receiving HU. 66.0% (jaktinib) and 69.6% (HU) had a baseline hemoglobin (Hb) < 100 g/L. 59.6% (jaktinib) and 69.6% (HU) were JAK2V617F positive. The SVR35 rates at wk 24 were 72.3% for jaktinib vs. 17.4% for HU ( p≤0.0001). The best spleen response rates were 80.9% of jaktinib-treat pts vs. 26.1% of HU-treated pts ( p≤0.0001). The median maximum percentage change from baseline in spleen volume were -46.59% vs. -18.50%. The TSS50 rates at wk 24 were 63.8% for jaktinib vs. 43.5% for HU ( p = 0.1163). 5 of 7 jaktinib-treated and two of 5 HU-treated pts who required RBC transfusion at baseline achieved a ≥50% decrease in RBC transfusion by wk 24. In transfusion-independent pts with baseline Hb ≤100 g/L, 39.3% for jaktinib and 15.4% for HU had a ≥20 g/L Hb increase. The most common grade ≥3 hematological treatment emergent adverse events (TEAEs) (jaktinib vs. HU) were anemia (25.5% vs. 43.5%), thrombocytopenia (17.0% vs. 39.1%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). Most common non-hematological TEAEs were upper respiratory tract infection (21.3% vs. 21.7%), elevated bilirubin (12.8% vs. 26.1%), fever (12.8% vs. 21.7%) and diarrhea (10.6% vs. 21.7%), predominantly of grade 1 or 2. TEAEs leading to treatment discontinuation occurred in 8.5% of jaktinib and 17.4% of HU. Conclusions: Jaktinib demonstrated significant clinical benefits over HU in MF pts for spleen response with improved symptom response and less cytopenias. Jaktinib may be a new treatment option for MF pts, especially for those with anemia. Clinical trial information: NCT04617028 .

Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.

In addition to genetic aberrations, accumulating evidence indicates that deregulation of histone methyltransferases, such as MMSET, EZH2 and KDM6A, plays crucial roles in the oncogenic transformation and development of multiple myeloma (MM). For example, overexpression of MMSET leading to a global increase in H3K36me2, is believed to be the driving force in the pathogenesis of t (4;14) MM. However, as the histone methyltransferase is responsible for H3K36me3, the role of SETD2 is not been known in myeloma.

Background Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Results Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 ( FLT3 -ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes. Conclusions The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3 -ITD mutations, may benefit from this regimen. Trial registration Clinical Trials, NCT02886559 . Registered 01 September 2016

In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-γ signaling and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

Endothelial microparticles (EMPs) upregulation has been observed in the pathological process of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) carried by EMPs in aGVHD after allo-HSCT are still open questions. Herein, we investigated the functional significance of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) delivered by EMPs in aGVHD. To address this question, in the present study, we performed a comprehensive analysis of the lncRNA NEAT1 expression and EMPs in aGVHD by a series of in vivo and in vitro experiments. We found that expressions of lncRNA NEAT1 in MPs were remarkably elevated in aGVHD mice than in non-aGVHD mice. Furthermore, the lncRNA NEAT1 levels in the MPs were remarkably higher than those in the plasma of the aGVHD mice. We then used TNF-α (100 ng/ml) to stimulate primary mouse aortic endothelial cells (MAECs) to shed EMPs, and the expression of lncRNA NEAT1 in the EMPs and their maternal cells was compared. The lncRNA NEAT1 levels in the EMPs produced by TNF-α-stimulated MAECs were significantly higher than that in both their maternal cells and non-stimulated EMPs. Our study demonstrates that EMPs could assemble and concentrate lncRNA NEAT1. Taken together, NEAT1 delivered by EMPs could be used as a diagnostic and prognostic surrogate marker for aGVHD, and its targeting could therefore represent a promising strategy for novel therapeutic options in life-threatening aGVHD after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

Emmanuel Kwateng Drokow Kai Sun Hafiz Abdul Waqas Ahmed Gloria Selorm Akpabla Juanjuan Song Mingyue Shi 1Department of Haematology, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital Henan, Zhengzhou, People’s Republic of China; 2Department of Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People’s Republic of China Purpose: Recent studies have validated microRNAs (miRNAs) as a diagnostic biomarker for haematological cancers. This study aimed to estimate the overall diagnostic accuracy of circulating miRNAs in haematological malignancies. Materials and Methods: Multiple databases (Google Scholar, PubMed, EMBASE, Cochrane Library,) were searched until 19 August 2017. Results: The meta-analysis included 50 studies from 20 publications. The diagnostic accuracy was assessed by pooled specificity, sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve area (AUC) by random effect model. We used QUADAS (Quality Assessment for diagnostic accuracy studies) to evaluate the quality of the included studies. To perform the metaanalysis, we used Meta-Disk 1.4, Revman 5.3 and Stata 12.0 software. High diagnostic accuracy was demonstrated, with a sensitivity of 0.81, a specificity of 0.85, a PLR of 5.28, an NLR of 0.22, a DOR of 30.39, and an AUC of 0.91. Subgroup analyses showed better outcomes for the African population, combined miRNAs and leukaemia patients compared with other subgroups. Conclusion: Our results indicated that circulating miRNAs especially combined miRNA can be used as a diagnostic marker in haematological cancers.

Purpose: Chimeric Antigen Receptor T(CAR-T) cell therapy is an immunotherapy approach used in treating cancer which has seen rapid development over the decades. It becomes the preferred treatment choice after patients have failed conventional chemotherapy. Methods: We conducted a meta-analysis in 320 patients from 14 studies to estimate the survival outcome, response rate and toxicity of autologous CD19 CAR-T cell therapy and predict other factors associated with a better prognosis. Results: The overall response rate was 71.88% (95% CI: 61.34-80.46%, p<0.01) and CRS toxicity was 60.15% (95% CI: 42.87-75.22%, p<0.01). Patients who received lymphodepletion was associated with a better response rate (77%, 95% CI: 67-83%; p-value = 0.001) in comparison to the other patients who did not (66%, 95% CI: 41-83%). Conclusion: Lymphodepletion regimen may play a crucial role in predicting the prognosis of patients with hematological malignancies. Lymphodepletion patients had better progression-free survival than those who did not.

Introduction: CD19-specific CAR-T cells have shown promise in the treatment of relapsed or refractory Ph+ ALL. It remains to be established whether allogeneic CAR-T cells have clinical activity in patients with relapsed CML lymphoid blast crisis with a history of allo-HSCT. Here we report our experience in two cases of allogeneic CAR-T cell therapy for treatment of relapse after allo-HSCT in patients with refractory CML lymphoid blast crisis.