Efficacy, safety, and survival findings after long-term follow-up of ZGJAK002: A phase 2 study comparing jaktinib at 100 mg twice daily (BID) and 200 mg once daily (QD) in patients with myelofibrosis.

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.

N6-methyladenosine-induced miR-182-5p promotes multiple myeloma tumorigenesis by regulating CAMK2N1.

Methyltransferase like 3 (METTL3) has been reported to promote tumorigenesis of multiple myeloma (MM), however, the molecular mechanism still needs further research. The N6-methyladenosine (m6A) level in tissues or cells was measured by m6A kit and dot blot assay. The mRNA and protein expression were detected by quantitative real-time PCR (RT-qPCR) and Western blot, respectively. The cell counting kit-8 and colony formation assay were used to detect the cell proliferation. Coimmunoprecipitation (Co-IP) experiment verified the binding of two proteins. The luciferase reporter experiment demonstrated the targeted binding of miR-182-5p and CaMKII inhibitor 1 (CAMK2N1). More importantly, tumor growth was measured in xenograft mice. Our data showed that the expression of METTL3 was significantly increased in MM patients' samples and MM cells. METTL3 overexpression promoted MM cells proliferation, and METTL3 knockdown inhibited MM cells proliferation. Mechanically, METTL3-dependent m6A participated in DiGeorge syndrome critical region 8 (DGCR8)-mediated maturation of pri-miR-182. Upregulation of miR-182-5p further enhanced the promoting proliferation effect of METTL3 overexpression on MM cells. Moreover, the luciferase reporter gene experiment proved that miR-182-5p targetedly regulated CAMK2N1 expression. Xenograft tumor in nude mice further verified that METTL3 promoted MM tumor growth through miR-182/CAMK2N1 signal axis. In summary, the METTL3/miR-182-5p/CAMK2N1 axis plays an important role in MM tumorigenesis, which may provide a new target for MM therapy.

Decitabine in patients with myelodysplastic syndromes: A multi-center, open-label, dose comparison trial.

BACKGROUND: The hypomethylating agent decitabine is the standard therapy for intermediate or high risk myelodysplastic syndrome (MDS). METHODS: In this trial, 191 adult patients with intermediate/high risk MDS (IPSS score ≥ 0.5) randomly received decitabine using a standard regimen (20 mg/m2 /day for 5 consecutive days; n = 94) or an extended regimen with lower daily dose (12 mg/m2 /day for 8 consecutive days; n = 97) every 4 weeks, for a total of 4 cycles. RESULTS: The median follow-up was 14 months (range 2-36). The primary end point of overall response rate in the intent-to-treat analysis was 41.5% and 38.1% in the standard and extended dosing arms, respectively (p = 0.660). Complete remission and marrow complete remission also did not differ between the two arms. Cytopenia was the most frequent adverse event (76.4%). The median duration of neutropenia per cycle did not differ between the two arms during the first two cycles, but significantly shorter in the extended dosing arm in the third cycle (8.5 vs. 15.5 days, p = 0.049) and in the fourth cycle (8 vs. 14 days, p = 0.294). CONCLUSION: The 5-day 20-mg/m2 /day and 8-day 12-mg/m2 /day decitabine regimens have similar efficacy and safety in patients with intermediate or high risk MDS.

Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.

Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC50 = 4.7 nM), which displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. The crystal structure demonstrates that 16 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. 16 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC50 = 28 nM). In addition, it inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants. In vivo, 16 inhibits 2-HG level in a HT1080 xenograft mouse model. Our study suggested that 16 would be a new pharmacological tool to study IDH1 mutant-related pathology and the covalent binding mode provided a novel approach for designing irreversible IDH1 inhibitors.

Recombinant human thrombopoietin (rhTPO) of different dosing regimens for refractory/relapsed primary immune thrombocytopenia: a multicenter, randomized controlled trial and pharmacokinetics study.

Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count ≤30 × 109/L or >30 × 109/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 × 109/L, interquartile range [IQR] 23.0-295.0 × 109/L), followed by the 30000-U QOD group (57.5 × 109/L, IQR 9.0-190.0 × 109/L) (ANCOVA P < .001; P = .266 with baseline count as a covariate). The TRR on day 14 was also the highest in the 15000-U QD group (63.2%), followed by the 30000-U QOD group (59.7%). The rate of grade 3 and above adverse events did not differ among the four groups. There were no new safety concerns. All 4 regimens are safe and well-tolerated. The 30000-U QOD regimen is practically indistinguishable in efficacy to the 15000-U QD regimen.

What is the context? Relative thrombopoietin deficiency is implicated in primary immune thrombocytopenia (ITP), which is characterized by increased platelet destruction and impaired megakaryopoiesis.Patients who are innately unresponsive to or have relapsed after glucocorticoid treatment have limited treatment options.Recombinant human thrombopoietin (rhTPO) improves treatment response of primary ITP patients when added to high-dose dexamethasone.What is new? This trial sought to identify an optimal dosing regimen of rhTPO for patients who had failed or relapsed after glucocorticoid therapy.Of the 4 regimens, once daily 15000 U rhTPO for 14 injections yielded the greatest median increase in platelet count (167.5 × 10⁹/L) from baseline and attained the highest total response rate on day 14 (63.2%).30000 U rhTPO once every other day for 7 injections was effective in rapidly increasing platelet counts in the first 7 days.All 4 regimens were safe and well-tolerated.What is the impact? The 30000 U rhTPO once every other day regimen may offer an effective and safe regimen with less frequent injections, but future trials with longer follow-up are needed.

[Corrigendum] Kinesin family member 2A acts as a potential prognostic marker and treatment target via interaction with PI3K/AKT and RhoA/ROCK pathways in acute myeloid leukemia.

Following the publication of the above article, the authors have realized that an error was made during the compilation of Fig. 9, as it appears on p. 10; essentially, the ß-actin bands featured in Fig. 9A were inadvertently copied across to Fig. 9B. The revised version of Fig. 9, now showing the correct ß-actin bands for Fig. 9B, is shown on the next page. All the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Oncology Reports for granting them the opportunity to publish this. The authors regret their oversight in allowing this error to be included in the published paper, and apologize to the readership for any inconvenience caused. [Oncology Reports 47: 18, 2022; DOI: 10.3892/or.2021.8229].

Anti-CD19 chimeric antigen receptor T-cell followed by interferon-α therapy induces durable complete remission in donor cell-derived acute lymphoblastic leukemia: A case report.

Donor cell-derived leukemia (DCL) is a special type of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with DCL generally have a poor prognosis due to resistance to conventional chemotherapy. Here, we report a case of donor cell-derived acute lymphoblastic leukemia after umbilical cord blood transplantation. The patient didn't respond to induction chemotherapy. She then received anti-CD19 CAR-T cell therapy and achieved MRD-negative complete remission (CR). However, MRD levels rose from negative to 0.05% at 5 months after CAR-T cell therapy. Higher MRD levels were significantly associated with an increased risk of leukemia recurrence. Afterward, preemptive interferon-α treatment was administrated to prevent disease recurrence. To date, the patient has maintained MRD-negative CR for 41 months. Our results suggested that anti-CD19 CAR-T cells followed by interferon-α therapy are effective in treating donor cell-derived acute lymphoblastic leukemia. This report provides a novel strategy for the treatment of DCL.

Safety and efficacy of jaktinib in the treatment of Janus kinase inhibitor-naïve patients with myelofibrosis: Results of a phase II trial.

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.

iRGD-modified exosomes-delivered BCL6 siRNA inhibit the progression of diffuse large B-cell lymphoma.

Clinical applications of siRNA therapeutics have been limited by the immunogenicity of the siRNA and low efficiency of siRNA delivery to target cells. Recently, evidence have shown that exosomes, endogenous nano-vesicles, can deliver siRNA to the tumor tissues in mice. Here, to reduce immunogenicity, we selected immature dendritic cells (DCs) to produce exosomes. In addition, tumor targeting was achieved by engineering the DCs to express exosomal membrane protein (Lamp2b), fused to av integrin-specific iRGD peptide (CRGDKGPDC). Next, iRGD targeted exosomes (iRGD-Exo) were isolated from the transfected DCs, and then the isolated exosomes were loaded with BCL6 siRNA by electroporation. Our results found that integrin (αvß3) receptors were highly expressed on OCI-Ly8 cells. In addition, iRGD-Exo showed high targeting ability with avß3 integrins positive OCI-Ly8 cells. Significantly, iRGD-Exo loaded with BCL6 siRNA suppressed DLBCL cell proliferation in vitro. Furthermore, intravenously injected iRGD-Exo delivered BCL6 siRNA to tumor tissues, resulting in inhibition of tumor growth in DLBCL. Meanwhile, exosomes mediated BCL6 siRNA delivery did not exhibit appreciable toxicity in mice. Collectively, our study demonstrates a therapeutic potential of exosomes as a promising vehicle for RNAi delivery to treat DLBCL.

Application of High-Efficiency Cell Expansion and High-Throughput Drug Sensitivity Screening for Leukemia Treatment.

This study is to assess the clinical value of in vitro primary cell high-efficiency expansion and high-throughput drug sensitivity screening (HEHDS) system in leukemia, and we evaluated a cohort of 121 patients with acute myeloid leukemia (AML) and 27 patients with acute lymphoblastic leukemia (ALL) using HEHDS. Bone marrow aspirates were collected from patients with leukemia. Purified leukemic cancer cells were obtained, cultured, and screened with a panel of 247 FDA-approved compounds by HEHDS technology. Ninety-six patients received HEHDS-guided therapy while 52 patients who were subjected to physician directed therapy served as controls. ALL patients who received treatment guided by HEHDS showed higher rate of complete remission (CR) than that of patients in the non-HEHDS group (90.91% vs. 56.25%). Similarly, AML patients received HEHDS-guided therapy were found to have greater CR rate, when compared with patients who received physician-directed therapy (45.88% vs. 25%). There was a significantly higher rate of CR in HEHDS-guided therapy group compared to the non-HEHDS group. The application of HEHDS could be beneficial for leukemia treatment.

Delayed Diagnosis and Multi-TKI Intolerance: A Case Report of CML Concurrent With COVID-19.

Introduction: The hematological manifestations of corona virus disease 2019 (COVID-19) can confound the diagnosis and therapy of other diseases. In this paper, we firstly reported a case of chronic myeloid leukemia (CML) of delayed diagnosis and intolerance to tyrosine kinase inhibitors (TKIs) concurrent with COVID-19. Case Presentation: A 56-year-old female was diagnosed as COVID-19 with no obvious leukocytosis [white blood cell (WBC), ≤17 × 109/L] or splenomegaly until ablation of the virus. Bone marrow aspiration was conducted to establish the diagnosis of CML. She accepted an adjusted dosage of imatinib initially and had to suspend it after myelosuppression (day 41). After hematopoietic therapy, imatinib was given again (day 62), but she was still non-tolerant, and nilotinib at 150 mg twice a day was prescribed from day 214. At just about 4 weeks later, nilotinib was discontinued due to myelosuppression. Then, it was reduced to 150 mg per day and was re-initiated (day 349), but she was still non-tolerant to it. Similarly, from day 398, flumatinib at 200 mg per day was tried, but she was non-tolerant. Her white blood cell or platelet count fluctuated markedly with poor therapeutic response. Considering that she was relatively tolerant and responsive to imatinib, the medication was re-initiated at 200 mg and reduced to 100 mg per day. Her follow-up revealed stable WBC and PLT counts. The latest BCR-ABL-210/ABL was decreased to 0.68% at about 6 months after imatinib was re-initiated, which means an improved response. Conclusion: The offset effect between CML and SARS-CoV-2 infection was supposed to be the underlying mechanism for the absence of leukocytosis or splenomegaly. The impact of immune network by SARS-CoV-2 preserved and disrupted the patient's response to TKIs despite the virus' ablation. We suggest that a continued elevation of basophils may be a useful indicator for CML concurrent with COVID-19, and individualized treatment with adjusted dosage and suitable type of TKIs should be considered to improve the patient's health outcome.

[Effect of rhTPO and rhIL-11 on Thrombocytopenia after Chemotherapy in Leukemia].

OBJECTIVE: To analyze and compare the efficacy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of thrombocytopenia after chemotherapy in acute leukemia patients. METHODS: 180 patients with acute leukemia complicated with thrombocytopenia after chemotherapy in the First Affiliated Hospital of Anhui Medical University were analyzed retrospectively. Among them, 50 patients who treated with rhTPO and did not receive platelet transfusion were set as group A, 50 patients treated with rhTPO and receive platelet transfusion were set as group B, Forty patients treated with rhIL-11 without platelet transfusion were set as group C, Forty patients who treated with rhIL-11 and received platelet transfusion were set as group D. The duration of PLT below 20×109/L, the days it takes for PLT to recover to more than 100×109/L, and the incidence of different bleeding degrees were compared among several groups. RESULTS: The duration of PLT<20×109/L in group A(3.72±1.14 d) was significantly shorter than that in group C(4.93±1.33 d) (P<0.001), and there was no significant difference from group B (P>0.05). The duration of PLT<20×109/L in group B(3.06±0.91 d) was significantly shorter than that in group D(4.65±0.98 d) (P<0.001), while the difference in duration of days between group C and D was not statistically significant (P>0.05). The times for PLT to recover to 100×109/L in group A(13.46±1.67 d) were significantly shorter than that in group C(16.85±2.13 d) (P<0.05), but there was no significant difference from group B (P>0.05). The time required for PLT to recover to 100×109/L in group B(13.36±1.49 d) were significantly shorter than that in group D(16.18±1.78 d) (P<0.05), while the difference in the days required for group C and group D was not statistically significant (P>0.05). The incidence of high bleeding risk in group B was significantly lower than that in group A (22% vs 44%, P<0.05), the incidence of high bleeding risk in group D was significantly lower than that in group C (32% vs 65%, P<0.05), and the incidence of high bleeding risk in group A was significantly lower than that in group C (44% vs 65%, P<0.05). The incidence of high bleeding risk in group B(22%) was lower than that in group D(32.5%), and the difference was not statistically significant (P>0.05). CONCLUSION: In the treatment of acute leukemia patients with thrombocytopenia after chemotherapy, compared with rhIL-11, rhTPO can significantly shorten the duration for patients in a status with extremely low levels of PLT and the recovery time of PLT to normal range. In addition, PLT transfusion cannot speed up the time for patients to raise platelets to a safe range, nor can it shorten the duration of low PLT levels, but it can reduce the incidence of high bleeding risk events.

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes.

Background: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) expresses on leukemic stem and progenitor populations of non-M3 acute myeloid leukemia (AML) as well as T lymphocytes. TIM-3 is thought to be involved in the self-renewal of leukemic stem cells and the immune escape of AML cells, however its correlation with AML prognosis is still controversial and worthy of further investigation. Methods: we simultaneously assessed TIM-3 expression levels of leukemic blasts and T lymphocytes in the bone marrow of de novo AML patients using flow cytometry. The correlations of TIM-3 expression between leukemic blasts and T lymphocytes and the correlations of TIM-3 expression with various patient parameters were analyzed. In addition, the Cancer Genome Atlas (TCGA) data of AML patients were acquired and analyzed to verify the results. Results: TIM-3 expression of CD34+ leukemic blasts (R2 = 0.95, p<0.0001) and CD34+CD38- leukemic stem cells (R2 = 0.75, p<0.0001) were significantly and positively correlated with that of the whole population of leukemic blasts. In addition, TIM-3 expression level of leukemic blasts correlated significantly and positively with that of CD8+ (R2 = 0.44, p<0.0001) and CD4+ (R2 = 0.16, p=0.0181) lymphocytes, and higher TIM-3 expression of leukemic blasts was significantly associated with a greater proportion of peripheral CD8+ T lymphocytes (R2 = 0.24, p=0.0092), indicating that TIM-3 on leukemic blasts might alter adaptive immunity of AML patients. Regarding clinical data, the presence of core binding factor (CBF) translocations was significantly correlated with higher TIM-3 expression of leukemic blasts (CBF versus non-CBF, median 22.78% versus 1.28%, p=0.0012), while TIM-3 expression levels of leukemic blasts were not significantly associated with the remission status after induction chemotherapy (p=0.9799), overall survival (p=0.4201) or event-free survival (p=0.9873). Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660). Conclusion: TIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.

LncRNA FIRRE stimulates PTBP1-induced Smurf2 decay, stabilizes B-cell receptor, and promotes the development of diffuse large B-cell lymphoma.

Sustained expression of B-cell receptor (BCR) critically contributes to the development of diffuse large B-cell lymphoma (DLBCL). However, little is known on the mechanism regulating BCR expression. In the present study, we explored the biological significance of functional intergenic repeating RNA element (FIRRE) in DLBCL and its regulation on BCR. Functional impacts of FIRRE on cell viability, transformation, and apoptosis were examined by MTT, colony formation, and flow cytometry, respectively. The interaction between FIRRE and polypyrimidine tract binding protein 1 (PTBP1) was identified by RNA pull-down and verified using RNA immunoprecipitation (RIP) assays. The effects of FIRRE and PTBP1 on Smurf2 mRNA were examined by RIP, RNA pull-down, and mRNA stability assays. Smurf2-mediated BCR ubiquitination was investigated using co-immunoprecipitation, ubiquitination, and protein stability assays. In vivo, xenograft models were used to assess the impacts of targeting FIRRE on DLBCL growth. FIRRE was specifically up-regulated in and essentially maintained multiple malignant behaviors of BCR-dependent DLBCL cells. Through the interaction with PTBP1, FIRRE promoted the mRNA decay of Smurf2, a ubiquitin ligase for the degradation BCR protein. Targeting FIRRE was sufficient to regulat Smurf2 and BCR expressions and inhibit DLBCL malignancy both in vivo and in vitro. FIRRE-PTBP1 interaction, by simulating Smurf2 mRNA decay and stabilizing BCR, promotes the development of DLBCL. Consequently, targeting this signaling mechanism may provide therapeutic benefits for DLBCL.

CDK12 activates MYC to repress miR-28-5p/EZH2 and amplifies tonic BCR signaling to promote the development of diffuse large B-cell lymphoma.

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes. However, its regulatory role in the progression of diffuse large B-cell lymphoma (DLBCL), which is the most prevalent subtype of non-Hodgkin lymphoma (NHL), is still elusive and controversial.The expression of CDK12 was detected by immunohistochemistry (IHC), RT-qPCR was performed to detect miR-28-5p expression of OCI-LY3 and SU-DHL-4 cells. MTT and soft agarose colony formation assays were used to detect cell proliferation. The cell apoptosis was determined by flow cytometry. The protein expressions changes of MYC, EZH2 and the biomarkers of BCR signaling were also detected. A subcutaneous transplantation tumor model of OCI-LY3 cells in nude mice was established to evaluate anticarcinogenic activities of CDK12 knockdown. Elevated expression of CDK12 was observed while miR-28-5p was downregulated in DLBCL tissues. CDK12 knockdown or miR-28-5p overexpression could inhibit proliferation and promote apoptosis of DLBCL cells. miR-28-5p inhibition could reverse the effect of CDK12 knockdown on proliferation and apoptosis of DLBCL cells. In addition, CDK12 knockdown could inhibit DLBCL tumor growth in the mice model. CDK12 activated MYC to repress miR-28-5p/EZH2 and amplified tonic BCR signaling to promote the development of DLBCL, which might provide potential therapeutic targets for future therapeutic intervention in DLBCL.

Efficacy and safety of CD22-specific and CD19/CD22-bispecific CAR-T cell therapy in patients with hematologic malignancies: A systematic review and meta-analysis.

Background: CD22 single and CD19/CD22 bispecific targeted chimeric antigen receptor T (CAR-T) cell therapy are promising immunotherapy modalities for the treatment of hematologic malignancies. The aim of this study was to assess the efficacy and safety of CD22 and CD19/CD22 targeted CAR-T cell therapy by summarizing the existing evidence. Methods: Electronic databases including PubMed, Embase, and Scopus were comprehensively searched from inception up to November 30, 2022. Pooled response rates and minimal residual disease (MRD) negative response rates, cytokine release syndrome (CRS) rates and neurotoxicity rates were calculated. Subgroup analysis was performed based on the type of immunotherapy. Results: Ten clinical studies including 194 patients with hematologic malignancies were included after a systematical screening of literature. The pooled complete response (CR) rates of CD22 and CD19/CD22 CAR-T cell therapy for relapsed or refractory B-cell lymphoblastic leukemia (B-ALL) were 0.75 (95% CI: 0.60 - 0.88) and 0.87 (95% CI: 0.76 - 0.96). The overall MRD negative response rates of CD22 and CD19/CD22 CAR-T were 0.54 (95% CI: 0.42 - 0.66) and 0.91 (95% CI: 0.47 - 0.88). Pooled CRS rates of CD22 targeted and CD19/CD22 targeted immunotherapy were 0.92 (95% CI: 0.82 - 0.98) and 0.94 (95% CI: 0.82 - 1.00), respectively. Conclusion: Both CD22 and CD19/CD22 CAR-T immunotherapy demonstrated favorable efficacy and acceptable adverse events in the treatment of hematologic malignancies. Well-designed and large sample-sized clinical trials are warranted.

Kinesin family member 2A acts as a potential prognostic marker and treatment target via interaction with PI3K/AKT and RhoA/ROCK pathways in acute myeloid leukemia.

KIF2A has been shown to be involved in the regulation of AML pathology, however, the mechanistic role of KIF2A in AML has not been fully identified. The present study aimed to identify the underlying mechanism of KIF2A regulation of AML cell function and chemosensitivity. A total of 58 patients with AML and 30 healthy subjects were enrolled for clinical analysis. AML cells (KG­1 and Kasumi­1) were transfected with KIF2A or control small interfering (si)RNA. PI3K/AKT pathway activator (740 Y­P) and RhoA overexpression plasmid were added to rescue the effect of KIF2A siRNA. Cell proliferation, apoptosis, chemosensitivity to ADR and AraC, expression levels of mRNA/proteins associated with PI3K/AKT and RhoA/ROCK pathways were measured by Cell Counting Kit­8, flow cytometry, reverse transcription­quantitative PCR and western blotting. KIF2A was overexpressed, and correlated with higher levels of bone marrow blast, poor risk classification, lower treatment response and unfavorable survival profile in patients with AML. KIF2A siRNA inhibited proliferation but enhanced apoptosis and chemosensitivity to ADR and AraC in KG­1 and Kasumi­1 cells, which also inactivated PI3K/AKT and RhoA/ROCK pathways. Subsequent rescue experiments showed that 740 Y­P and RhoA overexpression plasmid promoted cell survival and decreased chemosensitivity, which reversed the effect of KIF2A siRNA in KG­1 and Kasumi­1 cells. KIF2A was correlated with worse clinical features and survival in patients with AML; its knockdown promoted apoptosis and chemosensitivity by inactivating PI3K/AKT and RhoA/ROCK signaling pathways in AML cells. These data suggested KIF2A may be a potential prognostic marker and treatment target for AML management.

Dose tapering to withdrawal stage and long-term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open-label extension study.

BACKGROUND: The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). OBJECTIVE: This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. PATIENTS/METHODS: Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. RESULTS: Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30 × 109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n = 339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. CONCLUSION: The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

LncRNA HCP5 acts as a miR-128-3p sponge to promote the progression of multiple myeloma through activating Wnt/ß-catenin/cyclin D1 signaling via PLAGL2.

BACKGROUND: Although long non-coding RNA (lncRNA) HCP plays essential roles in human cancers, its function and mechanism in multiple myeloma (MM) have not crystallized. METHODS: HCP5 level in MM was assessed through qRT-PCR. A series of functional investigations were conducted to evaluate the influences of HCP5 on proliferation and apoptosis. Bioinformatics analysis and RIP/RNA pull-down assays were carried out to determine the relationships among HCP5, miR-128-3p, and PLAGL2. Relative protein level was determined through Western blot. A xenograft tumor model was applied for validating the roles of HCP5/miR-128-3p/PLAGL2 axis in vivo. RESULTS: HCP5 was significantly increased in MM. HCP5 knockdown effectively thwarted the proliferative rate and cell cycle of MM cell lines and suppressed tumor growth. HCP5 regulated PLAGL2 expression by sponging miR-128-3p. PLAGL2 overexpression effectively rescued cells from influences by sh-HCP5 on cell proliferative and apoptotic rates. Additionally, HCP5 knockdown significantly inhibited Wnt/ß-catenin/cyclin D1 signaling, and these effects were eliminated by PLAGL2 overexpression. CONCLUSION: Our study revealed that HCP5/miR-128-3p/PLAGL2 is closely correlated to MM development by modulating Wnt/ß-catenin/cyclin D1 signaling. HCP5 promoted cell proliferation and tumor formation of MM cells by activating the Wnt/ß-catenin/CCND1 signaling pathway by sponging miR-128-3p to increase PLAGL2 expression.

Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective.

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.