Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Anti-Tumor Effects in T-Cell Acute Lymphoblastic Leukemia.

We report on the antileukemic activity of homoharringtonine (HHT) in T-ALL. We showed that HHT inhibited NOTCH/MYC pathway and induced a significantly longer survival in T-ALL mouse and patient-derived xenograft models, therefore supporting HHT as a promising agent for T-ALL.

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.

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: A single-arm, open-label, phase 2, multicenter study.

Although ruxolitinib improves splenomegaly and constitutional symptoms in patients with myelofibrosis (MF), a substantial proportion of patients discontinue ruxolitinib because of intolerance. This phase 2 trial investigated the safety and efficacy of jaktinib, a novel JAK inhibitor in patients with ruxolitinib-intolerant MF. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profiles. Between December 18, 2019, and November 24, 2021, 51 patients were enrolled, 45 treated with jaktinib 100 mg bid (100 mg bid group) and six received non-100 mg bid doses (non-100 mg bid group). The SVR35 at week 24 in the 100 mg bid group was 43.2% (19/44, 95% CI 29.7%-57.8%). There were 41.9% (13/31) of transfusion-independent patients with hemoglobin (HGB) ≤100 g/L who had HGB elevation ≥20 g/L within 24 weeks. The proportion of patients with a ≥50% decrease in the total symptom score (TSS 50) at week 24 was 61.8% (21/34). The most commonly reported grade ≥3 treatment-emergent adverse events (TEAEs) in the 100 mg bid group were anemia 31.1%, thrombocytopenia 22.2%, and infectious pneumonia 17.8%. A total of 16 (35.6%) in the 100 mg bid group had serious adverse events, and 4 (8.9%) were considered possibly drug related. These results indicate jaktinib can provide a treatment option for patients with MF who are intolerant to ruxolitinib.

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study.

Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3-6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high-risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib-refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%-49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%-56.3%) in the intermediate 2 or high-risk group. A total of 50% (8 of 16) transfusion-independent patients with hemoglobin (HGB) <100 g/L at baseline had HGB elevation ≥20 g/L within 24 weeks. Furthermore, 46.4% (13 of 28) of patients had a ≥ 50% decrease in the total symptom score (TSS 50) at week 24. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (32.4%), anemia (32.4%), and leukocytosis (20.6%). In total, 13 (38.2%) of 34 patients had serious adverse events (SAE), of which drug-related SAEs were found in 5 patients (14.7%). These results indicate that jaktinib can be a promising treatment option for patients with MF who have either become refractory to or relapsed after ruxolitinib treatment.

Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy.

Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.

Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages.

Bone marrow-derived macrophages (BMMs) treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), differentiate into GM-CSF-induced mouse bone marrow-derived macrophages (GM-BMMs) or M-CSF-induced mouse bone marrow-derived macrophages (M-BMMs), which have an M1 or M2 profile, respectively. GM-BMMs produce large amounts of proinflammatory cytokines and mediate resistance to pathogens, whereas M-BMMs produce antiinflammatory cytokines that contribute to tissue repair and remodeling. M-BMMs stimulated with lipopolysaccharide (LPS) are in an antiinflammatory state, with an IL-12(low) IL-10(high) phenotype. However, the regulation of this process remains unclear. Klf10 belongs to the family of Krüppel-like transcription factors and was initially described as a TGF-ß inducible early gene 1. IL-12p40 is upregulated in LPS-stimulated M-BMMs from Klf10-deficient mice, but downregulated during Klf10 overexpression. Klf11, another member of the Krüppel-like factor family, can also repress the production of IL-12p40. Furthermore, Klf10 binds to the CACCC element of the IL-12p40 promoter and inhibits its transcription. We have therefore identified Klf10 as a transcription factor that regulates the expression of IL-12p40 in M-BMMs.

Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy.

Arsenic trioxide (ATO) is an effective therapy for relapsed acute promyelocytic leukemia (APL) patients; however, the optimal treatment strategy remains unclear, and knowledge of the prognostic factors is still limited. We retrospectively analyzed the outcomes of 64 consecutive first relapsed APL patients (12 with molecular relapse and 52 with hematologic relapse). Patients received re-induction with intravenous ATO-based regimens. Patients who achieved a CR2 were offered further courses of alternating ATO/conventional chemotherapy with or without stem cell transplantation (SCT). With a median follow-up of 27 months (range, 6-57) in the molecular relapsed subgroup, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 81.5 % and 100 %, respectively. With a median follow-up of 38 months (range, 0-129) in the hematologic relapse group, the 3-year RFS and OS rates were 57.1 % and 72.1 %, respectively. Furthermore, in the hematologic relapse group, we compared the outcome between relapsed patients after previous ATO therapy (n = 20) with those who did not receive prior ATO therapy (n = 32). The CR2 rate was 80 % (16/20) vs. 93.8 % (30/32), (p = 0.189). However, the relapse rate was 68.8 % (11/16) vs. 33.3 % (10/30), (p = 0.03). The 4-year OS rate was 62.4 % vs. 71.2 %, (p = 0.816), and the 4-year RFS rate was 29.8 % vs. 66.2 % (p = 0.023). The results indicate that, irrespective of frontline therapy with ATO, salvage therapy with an ATO-based regimen remains effective. However, the long-term survival for those patients who received previous ATO-based treatment was inferior compared to those who did not receive prior ATO. In addition, the alternating ATO/chemotherapy strategy can be a post-remission treatment option in a subset of patients.

Spred1 deficit promotes treatment resistance and transformation of chronic phase CML.

Spred1 is highly expressed in normal hematopoietic stem cells (HSCs). Lack of Spred1 function has been associated with aberrant hematopoiesis and acute leukemias. In chronic myelogenous leukemia (CML), Spred1 is reduced in patients with accelerated phase (AP) or blast crisis (BC) CML, thereby suggesting that deficit of this protein may contribute to disease transformation. In fact, Spred1 knockout (KO) in SCLtTA/BCR-ABL CML mice either globally, or restricted to hematopoietic cells (i.e., HSCs) or to endothelial cells (ECs), led to transformation of chronic phase (CP) CML into AP/BC CML. Upon BCR-ABL induction, all three Spred1 KO CML models showed AP/BC features. However, compared with global Spred1 KO, the AP/BC phenotypes of HSC-Spred1 KO and EC-Spred1 KO CML models were attenuated, suggesting a concurrent contribution of Spred1 deficit in multiple compartments of the leukemic bone marrow niche to the CML transformation. Spred1 KO, regardless if occurred in HSCs or in ECs, increased miR-126 in LSKs (Lin-Sca-1+c-Kit+), a population enriched in leukemic stem cells (LSCs), resulting in expansion of LSCs, likely through hyperactivation of the MAPK/ERK pathway that augmented Bcl-2 expression and stability. This ultimately led to enhancement of Bcl-2-dependent oxidative phosphorylation that supported homeostasis, survival and activity of LSCs and drove AP/BC transformation.

Characteristics of chemotherapy-induced diabetes mellitus in acute lymphoblastic leukemia patients.

Acute lymphocytic leukemia (ALL) is one of the most common malignancies, especially in young people. Combination chemotherapy for ALL typically includes corticosteroids (Kantarjian et al., 2000). Hyperglycemia is a well-recognized complication of corticosteroids, and chemotherapy-induced diabetes (CID) is not uncommon (27.5%-37.0%) during the treatment of ALL (Hsu et al., 2002; Weiser et al., 2004; Alves et al., 2007). Besides the effect of corticosteroids, potential factors triggering hyperglycemia in ALL also include direct infiltration of the pancreas by leukemia cells and ß cell dysfunction induced by chemotherapeutic agents such as L-asparagine (Mohn et al., 2004).

Clinical features and treatment of 7 Chinese TAFRO syndromes from 96 de novo Castleman diseases: a 10-year retrospective study.

BACKGROUND: Castleman disease (CD) is a rare polyclonal lymphoproliferative disorder with unknown etiology. TAFRO syndrome is now regarded as a specific subtype of CD, and is still a huge challenge for clinicians. METHODS: To clarify the clinical features and management of TAFRO syndrome in China, we retrospectively analyzed 96 patients with HIV-negative CD (52 with unicentric CD and 44 with multicentric CD), who were diagnosed and treated at our center between 2008 and 2017. Specially, we systematically reviewed the 7 TAFRO syndrome cases based on the 2015 criteria proposed by Masaki. RESULTS: Among the 7 cases, there were 3 men and 4 women, and the median age was 53 years. The main symptoms included thrombocytopenia (7/7), anasarca (7/7), fever (4/7), renal dysfunction (7/7), and organomegaly (6/7). One patient was treated with corticosteroid monotherapy, one received RD (Rituximab, dexamethasone), and 5 received CHOP/COP like chemotherapy as first-line treatment, 2 of the 5 combined with Rituximab. Four patients needed hemodialysis or CRRT because of progressive renal failure. The outcome for TAFRO syndrome was significantly worse compared to other types of CD. Although 3 patients improved after early treatment, 4 patients died due to disease progression, and only one patient achieved complete resolution of all the symptoms after changing to lenalidomide based regimen. CONCLUSIONS: This study reveals that TAFRO syndrome is more severe and has more systemic symptoms than other iMCD, most cases need active treatment, and their prognoses are poor. Lenalidomide based regimen may be as a promising new therapy for TAFRO syndrome.

miR-221-3p Delivered by BMMSC-Derived Microvesicles Promotes the Development of Acute Myelocytic Leukemia.

Objective: The study aims to investigate the effects of miR-221-3p in bone marrow mesenchymal stem cell (BMMSC)-derived microvesicles (MVs) on cell cycle, proliferation and invasion of acute myelocytic leukemia (AML). Methods: Bioinformatics was used to predict differentially expressed miRNAs (DEmiRNAs) in AML. The morphology of BMMSC-derived MVs was observed under an electron microscope, and the positional relation of MVs and OCI-AML2 cells was observed by a fluorescence microscope. MTT, Transwell, and flow cytometry assays were used to analyze the effects of MVs on OCI-AML2 cells. The targeted relationship between miR-221-3p and CDKN1C was detected by dual luciferase assay. Results: It was verified that miR-221-3p promoted the proliferation, invasion and migration of OCI-AML2 cells, and induced the cell cycle arrest in G1/S phase as well as inhibited cell apoptosis. Further studies showed that MVs promoted the proliferation, migration and invasion of AML, and induced the cell cycle arrest in G1/S phase through miR-221-3p. It was confirmed that miR-221-3p can directly target CDKN1C to regulate cell cycle, proliferation and invasion of AML. Conclusion: miR-221-3p in BMMSC-derived MVs regulated AML cell cycle, cell proliferation and invasion through targeting CDKN1C. miR-221-3p and CDKN1C were considered to be potential targets and biomarkers for the treatment of AML in clinic.

Expression of hypoxia-inducible factor-1a predicts benefit from rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in diffuse large B-cell lymphoma.

Hypoxia-inducible factor-1α (HIF-1α) has been identified as an unfavorable prognostic factor in most solid tumors. However, HIF-1α was suggested to predict improved survival in Western patients with diffuse large B-cell lymphoma (DLBCL) under rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment. We studied HIF-1α protein expression by immunohistochemical staining of 155 paraffin-embedded specimens from Chinese patients with DLBCL treated with R-CHOP or CHOP. Results were correlated with patient outcome. HIF-1α expression had no impact on survival for the patients treated with CHOP. In the R-CHOP-treated group, however, HIF-1α expression was significantly correlated with superior OS and EFS (P = 0.048 and 0.040, respectively). Moreover, HIF-1α expression maintained independent prognostic value for OS (RR, 0.41; 95% CI, 0.19-0.92; P = 0.030) and EFS (RR, 0.53; 95% CI, 0.31-0.90; P = 0.020) when it was adjusted by IPI stratification. Therefore, HIF-1α expression benefits from R-CHOP in DLBCL.

Homoharringtonine targets Smad3 and TGF-ß pathway to inhibit the proliferation of acute myeloid leukemia cells.

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-ß pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-ß pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-ß pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT.

[Efficacy of HAA regimen in the treatment of 64 patients with refractory/relapsed acute myeloid leukemia].

OBJECTIVE: To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML). METHODS: We retrospectively analyzed 64 patients with refractory/relapsed AML who received the HAA regimen as salvage chemotherapy. The complete remission (CR)rate was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test. RESULTS: The overall CR rate was 70.1%, and 67.1% of the patients attained CR after the first induction course. The early death rate was 0. The median follow-up time was 61 (range:6-120) months. The estimated 3-year OS rate was 46.8% and the estimated 3-year RFS rate was 42.8%. The CR rates of patients with favorable/intermediate and unfavorable cytogenetics were 76.4% and 33.3%, respectively. The 3-year OS of favorable/intermediate and unfavorable group were 53.7% and 10.0%, respectively. The median survival time of unfavorable group was only 8 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection. CONCLUSION: HAA regimen is associated with a higher rate of CR and longer-term survival and its toxicity can be tolerated. The regimen is suitable for refractory/relapsed AML patients with favorable or intermediate risk .

Hypofibrinogenemia as a clue in the presumptive diagnosis of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a medical emergency. In order to evaluate the usefulness of initial coagulation parameters in the predictive value of APL diagnosis, 1304 consecutive newly diagnosed acute leukemia patients, including APL (n=211), non-APL acute myeloid leukemia (n=781) and acute lymphoblastic leukemia (n=312) were retrospectively evaluated between January 2011 and May 2015. The area under curve (AUC) of fibrinogen was the largest among the coagulation markers based on receiver operating characteristic (ROC) analysis. The optimum cutoff value of fibrinogen was 1.87g/L (AUC=0.912, sensitivity 80.1% and specificity 88.8%). The optimum cutoff value of D-dimer was 2191µg/L (AUC=0.786, sensitivity 81.1% and specificity 67.8%). The AUC difference between the fibrinogen and D-dimer was significant (P<0.001). Other coagulation markers showed less predictive power. Importantly, in the analysis of high white blood cell count (over 10×109/L) subgroup, a low fibrinogen level could efficiently discriminate APL patients from controls (AUC=0.983, sensitivity 96.4% and specificity 94.4%) with a criterion value ≤1.71g/L. Thus, our results suggest that a low fibrinogen level could be a key marker in early prediction of APL diagnosis.

Acute myocardial/cerebral infarction as first/relapse manifestation in one acute promyelocytic leukemia patient.

In the clinical setting, bleeding is a common manifestation of acute promyelocytic leukemia (APL), whereas thrombosis is relatively rare, especially as an initial symptom. Here, we report an unusual case of APL with acute myocardial infarction as the first manifestation and cerebral infarction as the relapse manifestation in a healthy young woman. This unique case emphasizes that a thrombotic event could be the first manifestation of an underlying hematological disorder such as APL and could also be a sign of relapse. Rapid detection of the underlying disorder and the timely use of anticoagulation therapy and ATRA are crucial for preventing further deterioration of the disease and saving the patient's life.

Identification and functional analysis of the autofluorescent substance in Limonium bicolor salt glands.

Limonium bicolor is a typical recretohalophyte with salt glands for the secretion of excess salts into the environment. We observed that L. bicolor salt glands showed obvious blue autofluorescence under UV excitation (330-380 nm). The aim of the present study was to identify and clarify a role for this autofluorescent substance in salt secretion. Sudan IV staining showed that the autofluorescent substance was localized in the cuticle of the salt glands. Moreover, the primary autofluorescent substance was identified as ferulic acid after treatment with 0.1 M ammonium hydroxide solution, alkaline and enzymatic hydrolysis. Additional experiments using two mutants exhibiting increased (fii) and decreased (fid) salt gland fluorescence indicated that the fluorescence intensity of salt glands under UV excitation was positively correlated with the content of ferulic acid in the cuticle, strongly suggesting that the primary autofluorescent substance in the salt glands was ferulic acid. Salt gland secretion was determined using leaf discs, and the results showed that the Na(+) secretion rate per single salt gland was also positively correlated with the content of ferulic acid in the cuticle, suggesting that ferulic acid in the cuticle was directly involved in salt secretion of salt gland.