Treatment and outcome patterns of patients with Waldenström's macroglobulinemia: a large, multicenter retrospective review in China.

In this study, we aimed to investigate treatment options and the prognosis of patients with WM in China. This retrospective study included 1141 patients diagnosed with symptomatic WM between January 2003 and December 2019 at 35 tertiary hospitals in 22 provinces of China. Fifty-four patients (7.3%) received monotherapy, 264 (36.0%) received chemoimmunotherapy, 395 (53.8%) received other combination regimens without rituximab, and 21 (2.9%) received ibrutinib. Using a multivariable Cox regression model, age > 65 years old, platelets <100 × 109/L, serum albumin <3.5 g/dl, ß2 microglobulin concentration ≥4 mg/L and LDH ≥250 IU/L predicted poor OS. In summary, our study showed that frontline treatment choices for WM are widely heterogeneous. We validated most of the established prognostic factors in the rIPSS (age >65 years, LDH ≥250 IU/L, ALB <3.5 g/dl and ß2 microglobulin ≥4 mg/L) together with PLT ≤ 100 × 109/L indicate a poor prognosis for patients with WM.

[Inhibitory Effect of Decitabine-inhibeting Methylation of SHP-1 Gene on Proliferation and Apoptosis of MDS Cell Line Skm-1].

OBJECTIVE: To investigate the phenotype and molecular mechanism of DCA on MDS cell model, and to study the response of chemotherapeutic medicines to MDS cells through multiple dimensions, such as cell proliferation, invasion, migration and apoptosis, thus revealing the molecular mechanism of DCA treatment of MDS and its relationship with SHP-1 gene methylation. METHODS: MTT assay was used to determine the survival rate of MDS cells after treated by different concentrations of DCA. The effect of DCA on the invasion and migration of MDS cells was detected by Transwell assay method. Apoplexin V-FITCPI was used to detect apoptosis, the MDS treatment on the mechanism of DCA was investigated by Western blot and Real-time PCR experiment. RESULTS: According to the experiment, it was found that tumor proliferation could be inhibited when MDS skm-1 cells was treated by DCA, and the absorbance was lower and the inhibitory effect was more obvious in the 2.0, 5.0 µmol/L DCA group than in the 0.5 µmol/L DCA group and the negative control group. Compared with the control group, the number of MDS skm-1 cells crossing through the transwell upper chamber was significantly decreased after DCA application. After treated with 0.5, 2.0 and 5.0 µmol/L DCA, the apoptosis rate of MDS cells was 4.54%, 9.31% and 16.58% respectively, while the apoptosis rate of the control group was 3.20%, which shows the apoptosis rate increased significantly with the concentration of DCA. After treatment of MDS cell lines with different concentration of DCA, the methylation status of SHP-1 gene was decreased with the increase of drug concentration, the expression of SHP-1 was increased, the expression of STAT3 was decreased and the level of phosphorylation was decreased. CONCLUSION: By analyzing the phenotypic response of DCA treatment on MDS cells, it was found that interfere with MDS can be performed by inhibiting proliferation, metastasis, and inducing apoptosis in a dose-dependent way. It revealed that the molecular mechanism by DCA treatment can improve the methylation of SHP-1 gene and inhibit the expression of p-STAT3.

[Predicting Therapeutic Response by Lymphocyte Level at 28th Day after DAC Treatment in Patients with MDS].

OBJECTIVE: To investigate a reliable clinical indication for predicting the therapeutic response of decitabine therapy in the patients with myelodysplastic syndromes (MDS). METHODS: The clinical efficacy of decitabine for 55 cases of MDS was analyzed retrospectively. According to the lymphocyte level at d28 after the first time treatment with decitabine, the patients were divided into high lymphocyte level group (H-Lym≥1.2×109/L) and low lymphocyte level group (L-Lym<1.2×109/L), and the overall response rate (ORR) and the progression-free survival (PFS) time in 2 groups were compared. RESULTS: As compared with L-Lym group, the ORR and PFS time in H-Lym group were significantly enhanced ï¼»(76.0% vs 50.0%) (P<0.05) and median time (15.7 months vs 8.5 months)(P<0.05), respectivelyï¼½;the ratio of platelet level ≥100×109/L in H-Lym group was very significantly higher than that in L-Lym group (72.0% vs 20.0%)(P<0.01). Multivariat analysis showed that the risk of disease progression in L-Lym group was 4.45-fold of H-Lym group (95% CI:1.58-12.59)(P<0.05). CONCLUSION: The patients with lymphocyte level ≥1.2×109/L at day 28 after the first time treatment with decitabine show the higher ORR and longer PFS time, therefore. the lymphocyte level at day 28 after first time treatment with decitabine can be used as an early clinical indicator for predecting the response to decitabine treatment.

[Mechanism and Its Countermeasure of Hypomethylating Agent Resistance in Patients with Myelodysplastic Syndrome--Review].

Hypomethylating agents(HMA) currently are widely used in the treatment of myelodysplastic syndromes (MDS), provide a significant improvement in the treatment of MDS. However, resistance to HMA is an almost universal phenomenon. This review was focused on immune effects related to DNA methylation, and to explore the mechanism underlying HMA resistance involved in immune checkpoint pathways. However, the optimal role of checkpoint blockade therapy (CBT) and immune checkpoint pathways remain in HMA failure questionable. The better understanding of immune checkpoint pathways in resistance of HMA offers a compelling rationale to introduce CBT in patients as a novel treatment option. CBT is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies, therefore, may alter the treatment landscape in MDS. The suitability and effectiveness of combining HMA with CBT need to be confirmed by the results of ongoing clinical trials, so as to find novel strategies to improve outcome after failure of HMA.

[Lymphocyte Count before First Consolidation Therapy Is A Predictor of Relapse free Survival in Acute Myeloid Leukemia].

OBJECTIVE: To investigate the effects of absolute lymphocyte count(ALC) before start of the first cycle of consolidation chemotherapy(CC) on the relapse free survival in the patients with acute myeloid leukemia(AML), so as to explore a simple and easy method for predicting AML relapse. METHODS: The clinical data of 132 patients with newly diagnosed AML (all non-acute promyelotic leukemia) from 2011 to 2017 were analyzed retrospectively. The 132 AML patients were treated with standard induction chemotherapy (IC) and consolidation chemotherapy (CC). According to lymphocyte count of patients before start of the first cycle of CC, the AML patients were divided into 2 group: high lymphocyte count group (H-Lym≥1.2×109/L) and low lymphocyte count group (L-Lym<1.2×109/L). The differences in ralapse rate and relapse-free survival between 2 groups were analyzed. RESULTS: Among 132 patients with AML, patients who could be valuated and were elicible for the study accounted for 65 (49.24%). The absolute leukocyte count, age, chromosome karyotypes before IC of patients did not show statistical difference between H-Lym group (40 cases) and L-Lym group (25 cases). Unvarvate analysis showed that the Low lymphocyte count and unfavorable chromosome karyotypes were poor prognostic factors for the relapse-free survival time, and there was significant difference between 2 groups (P<0.01). The relapse risk in patients of L-Lym group increased, the hazard ratio (HR)=3.01 (95% CI=1.55-4.98) (P<0.01). In multivariate analysis containing unfavorable prognostic karyotypes, this trend still existed (HR=2.52, 95% CI 1.28-9.98)(P<0.01). CONCLUSION: The AML patients with high lymphocyte count before the first CC have more long relapse free survival time suggesting that the lymphocyte count before the first CC may be prognostic factor for relapse free survival of AML patients.

[Research Advances of Molecular Genetic Abnormality in Myelodysplastic Syndrome--Review].

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myelogenous leukemia (AML). The treatment of MDS is highly dependent on the reliability of the prognostic evaluation model. Current clinical prognostic scoring systems are comprised of morphology, pivotal clinical trials and cytogenetic findings. However, none of the available prognostic systems incorporates disease-related molecular abnormalities, such as somatic mutations. Cumulative evidence suggests that genomic data can also be used clinically to assist the diagnosis, prognosis, prediction of response to specific therapies, and the development of novel and accurate targeted therapies. Therefore, it is not possible to predict the response of patients to molecular targeted drugs, such as demethylation drugs. With the recent advance in whole- genome sequencing technologies, cumulative evidence suggests that genomic data can also be associated with the genesis, prognosis, prediction of response to specific therapies, and the development of novel accuvate targeted therapies, the issue of having some mechanism to dissect this heterogeneity and precision treatment is coming to the fore. However, there are still several hindrances to its clinical application. If these problems can be solved, molecular genetics will further provide a theoretical basis for the application of precision medicine in MDS.

[Efects of Inhibiting miR-155 Expression on the Proliferation and Apoptosis of Leukemia THP-1 Cells].

The aim of this study was to investigate the effects of miR-155 inhibitor transfection on the proliferation and apoptosis of THP-1 cells. The miR-155 inhibitor was transfected into THP-1 cells (THP-1I) by using X-treme GENE siRNA transfection reagent. Cells without transfection (THP-1C) and cells with negative transfection (THP-1IC) were used as controls. Quantitative real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of miR-155 and relative expression of SHIP1 mRNA in the cells. Cell proliferation was assayed using CCK-8 method. Cell apoptosis were detected by flow cytometry. The expression of SHIP1, TAKT and pAKT in THP-1 cells were detected by Western blot. The results indicated that compared with THP-1C and THP-1IC, the expression of miR-155 in THP-1I cells was significantly reduced; miR-155 inhibition significantly increased apoptosis rate in THP-1 cells (P < 0.05) ; miR-155 inhibition in THP-1 cells caused no significant alteration in SHIP1 mRNA level but significantly increased its protein content, indicating some post-transcriptional modulations might exist underlying the modulation of miR-155 to SHIP1, the miR-155 caused significantly reduced protein level of pAKT (P < 0.05) without interfering TAKT protein content. It is concluded that the miR-155 inhibition may promote THP-1 cell apoptosis through increasing SHIP1 protein content and impairing its downstream PI3K/AKT signaling pathway. This study suggests that miR-155 inhibition may be a promising therapy strategy for treating acute myeloid leukemia (AML).

SHIP1 is targeted by miR-155 in acute myeloid leukemia.

The SH2 domain-containing inositol 5'-phosphatase 1 (SHIP1) has been implicated as a suppressor of hematopoietic transformation as its activity can inhibit the PI3K/Akt signaling pathway. Reduced activity of SHIP1 has been observed in acute myeloid leukemia (AML). SHIP1 is a target of microRNA-155 (miR-155). Therefore, the aim of the present study was to investigate the role of miR-155/SHIP1 in the pathogenesis of AML. We examined the levels of SHIP1 protein and miR-155 in tissue samples of patients with AML and in AML cell lines. In addition, we investigated cell proliferation, apoptosis and expression of SHIP1/PI3K/AKT pathway molecules in the THP-1 and U937 cell lines after miR-155 inhibitor or mimics were transfected. We showed that the levels of SHIP1 protein were significantly decreased in tissue samples of patients with some subtypes of AML (M4 or M5) and in AML cell lines with concomitant overexpression of miR-155. In addition, we demonstrated that decreased expression of SHIP1 in the AML cell lines was a consequence of increased levels of miR-155 and can therefore be reversed in vitro through inhibition of miR-155, with subsequent inhibition of cell proliferation and promotion of cell apoptosis. In conclusion, expression of the SHIP1 protein is targeted by miR-155 in AML. miR-155 acts as an onco-miR, and the miR-155/SHIP1/PI3K/AKT signaling pathway could play an important role in the pathogenesis of AML.

[Relationship between microRNA-155 and hematological malignancies].

MicroRNA (miRNA) are small non-coding RNA that act at the post-transcriptional level, regulating protein expression by repressing translation mRNA target. They can be detected in plants, animal species and viruses, and are involved in numerous cellular processes. MicroRNA-155 (miR-155) which is a kind of microRNAs expressed in hematopoietic cells. Recent data indicate that MiR-155 plays a key role in the pathogenesis of hematological malignancies through regulating cell signal transduction pathways of cell proliferation, differentiation and apoptosis, acting predominantly as an oncomir. MiR-155 may be an important indicator to assess the diagnosis, treatment and prognosis of patients with hematological malignancies, including malignant lymphoma, acute myeloid leukemia, and myelodysplastic syndrome. It could be suggested that drugs such as antisense oligonucleotides able to down-regulate miR-155 expression would provide a novel, and possibly specific way to control the growth of a range of haematopoietic malignancies in conjunction with classical cytotoxic therapy. The purpose of this review is to summarize current findings on the role of miR-155 in hematopoietic malignancies and, moreover, to highlight their role as potential therapeutic tools.