Anti-tumor activity of niclosamide-mediated oxidative stress against acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a heterogeneous clonal disease originated from B- or T-cell lymphoid precursor cells. ALL is often refractory or relapses after treatment. Novel treatments are anxiously needed in order to achieve a better response and prolonged overall survival in ALL patients. In the present study, we aimed at examining the anti-tumor effect of niclosamide on ALL. We investigated the effects of niclosamide on the proliferation and apoptosis in vitro, the growth of ALL cells in xenografted NCG mice. The results showed that niclosamide treatment potently inhibited the growth of ALL cells and induced apoptosis via elevating the levels of reactive oxygen species (ROS) and activating TP53. These findings suggest that niclosamide may be a promisingly potential agent for ALL therapy.

Early M-protein immune reconstitution after autologous haematopoietic stem cell transplantation is a good prognostic marker for patients with high-risk cytogenetic multiple myeloma.

The presence of transient abnormal protein banding (M-protein immune reconstitution) in serum immunofixation electrophoresis after autologous haematopoietic stem cell transplantation in patients with multiple myeloma has been reported. The purpose of this study was to investigate the impact of post-transplant M-protein immune reconstitution on the prognosis of patients with multiple myeloma. M-protein immune reconstitution was observed in 25.9% (75/290) of patients. The CR rate and MRD negativity were higher in the M-protein immune reconstitution group (85.3% vs. 69.3%, p = 0.013, 81.9% vs. 66.5%, p = 0.014). Although there were no significant differences between the groups, the overall median survival time was longer in the M-protein immune reconstruction group (80 vs. 72 m, p = 0.076; not reached vs. 105 m, p = 0.312). Among patients in the cytogenetic high-risk group, the occurrence of M-protein immune reconstitution predicted better PFS and OS (80 vs. 31 m, p = 0.010; not reached vs. 91 m, p = 0.026). Additionally, in revised-International Staging System stage III patients, PFS and OS were better in those who achieved M-protein immune reconstitution (80 vs. 20 m, p = 0.025; 57 vs. 32 m, p = 0.103). The better prognosis of M-protein immune reconstitution patients may be associated with the acquisition of a deeper response. In high-risk patients, early acquisition of M-protein immune reconstitution may suggest a better prognosis.

Efficacy of prophylactic antibiotics for the prevention of neutropenic fever in patients with multiple myeloma receiving high-dose cyclophosphamide for stem cell mobilization.

High-dose cyclophosphamide (HD-Cy) (3 g/m2) plus granulocyte colony-stimulating factor (G-CSF) is a very effective regimen for peripheral blood stem cell (PBSC) mobilization. Unfortunately, it is associated with an increased risk of neutropenic fever (NF). We analyzed the effect of NF on PBSC apheresis results and the efficacy of prophylactic antibiotics for the prevention of NF associated with HD-Cy plus G-CSF for PBSC mobilization in patients with newly diagnosed multiple myeloma (MM). First, patients were divided into NF ( +) and NF ( -) groups according to whether they suffered from NF during mobilization. Second, we divided patients into an antibiotic prophylaxis group and a nonantibiotic prophylaxis group according to whether antibiotic prophylaxis was used during the mobilization period. Our study showed that NF( +) patients (n = 44) had lower CD34 + cell dose collection (median 2.60 versus 5.34 × 106/kg, P < 0.001) and slower neutrophil engraftment and platelet engraftment (median 11 versus 10 days, P = 0.002, and median 13 versus 11 days, P = 0.043, respectively) than NF( -) patients (n = 234). Of note, the nonantibiotic prophylaxis group patients (n = 30) had a 26.7% incidence of NF. In the patients receiving antibiotic prophylaxis (n = 227), the incidence was reduced to 9.3% (P = 0.01). The antibiotic prophylaxis patients had higher CD34 + cell collection (median 5.41 versus 2.27 × 106/kg, P < 0.001) and lower hospitalization cost of mobilization ($ median 3108.02 versus 3702.39, p = 0.012). Thus, our results demonstrate that NF is associated with lower CD34 + cell collection and that antibiotic prophylaxis can reduce the incidence of NF and improve stem cell mobilization and collection outcomes, which reduces the hospitalization cost of mobilization.

[Bortezomib-based induction therapy followed by autologous hematopoietic stem cell transplantation in multiple myeloma].

OBJECTIVE: To evaluate the short-term and long-term effect of novel agents followed by autologous hematopoietic stem cell (ASCT) in Chinese multiple myeloma(MM) patients in order to find out the optimal therapeutic regimen for transplant-eligible patients. METHODS: Clinical data of 100 active MM patients receiving bortezomib-based induction regimens followed by high-dose melphalan and ASCT were retrospectively analyzed from June 1, 2006 to January 30, 2014. RESULTS: The overall response rates(ORR) after induction therapy, transplantation and consolidation and maintenance therapy were respectively 90.0%, 97.0%, and 98.9%. The median progress free survival(PFS) was 42.3 months. The median overall survival(OS) was not reached. The cumulative near complete response (nCR)+complete respanse(CR) rate was no longer improved after 4 cycles of induction therapy for non-light chain type MM and two cycles for light-chain type. In newly-diagnosed light-chain type MM patients, the cumulative nCR+CR rate after 4 cycles of bortezomib plus dexamethasone (VD) regimen was similar to that of bortezomib, doxorubicin and dexamethasone (PAD). While for those non-light-chain types, three drug-based regimen was better than two drug-based. PFS of patients receiving early ASCT was longer than that of late ASCT (50.7 months vs 26.6 months, P = 0.023) . PFS in patients receiving autologous bone marrow stem cell transplantation (ABMSCT) was longer than that of autologous peripheral blood stem cell transplantation (APBSCT) (NA vs 36.1 months, P = 0.049) . Maintenance therapy was beneficial regardless of the response rate after ASCT. Patients with CR at any time during the therapy had longer PFS than those with nCR. CONCLUSIONS: Bortezomib-based therapy followed by ASCT is the first line therapy for transplant-eligible MM patients. Patients with different types of M protein require different induction regimens. Maintenance is beneficial to patients after ASCT, no matter whether a CR is reached or not. Patients with CR after induction or ASCT tend to have longer survival.

Patient Versus Physician Perspective in the Management of Chronic Myeloid Leukemia During Treatment with Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. However, various factors may influence adherence to international guidelines for CML management. This study aimed to compare the reporting of care between patients with CML and their treating doctors. METHODS: Parallel patient and physician online surveys were conducted between September 22, 2021, and March 15, 2022, which focused on the perceptions of 1882 adult patients with CML and 305 physicians regarding tyrosine kinase inhibitor (TKI) treatment options, monitoring and toxicities, TFR, and challenges faced. RESULTS: Among the enrolled patients, 69.9% received first-line imatinib treatment, 18.6% received nilotinib, and 4.7% received dasatinib. Among the patients treated with imatinib, 36.7% switched to other TKIs due to imatinib resistance/intolerance (71.1%), exploration of more potent TKIs to achieve TFR (8.9%), and treating physicians' recommendation (14.0%), with a median duration of initial treatment of 14 months [interquartile range (IQR) 6-36]. Most (91.8%) physicians agreed that the breakpoint cluster region-Abelson 1 (BCR::ABL1) transcript level should be assessed every 3 months, but only 42.7% of individuals committed to 3-monthly testing and only 17.8% strictly followed their treating physicians' recommendation. Half of the patients aimed for TFR; however, just 45.2% of physicians considered TFR as one of the top three goals for their patients. The major concern in obtaining TFR was patients' adherence. Fatigue was often distressing for patients with TKIs, while physicians were more concerned about platelet and neutrophil counts. A total of 12% and 20.8% of patients reported moderate/severe anxiety and depression, respectively, while only 53.7% of physicians had concerns about their patients' mental health. During the coronavirus disease 2019 (COVID-19) pandemic, 69.2% of patients reported a reduction in their income. Among these patients, 61.8% maintained their current treatment, while 7.3% switched to cheaper alternatives or discontinued treatment, with over 80% of these patients belonging to the low-income group. CONCLUSIONS: Overcoming challenges in patient-physician communication and treatment access is key to improving disease management and quality of life, especially for patients with low income. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05092048.

Hepatitis B virus infection status is an independent risk factor for multiple myeloma patients after autologous hematopoietic stem cell transplantation.

The purposes of this study were to evaluate the infection by hepatitis B virus (HBV) and its impact on survival and to provide a clinical reference for monitoring and treating HBV during and after autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A retrospective analysis of HBV infections was performed in 70 MM patients who received a sequential bortezomib-containing induction therapy and ASCT in our department from June 2006 to February 2012. Among the 70 patients in our study, 11 cases (15.7 %) were hepatitis B surface antigen positive (HBsAg+), and 23 cases (33.3 %) were hepatitis B core antibody positive (HBcAb+). Eight cases were HBsAg, hepatitis B e antibody (HBeAb), and HBcAb positive, while one case was HBsAg, hepatitis B e antigen (HBeAg), and HBcAb positive. The median follow-up times for the HBsAg+ group and the HBsAg-negative (HBsAg-) group were 27.0 (7.6-85.2) months and 28.7 (7.1-111.0) months, respectively. The 1-year, 2-year, and 3-year overall survival rates of the HBsAg+ group were 90.9, 80.8, and 34.6 %, respectively, and the median survival time was 31.2 months (95 % CI, 24.8-37.6). The 1-year, 2-year, and 3-year overall survival rates of the HBsAg- group were 98.2, 94, and 84.6 %, respectively, while the median survival time was not yet available. There was a statistically significant difference (p=0.008) in the overall survival rate between the two groups. By Cox regression analysis, we found that the HBsAg+ status was a prognostic factor, which could independently influence the overall survival rate for ASCT. In conclusion, the HBsAg+ status is an independent risk factor for patients with MM receiving ASCT. The application of standard antiviral treatment might help to overcome this risk factor.

Determining the optimal time for bortezomib-based induction chemotherapy followed by autologous hematopoietic stem cell transplant in the treatment of multiple myeloma.

In our study, we determined the efficacy of bortezomib-based induction therapy followed by autologous stem cell transplant (ASCT) in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM) patients and compared the advantages of early versus late transplant. We used a retrospective analysis to examine 62 patients, including 46 cases of newly diagnosed MM (early transplant group) and 16 cases of relapsed/refractory MM (late transplant group). All of these patients received bortezomib-based induction therapy followed by ASCT. The efficacy and side effects of the treatment regimen were analyzed. Patients' overall survival (OS) and progression-free survival (PFS) times were determined. The ratio of complete remission to near-complete remission (CR/nCR) was 69.5% versus 56.2% (P=0.361), respectively, for the early transplant group versus the late transplant group, respectively, after receiving bortezomib-based induction therapy; the overall response rates of the two group were 91.3% and 81.2%, respectively (P=0.369). After receiving ASCT, the CR/nCR of the two groups increased to 84.8% and 81.3%, respectively. The median time required for neutrophil engraftment of the early transplant group and the late transplant group was 11 and 14.5 days, respectively (P=0.003); the median time required for platelet engraftment was 13 and 21.5 days (P=0.031), respectively. There were no significant differences in the toxic side effects observed during induction therapy and ASCT between the two groups. The OS of the two groups was not statistically different (P=0.058). The PFS of the early transplant group and the late transplant group was 41.6 and 26.5 months, respectively (P=0.008). Multivariate analysis demonstrated that the time of receiving ASCT, the types of M protein, and the International Staging System (ISS) stage were all independent factors that influenced PFS. In conclusion, patients in a suitable condition for ASCT should be recommended to have an early ASCT immediately after diagnosis.

On-demand plerixafor added to high-dose cyclophosphamide and pegylated recombinant human granulocyte colony-stimulating factor in the mobilization of patients with multiple myeloma: a treatment with high effectiveness, convenient, and affordable cost.

Objective: The combination of high-dose cyclophosphamide (HD-Cy) (3g/m2) plus granulocyte colony-stimulating factor (G-CSF) and on-demand plerixafor (PXF) has been considered an effective mobilization regimen of patients with multiple myeloma(MM). However, the daily multi-injection regimen of G-CSF poses challenges. This study delves into the efficiency and cost implications of a novel approach, using HD-Cy alongside pegylated G-CSF (PEG G-CSF) and on-demand PXF. Unlike G-CSF, which necessitates daily injections, the half-life of PEG G-CSF extended allows for a single injection. Methods: A retrospective analysis was conducted on 350 MM patients, which were categorized based on their mobilization regimens: Cy+PEG G-CSF+/-PXF (n=66), Cy+PEG G-CSF (n=91), Cy+ G-CSF (n=169), and G-CSF+PXF (n=24). Results: Mobilization with Cy+PEG G-CSF+/-PXF(8.79)yielded a notably higher median CD34+ cell count compared to the other regimens: Cy+PEG G-CSF(4.96), Cy+G-CSF (4.65), and G-CSF+PXF (2.99) (P<0.001). The percentage of patients who achieved >6×106/kg CD34+ cells was significantly higher in the Cy+PEG G-CSF+/-PXF group (77.3%) than in the other mobilization regimens: Cy+PEG G-CSF (41.8%), Cy+ G-CSF (37.3%), and G-CSF+PXF (8.3%) (P<0.001). From a cost perspective, the Cy+PEG G-CSF+/-PXF approach was more economical than the G-CSF+PXF strategy but was marginally costlier than the other two methods. A multivariate assessment highlighted that the combination of Cy+PEG G-CSF with on-demand PXF had a superior potential to achieve the desired harvest (6×106/kg) compared to the Cy+PEG G-CSF protocol without PXF. The incremental cost-effectiveness ratio for each 1% increase in the probability of achieving a successful optimal harvest was $ 97.02 per patient. The incidence of neutropenic fever was 3.0% in the Cy+PEG G-CSF+/-PXF group. Conclusion: The combination of on-demand PXF with HD-Cy and PEG G-CSF offers a cost-effective approach with a high mobilization success rate, manageable side effects, and the convenience of fewer injections. It stands as a promising mobilization strategy for MM patients.

[The efficacy and safety of bortezomib-based induction regimen before autologous hematopoietic stem cell transplantation in patients with multiple myeloma].

OBJECTIVE: To investigate the efficacy and safety of bortezomib-based induction regimen followed by autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM). METHODS: A retrospective analysis was performed upon clinical data of 62 MM patients who received bortezomib-based induction regimen followed by ASCT from June 2006 to June 2011. All patients were followed up to September 30, 2011. RESULTS: Overall response rate [complete remission (CR) + near complete remission (nCR) + partial remission (PR)], ≥ nCR rate (CR/nCR) and CR rate of post-induction with bortezomib-based regimen were 88.7%, 66.1% and 24.2%, respectively. After ASCT, CR rate and CR/nCR rate were increased to 50.0% and 82.3%, respectively, with significant differences (P = 0.003 and P = 0.032). The median time of neutrophil and platelet engraftment was 12.0 (9 - 43) days and 13.5 (0 - 120) days, respectively. Significances were found in neutrophil and platelet engraftment between MM patients with and without prior exposure to alkylating agents. Furthermore, engraftment of neutrophil and platelet in patients receiving peripheral blood stem cell transplantation were faster than those receiving bone marrow transplantation. No unexpected side effects occurred. The median time of follow-up was 26.5 (7-61) months. The median overall survival (OS) was not reached and the median progression-free survival (PFS) was 30 months. There were significant differences in OS and PFS between patients obtaining CR/nCR and those with ≤ PR before ASCT. CONCLUSIONS: Bortezomib-based induction regimen can improve the efficacy of ASCT in MM patients. The side effects are tolerant. Higher response quality before ASCT can translate to high rates of OS and PFS following high-dose therapy and stem cell transplantation.

Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML.

Our group has reported previously on the role of various members of the protein arginine methyltransferase (PRMT) family, which are involved in epigenetic regulation, in the progression of leukemia. Here, we explored the role of PRMT7, given its unique function within the PRMT family, in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Genetic loss of Prmt7, and the development and testing of a small-molecule specific inhibitor of PRMT7, showed that targeting PRMT7 delayed leukemia development and impaired self-renewal of LSCs in a CML mouse model and in primary CML CD34+ cells from humans without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 resulted in reduced expressions of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to LSCs. These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML.

[The clinical features of infection in multiple myeloma undergoing autologous hematopoietic stem cell transplantation].

OBJECTIVE: To explore the clinical features of infection in multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (ASCT). METHODS: Thirty-seven patients with MM undergoing ASCT were retrospectively analyzed for type and time of infection, pathogen, and outcome. RESULTS: Fifty-nine cases of infectious complications occurred in 33 patients (89.2%) after ASCT, with 34 cases (57.6%) of bacterial infections in 30 patients, 15 cases (25.4%) of fungal infections in 12 patients, 4 cases (6.8%) of cytomegalovirus (CMV) infection, 3 cases (5.1%) of herpes zoster virus infection and 3 cases (5.1%) of HBV reactivation. The proportion of bacterial infection, fungal infection and virus infection were 62.8%, 28.6% and 8.6% respectively in the early stage after ASCT, and 50.0%, 20.8% and 29.3% respectively in the median stage. Response to first-line antibiotic therapy was seen in 38 cases (64.4%). Infection-related mortality was 8.1% (3 cases). CONCLUSIONS: The incidence of infection in MM patients undergoing ASCT is high and they are susceptible to all pathogens. It is important to choose the right antifungal agents as quickly as possible to reduce infection-related mortality.

Recombinant human thrombopoietin improved platelet engraftment after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.

BACKGROUND: To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) for hematopoietic reconstitution after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM). METHOD: Thirty-five cases with NDMM had been enrolled into a prospective clinical trial from March 2014. The hematopoietic reconstitution was compared between these 35 cases (rhTPO group) and 98 historic cases not receiving rhTPO (control group) after stem cell reinfusion. RESULTS: Thirty-five (100%) cases receiving rhTPO achieved both neutrophil and platelet engraftment within 30 days post-transplant. The median time to neutrophil and platelet engraftment was the 10th day and 11th day after stem cell reinfusion, respectively. Multivariate analysis showed that rhTPO administration was an independent factor for accelerating platelet engraftment (HR 2.013, 95% CI 1.336-3.034, p = 0.001). Subgroup analysis showed that rhTPO improved platelet engraftment and alleviated platelet transfusion needs in patients with inadequate re-infused CD34+ cell counts of <2 × 109 /L. All the 35 patients tolerated rhTPO well. Survival analysis showed no decrease in time to progression (TTP) or overall survival (OS) by rhTPO administration. CONCLUSION: rhTPO accelerated the platelet engraftment after ASCT in patients with NDMM with good tolerability and long-term safety, especially for those patients with poor CD34+ cell reinfusion. rhTPO might be recommended to be used early after ASCT for patients with NDMM.

Comparison of efficacy, safety, patients' quality of life, and doctors' occupational stress between lenalidomide-based and bortezomib-based induction in patients with newly diagnosed multiple myeloma.

BACKGROUND: In the new therapeutic era, comparisons between regimens containing lenalidomide and bortezomib are needed. METHODS: In this single-center, prospective study, patients received four to six cycles of lenalidomide+liposomal doxorubicin+dexamethasone (RAD) or bortezomib+liposomal doxorubicin+dexamethasone (PAD) every 4 weeks, with subsequent autologous stem cell transplantation (ASCT) and maintenance therapy. We compared the efficacy, safety, patients' quality of life, and doctors' occupational stress between RAD and PAD induction in newly diagnosed MM patients. RESULTS: The complete response (CR) rate was comparable between the RAD and PAD groups after induction (30.8% vs. 32.0%, p = 0.92). Common adverse events, including infections, peripheral neuropathy, and gastrointestinal disturbances, were more frequent in the PAD group, while leukopenia and rashes were more common in the RAD group. Compared with PAD, RAD improved patients' quality of life more quickly and caused less occupational stress for doctors. However, only 31.6% of patients collected adequate CD34+ cells (≥2 × 106 /kg) in the RAD group, which was significantly lower than that in the PAD group (95.5%, p < 0.001). The number of CD34+ cells collected was significantly higher in patients within three courses of RAD than in patients with four or five to six courses (14.18 ± 13.57 vs. 2.07 ± 2.42 vs. 1.51 ± 1.81 × 106 /kg, p = 0.028). The median progression-free survival and overall survival of the two groups were not reached by the end of follow-up. CONCLUSION: Compared to PAD, RAD induction had comparable efficacy and a significantly better safety profile, improved quality of life for patients, and reduced occupational stress for doctors. However, RAD induction may need to be limited to four cycles to avoid irreversible damage to hematopoietic stem cells. CLINICAL TRIAL REGISTRATION: This study was registered at www.chictr.org.cn (ChiCTR1900021558).

Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation.

PURPOSE: Resistance to STI571 is an emerging problem for patients with chronic myelogenous leukemia (CML). Mutation in the kinase domain of Bcr-Abl is the predominant mechanism of the acquired resistance to STI571. In the present study, we investigated the effect of triptolide on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. EXPERIMENTAL DESIGN: CML cell lines (KBM5 versus KBM5-T315I, BaF3-Bcr-Abl versus BaF3-Bcr-Abl-T315I) and primary cells from CML patients with clinical resistance to STI571 were treated with triptolide, and analyzed in terms of growth, apoptosis, and signal transduction. Nude mouse xenograft model was also used to evaluate the antitumor activity. RESULTS: Triptolide potently down-regulated the mRNA and protein levels of Bcr-Abl independently of the caspase or proteosome activation in CML cells. It induced mitochondrial-dependent apoptosis in Bcr-Abl-T315I CML cells and primary cells from CML patients with clinical resistance to STI571. Additionally, triptolide inhibited the growth of STI571-sensitive KBM5 and STI571-resistant KBM5-T315I CML cells in nude mouse xenografts. Triptolide also down-regulated the expression of survivin, Mcl-1, and Akt in CML cells, which suggests that it may have multiple targets. CONCLUSIONS: These findings suggest that triptolide is a promising agent to overcome STI571-resistant CML cells, and warrant a clinical trial of triptolide derivatives for CML with Bcr-Abl-T315I mutation.

Secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation: a case report.

OBJECTIVE: Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy and the most common type of leukemia, with the 5-year relative survival rate of 19% in Europe. Chronic myeloid leukemia (CML) is a slowly progressive clonal malignant disease, and a myeloproliferative disorder which is derived from biphasic hematopoietic stem cells but driven by progenitor cells. AML following CML is common, which can be caused by an antecedent myeloid malignancy, leukemogenic therapy, or without an identifiable prodrome or exposure to cytotoxic agents. However, the case of secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation is rare. METHODS: Here we report a unique case of secondary CML after AML treated by chemotherapy and autologous peripheral blood stem cell transplantation. The 34-year-old male was diagnosed with AML subtype M5b according to clinical features in 2011. The patient was treated with the MAE program (mitoxantrone, cytosine arabinoside, etoposide) for two courses, followed by the IAE program (idarubicin, cytosine arabinoside, etoposide) and cytosine arabinoside for consolidation chemotherapy. An autologous hematopoietic stem cell transplantation with prophylactic intrathecal methotrexate cytarabine and dexamethasone was initiated. RESULTS: Subsequently, the patient achieved complete remission in 2012. After 4 years, the patient presented with leukocyte elevation of more than 4 months, and then was diagnosed with secondary CML. Based on this diagnosis, and with respect to the patient's severely compromised overall condition, tyrosine kinase inhibitors (TKI) therapy was conducted in 2016. The patient achieved, and continue to be in, complete remission. CONCLUSIONS: The case expands the understanding of secondary CML and emphasizes the importance of oncological vigilance in patients with secondary CML after AML therapy.

A favorable inductive remission rate for decitabine combined with chemotherapy as a first course in <60-year-old acute myeloid leukemia patients with myelodysplasia syndrome features.

In acute myeloid leukemia (AML), myelodysplasia-related changes contribute to a poor prognosis. This retrospective, propensity score-matched study analyzed 108 newly diagnosed AML patients with features of myelodysplasia syndrome (MDS) (aged 14-60 years) from 2014 to 2018, who received either idarubicin and cytarabine (IA) or decitabine, idarubicin and cytarabine (DAC+IA), and compared efficacy and toxicity between the two regimens. After propensity score matching, there were 54 patients in each group. The rate of complete remission (CR) was higher in the DAC+IA group than in the IA group (85.2% vs 68.5%, P = .040) after the first course, and toxicities were comparable in both groups. Multivariate analysis indicated that the combination with DAC was independent factor for CR rate after the first induction therapy (OR = 2.978, 95% CI:1.090-8.137, P = .033). Subgroup analysis showed a CR advantage for DAC+IA (vs IA) for patients of intermediate-high risk status according to National Comprehensive Cancer Network prognostic stratification. In conclusion, DAC+IA is therefore offered as a new induction choice for newly diagnosed AML patients with features of MDS, aged <60 years old, especially in intermediate-high risk status.

The VAD Scheme versus Thalidomide plus VAD for Reduction of Vascular Endothelial Growth Factor in Multiple Myeloma: A Meta-Analysis.

The VAD (vincristine-doxorubicin-dexamethasone) regimen has been used for decades to treat multiple myeloma (MM). Based on reports that vascular endothelial growth factor- (VEGF-) mediated angiogenesis is critical for MM pathogenesis, the antiangiogenic compound thalidomide has been added to VAD (T-VAD). However, it remains unclear whether T-VAD is more efficacious than VAD for serum VEGF reduction or if the difference influences clinical outcome. Pubmed, Cochrane library, China Biomedical Literature (CBM) database, China National Knowledge Infrastructure (CNKI) database, Vip database, and Wanfang database were searched for relevant studies published up to June 2017. RevMan5.2 was used for methodological quality evaluation and data extraction. Thirteen trials (five randomized, seven nonrandomized, and one historically controlled) involving 815 cases were included. Serum VEGF was significantly higher in MM cases than non-MM controls (MD=353.01, [95%CI 187.52-518.51], P<0.01), and the overall efficacy of T-VAD was higher than that of VAD (RR=1.36, [1.21-1.53], P <0.01). Further, T-VAD reduced VEGF to a greater extent than VAD does ([MD=-49.85, [-66.28- -33.42], P<0.01). The T-VAD regimen also reduced VEGF to a greater extent in newly diagnosed MM patients than it did in recurrent patients ([MD=-120.20, [-164.60--39.80], P<0.01). There was no significant difference in VEGF between T-VAD patients (2 courses) and nontumor controls (MD=175.94, [-26.08-377.95], P=0.09). Greater serum VEGF reduction may be responsible for the superior efficacy of T-VAD compared to VAD.

Prostaglandin E2 promotes human CD34+ cells homing through EP2 and EP4 in vitro.

Recently, certain studies have demonstrated in vitro that prostaglandin E2 (PGE2) promotes human cluster of differentiation (CD)34+ cell homing. However, the sub­type receptors activated by PGE2 are unknown, as the PGE2 receptor EP1-4 subtypes (EP1-4) are expressed on the membrane of human CD34+ cells. Based on the above, the present study aimed to screen the receptor subtype activity by PGE2 to promote human CD34+ cell homing. It was observed that human CD34+ cells expressed the four PGE2 sub­receptors, particularly EP2 and 4. PGE2 increased EP2 and 4 mRNA expression significantly, while EP1 and 3 mRNA exhibited no significant alteration. PGE2, EP2 agonist (EP2A), and EP4A upregulated C­X­C chemokine receptor 4 mRNA and protein expression in human CD34+ cells, and promoted stromal cell­derived factor 1α (SDF­1α) expression in bone marrow mesenchymal stem cells (BMMSCs). These phenomena were inhibited by the associated receptor antagonists. PGE2, EP2A, and EP4A facilitated human CD34+ cell migration towards SDF­1α and BMMSCs. The results of the present study suggested that PGE2 promoted human CD34+ cell homing through EP2 and 4 receptors in vitro.

[Prostaglandin E2 Receptor 4 Agonist Promotes Human CD34+ Cell Proliferation in vitro by Activating Wnt/ß-Catenin Signaling Pathway].

OBJECTIVE: To investigate the potential signaling pathway that regulates the proliferation of human CD34+ cells stimulated by prostaglandin E2 receptor 4 agonist (EP4A) in vitro. METHODS: Twenty samples of peripheral blood containing stem cells were collected from the G-CSF mobilized healthy donors in our department of hematology. Human CD34+ cells were isolated by magnetic activated cell sorting (MACS) microbeads kit. The Cell Counting Kit-8 (CCK8) assay was used to determine the optimal concentration and time of EP4A to promote human CD34+ cell proliferation in vitro. Under the optimal condition, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA level of ß-catenin, and Western blot was used to assay protein expression of ß-catenin and P-GSK-3ß in human CD34+ cells treated with EP4A. RESULTS: Culturing with 10 µmol/L EP4A for 72 h, it was found that EP4A promoted human CD34+ cell proliferation significantly, and the proliferation rate of human CD34+ cells was 1.36 times higher than that of the control(P=0.002). Under the optimal condition, it was also found that EP4A enhanced the ß-catenin expression at both mRNA and protein levels, and up-regulated phosphorylation of GSK-3ß in human CD34+ cells, but these effects could be inhibited by the EP4A antagonist EP4AA. CONCLUSION: EP4A can enhance human CD34+ cell proliferation in vitro by activating Wnt/ß-catenin signaling pathway.

[Effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia].

OBJECTIVE: To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML). METHODS: Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase. Allo-HSCT from HLA identical siblings was performed for 35 patients, of whom 11 received bone marrow transplantation (BMT) and 24 peripheral blood stem cell transplantation (PBSCT). Conditioning regimens was TBI (total-body irradiation) + CY (CTX) protocol in 8 patients and BU/CY protocol in 27 patients. The average follow-up was 48 months (range 7 - 108 months). RESULTS: 34 (97.1%) patients were successfully engrafted. Among them, 21 patients (60.0%) had three years disease-free (DFS) survival. The overall 5-year survival (OS) was 57.1%. Two patients (5.7%) relapsed. Transplant-related mortality occurred in 12 patients. Hemorrhagic cystitis (HC) occurred in 5 patients and HVOD was observed in 1 patient. Acute graft-versus-host disease (aGVHD) occurred in 18 patients (51.4%), among them 7 patients (20.0%) were of grade III-IV. Chronic GVHD was in 17 patients (48.5%). There was no significant difference in 3-years DFS between BMT group and PBSCT group (54.5% vs. 62.5%, P > 0.05). The 3-year disease-free survival (DFS) was 42.9% in TBI/CY group and 55.6% in BU/CY group (P > 0.05). In univariate prognostic analysis model, the DFS at 3 years is 75% and 47.4% for < or =30 years patients and >30 years patients, respectively, P < 0.05. The 3-year DFS of patients with first chronic phase is higher than patients with advanced diseases (61.3% vs. 40%, P < 0. 05). The 3-year DFS in patients of grade I - II GVHD was higher than that in patients of grade III-IV GVHD (81.8% vs. 14.3%, P < 0.05). CONCLUSION: The patients who had transplantation done within 1 year after diagnosis during their first chronic phase of disease and who had low-grade GVHD have better prognosis. Those patients who had III-IV acute GVHD are prone to incorporate severe infection, which was a worse prognostic factor of allo-HSCT for chronic myelogenous leukemia.