Combination Of Thalidomide Research Articles

Arsenic Trioxide and Thalidomide Combination Induces Autophagy Along with Apoptosis in Acute Myeloid Cell Lines.

Objective Autophagy and apoptosis play key roles in cancer survival and pathogenesis and are governed by specific genes which have a dual role in both cell death and survival. Arsenic trioxide (ATO) and thalidomide (THAL) are used for treatment of many types of hematologic malignancies. ATO prevents the proliferation of cells and induces apoptosis in some cancer cells. Moreover, THAL has immunomodulatory and antiangiogenic effects in malignant cells. The aim of present study was to examine the effects of ATO and THAL on U937 and KG-1 cells, and evaluation of mRNA expression level of VEGFs genes, PI3K genes and some of autophagy genes. Materials and Methods In this in vitro experimental study, U937 and KG-1 cells were treated by ATO (0.4-5 µM) and THAL (5-100 µM) for 24, 48 and 72 hours. Cell viability was measured by MTT assay. The apoptosis rate and cell cycle arrest were evaluated by flow cytometry (Annexin/PI) and cell cycle flow cytometry analysis, respectively. The effect of ATO/THAL on mRNAs expression was evaluated by real-time polymerase chain reaction (PCR). Results ATO/THAL combination enhanced cell apoptosis in a dose-dependent manner. Also, ATO/THAL induced SubG1/ G1 phase arrest. mRNA expression levels of VEGFC (contrary to other VEGFs isoform), PI3K, AKT, mTOR, MEK1, PTEN, IL6, LC3 and P62 genes were upregulated in acute myeloid leukemia (AML) cells following treatment with ATO/THAL. ConclusionCombined treatment with ATO and THAL can inhibit proliferation and invasion of AML cells by down-regulating ULK1 and BECLIN1 and up-regulating PTEN and IL6, and this effect was more marked than the effects of ATO and THAL alone.

Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients: Meta-analysis of Efficacy in Pivotal Randomized Controlled Trials

For patients with newly diagnosed multiple myeloma (NDMM) who are not candidates for autologous stem cell transplantation (ASCT), lenalidomide and low-dose dexamethasone (Rd) is an established, alkylator-free, treatment option. The FIRST trial demonstrated the efficacy and safety of Rd, showing a significant improvement in overall survival (OS) with Rd over the combination of melphalan, prednisone, and thalidomide. Rd is a recommended treatment option in the European Society for Medical Oncology (ESMO) guidelines (Moreau et al.

PS1467 EARLY RESULTS OF A PHASE II STUDY OF COMBINED RUXOLITINIB AND THALIDOMIDE IN PATIENTS WITH MYELOFIBROSIS

Background:Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thalidomide (THAL) is an immunomodulatory agent which has demonstrated demonstrated improvements in anemia and thrombocytopenia in patients with MF.Aims:We sought to examine whether the combination of RUX and THAL could result in improvement in both disease‐ and therapy‐related cytopenias, as well as improve overall disease response in patients with MF.Methods:We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with myelofibrosis (NCT03069326). Patients taking RUX at the time of enrollment must have had less than PR per IWG‐MRT/ELN 2013 criteria. Patients must have been taking RUX for a minimum of 3 months. Treatment‐naïve patients received single‐agent RUX for 3 months (run‐in phase) per label, and went on to combination therapy if they achieved less then a PR. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG‐MRT/ELN 2013 criteria. Platelet response criteria (in patients with baseline thrombocytopenia) included: Major response (≥75% increase in platelet count), Intermediate Response (50–74% increase) and Minor Response (25–49% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG‐MRT criteria and by platelet response criteria.Results:A total of 25 patients are planned to be accrued. At the time of this writing, 24 have been accrued. The median age was 70 years (43–85). 9 patients had received prior therapies. 11 patients enrolled to the run‐in phase. 16 patients had received red blood cell transfusions prior to study enrollment. A significant increase in platelet count was observed by cycle 3 of therapy compared to baseline (Figure 1A, P < 0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1B). 12 of 21 accrued patients were evaluable for response assessment at the time of abstract submission. The overall response rate in these patients was 58.3% (7/12 patients). Four of 12 (33.3%) evaluable patients had stable disease. 1 patient progressed to accelerated phase. Clinical Improvement (anemia response, spleen response, or symptom response) occurred in 5 patients. Major platelet response was observed in 6 patients with baseline thrombocytopenia (Table 1). Grade 3/4 non‐hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope, and a thromboembolic event (one patient each).Summary/Conclusion:The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Reductions in spleen size, symptom burden, and improvements in hemoglobin and platelet count were observed. Improvement in platelet count is particularly important given the lack of treatment modalities for thrombocytopenia in this patient population. These data indicate a potential role for this regimen in patients with cytopenias and/or persistent disease manifestations while on RUX. Updated data on duration of response and overall response rate in all accrued patients will be presented.image

Synergistic effects of gefitinib and thalidomide treatment on EGFR-TKI-sensitive and -resistant NSCLC

EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most if not all of the patients who initially have responded to EGFR-TKIs later experience progression or deterioration of the disease while still on the treatment. Drug resistance becomes inevitable due to the emergence of the second-site EGFR T790M mutation within exon 20, MET and HER2 amplification, small cell histologic transformation and rare secondary BRAF mutations. The acquired drug resistance limits the efficacy of EGFR-TKIs in patients. Thalidomide is a widely used anti-angiogenic and immunomodulatory drug with anticancer effects. The current study was aimed to explore the combined effects of gefitinib and thalidomide on NSCLC. The combination of thalidomide and gefitinib induced antiproliferative and proapoptotic effects in HCC827, PC9, and PC9GR cells. The inhibition of EGFR phosphorylation and downstream signaling was more pronounced in the thalidomide and gefitinib co-treatment group as compared with the single agent treatment groups. Further study revealed that the inhibitors of AKT, MEK/ERK, and p38 increased the antiproliferative and proapoptotic effects of the combined treatment of thalidomide and gefitinib. However, JNK inhibition moderately abrogated cell apoptosis induced by the co-treatment. In conclusion, thalidomide and gefitinib exhibit synergistic effects on both TKI-sensitive and -resistant NSCLC cells by targeting the EGFR signaling pathways, suggesting that the combination strategy is promising for the treatment of NSCLC.

Thalidomide combined with chemo-radiotherapy for treating esophageal cancer: A randomized controlled study.

The aim of the present study was to investigate the efficiency and safety of a combination of thalidomide and chemo-radiotherapy (CRT) for treating esophageal cancer (EC). Eligible patients received two cycles of chemotherapy using paclitaxel liposome and cisplatin concurrently with three-dimensional radiotherapy. Following radiotherapy, two cycles of maintenance chemotherapy were performed. Patients with elevation of vascular endothelial growth factor (VEGF) during radiotherapy were randomly divided into: i) a test group (n=31), who received a combination of CRT and thalidomide; and ii) a control group (n=30), who received CRT only. Patients with locally advanced EC in the test group demonstrated a significantly improved 3-year overall survival (OS) rate, progression-free survival (PFS) rate, local control and median PFS time compared with the control group (P<0.05). Multivariate analysis indicated that Tumor-Node-Metastasis (TNM) stage was associated with the OS time, while TNM stage and the residence of cancer cells following radiotherapy were associated with PFS time. The present data indicate that thalidomide contributes to an improvement of prognosis for patients with locally advanced EC with elevated serum VEGF levels during radiotherapy. In addition, the toxicities induced by thalidomide were demonstrated to be tolerable.

Recurrent thrombosis in a multiple myeloma patient with low risk for thrombosis despite being on thromboprophylaxis

It is a well-known fact that multiple myeloma (MM) patients have an increased risk for thromboembolic events involving both the venous and arterial territories. The etiologies can be multifactorial, for example, activation of procoagulant factors, acquired protein C resistance, MM-specified and treatment-related factors. The risk of venous thrombosis is high when patients receive treatment with thalidomide or lenalidomide in combination with dexamethasone or multi-agent chemotherapy. Arterial thromboses occur less compared to venous thrombotic events. Nonetheless, thromboprophylaxis is important in preventing both types of thromboses. In this case study, we reveal a patient whom thrombosis occurred concurrently in both arterial and venous despite being on aspirin prophylaxis.

Improvement of the hematologic toxicities of ruxolitinib in patients with MPN-associated myelofibrosis using a combination of thalidomide, stanozolol and prednisone

ABSTRACTObjective: Anemia and thrombocytopenia are the most frequently reported adverse events of ruxolitinib in patients with MPN-associated myelofibrosis (MPN-MF). Although thalidomide, androgens and prednisone have previously demonstrated improvements in myelofibrosis-associated anemia, it is unclear whether these drugs are effective in patients taking ruxolitinib.Method: We conducted a retrospective cohort study to evaluate the efficacy and tolerability of combination therapy with low dose thalidomide, stanozolol and prednisone (TSP) in patients with IPSS intermediate-2 or high-risk myelofibrosis (MF) who received ruxolitinib treatment.Results: Sixty-five patients with MPN-MF who took ruxolitinib were enrolled in this retrospective study, of which 46 patients also took TSP while 19 did not take TSP (TSP and non-TSP groups). Within the first 24 weeks, the proportion of patients with anemia response and platelet count increase ≥50 × 109/L were 45.7% and 67.4% in the TSP group as compared to 0% and 10.5% in the non-TSP group (p < 0.001). The mean hemoglobin level in the non-TSP group reached the nadir after approximately 12–16 weeks of therapy, but gradually increased in the TSP group.Conclusion: In summary, TSP regimen can improve anemia and thrombocytopenia during ruxolitinib treatment in patients with MPN-MF, and the associated adverse events were manageable.

Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naive patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal:Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

Treatment Outcomes of Real Life Elderly Multiple Myeloma Patients:Â Analysis from Registry of Monoclonal Gammopathies (RMG)

Introduction: Multiple myeloma patients over the age of 65 represent the majority of myeloma population. The main goal was to evaluate treatment outcomes in terms of overall survival for elderly patients based on initial choice of anti-myeloma drugs, and to find potential factors affecting survival.Patients and Methods: This is a retrospective registry based analysis from the Registry of monoclonal gammopathies of the Czech Myeloma Group. Patients with multiple myeloma diagnosed between 2007-2016 over the age of 65 with symptomatic myeloma were included in the analysis. Basic demographic data and disease characteristics were obtained. The Kaplan-Meier estimates were completed by the Greenwood confidence interval. The log-rank test was used to estimate the statistical significance of the difference between the curves. The Cox proportional hazards model was performed to explore the univariate significance of risk factors.Results: Data from 1410 MM patients were obtained. Gender [HR 1.316 (1.124-1.541), p=0.001], age [above 75 vs. 66-75, HR 1.437 (1.221-1.692), p< 0.001], creatinine levels [at cutoff 152 µmol/L, HR 1.613 (1.365-1.905), p< 0.001] and ECOG performance status [0-1 vs. 2-4, 1.869 (1.594-2.191), p< 0.001] were found to significantly affect overall survival. Moreover these risk factors have cumulative effect on overall survival of the patients. Overall survival of patients regardless to above mentioned risk factors treated with upfront bortezomib (N = 880) was median OS 40.4 months (CI: 36.1-44.7), patients treated with upfront thalidomide (N = 370) had median OS 48.1 months (CI: 41.0-55.2), for lenalidomide (N = 64) median overall survival was 53.2 months (CI: 44.6-61.8) and for combination of bortezomib and thalidomide (N = 46) 32.2 months (CI: 26.6-37.8). When any of these risk factors was present the OS in each group shortened. In the group of patients with no risk factors (N = 255) the median OS for bortezomib (N = 126) was not reached, for thalidomide (N = 96) the median OS was 66.3 months (CI: 43.1-89.6), for lenalidomide (N = 17) 71.1 months (CI: 44.8-97.4) and for combination of bortezomib and thalidomide (N=8) was not reached. In the group of patients with 1 risk factor (N = 514) the median OS for bortezomib (N = 303) was 46.1 months (CI: 36.2-56.1), for thalidomide (N = 141) 56.2 months (CI: 47.5-64.9), for lenalidomide (N = 29) 49.0 months (CI: 9.7-88.2) and for combination of bortezomib and thalidomide (N=20) was not reached. In the group of patients with 2 risk factors (N = 420) the median OS for bortezomib (N = 288) was 34.0 months (CI: 24.7-43.4), for thalidomide (N = 87) 31.9 months (CI: 22.8-40.9), for lenalidomide (N = 14) 33.2 months (CI: 0.0-67.6) and for combination of bortezomib and thalidomide (N=20) 29.4 months (CI: 7.6-51.1). In the group of patients with 3-4 risk factors (N = 221) the median OS for bortezomib (N = 163) was 19.2 months (CI: 14.9-23.5), for thalidomide (N = 46) 18.9 months (CI: 13.0-24.7), for lenalidomide (N = 4) 6.1 months (CI: 0.0-63.0) and for combination of bortezomib and thalidomide (N=3) 14.3 months (CI:-).Conclusion: The overall survival of patients above the age of 65 shows promising results with the use of novel agents. The treatment outcomes seem to be generally affected by overall condition, age and gender of the patient rather than treatment modality used upfront. [Display omitted] DisclosuresHajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Maisnar:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Phase 2 Trial of the Combination of Ixazomib, Thalidomide and Dexamethasone (ITD) in Relapsed/Refractory Myeloma: Planned Preliminary Analysis

Introduction: Despite improved survival outcomes in multiple myeloma (MM), disease relapse is inevitable and further therapeutic options are required. Therapy with bortezomib (a proteasome inhibitor (PI)), thalidomide and dexamethasone (VTD) has been shown to be highly effective in relapsed/refractory MM (RRMM). Ixazomib (an oral PI) in combination with lenalidomide and dexamethasone (IRD) has been shown to increase progression-free survival (PFS) in RRMM. Currently there are limited data on the efficacy/tolerability of the combination of ixazomib, thalidomide and dexamethasone (ITD). ITD may prove to be an attractive “all oral” therapeutic alternative particularly in jurisdictions with less access to high cost therapeutics.Aim: To evaluate the efficacy and safety of the combination of ixazomib, thalidomide and dexamethasone (ITD) in RRMM.Methods: This is a planned preliminary analysis of a multi-centre, single arm, open label, phase 2 study of the combination of ITD in RRMM patients with 1-3 prior lines of therapy. ITD (Ixazomib: 4mg orally D1, 8, 15, Thalidomide 100mg orally nocte D1-28, Dexamethasone 40mg orally D1, 8, 15, 22 of a 28-day cycle) was continued until disease progression or unacceptable toxicity.We plan to enrol 45 patients and to date data for 33 patients who have received 4 cycles of therapy or are off study were available for analysis. Baseline characteristics, therapy/safety, response and outcome data were analysed. The primary endpoint is overall response rate (ORR) defined as at least a partial response (PR). As specified in the protocol, we calculated the posterior distribution for ORR using the currently available data and a minimally informative prior distribution (Bayesian updating of the posterior could commence after 12 patients became evaluable) and we report a 95% credible interval (CI) for ORR and also for the clinical benefit rate (CBR) defined as at least a minimal response (MR). We also report an interim summary of PFS. Analyses were performed using R and SAS9.4.Results: Thirty-three patients were enrolled from 2 Australian sites (M:F 24:9), median age: 66 years (41-85). Median number of prior lines of therapy was 1 (1-3). Patients received a median of 6 cycles (1-20). Nine patients (27.3%) received <4 cycles. ISS stage at diagnosis: 1: 12, 2: 14, 3: 4 (3 unknown). Of patients with known cytogenetic/FISH data (n=22) 8 had high risk features (del17p, +1q21, t(14;16), t(4;14)). Twenty patients had IgG disease (IgA: 7, Light chain only: 6).The ORR was 18/33 (54.5%; 95% CI: 37.6 - 70.1%) including complete response (CR) in 2 patients (6.1%). The posterior probability that the true ORR exceeds 45% is currently 86%. Median time to best response was 83 days for responders and 99 days when non-responders were censored at their dates of last contact. The CBR was 23/33 (69.7%; 95% CI: 52.4 - 82.5%). The posterior probability that the true CBR exceeds 45% is currently > 99%. Both median PFS and OS have not been reached.Safety/tolerability: Fourteen patients (42.4%) tolerated ITD dosing as per protocol with thalidomide dose reduced/ceased in 15 patients (reduced: 8, ceased: 7) and dexamethasone dose reduced in 6 patients. No patients remaining on study have dose reduced/ceased ixazomib. Eighteen patients remain on study therapy with 15 ceasing therapy (progressive disease (PD): 9, adverse event (AE): 2, consent withdrawal: 2, lack of response: 1, new diagnosis of AML: 1). Twenty-two patients experienced a total of ninety-two (all-grade) AEs regardless of relatedness to study treatment with new/worsening peripheral neuropathy (12/92, 13.0%) and infection (11/92, 12.0%) most common. Two patients had grade 3 adverse events (epistaxis/thrombocytopenia:1, constipation: 1).Conclusion: The combination of ITD is efficacious and tolerable in RRMM and would represent an attractive all oral therapeutic option for RRMM particularly in jurisdictions with limited access to other therapeutics such as lenalidomide.Figure 1. Progression-free survival (PFS) and conventional 95% confidence intervals in months from the date of day 1 of the first cycle of ITD (FAS1).1 Up to the cutoff date (23JUL2018) [Display omitted] DisclosuresBergin:Celgene: Consultancy; AMGEN: Other: Travel to education meeting. Kalff:Janssen: Honoraria; Amgen: Other: travel to preceptorship; Celgene: Honoraria; Takeda: Honoraria. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. .

Thalidomide Combined with Interferons for the Treatment of Recurrent or Refractory Non-Hodgkin's Lymphoma

This study examined the clinical efficacy and safety of thalidomide combined with interferons for the treatment of recurrent/refractory non-Hodgkin's lymphoma. We retrospectively analysed the clinical data of 42 patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) who were treated with a regimen of thalidomide combined and interferon α-1b (IFNα-1b) at Henan Tumour Hospital from July 2007 to January 2017. Specifically, the patients initially received 100 mg thalidomide in tablet form once daily at bedtime. If the patient tolerated the drug, the dose was increased to 200 mg. Recombinant human interferon α-1b was subcutaneously injected at a dosage of 60 μg every other day over a period of four weeks. The efficacy was monitored throughout each treatment cycle, adverse reactions were evaluated, and the progress of the disease was assessed during follow-up visits. Relevant indicators, such as the overall response rate (ORR), the overall survival (OS), the progression-free survival (PFS) for all patients, and the safety of the regimen, were analysed. Forty-two patients were treated with a regimen of thalidomide combined with interferons for at least 1 period. The efficacy of the treatment was evaluated for each patient. The objective response rate (CR + PR) was 73.8%. The median overall survival time was 28 months and the median progression-free survival (PFS) time was 21 months. According to the standards of lymphoid malignancies classified by the WHO in 2001, 36 patients were diagnosed with B-cell lymphoma, 24 of whom suffered from recurrent or refractory mantle cell lymphoma (MCL). The combination of thalidomide and interferons improved the conditions of 16 MCL patients, 8 of whom experienced CR and 8 of whom experienced PR. The median OS was 28 months, and the median PFS was 19 months for the patients with MCL. The primary adverse effects of the regimen were drug-induced fever and joint pain caused by the IFN and neurotoxicity and constipation caused by the thalidomide. The adverse reactions ranged in severity from degree I~II and could be alleviated by symptomatic treatment. Serious adverse reactions, such as anaphylactic shock, deep vein thrombosis and bradycardia, did not occur. DisclosuresNo relevant conflicts of interest to declare.

Ixazomib, Thalidomide and Dexamethasone Is an Effective and Well Tolerated Re-Induction Regimen Leading to Salvage Autologous Stem Cell Transplantation (sASCT): Results from the Re-Induction Interim Analysis of UK-MRA Myeloma XII (ACCoRD) Trial

Ixazomib, Thalidomide and Dexamethasone Is an Effective and Well Tolerated Re-Induction Regimen Leading to Salvage Autologous Stem Cell Transplantation (sASCT): Results from the Re-Induction Interim Analysis of UK-MRA Myeloma XII (ACCoRD) Trial

Association of CD117 and HLA-DR expression with shorter overall survival and/or progression-free survival in patients with multiple myeloma treated with bortezomib and thalidomide combination treatment without transplantation.

Certain immunophenotypes in multiple myeloma (MM), including CD56 and CD117, have been reported to be associated with overall survival (OS). However, previous reports have ignored the impact of different treatment regimens and the long-term prognostic value of immunophenotyping in MM when treated with novel agents, including thalidomide and bortezomib, in the absence of transplantation for autologous stem cell transplantation and allo-hematopoietic stem cell transplantation. To further understand the long-term prognostic value of immunophenotyping in MM, when treated with bortezomib combined with thalidomide-based regimens without transplantation, 80 patients who were newly diagnosed between January 2007 and December 2015, were analyzed retrospectively. In contrast to previous studies, no significant survival time difference was observed between CD56+/CD117+ and CD56-/CD117- groups. Multivariate analysis suggested that human leukocyte antigen-antigen D-related (HLA-DR)+ was independently associated with shorter OS and progression-free survival (PFS), while CD117+ was an independent prognostic factor for decreased PFS. In addition, the myeloma prognostic index (MPI), defined by HLA-DR+, age ≥65 years and international staging system stage III, was suitable for risk stratification of patients treated with novel agents for OS and PFS. The results of the current study suggested that HLA-DR+ patients had a shorter OS and PFS and CD117+ patients had shorter PFS. HLA-DR+ or CD117+ was sufficient to affect survival. Evaluating these markers may reveal valuable prognostic factors for MM in patients receiving bortezomib combined with thalidomide-based regimens without autologous stem cell transplantation and allo-hematopoietic stem cell transplantation). MPI may describe an accessible tool to predict the prognosis of patients with MM.

Thalidomide in Combination with Chemotherapy in Treating Elderly Patients with Acute Myeloid Leukemia

Background: Currently, the treatment decisions in elderly patients with acute myeloid leukemia (AML) are difficult and remain controversial. This study aims to evaluate the effect of thalidomide plus chemotherapy on elderly patients with AML. Methods: 70 elderly AML patients (median age 71 years) were enrolled into this prospective study and randomly assigned to either the control arm (PC, n = 35) or the investigational arm (TPC, n = 35). Patients in the PC arm received a non-intensive regimen composed of cytarabine, aclarubicin and G-CSF (CAG) chemotherapy for induction of remission, and patients in the TPC arm received in addition thalidomide at a maximum dose of 200 mg/day. Results: After 2 courses of induction therapy, complete response rate of TPC and PC arms was 54.3% and 57.1%, respectively (p = 0.810). At the last follow-up, the Kaplan-Meier estimate showed that the median overall survival (OS) and event-free survival (EFS) in patients in the PC arm was inferior to those of patients in the TPC arm. Using a stratified Cox model adjusted for randomized treatment, patients receiving thalidomide plus chemotherapy were shown to derive some survival benefit in both OS and EFS. Overall, the hematological and non-hematological toxicity were similar between the 2 treatment arms. Conclusions: Thalidomide in combination with chemotherapy is an alternative treatment option for elderly patients with AML.

Clinical study of reduced glutathione in prevention of peripheral neuropathy caused by thalidomide

Objective To evaluate the efficacy of reduced glutathione(GSH) for preventing thalidomide-induced peripheral neuropathy (TiPN) in multiple myeloma (MM). Methods A total of 40 cases of MM in Jiading District Central Hospital Affiliated to Shanghai University of Medicine & Health Sciences from October 2014 to September 2016 were chosen as research objects. According to the randomized double blind principle, the patients were divided into two groups, the patients in the treatment group were treated with GSH and thalidomide in combination with chemotherapy, and the patients in the control group were treated without thalidomide and chemotherapy. The occurrence of TiPN between the two groups were observed and analyzed. Results The total incidence of TiPN in the treatment group was 25% (5/20), while that in the control group was 45% (9/20), there was no significant difference between the two groups (χ 2= 1.758, P > 0.05). There were no statistically significant differences in neuromotor conduction velocity (MCV), compound muscle action potential (CMAP) and sensory conduction velocity (SCV) between the two groups (all P > 0.05). There were no statistically significant difference in SNAP of median nerve and ulnar nerve between the two groups (both P > 0.05). But the sensory nerve action potential (SNAP) of superficial peroneal nerve in the treatment group was higher than that in the control group [(7.5±4.6) vs. (4.9±2.6)], and the difference was statistically significant (t= 2.221, P < 0.05). Conclusion GSH has a certain effect on the prevention of TiPN. Key words: Multiple myeloma; Peripheral nervous system diseases; Thalidomide; Glutathione

Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma through suppression of NF-κB activation.

Treatment for high-risk neuroblastoma is still challenging. The purpose of the present study was to determine whether thalidomide suppresses etoposide-induced NF-κB activation and thus potentiates apoptosis in murine neuroblastoma. A murine neuroblastoma cell line, C1300, and A/J mice were used in this study. We evaluated NF-κB activation after using etoposide with or without thalidomide by quantitative analysis of NF-κB by ELISA and by Western blot analysis of IκB phosphorylation in vitro and in vivo. Induction of apoptosis was evaluated by Western blot analysis of the apoptotic signals caspase-3, 8, and 9 in vitro and by TUNEL assays in vivo. We also evaluated the efficacy of the combination of etoposide and thalidomide by assessing tumor growth and mouse survival in vivo. Etoposide activated NF-κB in C1300 cells. This activation was suppressed by thalidomide and IκB was re-upregulated. The apoptotic signals were enhanced by the combination of thalidomide and etoposide compared with etoposide alone in vitro, which was consistent with TUNEL assays. The combination of etoposide and thalidomide also slowed tumor growth and mouse survival. Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma by suppressing NF-κB.

Neuro- and nephroprotective effect of grape seed proanthocyanidin extract against carboplatin and thalidomide through modulation of inflammation, tumor suppressor protein p53, neurotransmitters, oxidative stress and histology.

The combination of thalidomide and carboplatin is one of the most potent chemotherapeutic strategies for the treatment of cancer. However, limited studies have been conducted on the neurotoxicity and nephrotoxicity of both chemotherapeutic agents. The aim of our study was to assess the toxicity of thalidomide and carboplatin combination on brain and kidney and investigate the protective effect of grape seed proanthocyanidin extract (GSPE). Thalidomide and carboplatin induced up-regulation of the expression of p53, tumor necrosis factor-α and interleukin-6 in brain and kidney. Acetylcholinesterase, dopamine and serotonin were decreased and norepinephrine was increased. Thiobarbituric acid reactive substances, nitric oxide, lipid profile, bilirubin and creatinine were elevated, while antioxidants enzymes (GST, GPX, CAT and SOD), total antioxidant capacity and the levels of glutathione were decreased. A microscopic examination showed shrinkage of capillaries, degeneration with pyknotic nuclei, loss of normal structure and neuronal degeneration. GSPE co-treatment with thalidomide and carboplatin reduced their brain and renal damage, oxidative stress, diminished cytokines, p53, neurotransmitters and biochemical parameters, and inhibited brain and renal cell apoptosis. It can be concluded that, the protective effects of GSPE against thalidomide and carboplatin induced-brain and renal damage was associated with the minimization of oxidative stress.

Thalidomide protects against acute pentylenetetrazol and pilocarpine-induced seizures in mice.

Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide's effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine.

Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells.

Lymphatic and hematogenous spread are the most common ways for tumors to metastasize. Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) particularly VEGF-A is important in the process of angiogenesis. The current research has indicated that thalidomide (THD) may be able to inhibit angiogenesis, stimulate the activity of the immune system and inhibit the adherence of cancer cells to stromal cells. These changes may lead to suppression of tumor occurrence and development. To date, to the best of our knowledge, the effects of THD on colon cancer SW480 cells have not been reported. In the present study, the effects of THD and a combination of THD and oxaliplatin (L-OHP) on the proliferation of SW480 cells have been investigated. Furthermore, the expression of VEGF-A and hypoxia-inducible factor 1 (HIF-1) was analyzed using MTT assay, quantitative polymerase chain reaction and western blot analysis. The results indicated that THD was able to inhibit SW480 cells in dose-and-time dependent manner and inhibit the expression of VEGF-A and HIF-1α. Furthermore, treatment with THD and L-OHP had synergistic inhibitory effect, which may provide a novel treatment strategy for advanced colorectal cancer.

Bortezomib Prescription Pattern for the Treatment of Multiple Myeloma by Hematologists in Nigeria.

PurposeNovel therapy has dramatically changed the outcome of patients with myeloma. Current National Comprehensive Cancer Network guidelines give bortezomib-based combinations a central role in the management of multiple myeloma (MM). The aim of this survey is to assess the use of bortezomib for the treatment of MM by hematologists practicing in Nigeria.Materials and MethodsThis is a cross-sectional observational survey. A structured, prevalidated questionnaire was self-administered to different cadres of hematologists. Data collected were analyzed using SPSS software version 21 (IBM, Chicago, IL).ResultsThere were 54 respondents from 24 centers across the country. The most frequently used drugs for first-line therapy were thalidomide (66.7%), dexamethasone (54.2%), and bortezomib (48%), and a combination of bortezomib, thalidomide, and dexamethasone (16.7%) was the most frequently used first-line regimen. Of the 54 hematologists, 39 (72.2%) had prescribed bortezomib previously; no one had used bortezomib as monotherapy. Drug unavailability (86.7%) and cost (46.7%) were the major reasons for those who had not prescribed bortezomib. Approximately 56.4% of responders had patients who had experienced adverse effects, of which neuropathy was the most common (86.3%).ConclusionBortezomib, thalidomide, and dexamethasone was the most frequently used first-line regimen to treat myelomatosis. Thalidomide and dexamethasone were the most frequently used drugs in myeloma treatment. Despite poor access to health care, coupled with the high cost and poor availability of bortezomib in our low- or middle-income country, those who prescribed bortezomib did so frequently (in more than half of their patients).