Cytarabine Group Research Articles

Protective effect of alpha‑lipoic acid against in utero cytarabine exposure-induced hepatotoxicity in rat female neonates.

Cytarabine, an anti-metabolite drug, remains the mainstay of treatment for hematological malignancies. It causes various toxic effects including teratogenicity. Alpha lipoic acid (ALA) is a natural antioxidant reported to offer protection against hepatotoxicity induced by various pathological conditions, drugs, or chemicals. We investigated the protective effect of ALA against prenatal cytarabine exposure-induced hepatotoxicity in rat female neonates. A total of 30 dams were randomly assigned to five groups and received normal saline, ALA 200 mg/kg, cytarabine 12.5 mg/kg, cytarabine 25 mg/kg, and cytarabine 25 mg/kg + ALA 200 mg/kg, respectively, from gestational day (GD)8 to GD21. Cytarabine and ALA were administered via intraperitoneal and oral (gavage) routes, respectively. On postnatal day (PND)1, all the live female neonates (pups) were collected and weighed. The blood and liver from pups were carefully collected and used for histopathological, and biochemical evaluations. A significant and dose-dependent decrease in maternal food intake and weight gain was observed in the pregnant rats (dams) of the cytarabine groups as compared to the dams of the control group. The pups exposed to cytarabine showed a significant and dose-dependent (a) decrease in body weight, liver weight, hepatosomatic index, catalase, superoxide dismutase, glutathione, glutathione peroxidase, serum albumin levels and (b) increase in malondialdehyde, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, AST/ALT ratio, and histopathological anomalies. Maternal co-administration of ALA ameliorated these biochemical changes and histopathological abnormalities by combating oxidative stress. Future studies are warranted to explore the molecular mechanisms involved in the ALA's protective effects against prenatal cytarabine-induced hepatotoxicity.

Attenuating Effects of α-tocopherol on Cytarabine-Induced Toxicity in Parotid Salivary Gland of Rabbits: A Histological and Immunohistochemical Study

Background: Cytarabine is considered a cornerstone of treating acute leukemia. Xerostomia is among the adverse effects that can dictate treatment cessation or the use of some agents that decrease its cytotoxic effects. Objectives: This study aims to identify the histological effects of cytarabine on the rabbits’ parotid gland and to assess the ameliorating α–tocopherol impact on these effects. Methods: The study rabbits were separated into 4 groups. Group A (control) was given 1 mL of intraperitoneal (IP) injection of normal saline/day for 10 days. Group B received α-tocopherol (800 IU) by gavage for 10 days. Group C received cytarabine (60 mg/kg/d) IP for 10 days. Group D received α-tocopherol (800 IU) by gavage before injection of cytarabine (60 mg/kg) at the same time for 10 days. The rabbits were euthanized, and tissue preparation for analyzing microscopically and immunohistochemically for B-cell lymphoma 2 (Bcl-2) and tumor-necrosis-factor (TNF)-α was achieved. Results: Microscopically, group B’s parotid salivary gland sections revealed increased thickness of connective tissue of the trabeculae, degeneration, and necrosis of serous acini cells with aggregation of inflammatory cells. In contrast to the histopathological alteration of the glands in group C, which is characterized by intact serous acini, intercalated duct, and normal thickness of trabeculae, in the cytarabine group, TNF-α immunohistochemical expression was of grade 3 and in the cytarabine with α-tocopherol group was of grade 1. The Bcl-2 immunohistochemical expression in the cytarabine group was of grade 0, and in the cytarabine with α-tocopherol group was of grade 1. Conclusion: α-Tocopherol decreases cytarabine toxicity in the rabbits’ parotid salivary glands.

Cytarabine induces cachexia with lipid malabsorption via zippering the junctions of lacteal in murine small intestine

Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel.

P-081 Effect of chemotherapy (cytarabine) and acute myeloid leukemia on the development of spermatogenesis, spermatogonial microenvironment and inflammatory factors at the adult age of immature-treated mice

Abstract Study question How do AML and cytarabine affect the development of spermatogenesis, germ cell microenvironment and testicular inflammatory factors at the adult age of immature-treated mice? Summary answer AML and cytarabine significantly damaged the normal histology of the seminiferous tubules and impaired different stages of spermatogenesis, testicular growth/inflammatory factor in the adult age. What is known already The effect of different types of cancers on male fertility was reported. AML constitutes around 20% of the diagnosed childhood leukemia. Cytarabine is used as anti-AML treatment. Cytarabine is involved in reduction of testes growth and induces testicular atrophy in adults. In adult AML patients, it was shown that AML affects semen parameters even before chemotherapy treatment. Furthermore, a significant reduction in semen quality of thawed cryopreserved semen from leukemia patients compared to control patients was reported. However, the effect of AML and cytarabine before puberty on the development of spermatogenesis in adult age was not yet reported. Study design, size, duration Two-week-old males C57/BLACK mice were used. 1. Control group – injected with saline. 2. AML group – injected (intraperitoneal; i.p) with 3x104 AML cells/100 ml (murine C-1498 AML cell line). 3. Cytarabine group - three injections of cytarabine (140 mg/kg/100 ml) were performed every 12 hours. 4. AML+cytarabine group – cytarabine was i.p injected 24 hours after AML injection (injections were performed every 12 hours 3 times). Mice were sacrificed 1,2,3,4,5 weeks after AML injection. Participants/materials, setting, methods Testes were removed, weighted and fixed in Bouin’s solution for histological evaluation, or kept at -70°C for RNA extraction. The presence of premeiotic (SALL4, PLZF), meiotic (CREM-1) and postmeiotic (ACROSIN) cells were examined by immunofluorescence staining analysis and/or RNA expression by qPCR analysis. Main results and the role of chance We have successfully developed a system of AML in immature mice by i.p injection of C1498 cells. Cytarabine prolonged life of AML-treated mice from 2.5 weeks to 4 weeks. AML had no effect on both body and testicular weight. However, cytarabine significantly reduced testicular weight (around 50% of the control in the first 3 weeks after treatment, and around 30% of the control from 3-4.5 weeks after treatment; p < 0.001). One and/or 2 weeks after the treatment showed that both AML and cytarabine alone or in combination significantly decreased seminiferous tubules normal histology compared to control, (30%, 20%, 10% respectively) (p < 0.001). Cytarabine, but not AML significantly increased the expression of PLZF and SALL4 after 2 weeks compared to control (p < 0.001). However, each treatment significantly increased the percentages of seminiferous tubules with apoptotic cells compared to control (p < 0.05). AML or cytarabine significantly decreased the percentages of tubules with meiotic and postmeiotic markers compared to control (p < 0.05). Also, AML or cytarabine significantly decreased the testicular protein levels of GDNF, CSF-1 (p < 0.01) but did not affect LIF compared to control. Furthermore, AML or cytarabine significantly decreased the protein levels of IL-10. However, AML significantly increased IL-6 when cytarabine increased it compared to control (p < 0.01). Limitations, reasons for caution Animal model of leukemia may behave different from human model. Wider implications of the findings We successfully developed AML disease in immature mice, and demonstrated its impairment the normal histology of the seminiferous tubules and spermatogenesis in the adult age. We showed that AML and cytarabine affect testicular microenvironmental and inflammatory factors. Our results may assist in development future therapeutic strategies for male fertility preservation. Trial registration number NON

Standard-Intensity Induction and Intermediate/High-Dose Cytarabine Consolidation Can Improve Survival for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective Cohort Study.

BackgroundThere is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients.MethodsA total of 149 consecutive newly diagnosed elderly AML patients (aged ≥60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed.ResultsAfter the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035).ConclusionOur results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.

Integrated RNAi screening identifies the NEDDylation pathway as a synergistic partner of azacytidine in acute myeloid leukemia

Treatment of acute myeloid leukemia (AML) remains challenging and novel targets and synergistic therapies still need to be discovered. We performed a high-throughput RNAi screen in three different AML cell lines and primary human leukemic blasts to identify genes that synergize with common antileukemic therapies. We used a pooled shRNA library that covered 5043 different genes and combined transfection with exposure to either azacytidine or cytarabine analog to the concept of synthetic lethality. Suppression of the chemokine CXCL12 ranked highly among the candidates of the cytarabine group. Azacytidine in combination with suppression of genes within the neddylation pathway led to synergistic results. NEDD8 and RBX1 inhibition by the small molecule inhibitor pevonedistat inhibited leukemia cell growth. These findings establish an in vitro synergism between NEDD8 inhibition and azacytidine in AML. Taken together, neddylation constitutes a suitable target pathway for azacytidine combination strategies.

Protective role of royal jelly to alleviate side effects of chemotherapy on submandibular salivary glands of albino rats (Histological and Electron Microscopic Study)

Abstract Chemotherapeutic agent induces severe tissue injury. Royal jelly has beneficial biological effects. Aim: To evaluate the protective role of royal jelly on salivary glands of rats treated with cytarabine. Methods: 21 male albino rats were divided into three groups. Group I (control group) normal without any medication. Group II (cytarabine group) at dose 100mg/kg/ I.P. Group III (cytarabine & Royal jelly group) was administrated royal jelly prior to cytarabine injection. After 2weeks the submandibular glands were dissected and prepared for histological and electron microscopic (TEM) examinations. Results: Light microscopic examination of cytarabine group revealed deformity of the secretory portions with numerous intracellular vacuoles, deeply stained atrophied nuclei. Dilated excretory ducts with degenerated epithelial lining. Some secretory cells were degenerated. While Royal jelly treated group revealed well defined serous acini and well form striated ducts. TEM examination of cytarabine group revealed pyknotic nucli with nuclear polymorphism. Swollen mitochondria and dilated RER. Striated duct has ill-defined cell boundaries and cytoplasmic vacuolizations. These changes were improved at Royal jelly treated group. Conclusion: Administration of Royal jelly produced a protective effect against cytotoxic changes induced by chemotherapy in rat submandibular salivary glands.

Comparison of Subcutaneous Injection Versus Intravenous Infusion of Cytarabine for Induction Therapy in Acute Myeloid Leukemia: Results of a Prospective, Randomized, Multicenter, Noninferiority Phase 3 Trial

Purpose: The aim of this study was to determine whether the efficacy and tolerability of subcutaneous cytarabine injection are non inferior to those of continuous intravenous infusion of cytarabine for patients with de novo acute myeloid leukemia.Methods: Patients with de novo acute myeloid leukemia were randomized into two groups: Patients in group A received idarubicin 10 mg/m2 for 3 days and subcutaneous cytarabine 50 mg/m2 injection twice daily for 7 days. Patients in group B received idarubicin 10 mg/m2 for 3 days and intravenous cytarabine 100 mg/m2 by continuous infusion daily for 7 days. The primary efficacy end-point was complete remission. A lower confidence bound greater than -15% indicated noninferiority.Results: One hundred and ninety-eight patients were analyzed in this study. The demographic characteristics were generally similar between two groups. The first complete remission rate was 74% and 68% for subcutaneous injection and intravenous infusion cytarabine groups, respectively. The difference between these two groups was 6%, with confidence interval ranging from 7% to 19%. These results indicated subcutaneous cytarabine injection group was non inferior to continuous intravenous infusion group with regard to the primary end point (Table 1). At the same time, adverse events were comparable between two groups.Conclusion: The efficacy and tolerability of cytarabine subcutaneous injection was found to have been non inferior to those of intravenously continuous infusion cytarabine for the standard induction therapy. Cytarabine subcutaneous injection offers a convenient alternative to therapy acute myeloid leukemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Real-World Outcomes of Patients with Acute Myeloid Leukemia in Taiwan: A Nationwide Population-Based Study, 2011-2015

BackgroundAcute myeloid leukemia (AML) is a hematological malignancy originating from myeloid precursor cells, with different cytogenetic abnormalities, genetic mutations and diverse clinical prognoses. We investigated the clinical characteristics, treatment patterns, and outcomes of adult AML patients in Taiwan. Materials and MethodsWe retrospectively included 3851 patients with AML in the Taiwan Cancer Registry Database from 2011 to 2015. We excluded patients younger than 20 years, with acute promyelocytic leukemia, and with no pathological confirmation. ResultsAmong the 3292 patients included, 2179 received induction chemotherapy and 1113 did not, because of older age and higher Charlson comorbidity index (CCI) score. Among the 2179 treated patients, 162 received high-dose cytarabine-based chemotherapy, 1535 received standard-dose cytarabine with anthracyclines, 209 received low-dose cytarabine-based chemotherapy, and 273 received chemotherapy without cytarabine. Patients in the low-dose cytarabine group had the oldest age and highest CCI scores compared with the other groups. In the analysis of overall survival (OS), the median OS of the overall study population was 6.27 months. Treated patients with AML had a longer OS than untreated ones (12.43 months treated vs. 2.03 months not treated; P < .0001). In the multivariate analyses of the treated patients with AML, several factors indicated better prognosis, including receiving standard-dose or high-dose cytarabine, female sex, younger age, lower CCI score, treatment at a medical center, favorable cytogenetic abnormalities, and allogeneic hematopoietic stem cell transplantation. ConclusionOur study was a population-based study that illustrates the real-world outcomes of adult patients with AML in Taiwan.

Increased Health Resource Utilization with the Introduction of Matrix for First-Line Treatment of Primary Central Nervous System Lymphoma

Introduction: Prior to 2016, Primary Central Nervous System Lymphoma (PCNSL) was treated using High-Dose Methotrexate (HD-MTX) +/- Cytarabine. Since 2016, the MATRix regimen (HD-MTX, Cytarabine, Thiotepa, Rituximab) was adopted based on the IELSG32 study (Ferreri et al. Lancet 2016). Information on health resource utilization (HRU) for the MATRix regimen compared to prior standards of care is limited. We sought to investigate HRU in PCNSL patients treated with the MATRix regimen compared to other HD-MTX regimens at a single institution. Methods: Adults (≥18years) with a diagnosis of PCNSL between January 1, 2009 and December 31, 2018 and treated with a HD-MTX regimen were included. All patients were treated in Hamilton, ON, Canada and had complete treatment data available. Patient characteristics, including age, sex, malignancy type, chemotherapy regimen, length and number of hospitalizations, and transfusion data were obtained through electronic health records. Patients treated for relapsed/refractory disease were excluded. Patients were categorized based on the treatment regimen received. Results: Fifty-one patients [20 (39.2%) female] were included. Median age was 69.0 [range, 41 to 87]. 17 (33.3%) patients were treated with MATRix, 14 (27.5%) with HD-MTX + Cytarabine, and 18 (35.3%) with HD-MTX only. 2 (3.9%) patients were treated with other drug regimens and excluded from analysis. The mean overall length of stay (LOS) was 92.6 days [95%CI, 48.9 to 136.3] in the MATRix group, 70.5 days [95%CI, 37.4 to 103.6] in the HD-MTX + Cytarabine group, and 40.6 days [95%CI, 25.6 to 55.5] in the HD-MTX group. Mean LOS was significantly shorter in the HD-MTX group compared to MATRix group (P = 0.04), all other comparisons for LOS were not statistically significant. The mean number of red blood cell units transfused per patient was 11.5 [95%CI, 8.4 to 14.5] in the MATRix group, 10.6 [95%CI, 3.5 to 17.8] in the HD-MTX + Cytarabine group, and 1.9 [95%CI, 0.7 to 3.2] in the HD-MTX group. There were significantly more red blood cell units transfused per patient with MATRix compared to HD-MTX (RR 1.54, 95%CI, 1.05 to 2.27, P = 0.03) but not HD-MTX + Cytarabine compared to HD-MTX (RR 1.40, 95%CI, 0.92 to 2.15, P = 0.12) or HD-MTX + Cytarabine compared to MATRix (RR 1.10, 95%CI, 0.86 to 1.40, P = 0.45). The mean number of pooled platelet units transfused was 8.1 [95%CI 4.0 to 12.1] for the MATRix group, 5.3 [95%CI, 0.9 to 9.7] for the HD-MTX + Cytarabine group, and 0.7 [95%CI, 0 to 1.5] for the HD-MTX group. There were significantly more platelet blood cell units transfused per patient in the MATRix group compared to the HD-MTX group (RR 2.47, 95%CI, 1.24 to 4.92, P = 0.01), all other comparisons were not significant. Conclusion: Our institution observed that the HRU, assessed through LOS, and number of red blood cell and platelet transfusions, in PCNSL patients was significantly higher for patients treated with a MATRix regimen in comparison to a HD-MTX only regimen but not a HD-MTX + Cytarabine regimen. These findings highlight important implications for assessing the impact to patients and systems when a new standard of care is adopted. Additionally, beyond drug acquisition costs these considerations may make the adoption of regimes such as MATRix prohibitive for resource limited settings. Disclosures Hillis: Roche: Honoraria.

Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia.

Cytarabine, 100-200 mg/mE+2/day, is commonly used in induction therapy of acute myelogenous leukemia (AML). Whether a higher dose of cytarabine would be more effective is unknown. Also, there is controversy whether high-dose cytarabine is better than an intermediate-dose combined with other drugs for post-remission therapy. In this open-label, randomized controlled, parallel group study, roles of intermediate-dose cytarabine were investigated. Subjects with AML age 15-55 years were randomized to receive daunorubicin, omacetaxine mepesuccinate, and conventional- or intermediate-dose cytarabine. Subjects achieving complete remission were randomized to receive 3 courses of high-dose cytarabine or 2 courses of intermediate-dose cytarabine with daunorubicin in the 1st and mitoxantrone in the 2nd course. The primary endpoint was disease-free survival (DFS). 591 subjects were randomized to intermediate- (N = 295) or conventional-dose (N = 296) cytarabine group. Three-year DFSs were 67% [95% confidence interval (CI), 61-73] in the intermediate-dose cohort compared with 54% (95% CI, 48-61) in the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, 0.51-0.89; P = 0.005). Three-year survivals were 68% (95%CI, 63-74) and 59% (95%CI, 53-65; HR, 0.720; 95%CI, 0.56-0.94; P = 0.014). Two courses of intermediate-dose cytarabine with daunorubicin or mitoxantrone resulted in similar DFS and survival as three courses of high-dose cytarabine when used for post-remission therapy. Induction therapy with intermediate-dose cytarabine with daunorubicin and omacetaxine mepesuccinate increases DFS and survival in persons with AML ages 15-55 years compared with conventional-dose cytarabine.See related commentary by Watts and Bradley, p. 3073.

Effect of Rutin on Cytarabine-Associated Pulmonary Oedema and Oxidative Stress in Rats.

Cytarabine is effectively used in the treatment of adult acute leukemia, but it has a dose-limiting side effect of fatal pulmonary oedema because it increases the vascular permeability of the alveolar capillaries. The aim of the present study was to conduct a radiological, biochemical and histopathological investigation of the effect of rutin on cytarabine-associated pulmonary oedema in rats. Rats were treated with a combination of rutin+cytarabine by administering oral rutin at a dose of 50 mg/kg; other rat groups were orally administered the same volume of physiological saline. One hour after administration of rutin or saline, the rutin+cytarabine and cytarabine groups received an intraperitoneal injection of cytarabine (200 mg/kg). This administration procedure was repeated once a day for 14 days. Radiologically, 50% of the animals given cytarabine alone showed lung oedema, but the rutin+cytarabine group showed no oedema. The inclusion of rutin decreased the amounts of cytarabine-associated malondialdehyde, tumour necrosis factor-α, and nuclear factor-κB in the lung tissue. Rutin also inhibited the reduction of total glutathione by nitric oxide. These findings suggest that rutin may be a beneficial adjunct that can minimise the development of cytarabine-associated pulmonary oedema.

Analysis of Clinical Characteivstics and Therapeutic Efticacy of 54 Patients with Mantle Cell Lymphoma

To analyse the clinical characteristics and therapeutic efticacy of patients with mantle cell lymphoma(MCL). The clinical data including cliniced parameters and laboratorial test results of 54 patients with MCL were collected and restrospectively analyzed to clarity the clinical characteristics of MCL and to evaluate the survival and factors affecting prgnosis of patients. The incidence of MCL accounted for 4.0% of NHL in our center. The median age of MCL patients was 63 years old, the male and female ratio was 1.4∶1. The MCL patients inⅢ-Ⅳ stage accounted for 96.3%; the extranodal organ involvement existed in 98.1% patients, the most common extranodal involvement sites were bone marrow(72.2%), spleen(51.9%), gastrointestinal tract(25.9%). The overall response rate(ORR) was 66.7%, among which the complete remisson (CR) rate was 37.1%, 3 year and 5 year-progression free survival rate was 52.7% and 34.7% respectively, 3 year and 5 year overall survival rate was 60.4% and 49.6% respectively. The therapeutic efficacy in chemotherapy combined with cytarabine group was suprior to that in chemotherapy group without cyteratine, the chemotherapy comtined with auto-HSCT could further improve the prognosis of patients. The unvariatc analysis showed that the KI67 level, B sgmptom, liver function, LDH and C-RP levels, initial therapeutic efficacy, high dose cytarabine regimen, auto-HSCT and relapse-refractroy status were prognosis-related factors; the multi-variate analysis showed that the initial therapeutic efficacy and relapse rcfractory stasus were independent prognostic risk factors. Analysis showed that the surival of patients stratified according to MIPI and MIPI-c indexes was significantly different from that stratified by IPI index. The MCL patients commonly complicated by extranodal involvement and have poor prognoss. Using the chenotherapy regimen combined with high doge of cytarabine as induction therapy and auto-HSCT as consotidatory therapy shows the significont efficacy for survival of young patients with MCL. The MIPI and MIPIc indexe are more much suitable for prognosis evaluation of MCL patients.The initial therapeuntic efficacy and relapse-refractrong status are the independant prognosis-related factors.

Cytarabine assures a high concentration of circulating CD34+ cells during haematopoietic stem cells mobilization in lymphoma patients

Mobilization of haematopoietic stem cells for autologous transplantation in lymphoma patients currently lacks optimal and universally accepted protocol guidelines. Available mobilization procedures use either cytokines alone, predominantly granulocyte colony-stimulating factor, or cytokines in combination with chemotherapy. Chemomobilization may increase the CD34+ cell yield, and some studies indicate that a higher number of CD34+ cells reinfused is associated with better outcome after autologous haematopoietic stem cells transplantation. We aimed to compare the peak of CD34+ cells in peripheral blood between two alternative mobilization therapies in a retrospective cohort of patients affected by lymphoma. Between 2001–2012, 125 retrospectively observed lymphoma patients were treated with either cytarabine ( $n = 36$ ) or cyclophosphamide ( $n = 89$ ), both combined with granulocyte colony-stimulating factor. The difference in the peak of circulating CD34+ cells was the study primary endpoint. The peak of circulating CD34+ cells were significantly higher in the cytarabine group compared with the cyclophosphamide group (median 129/μL vs 77/μL; $p < 0.05$ ), even when accounting for the timing at collection (169% higher in the cytarabine group, $p < 0.01$ ). Haematopoietic stem cells median time collection started 3 days later in the cytarabine group (16 vs 13 days; $p < 0.01$ ). A leukaphaeresis single session was adequate to collect an optimal number of CD34+ cells (greater than $5 \times 10^{6}/\text{kg}$ ) in 69% patients in the cytarabine group compared with 57% in the cyclophosphamide group ( $p = 0.21$ ). Cytarabine gives a higher peak of circulating CD34+ cells in comparison with cyclophosphamide in a retrospective observational cohort of lymphoma patients submitted to chemomobilization.

Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network

Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups. Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. European Commission, Lymphoma Research Foundation, and Roche.

B7-H3 Silencing By RNAi Inhibits Tumor Progression and Enhances Chemosensitivity in U937 Cells

Background: Aberrant expression of the immunoregulatory protein B7-H3 in B7 family has been associated with more advanced disease and poor prognosis in a wide range of cancer. However, the role of B7-H3 in acute monocytic leukemia U937 cells has not been thoroughly investigated. In this study, we examined the gene expression and subcellular localization of B7-H3 in human peripheral blood cells and hematologic malignancy cell lines. Then, we determined the effects of down-regulating B7-H3 expression on U937 cells, which has the highest B7-H3 protein expression in the detected cell lines.Methods: B7-H3 expression in 12 healthy volunteer peripheral blood cell samples and 13 human hematologic malignancy cell lines was determined by RT-PCR, western blot and flow cytometry. B7-H3 knockdown in the U937 cell line was performed using shRNA lentivirus transduction. The effects on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and transwell assays in vitro. U937 xenograft models were used to assess the effects of B7-H3 on tumorigenicity and Ki-67 and PCNA was detected through immunohistochemical. Changes in cell growth inhibition and apoptosis, when combined with chemotherapy drugs, were determined using CCK-8, Annexin V-FITC/PI and Hoechst 33342 staining assays in vitro. The therapeutic effect of B7-H3 knockdown in combination with chemotherapy drugs were also studied by U937 xenograft models in vivo.Results: B7-H3 mRNA was widely expressed in the 12 hematologic malignancy cell lines except for CZ1 and PB MNCs of volunteers. But the protein level of B7-H3 was only abnormally overexpressed in 12 hematologic malignancy cell lines except for CZ1, with subcellular localizations in nucleus and cytoplasm mostly determined. The down-regulation of B7-H3 in U937 cells significantly decreased cell growth and the rate of colony formation by 32.8% in 72 h and 70.3% in 14 d. Mean inhibition rate of tumor growth with B7-H3 knockdown was 59.4%, and expression of both Ki-67 and PCNA in xenografts was significantly reduced. After B7-H3 silencing, U937 cell cycle was arrested at G0/G1 phase, and the cell cycle-related proteins Cyclin D1 and CDK4 were lower. Cell migration rate of B7-H3 knockdown cells was reduced more than five-fold, and invasion capacity was decreased by 86.7%. The rates of distant metastasis in B7-H3 knockdown xenografts were significantly decreased. The invasion-related proteins MMP-2 and MMP-9 were lower in both B7-H3 knockdown cells and xenografts. B7-H3 RNAi profoundly increased the anti-tumor effect of chemotherapy and enhanced the activity of caspase-3 in vitro and in vivo. At the end of observation (on day 19 after inoculation), inhibition rates of tumor growth in B7-H3 shRNA combined with idarubicin, cytarabine, and idarubicin plus cytarabine groups were 70.5%, 80.0%, and 90.0%, respectively (P =0.006, 0.004 and 0.016). The TUNEL positive cells were significantly increased in the B7-H3 shRNA combined with chemotherapy drugs groups.Conclusions: B7-H3 protein was abnormally overexpressed in 12 hematologic malignancy cell lines except for CZ1, with subcellular localizations in nucleus and cytoplasm mostly determined. B7-H3 may promote U937 cell progression, and shRNA targeting B7-H3 significantly enhances sensitivity to chemotherapeutic drugs. These results may provide new insight into the function of B7-H3 and a promising therapeutic approach targeting B7-H3 in acute monocytic leukemia. DisclosuresNo relevant conflicts of interest to declare.

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study

Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Sunesis Pharmaceuticals.

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial

No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. Schering-Plough/Merck and French Government.

Decitabine Compared with Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia: A Pilot Study of Safety, Efficacy, and Cost-Effectiveness.

Introduction. The incidence of Acute Myeloid Leukemia (AML) increases progressively with age and its treatment is challenging. This prospective case control study was undertaken to compare the safety, efficacy, and cost-effectiveness of decitabine with those of cytarabine in older patients with newly diagnosed AML who are not fit for intensive chemotherapy. Materials and Methods. 30 eligible patients above 60 years old with newly diagnosed AML were assigned to receive decitabine or cytarabine. The primary end point was overall survival (OS). The secondary objective was to compare adverse events and cost-effectiveness of therapy in the two study groups. Results. In this study, 15 patients received decitabine and 15 patients received cytarabine. The median OS was 5.5 months for each of the treatment groups. The hazard ratio between the treatment groups was 0.811 with 95% CI of 0.390 to 1.687. Toxicity profile was similar in both groups. Cost per cycle of chemotherapy in INR was 24,200 for decitabine and 1,600 for low-dose cytarabine group. Median of simplified cost-effectiveness ratio was 0.00022 for decitabine group and 0.0034 for low-dose cytarabine group. Conclusions. For elderly patients with AML, decitabine and low-dose cytarabine should be chosen based on the patient's choice and affordability. Our study has shown that both of these agents have similar OS and toxicity. Low-dose cytarabine scores over decitabine in developing countries as it is more cost-effective.

Enhanced skin toxicity associated with the combination of clofarabine plus cytarabine for the treatment of acute leukemia.

Skin toxicity is associated with a number of different chemotherapeutic agents used to treat acute leukemias. The term "toxic erythema of chemotherapy" (TEC) has been coined to describe a spectrum of skin findings, ranging from palmar-plantar erythrodysesthesia to erythema of major body folds, with erythroderma representing its most severe form. To clarify the types and frequencies of cutaneous reactions associated with clofarabine plus cytarabine chemotherapy and to compare these to those observed with clofarabine alone, we reviewed our institutional experience over a 5-year period. We reviewed the medical records of 49 patients who were treated with either regimen for acute leukemia. To facilitate comparison of the cutaneous toxicities, only patients treated with clofarabine 40 mg/m(2) daily for 5 days (days 1-5) with or without cytarabine 1 g/m(2) daily for 5 days (days 2-6) were included. Ten patients were treated with clofarabine alone, and 40 patients received clofarabine plus cytarabine; one patient received both regimens. Treatment-associated skin toxicity developed 3-9 days following the initiation of chemotherapy and was more common in the group receiving the two-drug combination as compared to those receiving clofarabine alone [22/40 (55%) vs. 1/10 (10%) respectively, p = 0.014]. The majority of chemotherapy-related cutaneous side effects represented TEC. Cutaneous toxicity was common and more frequent in the clofarabine plus cytarabine group when compared to patients treated with clofarabine alone. This finding is relevant for both clinicians and patients.