Hepatotoxicity Grade Research Articles

Efficacy and Toxicity of Vincristine and CYP3A5 Genetic Polymorphism in Rhabdomyosarcoma Pediatric Egyptian Patients.

Rhabdomyosarcoma (RMS) is a rare cancer that develops in soft tissue, particularly skeletal muscle tissue and occasionally hollow organs like the bladder or uterus. Vincristine (VCR) is the main therapy used in treatment of RMS, it is an alkaloid produced from vinca and it is one of the most commonly prescribed drugs in pediatric oncology for the treatment of a number of tumors. The CYP3A5 enzyme is responsible for vincristine metabolism. The effect of CYP3A5 genetic polymorphism on the efficacy and toxicity of VCR on RMS patients still needs further research. Genotyping for CYP3A5 SNPs rs776746, rs10264272 and rs41303343 was performed using Taqman Real-Time PCR assays in a retrospective cohort study of 150 RMS pediatric patients treated with vincristine. The relationship between these genotypes and RMS survival was then examined. We found that patients with CYP3A5*3/*3 had the highest incidence of vincristine-induced neuropathy reaching 61.3%. Patients with CYP3A5*1/*3, CYP3A5*3/*6 and the normal metabolizers with CYP3A5*1/*1 had frequencies of 22%, 10.7%, and 4.7%. patients with the lowest frequency of 1.3% were those with the CYP3A5*1/*6 genotype. There was no correlation between the genotypes of CYP3A5*3, CYP3A5*6, CYP3A5*7, and RMS survival. Initial risk, metastasis, response, convulsions, unsteady gait and hepatotoxicity grade had a significant effect on overall survival with p<0.05. CYP3A5*1/*1 have less severe vincristine-induced neuropathy than CYP3A5 *1/*3, CYP3A5 *1/*6 and CYP3A5 *3/*3, CYP3A5 *3/*6. There is a significant influence of CYP3A5 mutation on neuropathy grade and assist of ADL as a part of neurotoxicity.

Exploring Indicators of Hepatotoxicity-Related Post-Marketing Regulatory Actions: A Retrospective Analysis of Drug Approval Data

Background: Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. Objective: To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Methods: Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. Predictors (Covariates): We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Outcome (Dependent Variable): Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. Statistical Analysis: Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. Results: A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. Conclusion: Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.

High-dose rifampicin for the treatment of tuberculous meningitis: a meta-analysis of randomized controlled trials.

Tuberculous meningitis (TBM) is one of the most serious types of extrapulmonary tuberculosis and has caused distress to human. Effective treatment is particularly important. The aim of this meta-analysis is to compare the efficacy of high-dose and standard-dose rifampicin. Databases including PubMed, Web of Science, Embase, Scopus and the Cochrane Library databases were electronically searched to identify randomized controlled trials that reported high-dose rifampicin in treatment of patients with TBM. The retrieval time is limited from inception to June 2021. Two reviewers independently screened literature, extracted data and assessed risk bias of included studies. Meta-analysis was performed by using STATA 12.0software. A total of 12studies involving 1596 patients were included. The meta-analysis results showed no significant differences in 6-month mortality, 9-month mortality, Grade I-II AE, Grade III-V AE, hepatotoxicity, hepatotoxicity Grade I-II and cardiologic events between high-dose rifampicin (or high-dose rifampicin plus moxifloxacin or levofloxacin) and standard-dose groups. The log(Cmax ) (WMD 0.69, 95%CI 0.59-0.79, p 0.001) and log(AUC0-24h ) (WMD 0.79, 95%CI 0.71-0.88, p 0.001) were higher with high-dose rifampicin. Subgroup analysis revealed the rise of log(Cmax ) in high-dose rifampicin orally was consistent with intravenous administration compared with the control (WMD 0.69, 95%CI 0.66-0.73, p 0.001). High-dose rifampicin was not a protective factor for 6-month mortality, despite increased plasma Cmax and AUC0-24h . However, the above conclusions are still required to be verified through more RCTs due to the limited quantity of included studies.

Effect of Renal and/or Hepatic Impairment on the Pharmacokinetics and Safety of Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

▪Introduction: Inotuzumab ozogamicin (InO) is an antibody drug conjugate targeting CD22 antigen linked to N-acetyl-g-calicheamicin dimethyl hydrazide, a potent cytotoxic antibiotic that induces double strand DNA breaks. The pharmacokinetics of InO has been characterized in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The primary objective of this analysis was to assess the pharmacokinetics and safety of InO in patients with renal and/or hepatic impairment.Methods: The effects of renal and hepatic impairment on the pharmacokinetics of InO clearance (CL) were evaluated in adult patients with relapsed or refractory ALL (n=234) following administration of 1.2-1.8 mg/m2 fractionated over 2 or 3 doses given weekly. For assessment of renal function, patients were stratified into 5 subgroups using baseline creatinine clearance (BCrCL): normal (≥90 mL/min), mild (60-89 mL/min), moderate (30-59 mL/min), severe (15-29 mL/min), and end-stage renal disease (<15 mL/min).For assessment of hepatic impairment, patients were stratified into 5 subgoups per criteria from the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), which categorizes impairment based on baseline total bilirubin (TB) and aspartate aminotransferase (AST): normal (TB and AST ≤ upper limit of normal [ULN]), mild B1 (TB ≤ ULN and AST > ULN), mild B2 (TB >1-1.5 x ULN, any AST), moderate (TB >1.5-3 x ULN, any AST), and severe (TB >3 x ULN, any AST).Data from adult patients with relapsed or refractory ALL (n=161) who received InO at a starting fractionated dose of 1.8 mg/m2 were used to evaluate the safety of InO in patients with some degree of renal and/or hepatic dysfunction. For each of the renal function and NCI ODWG hepatic impairment subgroups, the percentage of patients exhibiting Grade ≥3 for any adverse events and Grade ≥3 hepatoxicity adverse event, respectively, was reported. Severity of hepatoxicity was determined through standardized search criteria with Standard Medical Dictionary for Regulatory Activities queries (cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, noninfectious; and liver-related investigations, signs, and symptoms) and preferred terms (veno-occlusive liver disease or veno-occlusive disease; hepatic vein occlusion or thrombosis; portal vein thrombosis; Budd-Chiari syndrome; chronic graft versus host disease in liver; and acute graft versus host disease in liver).Results: For renal impairment, the median InO CL was 0.0394, 0.0403, 0.0308, and 0.0273 L/h, respectively, in individuals with normal (n=184), mild (n=32), moderate (n=17), and severe renal impairment (n=1). There were no patients with end-stage renal disease. Grade ≥3 adverse events were reported in 91.7% of patients with normal, 81.8% with mild, 100% with moderate, and 0% with severe or end-stage renal disease renal impairment.For hepatic impairment, the median InO clearance was 0.0363, 0.0520, 0.0382, and 0.0238 L/h, respectively, in individuals with normal (n=167), mild B1 (n=58), mild B2 (n=8), and moderate hepatic impairment (n=1). There were no patients with severe hepatic impairment. Hepatotoxicity Grade ≥3 adverse events were reported in 23.6% of patients with normal, 6.8% with mild B1, and 3.1% with mild B2 hepatic function; no such events occurred in patients with moderate or severe hepatic impairment.Conclusions: InO pharmacokinetics were not affected by renal or hepatic impairment status, and safety was similar regardless of renal and/or hepatic function. Therefore, no starting-dose adjustment is required for patients with relapsed or refractory ALL with pre-existing mild to severe renal dysfunction or mild hepatic impairment. DisclosuresGarrett:Pfizer: Employment. Kantarjian:Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. DeAngelo:Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

Smoking and Hepatitis B Virus-Related Hepatocellular Carcinoma Risk: The Mediating Roles of Viral Load and Alanine Aminotransferase.

Smoking interacts with hepatitis B virus (HBV) to increase the risk of hepatocellular carcinoma (HCC), which might be explained by its role in antiviral immunity. We evaluated the potential mediating role of viral load and/or alanine aminotransferase (ALT) in the relation of smoking with HBV-associated HCC risk. Using multiple mediation analyses to analyze data from 209 HCC cases and 1,256 controls nested within a cohort of 4,841 male HBV carriers, we found that the effect of smoking on the risk of subsequent HCC was substantially mediated through viral load (percent mediated, 31.7%; P = 0.0054), and a significant mediation effect by both viral load and ALT was also evidenced. Among the 1,143 subjects with repeated measures of viral load and ALT over periods of up to 16 years, we further observed that a higher number of pack-years of smoking was associated with higher viral load, maintenance of a high viral load (>4.39 log copies/mL), more severe hepatotoxicity grade, and increased likelihood of ALT ≥80 U/L (odds ratio, 3.14; 95% confidence interval, 1.03-9.64; odds ratio, 6.06; 95% confidence interval, 1.10-33.25, respectively, for 10-19 and ≥20 pack-years versus nonsmokers) during follow-up. Furthermore, plasma interferon-γ levels were reduced in smokers compared with nonsmokers (interferon-γ-positive rate, 14.9% versus 28.7%; P < 0.0001) at baseline. Smoking was also associated with a reduced natural killer (NK) cell frequency in peripheral blood, characterized by reduced NK function through a systems immunology approach, after long-term follow-up in a subsample (n = 171). The combination of smoking and reduced NK cell frequency further increased viral load and the likelihood of ALT ≥80 U/L. Conclusion: The data highlight a role of smoking in HBV viral load, underlining the importance of smoking prevention and cessation in hepatitis B management.

Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists

Tumor necrosis factor (TNF) antagonists are the first-line treatment for many autoimmune diseases. However, they have been associated with reactivation of hepatitis B virus (HBV). We determined the rate of HBV reactivation and hepatotoxicity grade 3 or 4 (HT ≥3) in patients treated with an anti-TNF agent for an autoimmune disease. We collected data from 8887 adult patients in the Kaiser Permanente Northern California database who began treatment with TNF antagonists for autoimmune diseases (dermatologic, rheumatologic, or gastrointestinal) from 2001 through 2010, followed through December 2012. We obtained data on HBV infection (52% of patients were screened for HBV before treatment), demographic features, comorbidities, and use of immunosuppressive agents. HBV reactivation was defined as 1 of the following: >1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA >2000 IU/mL if no baseline level was available, or reverse seroconversion. HT ≥3 was defined according to the National Cancer Institute Common Toxicity Criteria. We performed multivariable logistic regression to identify factors associated with HT ≥3. Twenty-three patients tested positive for HB surface antigen (HBsAg) at baseline and 9 of these had HBV reactivation; of the 4267 patients with unknown HBV status at baseline, 2 had HBV reactivation. None of the 178 patients who were HBsAg negative and positive for the hepatitis B core antibody (anti-HBc+) had HBV reactivation. HBV reactivation occurred in 1/5 HBsAg+ patients who received prophylactic antiviral therapy and 8/18 who did not (P=.61). No one with HBV reactivation had liver failure. HT ≥3 occurred in 273 patients (2.7%), but only 3 cases were attributed to HBV. Cirrhosis was significantly associated with HT ≥3 (P < .001). In a retrospective analysis of patients treated with TNF antagonists for autoimmune diseases, we found HBV reactivation in 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy. Patients should be screened for HBV infection before anti-TNF therapy; HBsAg+ patients should receive prophylactic antiviral therapy, but not HBsAg-negative, anti-HBc+ patients.

Effect of Anti-tuberculosis Drugs on Liver Damage Based on Alanine Aminotransferase Level in Pulmonary Tuberculosis Patients

Background : Antituberculosis (anti-TB) drugs could cause serious effect such as hepatotoxicity signed by the increase of Alanine Aminotransferase (ALT) level. Anti-TB drugs are still needed by TB patients who have hepatotoxicity, although clinicians who manage this condition have not recognize whether the advantage of anti-TB drugs is higher than its adverse effect, and there is no data describing about that issue. This study was conducted to discover the liver damage based on the ALT changes before and 12 days after initial anti-TB treatment. Methods : This was a cross-sectional study with total sampling of medical records of pulmonary tuberculosis inpatients from 1st January 2013–31th December 2014 at the Department of Internal Medicine of Dr. Hasan Sadikin.General Hospital. From 141 data, only 14 medical records were eligible to be included in this study. The data used were ALT level before and after therapy. These data were analyzed using Wilcoxon test and considered as significant if p<0.05. Results : The median age of the subject study was 48(18-65) years. Among 14 patients, 8 were female and 6 were male. Five out of fourteen patients developed hepatotoxicity. Four out of five developed grade 1 hepatotoxicity and one out of five developed hepatotoxicity grade 4. The analysis of the data showed the differences of ALT level before anti-TB therapy (22(4-447)) and 12 days after initial therapy (18.5(4-1206)) was not significant (p=0.660). Conclusions : There is no liver damage based on ALT changes after anti-TB treatment so the treatment can be continued.

P3.02c-100 Nivolumab beyond First-Line (1L) Treatment in Metastatic Non-Small Cell Lung Cancer (NSCLC): Topic: IT Clinical

Patients with metastatic NSCLC progressing to 1L have a poor prognosis. Nivolumab is an anti-PD-1 monoclonal antibody, which has shown to prolong overall survival (OS) in patients who have progressed to platinum-based chemotherapy. We report our experience with nivolumab in pretreated metastatic NSCLC patients. Retrospective study of patients with metastatic NSCLC treated with nivolumab (3 mg/kg every 2 weeks) in second line (2L) and subsequent lines (SL). We evaluate response rate (RR), progression-free survival (PFS), OS and toxicity. Twenty patients were included (2L: 17, SL: 13). Median age: 68 years. Histology: Adenocarcinoma (60%), Squamous cell (33%), Large cell (7%). ECOG PS: ECOG 0-1 (83%), ECOG 2 (17%). Median number of cycles: 8. RR (Twenty-three patients evaluable for response): Complete response (9%), partial response (35%), stable disease (26%), disease progression (30%). Objective response rate (ORR) in 2L vs SL: 55% vs 33%, p=0.30. ORR in squamous vs non-squamous: 25% vs 47%, p=0.40. Median follow-up: 6 months. PFS and OS events at the time of analysis: 43% and 33%, respectively. Median PFS and OS: 7 months and not reached (NR), respectively. PFS in 2L vs SL: NR vs 5 months, HR 0.81, p=0.71. PFS in squamous vs non-squamous: 5 months vs NR, HR 1.39, p=0.58. OS in 2L vs SL: NR vs NR, HR 1.53, p=0.50. OS in squamous vs non-squamous: 7 months vs NR, HR 2.61, p=0.14. The incidence of adverse events was low. The most frequent toxicity (any grade) was asthenia (67%). A patient with chronic liver disease had hepatotoxicity grade 1 and continued treatment. Three patients discontinued treatment due to toxicity: pneumonitis grade 3 (1), rash grade 3 (1), impaired renal function grade 3 (1). There were no toxic deaths. In clinical practice, nivolumab is effective and safe in 2L and SL in patients with metastatic NSCLC.

The frequency of hepatotoxicity and myelotoxicity in leukemic children with different high doses of methotrexate.

Background and objectivesMethotrexate (MTX) is a chemotherapeutic agent that functions as a folic acid antagonist. The frequency of high dose methotrexate (HDMTX)-associated toxicity is variable. In this study, we investigated the frequency of myelotoxicity and hepatotoxicity 7 days after HDMTX infusion.Patients and methodsThis study included children diagnosed with acute lymphoblastic leukemia (ALL) between January 2010 and April 2015. The patient blood counts and biochemical parameters measured before and after 7 days of HDMTX infusion were retrospectively recorded. We assessed HDMTX infusions for 48 children. The number of patients and drug doses included the following: 17 children receiving 1 g/m2 (68 infusions), 14 children receiving 2 g/m2 (56 infusions), and 17 children receiving 5 g/m2 (68 infusions). The classification of toxicity was made based on the Common Terminology Criteria for Adverse Events (CTCAE) 2010 criteria. Myelotoxicity was defined as a hemoglobin level <10 g/L and absolute neutrophil count <1 × 109/L or platelet count <75 × 109/L. The presence of transaminase levels ≥5 times the upper limit was considered to be hepatotoxicity grade ≥3. The MTX levels at 42 h in patients with and without toxicity were compared to evaluate the correlation between MTX levels, hematologic parameters, and transaminase levels.ResultsMyelotoxicity was observed in 35.2%, 37.5%, and 33.8% of the infusions, and hepatotoxicity grade ≥3 was detected in 13.2%, 12.5%, and 11.7% of the infusions in patients receiving 1, 2 and 5 g/m2 HDMTX after 7 days, respectively. There was no statistically significant difference between MTX levels at 42 h in patients with and without toxicity (P > .05, for all). There was no correlation between hematologic parameters and transaminase levels and MTX levels at 42 h.ConclusionHematologic toxicity was the most common toxicity observed. The data indicate the hematologic toxicity increased after repeated cycles in patients receiving 5 g/m2. However, the hepatic toxicity decreased with additional cycles. Our results show the level of MTX at 42 h is not effective to identify toxicity.

Multimodal treatment with ALL-like chemotherapy, Auto-SCT and radiotherapy for lymphoblastic lymphoma

Background. Recommended treatment for lymphoblastic lymphomas, a highly aggressive, relatively rare lymphoma entity predominantly seen in teenagers and young adults, includes acute lymphoblastic leukemia (ALL)-like induction chemotherapy. Whether these patients should be consolidated with maintenance chemotherapy or autologous stem cell transplantation (Auto-SCT) and the use of radiotherapy are matters of debate. Methods. We reviewed treatment and outcome for 25 consecutive patients above the age of 15 years with lymphoblastic lymphoma (T-lineage; T-LBL, n = 19; B-lineage; B-LBL, n = 6) seen at a single center during a 12-year period (1999–2011). Patients were given an ALL-like chemotherapy induction regimen, and responding patients were consolidated with Auto-SCT and local radiotherapy when applicable. Results. Median age at diagnosis was 33 years (range 15–65). Seventeen of the T-LBL patients had a mediastinal mass, three patients had central nervous system (CNS) involvement. Chemotherapy with intensified CNS prophylaxis induced an overall response rate of 92% (CR 84%, PR 8%). In total 23/25 (92%) patients underwent Auto-SCT in first remission while 13 of 14 eligible patients with mediastinal involvement received local radiotherapy. Twenty percent of the patients had hepatotoxicity grade 3–4 and 32% thromboembolic events (TE). Two patients (8%) died of treatment-related toxicity. One patient had progressive disease and died of lymphoma. Three patients have relapsed, but two of these (both B-LBL) are currently alive in second CR after Allo-SCT. With a median follow-up of 98 months (range 1–163) the 5- and 8-year PFS and OS are 76% and 84%, respectively. Conclusions. Combined intensive ALL-like induction and early consolidation chemotherapy followed by Auto-SCT and local radiation therapy resulted in high sustained cure rates.

French “real life” experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia

BackgroundClofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization.MethodsWe retrospectively analysed data for 38 patients, up to 21 years old, attending 17 French centres. Thirty patients received clofarabine alone or in combination for a bone marrow relapse of acute lymphoblastic leukaemia (ALL) or refractory disease and eight patients for a high level of minimal residual disease (MRD). Survival and response durations were estimated by the Kaplan-Meier method.ResultsFor the 30 patients who received clofarabine for a bone marrow relapse of ALL (number of relapse, 1-3; median, 1), the overall remission rate (ORR) was 37%: eight complete remission (CR) and three complete remission without platelet recovery (CRp). Ten of the 11 responding patients subsequently underwent haematopoietic stem cell transplantation (HSCT).Only four of the eight patients who received clofarabine while in remission for a high level of MRD, showed a moderate improvement of MRD. Seven of these eight patients received HSCT and six of them were alive at the end of the study. One other patient was alive without receiving HSCT.However, clofarabine treatment was associated with a high risk of infection and hepatotoxicity. Febrile neutropenia grade ≥ 3 was reported in 79% of patients and documented infections grade ≥ 3 occurred in nine patients (24%). Hepatotoxicity grade 3 was reported in nine patients (24%). We observed four deaths related to treatment.ConclusionIn our experience, the efficacy of clofarabine is poorer than previously reported. Its toxicity is high and can be life threatening. Prospective studies on clofarabine used during earlier phases of the disease may help to define how best this new drug can be exploited for childhood and adolescent ALL.

Rituximab Plus Gemcitabine and Oxaliplatin As Salvage Therapy in Patients with Relapsed/Refractory Mantle-Cell Lymphoma

Abstract 1627Front line treatment with chemoimmunotherapy in mantle cell lymphoma (MCL) is able to obtain a high CR rate. Regrettably, all patients with MCL eventually relapse, a situation for which no effective therapies are available. Gemcitabine plus Oxaliplatin have shown promising results in “in vitro” and in clinical studies for several types of lymphoma, its activity being improved by the addition of rituximab. Against this background, we conducted a pilot study aimed to assess the efficacy and toxicity of the combination of Rituximab, Gemcitabine and Oxaliplatin (R-GemOx) in pts with relapsed/refractory MCL. Inclusion criteria were age > 18 years and a histologically proved MCL that relapsed or was refractory to previous treatment. Patients were excluded if they had neutrophil count < 1,500 μL, platelet count < 100,000 μL, creatinine > 2.5 mg/dL, > 3 times the upper limit of laboratory normal for AST and ALT, or bilirubin > 3 mg/dL. The regimen consisted of Rituximab 375 mg/m2 day 1, Gemcitabine 1000 mg/ m2 and Oxaliplatin 100 mg/ m2 day 2, every 14 days for a total of 8 cycles. Dose and interval adjustment was done according hematological and extrahematological toxicities. Twenty-eight patients (71% male, median age 68 years, range 41–84 years) were included in this study. Median number of previous treatments was one (range: 1–4). Fifteen (53%) pts had relapsed after previous CR/uCR, 10 (36%) had progressed after a PR, and three (11%) were refractory to the previous treatment. Bone marrow infiltration was observed in 85% of evaluated patients. Median number of cycles administered was 8 (range 2–8). Toxicity was mainly hematological, with a grade 3–4 neutropenia and thrombocytopenia observed in 9 (4.7%) and five (2.6%) cycles, respectively. Main non-hematologic toxicities were hepatotoxicity grade 1–2(21%), sensitive neurotoxicity grade 1–2 (43%), and nefrotoxicity grade 2 (4%). Dose reduction was performed in only two pts for a total of eight cycles, and treatment was delayed in six pts for a total of 17 cycles. After completion of treatment, 21 pts (75%) achieved a CR/uCR, 1 (3.5%) a PR, 1 (3.6%) SD and 5 (17.8%) progressed. Stem-cell transplantation was subsequently performed in nine pts (6 allogeneic and 3 autologous). After a median follow-up of 23 months, 4 patients are alive without progression, 7 relapsed, and 17 died (13 due to progression, 2 due to aGVHD, and 2 due to post-transplant infection). Median PFS and OS of this series were 18 and 30 months, respectively. In conclusion, the R-GemOx combination showed an encouraging efficacy in relapsed/refractory pts with MCL. Hematological and non-hematological toxicity were mild. This is a feasible combination to be employed in salvaging pts prior stem-cell transplantation. Based on the above mentioned data from this pilot study, a national prospective multicenter phase II clinical trial is currently ongoing. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Rituximab Plus Gemcitabine and Oxaliplatin as Salvage Therapy In Patients with Relapsed/Refractory Mantle-Cell Lymphoma.

AbstractAbstract 2825Mantle cell lymphoma (MCL) constitutes one of the lymphomas with poorest prognosis at relapse and there are no effective salvage.The activity shown by the combination Gemcitabine and Oxaliplatin in several types of limfoma, along with its “in vitro” synergistic effect, made this regimen an attractive regimen for salvaging patients with MCL. Against this background, we performed an off-label pilot study in order to assess efficacy and toxicity of the combination R-GemOx in relapsed or refractory patients with MCL.For this, 27 patients (70% male, median age 70 years) diagnosed with MCL between November 2004 and January 2010 were included in this study. Inclusion criteria were adequate performance status, confirmed diagnosis of MCL and relapse or refractoriness to the previous treatment. The regimen consisted of Rituximab 375 mg/m2 on day 1, Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 on day 2, every 14 days, up to 8 cycles. Dose and interval were adjusted according to hematological and extrahematological toxicities. Median number of previous regimens was 1 (range 1 to 3), being EPOCH-R (n=14), R-CHOP (n=6), and RFC (n=3) the most frequently used induction therapies. Twelve patients relapsed after prior CR, 10 progressed after achieving a PR, whereas 5 were refractory to therapy. At inclusion, 85% of patients were in advanced (III/IV) clinical stage, 40% had bone marrow infiltration, 28% gastrointestinal involvement, and 17% cavum infiltration. Median number of cycles administered was 8 (range, 3 to 8). Doses were reduced in 9 cycles and delayed in 15 cycles. Neutropenia grade 3–4 was observed in 9 cycles and thrombocytopenia grade 3–4 in 6. Hepatotoxicity grade 1–2 in 5 pts and grade 3 in 1, sensitive neurotoxicity grade 1–2 in 12 pts, and renal impairment grade 2 in 1 patient. After completion of the treatment, 21 pts (77%) were considered in CR/uCR, 1 (4%) achieved a PR, 1 a SD, whereas 4 PD. Six patients subsequently received a stem-cell transplantation (4 allogeneic, 2 autologous). Thirteen pts are still alive and out of progression. Ten pts have died (8 due to progression and 2 due to acute GVHD). With a median follow-up of 23 months (range: 3–57), PFS and OS at 2 years are 41% and 58%, respectively. The R-GemOx combination showed a significant activity in relapsed or refractory pts with MCL with a very acceptable toxicity profile. These results prompted us to conduct a multicenter phase II clinical trial that is now ongoing. [Display omitted] Disclosures:López:Roche Farma: Research Funding, Travel Support. Bosch:Roche Farma: Research Funding.

Neoadjuvant cetuximab, capecitabine, and radiotherapy (RT) in locally advanced resectable rectal cancer: results of a phase II trial

e15029 Background: Preoperative chemoradiotherapy (CRT) with capecitabine is a treatment of choice for locally advanced rectal cancer. The radiosensitizing effect of cetuximab, an EGFR-targeting monoclonal antibody, may further enhance the tumor response. The aim of this prospective, nonrandomized, open-label phase II study was to establish the efficacy and safety profile of cetuximab combined with capecitabine and concurrent RT for locally advanced resectable rectal cancer. Methods: Patients (pts) with stage II or III rectal cancer confirmed by MRI were treated with capecitabine 1250 mg/m2 twice daily for 2 weeks. Cetuximab 400mg/m2 was intravenously administered on week 3, followed by cetuximab 250mg/m2/week and capecitabine 825 mg/m2 bid including weekends during RT. The RT dose was 45 Gy (25×1.8 Gy, 3D conformal technique), starting on week 4. Total mesorectal excision was scheduled 4–6 weeks after completion of CRT. Tumor regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was complete pathologic response (pCR). Results: Thirty-seven pts were eligible for safety and efficacy analyses. Median age was 55 (range: 33–72) years, 81% of pts were male. Three pts (8.1%) had T3N0 tumors, 1 pt (2.7%) T2N1, 13 pts (35%) T3N1, 1 pt (2.7%) T2N2, 15 pts (40.5%) T3N2 and 4 pts (11%) T4N2. The median tumor distance from anal verge was 6 (range: 1–11) cm. All pts received 45 Gy RT. Dose reduction/treatment interruption was necessary for 9/37 (24.3%) pts owing to hypersensitivity reaction (n=4), hepatotoxicity grade 3 (n=1) or diarrhea grade 3 (n=4). Other grade 3 toxicities included dermatitis (n=6, 16.2%), anorexia (n=1, 2.7%) and infection (n=1, 2.7%). TRG 4 (pCR) was recorded in 3 pts (8.1%) and TRG 3 in 7 pts (18.9%). T-, N- and overall downstaging rates were 56.8%, 81.1% and 73.0%, respectively. The total sphincter preservation rate was 75.7%; in 17 pts whose tumors were located ≤5 cm of the anal verge, the rate was 53%. Conclusions: Preoperative CRT with cetuximab and capecitabine is safe and feasible. A high pathologic downstaging rate was achieved, although the pCR rate appeared to be in the range previously reported for CRT with capecitabine. No significant financial relationships to disclose.

Treatment of unresectable or metastatic gallbladder cancer with single-agent gemcitabine or in combination with cisplatin

4211 Background: Gallbladder carcinomas (GC) are often diagnosed at an advanced/metastatic stage amenable only to palliative surgery. Published data on palliative CT for GC are quite scarce and frequently, erroneously mixed with others biliary tract cancers, their median survival is only around 8 to 12 weeks. Results of chemotherapy for advanced GC are extremely poor with traditional treatment based on 5-FU. Methods: Since 1997 we have been studying the effect of gemcitabine. We retrospectively reviewed data of two different protocol treatments, we made possible. In both trials pts had similar characteristics, they all pts had measurable locally or metastatic GC with histological or cytological proof, no prior chemotherapy or radiotherapy. The main endpoint was RR and secondary endpoints were treatment toxicity and overall survival. We reviewed pts data and outcomes. In first trial 26 pts with advanced GC were treated with GEM 1000 mg/m2 i.v. for 30 minutes weekly for 3 weeks out of every 4 until disease progression and/or toxicity. In second cohort, 44 pts received Gem 1200 mg/m2 and Cis 35 mg/m2 on d1and 8, every 21d for a total of 6 courses. RR was evaluated by abdominal CT scan. Pts were treated on an outpatient basis. Results: Twenty-five pts and 42 pts were, evaluated for response. There were 0/4 CRs and 9/16 PRs for gem vs gem + cispl. All pts were evaluated for toxicity. Four and 1 died due to disease progression, one pt. died due to renal toxicity in the arm gem +cispl. In one pt occurred hepatotoxicity grade 4 in arm gem alone. The main grade 3 hematology toxicities included thrombocytopenia (0% vs 2%), neutropenia (3.8% vs 23%) and anemia (3.8% vs 14%) in the group gem vs gem + cispl. Median survival time was 8.7 mos. vs 7 mos. for the entire population, 14.1 mos. vs 9 mos. for responders, and 6.1 mos. vs. 5 mos. for non-responders. Conclusions: GEM is active against advanced, unresectable recurrent and/or metastatic GC with a good tolerability. The low toxicity profile of GEM should be considered when a treatment choice is to be made for a patient with advanced GC. GEM combined cisplatin, resulting in an increased frequency and severity of side effects and not improved rates responses in comparison with gem alone No significant financial relationships to disclose.