Second-line Therapy For Treatment Research Articles

Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial

The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment. Bristol Myers Squibb.

Options beyond BRAF targeted therapy in second-line treatment of patients with BRAFV600E mutant (BRAFmt) metastatic colorectal cancer (mCRC).

47 Background: BRAFmt is a negative prognostic factor in mCRC but also identifies a patient population that may benefit from BRAF targeted therapy. Results from recent trials (BEACON and SWOG1406) demonstrate improved survival outcomes in second- and third-line settings when combining a BRAF inhibitor, an EGFR inhibitor (EGFRi) +/- a MEK inhibitor. In both trials, irinotecan and cetuximab was the control arm with a dismal response rate of 2-4% and progression free survival (PFS) of only 2 months. This suggests chemotherapy plus an EGFRi may not be the optimal approach where BRAF-targeted therapies are not available or have failed. Methods: Data from July 2009 to September 2021 was analysed from TRACC, a multi-site Australian mCRC comprehensive prospective registry enrolling consecutive patients. Patient characteristics, treatment and survival outcomes were examined for patients treated with chemotherapy (CT) alone, with bevacizumab (BEV) or with an EGFRi. Results: Of 2046 registry patients, 256 (13%) harboured a BRAFmt. 72 BRAFmt patients had received second-line (28%) treatment, including CT alone (n = 28), CT plus BEV (n = 26), and CT plus EGFRi (n = 18). Baseline characteristics are shown in the table. Median second-line PFS was 3.3, 4.7 and 1.8 months, for CT alone, CT plus BEV and CT plus EGFRi respectively. Median overall survival (OS) was 8.7, 7.9 and 2.5 months respectively. In multivariate analysis, PFS when treated with CT plus EGFRi trended inferior to CT alone (p = 0.054) and CT plus BEV (p = 0.061), whereas for OS, treatment with CT plus EGFRi was inferior to CT alone (p = 0.038) and CT plus BEV (p = 0.015). Poor PFS was associated with age ≥ 65 years (HR 3.03, p < 0.001) and ECOG ≥ 2 (HR 2.62, p = 0.004), but not associated with a right side primary (p = 0.17), mismatch repair (MMR) status (p = 0.86), or ≥ 3 organs with metastases (p = 0.32). Poor OS was associated with age ≥ 65 years (HR 3.11, p < 0.001), ECOG ≥ 2 (HR 7.32, p < 0.001), right side primary (HR 3.03, p = 0.002) and proficient MMR status (HR 3.57, p = 0.018), but not associated with ≥ 3 organs with metastases (p = 0.17). Conclusions: Less than one-third of BRAFmt mCRC patients received second-line therapy in a real-world setting, indicating an urgency to explore activity of BRAF targeted therapy in the first line setting. Treated patients received limited benefit, with CT plus EGFRi PFS outcomes comparable to BEACON control arm (1.8 vs 2.0 months) and trending inferior to other options. The best OS outcomes were achieved with CT alone or CT plus BEV.[Table: see text]

Efficacy of Twice a Day Bismuth Quadruple Therapy for Second-Line Treatment of Helicobacter pylori Infection.

Bismuth quadruple therapy (BQT) is an effective treatment for Helicobacter pylori infection. However, frequent dosing schedules of BQT regimen often compromise drug adherence and may affect treatment outcomes. This retrospective study aimed to investigate the efficacy of twice-daily BQT compared to that of four times a day therapy. From August 2018 to November 2020, adult patients who failed first-line standard triple therapy and underwent BQT were eligible. Patients were categorized into two groups according to dosing schedule: (i) the BQT group (n = 213) who received standard BQT administered four times a day; and (ii) the BQTb group (n = 141) who received proton pump inhibitor, bismuth 600 mg, metronidazole 500 mg, and tetracycline 1 g twice a day. The eradication rate did not differ between the BQT (92.5%) and the BQTb groups (90.1%) (p = 0.441). Adherence and adverse event rate were similar between the two groups. Multivariate analysis showed that current smoking was associated with eradication failure; however, dosing frequency was not associated with the efficacy of eradication therapy. This study suggested that twice a day BQT is as effective as four times a day therapy for second-line treatment of H. pylori infection.

3095 – IMMUNE THROMBOCYTOPENIA AND BONE MARROW HEMOPHAGOCYTOSIS ASSOCIATED WITH SARS COV-2

The clinical presentation of patients infected with SARS-CoV-2 is remarkably diverse. Likewise, the underlying pathophysiological mechanisms are proving complex. Disturbances in the blood coagulation system and cytokine storm, such as seen in hemophagocytic syndrome, are among the most serious ones. We present the case of a female 79-year-old patient with marked thrombocytopenia of 4 (150-450) x10^9/L occurring in the context of a confirmed SARS-CoV-2 infection. Clinically, one episode of epistaxis and petechiae was observed, otherwise no signs of bleeding occurred. Diagnostic workup included microscopic blood smear analysis, bone marrow cytologic evaluation and flow cytometric immunophenotyping. Hematological malignancies, thrombotic microangiopathies and common infections were excluded as cause of the low platelet count. In the bone marrow, cytology, the megakaryocytic lineage presented normocellular. However, several large hemophagocytes with engulfed hematopoietic cells were detected. A further evaluation of markers frequently associated with hemophagocytic syndrome was performed. Ferritin was 2888 (0-150) ng/mL, CRP and GOT were slightly elevated. The white blood count was normal with a marked decrease of lymphocytes to 0.13 (1.10-3.60) × 10^9/L. There was no fever or organomegaly and the patient was in good clinical constitution. Thus, we did not diagnose hemophagocytic syndrome. Due to no other explanation for the clinical and laboratory findings, the patient was diagnosed with immune thrombocytopenia and concomitant bone marrow hemophagocytosis associated to SARS-CoV-2. The first-line treatment consisting of prednisolone and intravenous immunoglobulins failed to induce an increase in the platelet count. As second-line treatment therapy with Eltrombopag, a TPO-agonist, was started and a sustainable response with platelets in the normal range was achieved.

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives.

Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.

Cost-effectiveness analysis of empagliflozin versus sitagliptin as second-line therapy for treatment in patients with type 2 diabetes in the United States.

AimTo estimate the cost‐effectiveness of sequential addition of empagliflozin versus sitagliptin after metformin in patients with type 2 diabetes (T2D) with or without cardiovascular disease (CVD) from the perspective of the US healthcare payer.MethodsAn individual simulation model predicted lifetime diabetes‐related complications, using UKPDS‐OM2 equations in patients without CVD, and EMPA‐REG OUTCOME equations in patients with CVD. Additional US‐based sources informed inputs for population characteristics, adverse events, non‐CV death, treatment escalation, quality of life and costs. Costs and quality‐adjusted life‐years (QALYs) were discounted 3.0% annually.ResultsThe incremental cost‐effectiveness ratio (ICER) for second‐line empagliflozin versus sitagliptin in the overall T2D population was $6967/QALY. Empagliflozin led to longer CVD‐free survival (0.07 years) and an 11% reduction in CV death in patients with CVD compared with sitagliptin. Empagliflozin resulted in greater benefits with greater costs in patients with versus without baseline CVD, yielding ICERs of $3589/QALY versus $12 577/QALY, respectively. Results were consistent across a range of deterministic and probabilistic sensitivity analyses and scenarios.ConclusionCompared with sitagliptin, empagliflozin was cost‐effective (at $50 000/QALY US threshold) as a second‐line treatment to metformin for T2D patients with or without CVD in the United States. Our findings lend additional support for more widespread adoption of guidelines by healthcare decision‐makers for T2D treatment.

A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.

e17113 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefit from the treatment of RC48-ADC.The study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, one-arm, non-randomized phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary objectives were activity (ORR) and safety. Progress-free survival, disease control rate and overall survival will also be assessed. Results: As of February 2020, 8 patients were enrolled in the study. The median age was 65 years old. At baseline, most patients (6/8) had visceral metastasis. 6 (75%) patients had received≥2 lines treatment and 4 (50%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 25% (2/8) and the DCR was 75% (6/8). The ORR was 33.3% (2/6) in patients with visceral metastasis and was 50.0% (2/4) in liver metastasis patients. The ORR was 33.3% (2/6) in patients post to ≥ 2 lines of treatment and 25% (1/4) in patients post to immunotherapy. Common treatment-related AEs were AST increase (62.5%), ALT increase (50.0%), nausea (50.0%), leukopenia (37.5%), fatigue (37.5%), vomiting (37.5%), hypoesthesia (25.0%), alopecia (25.0%), and neutropenia (25.0%). Most of these AE were Grade 1 or 2. The AE of Grade 3 was neutropenia (12.5%). The SAE was CPK increased (12.5%). Conclusions: The study showed that RC48-ADC was safety and the ORR was 25% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. Clinical trial information: NCT04073602.

Randomized controlled study on the effects of triple therapy including vonoprazan or rabeprazole for the second-line treatment of Helicobacter pylori infection.

Background and Aim:Inhibition of gastric acid secretion is important for eradicating Helicobacter pylori. Vonoprazan (VPZ) is a strong, long-lasting inhibitor of gastric acid secretion. Studies that examined the effectiveness of VPZ-based triple therapy in second-line treatment have been performed. However, there have been no randomized controlled studies to compare the effect between VPZ-based triple therapy and proton pump inhibitor (PPI)-based triple therapy in second-line treatment, and it is not known which is more effective between VPZ-based and PPI-based therapies. This study aimed to compare the effectiveness of second-line triple therapies including VPZ or rabeprazole (RPZ) as the PPI.Methods:Eligible patients with H. pylori infection who failed first-line triple therapy were assigned randomly to the VPZ [VPZ40 mg/day, amoxicillin (AMPC) 1500 mg/day, metronidazole (MNZ) 500 mg/day] or RPZ (RPZ20 mg/day, AMPC1500 mg/day, MNZ500 mg/day) group. A 13C-urea breath test result of less than 2.5% was considered as successful eradication.Results:In total, 46 and 41 patients were analyzed as intention to treat (ITT) and per protocol (PP), respectively. Eradication rates in the VPZ and RPZ groups were 73.9% [95% confidence interval (CI) 51.6–89.8%] and 82.6% (95% CI 61.2–95.0%) based on ITT analysis, respectively (p = 0.72). Based on PP analysis, the eradication rates in the VPZ and RPZ groups were 89.5% (95% CI 66.9–98.7%) and 86.4% (95% CI 65.1–97.1%), respectively (p = 1.00). Two patients in the VPZ group and one in the RPZ group discontinued treatment due to side effects (p = 1.00).Conclusion:There were no significant differences in efficacy and safety between second-line therapies including VPZ or RPZ.

A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma.

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.

PMS14 - Budget Impact of a Fixed-Dose Combination Therapy of Lesinurad and Allopurinol for Second-Line Gout Therapy: A US Commercial Health Plan Perspective

Estimate budget impact on US commercial payers adopting fixed-dose combination therapy of lesinurad and allopurinol (L/A) as second-line urate-lowering therapy in gout patients for whom allopurinol (ALLO) therapy has failed. This budget impact model used a Markov model to estimate costs, survival, and discontinuation in a 1-million-member health plan. Model parameters were derived from CLEAR 1 and CLEAR 2 Phase III trials of lesinurad, published literature, and market share estimates. The model population included patients failing first-line ALLO monotherapy; the time horizon is 5 years. A scenario based on ALLO therapy was compared with a future scenario in which L/A is provided to a portion of ALLO patients not meeting sUA goal. The uptake of L/A population was assumed to increase from 1.2% to 5.2% over 5 years. Annual and cumulative incremental costs were reported as total cost, per-member per-month (PMPM) cost, and cost-per-treated patient per year. One-way sensitivity analysis, to identify parameters that most influence the model, was conducted (±10% variation for each model parameter). US payer perspective for commercial health care plans is modeled. A total of 8205 patients would be treated with second-line therapy in treatment mixes with and without L/A, respectively. The budget impact of L/A is estimated to be $231,451 in the first year and $1,049,637 in the fifth year, for a cumulative 5-year incremental cost of $3,473,891. Cumulative 5-year cost-per-treated gout patient per year was $107, and cumulative incremental 5-year PMPM was estimated at $0.06. Sensitivity analysis indicated the model was most sensitive to L/A cost and L/A market shares, each affecting PMPM by approximately $0.01. From the commercial payer perspective, adding L/A as a second-line gout therapy to a hypothetical 1 million–person health plan over a 5-year time horizon results in cumulative total incremental PMPM costs of approximately $0.06.

Post Relapse Survival Rates in Diffuse Large B-Cell Lymphoma

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most frequently observed hematologic malignancy with 45,000 patients newly diagnosed globally each year. DLBCL patients can be cured if successfully treated with first line therapy, but patients who relapse face a poor prognosis. OBJECTIVES: The aim of this analysis was to assess the prognosis for patients who relapse after first line treatment and to assess the impact of patient age on outcomes through a systematic review of the literature. METHODS: A systematic review of observational and interventional studies that describe survival outcomes in DLBCL was conducted. The review included studies published internationally since 2000 that enrolled adult patients with DLBCL who had relapsed or progressed following first line treatment with rituximab. Phase I interventional studies, case reports, and studies assessing novel therapies in second line treatment were excluded. Data were collected on median overall survival (OS), and 1-yr and 5-yr survival rates. OS data were reported according to the time point from which they were calculated: from the point of relapse (studies including patients who may or may not have received second line treatment), from initiation of treatment post relapse (studies including patients who received active treatment post relapse), and from the time of autologous stem cell transplant (ASCT) post relapse. Results were further analysed by patient age. RESULTS: The search retrieved 2,275 citations, of which 28 studies met the inclusion criteria. In studies reporting OS from the time of relapse, median survival was 10 months (range 4 - 22) (Table 1). The proportions of patients alive at 1 and 5 years post relapse were on average (range) 41% (20% - 68%) and 27% (12% - 42%) respectively. The patients included in these studies were a mix of those who went on to receive a second line treatment and those who did not. In studies of patients who relapsed and received a subsequent line of treatment, median survival from the initiation of treatment post relapse was 13 months (9 - 28) and the proportions of patients alive at 1 and 5 years post second line treatment initiation were on average 60% (41% - 70%) and 30% (14% - 100%) respectively. In studies where survival was calculated from the time of ASCT post relapse, median survival was 40 months (36 - 44), while the proportions of patients alive at 1 and 5 years post ASCT were 73% (70% - 75%) and 45% respectively. The longer survival times for patients who received treatment post relapse likely reflects the better prognostic profile of patients deemed suitable for subsequent treatment versus those post relapse who may not have received second line treatment. Survival after ASCT is significantly influenced by the usual practice of selecting for transplant only patients showing chemo-responsiveness to salvage therapy. In studies that reported survival by patient age, median survival was more than twice as long for patients aged CONCLUSIONS: The prognosis for patients with DLBCL who relapse is poor, with median survival of less than one year and less than half of patients who relapse still alive at one year post relapse. Despite the use of ASCT treatment, less than half of patients who met the eligibility criteria for and underwent ASCT were alive at 5 years post ASCT. Age was seen to be an important prognostic indicator in DLBCL patients who relapse, with poorer prognosis in patients aged ≥65 years than in those aged Disclosures McMillan:Celgene: Honoraria; Roche: Honoraria. Martin:Sevier: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria. Haioun:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Chiappella:Pfizer: Speakers Bureau; Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau. Di Rocco:Celgene: Honoraria. Rueda:Roche: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Mundipharma: Speakers Bureau. Palaska:Celgene: Consultancy. Davies:Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria; GSK: Research Funding; Karyopharma: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

Targeted therapy in gastric cancer.

SummaryBackgroundGastric cancer is the fourth most common cancer worldwide. Surgery in combination with multimodal therapy provides the only curative therapy until now. The importance of targeted therapy became clear over the last few years. Due to the implication of HER2 and angiogenesis-directed targeted therapies major advances in the treatment of gastric cancer could be reached. Nevertheless, benefits in survival remain unsatisfactory and the development of resistance to monoclonal antibodies is arising.MethodsA comprehensive and comparative literature research was performed to evaluate the status of HER2 and angiogenesis-directed targeted therapy in gastric cancer.ResultsUp to now, trastuzumab and ramucirumab are the only agents showing remarkable benefits in the therapy for the patients suffering from gastric cancer. The limitations of targeted therapies in gastric cancer are mainly associated with the development of secondary resistance.ConclusionAddition of targeted therapy in second-line treatment is beneficial when compared with chemotherapy alone. Nevertheless, results in first-line treatment remain modest. Therefore, new therapeutic agents and combinations in the first-line treatment of gastric cancer are urgently needed and remain to be validated in clinical trials.

Local Graft Irradiation for Kidney Allograft Rejection: A Case Series and Review of the Literature

Introduction:Due to its immunosuppressive properties, local graft irradiation (LGI) has been proposed as a second line therapy for treatment of acute kidney rejection.Case Presentation:In this case-series we report 6 patients with biopsy proven acute kidney allograft rejection refractory to conventional antirejection therapy who underwent LGI for treatment of acute rejection at our center. Three of these patients had living donor transplants, 2 had deceased donor transplants, and one had received a simultaneous kidney/pancreas transplant. All patients were treated with anti thymocyte-globulin or muromonab-CD3, and intravenous steroids for initial treatment of rejection. Three patients also received intravenous immunoglobulin. LGI was tried as a last resort and was well tolerated and resulted in either improvement or stabilization of renal function in 5 patients. One patient could not be given the complete course of chemical immunosuppression for treatment of rejection due to concomitant cryptococcal meningitis and was switched to LGI with good short-term response.Discussion:Our results suggest that LGI could be considered a second line therapy to the conventional anti-rejection therapy for patients with refractory acute kidney allograft rejection, or for patients who cannot receive systemic immunosuppression due to severe infection.

Impact ofLactobacillus reuteriSupplementation on Anti-Helicobacter pyloriLevofloxacin-Based Second-Line Therapy

Introduction. Helicobacter pylori eradication therapy has the potential burden of antibiotic-associated gastrointestinal (GI) side effects. The occurrence of side effects is among the major drawbacks of such regimens. GI manifestations may be related to alterations in the intestinal microflora. Probiotics can prevent or reduce antibiotic-associated side effects and have an inhibitory effect on H. pylori. Methods. To define the efficacy of Lactobacillus reuteri supplementation in H. pylori eradication and in preventing GI-associated side effects during a second-line levofloxacin triple therapy. 90 H. pylori-positive patients receive for 7 days a second-line triple therapy with esomeprazole, levofloxacin, and amoxicillin with L. reuteri for 14 days (group 1) and without probiotic supplementation (group 2). Each subject received a validated questionnaire to record symptoms everyday for 4 weeks from the start of therapy. H. pylori status and side effects were assessed 6 weeks after treatment. Results. The eradication rate was significantly influenced by probiotic supplementation with L. reuteri (group 1: 36/45, 80%; group 2: 28/45 62%; P < 0.05). The incidence of nausea and diarrhoea in group 1 was significantly lower than that in group 2. Conclusion. In H. pylori-positive subjects L. reuteri supplementation increases the eradication rate while reducing the incidence of the most common side effects associated with antibiotic therapy in second-line treatment.

Wann soll eine systemische Chemotherapie beim Harnblasenkarzinom eingesetzt werden?

The perioperative use of chemotherapy regimens in urinary bladder carcinoma is still under debate. Evidence from clinical trials has not changed over the last decade and therefore current guidelines lack high grade recommendations for the use of perioperative chemotherapy, especially with regard to adjuvant chemotherapy. Neoadjuvant chemotherapy is capable of downsizing locally advanced tumors which leads to better operability. However, the quality of the surgical procedure has a major impact on the risk of recurrence and prognosis of patients and may therefore negatively influence the results of perioperative chemotherapy trials. A number of retrospective studies analyzing the outcome of patients after radical cystectomy have demonstrated that especially patients with node positive bladder carcinoma may benefit from adjuvant chemotherapy. Gemcitabine plus cisplatin still represents the gold standard in the treatment of metastastic bladder carcinoma. Vinflunin has become the standard therapy in second-line treatment and should represent the comparator for further clinical trials in this setting.

Outcome of Elderly Patients with DLBCL Failing R-CHOP: The Role of Rituximab and High Dose Therapy in Second Line Treatment. A Retrospective Analysis From the RICOVER 60 Trial.

Abstract 3714Poster Board III-650 BackgroundThe integration of rituximab into first line treatment dramatically improved the outcome of patients with aggressive NHL. However, there is little published information about patients with treatment failure after modern first-line immuno-chemotherapy. In particular the roles of high-dose chemotherapy with stem-cell support and of rituximab as part of salvage therapy needs to be established. To shed light on the perspectives of patients with treatment failure after R-CHOP,we e analyzed the outcome of second-line treatment of patients within the RICOVER-60 trial Patients and MethodsIn the RICOVER-60 study patients 61 to 80 years of age received 6 or 8 cycles of CHOP chemotherapy in 14 days intervals (CHOP14) with or without 8 applications of rituximab. 301 of 1222 patients treated on study experienced lymphoma related treatment failure (L-TF) [PR: n=52 (17%), NC: n=8 (3%), progressive disease (PRO): n=93 (31%), relapse (REL): n=148 (49%)]. 4 patients were excluded from this analysis due to possible administration of rituximab after the RICOVER60 trial had been stopped. 297 patients were included in this analysis. ResultsRegardless of the primary treatment, the prognosis of patients with PRO was extremely poor with a median survival of 3 months and only 8% of patients surviving >3 years. In patients with REL there was a trend for better survival after primary treatment without rituximab (44% after 3 years) than after R-CHOP (23% after 3 years, p = 0.106). Of 297 patients, 222 (75%) were treated with salvage-therapy, 59 patients (20%) had no further treatment; for 16 patients (5%) further course is unknown. An attempt to induce a second remission by intensive chemotherapy was made in 70% of elderly patients with PRO and in 85% of patients with REL. Salvage therapy included rituximab in 59% of patients (39% after PRO, 67% after REL). HDT/ASCT was performed in 13% of these elderly patients (11% after PRO and 14% after REL). Survival was much better in patients receiving rituximab as part of salvage therapy than in patients receiving salvage therapy without rituximab (3-year-OS rate: 39% vs 18%, p < 0.001). The effect was most pronounced in patients receiving primary treatment without rituximab (3-year-OS 43% vs 24%, p < 0.001), but was still detectable in patients receiving primary R-CHOP. In the latter group no plateau of survival was achieved irrespective of whether rituximab was part of salvage therapy or not but median survival was prolonged significantly (median survival 6 vs 15 months, OS 3 y 12% vs 13%, p= 0.011). HDT / ASCT was effective only in patients receiving primary treatment without rituximab (OS 3y 66% vs 33%, p = 0.019) while the rate of long-term survival was only in the range of 10% in patients receiving primary R-CHOP. ConclusionThe outcome of second line treatment after primary immuno-chemotherapy of aggressive B-NHL in elderly patients is dismal and rarely results in long-term survival. Rituximab is useful as part of salvage therapy and results in prolonged survival, altough long term survival is achieved in a small minority of patients only. HDT with autologous SCT was effective after chemotherapy only, whereas the number of long-term survivors was low in those patients pretreated with R-CHOP-14. New modalities of second line therapy are urgently warranted. Disclosures:Glass:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Research Funding. Schmitz:Roche: Honoraria, Research Funding.

Hairy Cell Leukemia : Experience at a Tertiary Cancer Centre in Northern India

Background : The prognosis of Hairy cell leukemia (HCL) has improved markedly following treatment with cladribine (2- CdA), a nucleoside analogue. We reviewed data on patients with HCL treated in our department. Methods . Between 1995 and 2004, 23 patients with hairy cell leukemia (HCL) were diagnosed Patients median age was 48.5 years (range, 32 to 66 years), there were 18 males and 5 females. The common presenting symptoms were: fatigue (82.6%), fever (34.7%), abdominal discomfort (21.7%), arthralgia/bone pains (13%) and bleeding (17.3%). 22 of 23 (95.6%) patients had enlarged spleen, and hepatomegaly (65%). Lymph node enlargement was present in 17% of patients. Investigations revealedmedian Hb of 7.8g% (5.7 to 12.9 g%), thrombocytopenia (median 55000/cmm) and median WBC count of 3500/cmm (range, 600 to 20,200/cmm). Bicytopenia or pancytopenia was present in 87% and bone marrow fibrosis in 75% of cases. Immunophenotyping studies revealed expression of CD11C (60%), CD25 (60%), FMC7(47.8%), CD23(34.8%), CD103 in 39% of cases. 20 of 23 patients received treatment; two received treatment else where and one patient died of liver failure prior to treatment. 17 of 20 patients were treated with 2-CdA, 2 with interferon alfa (IFN-a) and one patient underwent splenectomy alone. Three patients received 2-CdA as second line therapy for treatment of relapse: this includes . one patient each, treated with IFN- α and splenectomy both and one patient received 2-cdA twice in view of relapse. Results . Following treatment with 2CdA . 95% of patients responded; complete-84.2% and partial response in 10.5%. one (5.2%) patient died of toxicity. Two patients relapsed at a mean follow up of 25 months. The common side effects were febrile episodes (n=10) and grade I-II myelosuppression. One patient died of toxicity to 2-CdA. This patient was a known case of multidrug resistant disseminated tuberculosis. He had severe myelosuppression with fungal sepsis with multiorgan failure and BM Aspirate was positive for AFB. Other infections documented were Pulmonary tuberculosis in 2 and herpes zoster in one patient. The patient who underwent Splenectomy achieved remission but relapsed after 3 years and was salvaged with 2-CdA again. Median time for normalization of blood counts after 2-CdA was 28 days and median time to regress spleen was 41.5 days . Conclusion . Present study confirms good outcome with 2-CdA (cladribine) therapy for patients of hairy cell leukemia.

10 days levofloxacin-based triple therapy in second-line treatment for Helicobacter pylori eradication

10 days levofloxacin-based triple therapy in second-line treatment for Helicobacter pylori eradication

37 P Use of 10 days levofloxacin-based triple therapy in second-line treatment for H. pylori eradication: A new strategy

37 P Use of 10 days levofloxacin-based triple therapy in second-line treatment for H. pylori eradication: A new strategy

Immune Thrombocytopenic Purpura

Thrombocytopenia is seen commonly in patients with rheumatic disorders. In general, thrombocytopenia is due to one of three mechanisms: reduced production, sequestration, or increased platelet destruction. In outpatients, the most common cause of thrombocytopenia is immune thrombocytopenia. Immune thrombocytopenia encompasses a broad group of disorders in which the rate of immune-mediated platelet destruction surpasses the rate of platelet production. This paper discusses the diagnosis of immune thrombocytopenia, its mechanisms, and potential therapies for this problem. Acute therapy is with corticosteroids and intravenous immunoglobulin. Splenectomy is used if these fail. There also are other second-line therapies for treatment of patients with refractory thrombocytopenia. Potential toxicities of therapy are reviewed within the context of patients with rheumatic disorders.