Approval For Treatment Of Patients Research Articles

Abstract A162: Continuous treatment with rociletinib in EGFR transgenic mice results in acquired resistance to both rociletinib and osimertinib and intra-“patient” tumor heterogeneity

Abstract Activating mutations in EGFR are key drivers in a subset of non-small cell lung cancer (NSCLC) patients, as well as effective predictors of response to first-generation reversible EGFR tyrosine kinase inhibitor (TKI) therapy. However, resistance develops in many patients due to acquisition of a T790M mutation in EGFR. Rociletinib and osimertinib target the T790M mutation, and have been evaluated in previously treated EGFR mutant lung cancer patients. Osimertinib recently received FDA approval for treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy. However, there is limited information on the mechanisms of resistance to these drugs, as well as limited in vivo models for acquired resistance to examine signaling pathways and/or possible treatments to abrogate resistance. We treated an EGFR-L858R-T790M transgenic lung adenocarcinoma mouse model daily with rociletinib to examine sensitivity and acquired resistance. Rociletinib exhibited potent antitumor activity as a single agent, resulting in complete tumor regression and suppression of phospho-EGFR. Despite the success of treatment, after long-term dosing (4-5 months) tumors acquired resistance to the drug, as evidenced by tumor regrowth on MRI. DNA from multiple tumor samples representing four individual drug-resistant mice was sequenced, and several novel mutations in EGFR were observed that may account for the resistant outgrowth of tumors in these mice. These included an insertion and a deletion mutation as well as missense mutations. Interestingly, in some cases different mutations arose in individual tumor nodules within the same mouse, suggesting that each tumor is an individual resistant clone. All mutations were located in the kinase domain of EGFR. For example, a de novo G796C mutation was one of the potential mechanisms of resistance to rociletinib found in two isolated nodules from one mouse lung. A mutation at the same amino acid has been found in a lung cancer patient after treatment with osimertinib; moreover, this mutation was found in a cell line mutagenesis screen to study the resistance to different EGFR TKIs. We generated Ba/F3 cell lines carrying each de novo identified EGFR mutation (along with the activating L858R and T790M mutations) and compared the potency of EGFR TKIs to cell lines carrying only the activating mutations. The cells that expressed putative acquired resistance mutations proved to be resistant to both rociletinib and osimertinib in vitro, suggesting that these mutations indeed mediated acquired resistance in vivo. Tumor nodules from drug-resistant transgenic mice were transplanted into recipient mice and expanded for further evaluation. Mice with transplanted resistant tumors did not respond to rociletinib or osimertinib treatment. Pathway analysis showed that phospho-EGFR was no longer suppressed in drug-resistant tumors carrying a deletion mutation, confirming that novel mutations result in drug resistance. We discovered that resistance to third-generation EGFR inhibitors may occur through novel mutations in EGFR. Heterogeneity of mutations in different nodules within the same lung is akin to intra-patient heterogeneity and highlights the utility of mouse models for examining acquired resistance to drugs. Citation Format: Rajaa El Meskini, Anthony Iacovelli, Alan Kulaga, Michelle Gumprecht, Myla Spencer, Lilia Ileva, Andrew Simmons, Zoë Weaver Ohler. Continuous treatment with rociletinib in EGFR transgenic mice results in acquired resistance to both rociletinib and osimertinib and intra-“patient” tumor heterogeneity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A162.

Evolution of Liver Transplantation Program in Shiraz, Iran

Background: Liver transplantation (LT) is the only approved treatment for patients with end stage liver disease (ESLD). Shiraz organ transplantation center (SOTC) was the first center in Iran to provide LT. This report is on the evolution of LT program in this center. Methods: We report the clinical features and outcomes of all those who received LT between May 15, 1993 to December 31, 2015 as well as donor features. All LT were performed at Namazi hospital in Shiraz, Iran. The Kaplan-Meier and multivariate Cox proportional hazards regression analyses were performed to determine prognostic factors and the overall long-term survival after liver transplantations. Results: During this period, 3191 recipient patients received LT from 3110 donors. Overall patient survival rates were 84% at 1 year, 80% at 5 years, and 73% at 10 years. The survival rates for recipients from living donors were 74.0% at 1 year and 70.0% at 5 years compared to 86.0% at 1 and 81.0% at 5 years for recipients from deceased donors (P < 0.0001). The survival rates of LT for 2 different Era I (1993 - 2005) and II (2006 - 2015) were estimated to be 76.0% vs. 85.0% at one year, 69.0% vs. 81% at 5 years, and 60.0% vs. 78.0% at 10 years, respectively (P < 0.0001).The most common indications for LT were cryptogenic cirrhosis, hepatitis B, primary sclerosing cholangitis, autoimmune hepatitis, and metabolic liver diseases during this period. Conclusions: LT is now an affordable treatment for patients with ESLD in Iran with acceptable survival, which has further been improved in recent years.

Case Series of Crohnʼs Disease Patients Refractory to Anti-TNF Alpha Therapy on Uztekinumab

Introduction: Uztekinumab blocks interleukins 12 and 23 through their common p40 subunit and has been previously used in the U.S. for the treatment of plaque psoriasis and psoriatic arthritis. It just recently got FDA approval for treatment of patients with moderate to severe Crohn's disease refractory to one or more Anti TNF-α after promising results from three pivotal phase 3 clinical trials with over 1300 patients. Our study aims to assess the effectiveness and safety of uztekinumab in refractory patients with Crohn's in real-life practice on our population. Methods: A retrospective chart review was performed with inclusion criteria of patients with Crohn's disease refractory to Anti TNF-α therapy and currently on uztekinumab. Demographic factors including age, sex, onset of disease with duration were gathered. Treatments previously received and number of surgeries were used to gauge disease severity. Remission was defined as lack of diarrhea, rectal bleeding, abdominal pain, nausea, vomiting. Data for side-effects of uztekinumab was also gathered. Results: There were a total of 5 patients: 2 were females and 3 were males. The age of onset ranged from 13-34 years with disease duration ranging from 15-25 years. All patients received a minimum of 3 months of therapy with one patient on uztekinumab for over 2 years. Induction therapy that was weight based starting 0, 4 and 16 weeks followed by maintenance of every 12 weeks was used on all patients. All of these patients could be classified as severe given all of them received at least one major surgery including proctocolectomy, Ileal resection, diverting ileostomy, ileocolectomy and had failed multiple medications (as mentioned on table 1). All our patients achieved clinical remission with 3 completely off steroids and 2 being tapered of steroids. Three patients had peri-anal disease with improvement after the start of therapy. Uztekinumab was tolerated well with no side-effects noted including opportunistic infections, allergic reactions, neurologic and cardiovascular side-effects. Conclusion: Uztekinumab which is just recently FDA approved is showing promising results in our series of patients. It should be strongly considered on patients refractory of Anti TNF-α therapy as it is able to achieve IBD quality measures with steroid sparing therapy and improved bone health which ultimately improves overall patient outcomes and quality of life.Table: Table. Patient characteristic and their outcomes

Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.

Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.

Population pharmacokinetics (popPK) and exposure-response (ER) analyses to confirm alectinib 600 mg BID dose selection in a crizotinib-progressed or intolerant population.

e20598Background: Alectinib, a potent and selective CNS-active ALK inhibitor, which has received FDA accelerated approval for treatment of patients with ALK+ NSCLC who have progressed on, or are in...

Systematic literature review of efficacy, safety, and tolerability outcomes of interventions in patients with distant metastatic Merkel cell carcinoma.

e21018Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with a poor prognosis once metastasized. There are currently no approved treatments for patients (pts) w...

Finding New Tricks for Old Drugs: Tumoricidal Activity of Non-Traditional Antitumor Drugs.

Chemotherapy, a traditional method, plays an important role in tumor therapy. Currently, common clinical antitumor drugs have several defects like poor efficacy, side effects, etc. Furthermore, developing new antitumor drugs takes a long time and requires many resources. Recent studies have found that oldies are newbies for the oncologist, such as flavonoid, metformin, aspirin, etc. These non-traditional antitumor drugs (NTADs) are widely used in management of non-cancer diseases, which gained FDA approval for treatment of patients. Increasingly, studies about antitumor action of NTADs have attracted many researchers' interests. A giant amount of studies showed a decrease in cancer incidence in NTAD-treated patients. Several reports outlined a direct inhibitory effect of NTADs on cancer cell growth and antitumoral actions. This review summarized the research progress on antitumor effects of ten NTADs. Retrospective and meta-analyses of trials also showed that these NTADs had preventive effects against cancer in vitro and in vivo. These drugs represent a promising option for cancer treatment, which have clear benefits including clinical safety, obvious curative effect, and saving medical and health resources. Judged from previous reports, future studies will yield valuable data about the profitable effects of these drugs. With a better understanding of its mechanisms of antitumor activity, NTADs may become available for combination with chemotherapy or targeted therapy in clinic.

A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761).

8019 Background: Crizotinib is an approved treatment for patients (pts) with ALK-rearranged (ALK+) NSCLC. However, progression on crizotinib, particularly in the CNS, frequently occurs within a yea...

Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Bristol-Myers Squibb.

Anti–CTLA-4 therapy broadens the melanoma-reactive CD8 + T cell response

Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.

Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer.

The revolution in individualized therapy for patients with advanced non-small cell lung cancer (NSCLC) has seen the emergence of a number of molecularly targeted therapies for distinct patient molecular subgroups. Activating anaplastic lymphoma kinase (ALK)-gene rearrangement has been detected in 3-7 % of NSCLC cases, and the ALK inhibitor crizotinib is now an approved treatment for patients with tumors harboring this event. However, resistance to ALK-targeted therapies is a ubiquitous problem in the management of advanced ALK-positive NSCLC and can be mediated by secondary kinase mutations or the activation of compensatory alternative oncogenic drivers. New, more potent ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802), and AP26113 are now emerging, together with an increased knowledge of the molecular basis of resistance. There is a need to evaluate the optimal clinical application of these new agents, either as sequential therapies or in combination with other targeted agents, to combat resistance and prolong survival in patients with ALK-positive NSCLC. The remarkable clinical activity of ALK inhibitors also emphasizes the importance of optimal diagnostic testing algorithms, to ensure that all eligible patients receive these breakthrough therapies.

Abstract P369: Impact of Enhanced External Counterpulsation on Exercise Duration in Patients With Chronic Stable Angina: A Meta-analysis

Introduction: Enhanced External Counterpulsation (EECP) is a non-invasive Food and Drug Administration approved treatment for patients with chronic stable angina and heart failure. Typical treatment regimen comprises of 35, 1-hour sessions of synchronized compressions of the calf, thigh, and sacral muscles over a seven-week period. Exercise duration measured using an exercise tolerance test is a commonly utilized marker of worsening ischemic disease and is predictive of cardiovascular mortality. Several studies have evaluated the impact of EECP on exercise duration with conflicting results. We sought to determine the magnitude of benefit of EECP on exercise duration. Methods: A literature search was performed in MEDLINE, CINAHL, and the Cochrane database along with hand searching of relevant articles limited to those published in the English language. Studies were included for analyses if assessing patients with stable angina and reporting exercise duration data using either the Bruce or modified Bruce exercise treadmill test. Appropriate data were extracted at baseline and after completion of the full course of EECP. Studies were excluded if presenting duplicate data or using a non-Bruce protocol. A weighted mean difference from baseline along with 95% confidence interval was calculated using the DerSimonian-Laird random-effects model. Sub-group analyses, the Cochran Q statistic, and JADAD scores were utilized to assess for heterogeneity, non-combinability, and quality of published studies respectively. Publication bias was assessed using visual inspection of funnel plots and the Egger bias statistic. Results: Our search strategy identified 1117 independent studies of which 15 were included for analyses. A total of 484 individual subjects were incorporated in the primary analysis. Exercise duration improved by 55.5 seconds (95%CI 36.1 to 74.9; Cochran Q, p=0.246) from baseline. The benefits were maintained when using a fixed-effects model, excluding small studies and limiting to studies using the Bruce protocol only. While the Egger statistic showed a lack of publication bias (p=0.121), it cannot be ruled out based on visual inspection of funnel plots. Conclusion: EECP significantly increases exercise duration by 56 seconds in patients with chronic stable angina. Further studies are needed to determine the impact of EECP on long-term outcomes. The views expressed in this material are those of the authors, and do not reflect the official policy or position of the U.S. Government, the Department of Defense or the Department of the Air Force.

Evolving therapies for the treatment of HCV viral hepatitis.

Evolving therapies for the treatment of HCV viral hepatitis.

Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS.

Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ⩾8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ⩾8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ⩾8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ⩾8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression.

Noninvasive Application of Alternating Electric Fields in Glioblastoma: A Fourth Cancer Treatment Modality

Tumor treating fields (TTF) therapy is a novel antimitotic, electric field-based treatment for cancer. This nonchemical, nonablative treatment is unlike any of the established cancer treatment modalities, such as surgery, radiation, and chemotherapy. Recently, it has entered clinical use after a decade of intensive translational research. TTF therapy is delivered to patients by a portable, battery-operated, medical device using noninvasive transducer arrays placed on the skin surface surrounding the treated tumor. TTF therapy is now a U.S. Food and Drug Administration (FDA)-approved treatment for patients with recurrent glioblastoma (GBM) who have exhausted surgical and radiation treatments. This article will introduce the basic science behind TTF therapy, its mechanism of action, the preclinical findings that led to its clinical testing, and the clinical safety and efficacy data available to date, as well as offer future research directions on this novel treatment modality for cancer.

A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults

Temsirolimus, a selective inhibitor of mammalian target of rapamycin, is an approved treatment for patients with advanced renal cell carcinoma (RCC). This study assessed the effect of intravenous (i.v.) temsirolimus 25mg, the recommended dose for patients with RCC, on the corrected QT (QTc) interval. This 3-period crossover study enrolled healthy subjects. In periods 1 and 2, subjects received i.v. placebo either alone or with open-label oral moxifloxacin. In period 3, subjects received a single dose of temsirolimus 25mg. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5h). Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc compared with placebo. In total, 58 subjects were enrolled. Temsirolimus had no effect on QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% confidence intervals for the time-matched change from baseline difference from placebo was <10ms, with no evidence of QTc trends or relationship to concentrations of temsirolimus or its major metabolite, sirolimus. Moxifloxacin, the positive control, produced a significant increase in the QTc interval compared with placebo 0.5-4h post-dose (P<0.0001). No subject had a QTc interval exceeding 450ms or a change from baseline of >30ms. Therapeutic exposure to temsirolimus is not associated with clinically significant changes in QTc intervals in healthy adults.

Eculizumab Treatment of Paroxysmal Nocturnal Hemoglobinuria Relapsing After Bone Marrow Transplant and Subsequent Clonal: Case Report

Abstract 5274 Background:Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by deficiency of the GPI-anchored complement inhibitory proteins CD55 and CD59 on blood cells. The resulting uncontrolled complement activation is responsible for chronic hemolysis and can lead to serious clinical morbidities including thromboembolism (TE) and chronic kidney disease (CKD), which have been shown to increase risk of mortality. Patients may also experience debilitating quality-of-life (QoL) issues, including fatigue, shortness of breath, erectile dysfunction, and abdominal pain, attributed to chronic hemolysis and resultant nitric oxide scavenging by free hemoglobin.Although hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for PNH, the risk for substantial morbidities and mortality still exist. In patients with PNH undergoing HSCT, up to 45% die or develop acute or chronic graft-versus-host disease. Eculizumab, a first-in-class terminal complement inhibitor, is the only approved treatment for patients with PNH. By inhibiting terminal complement activity and chronic hemolysis, eculizumab reduces the incidence of TE, CKD, and transfusion requirements, improves anemia and QoL, and normalizes survival in patients with PNH. Aim:Report the benefits of eculizumab in a patient with PNH who relapsed after HSCT. Case Report:A 27-year-old woman presented in December 1993 with fever, diarrhea, hemoglobinuria, and acute renal failure requiring temporary hemodialysis (Table). She was subsequently diagnosed with PNH. In February 1995, allogeneic HSCT from an HLA-identical sibling donor was performed. In 2003, 8 years after successful engraftment, the patient relapsed and presented with hemoglobinuria, abdominal pain, corticosteroid dependence requiring 20 to 40 mg methylprednisone, and high transfusional requirements. In November 2007, she had a granulocyte clone size of 37.2% as determined by flow cytometry. In June 2009, she started eculizumab therapy which was associated with a rapid reduction in lactate dehydrogenase (LDH) from 4964U/L to 456U/L. She subsequently achieved resolution of asthenia, disabling fatigue, and abdominal pain, as well as transfusion independence and improvement in hemoglobin. In May 2010, she had a granulocyte clone size of 86.1% as determined by both CD55- and CD59-negative cells, and a granulocyte clone size of 98.7% as determined by CD16b-negative cells. Conclusions:The only potential cure for PNH—bone marrow transplantation—is associated with high risks of morbidity and mortality; therefore, for most patients the associated risks preclude this option. In this case study, we show that HSCT may not be curative in all patients and the PNH associated symptoms can arise after BMT. The potential benefits of eculizumab in this patient population should be considered in light of recent data that demonstrated normalized survival in PNH patients receiving long-term eculizumab treatment.TableLaboratory CharacteristicsJanuary 1994March 10, 1995June 19, 2009aAugust 31, 2009Hemoglobin, g/dL5.311.86.289.2White-cell count, per mm≥7,8008,1006,0602,600Neutrophils, %—685338Neutrophils, mL—5,5082,69898Platelet count, per mm≥213,000250,000416,000327,000Lactate dehydrogenase, U/L——4,964456Indirect bilirubin, mg/dL1.1—2.203.82baStarted eculizumab June 23, 2009.bExtravascular hemolysis for C3. Disclosures:Brodsky:Alexion Pharmaceuticals, Inc.: Consultancy, Speakers Bureau. Velez:Alexion Pharmaceuticals, Inc.: Consultancy.

Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma

Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1–21) and dexamethasone 40 mg/d (days 1–4, 9–12, and 17–20 of cycles 1–4; days 1–4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, ∼60% were male, median age was 64 years, and 61·7% had Durie-Salmon stage III disease. Median time on study was 15·4 weeks (range: 0·1–49·1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade ≥3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.

Fixed-dose combination of sitagliptin and metformin for the treatment of type 2 diabetes

Janumet(TM,) a fixed dose combination of sitagliptin/metformin HCL manufactured by Merck Pharmaceuticals, has received US Food and Drug Administration approval for treatment of patients with type 2 diabetes, that are inadequately controlled, either by sitagliptin or metformin alone or together in free-dose combination form. Sitagliptin, an inhibitor of the enzyme DDP-4, assists patients with type 2 diabetes mellitus to achieve glycemic control. It has been shown to be safe and effective at 100 mg daily doses. The effect of giving sitagliptin in combination with metformin is thought to have a complimentary and possibly additive effect on glycemic control.

Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens

The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens. We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied. Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells. Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.