Expected Side Effect Research Articles

Why the eye? Current understanding on the pathogenesis of ocular toxicities

SummaryThe increased use of several different pharmaceutical agents has provided a positive impact to patients benefits. On the other hand, the ophthalmologist is seeing more patients with ocular side effects secondary to such agents. In particular, ocular toxicity induced by cancer chemotherapy, biologic agents and immunesuppressive drugs includes a broad spectrum of disorders, which reflect the peculiar physiological, anatomical and biochemical characteristics of the eye. The progresses achieved by the science in understanding ocular biostructure has allowed a better knowledge on ocular side effects. This achievement assists the ophthalmologist and other specialists to recognize them early and intervene before severe visual impairment occurs. A prompt intervention for the treatment‐related toxicities may also provide the opportunity for a minimization or resolution of an expected side effect. Therefore, ophthalmologist should examine patients for any therapy that can present potential ocular side effects, according to the type of used drug. The biostructure and pathophysiology of potential toxicity of different drugs will be reviewed.

LEUKOCYTOSIS- A TIGHT ROPED WALK

It is common for patients to reveal a leukocytosis (increased white blood cell count) within twenty four hours of initiation of a glucocorticoid. It is important for clinicians to be aware of this expected side effect and to understand the rationale for such an increase. Here, we present a case of nine years old boy with intracranial space occupying lesion (medulloblastoma) posted for surgery who was on oral steroids and had leucocytosis which gradually subsided on stopping steroids. Keywords: Steroids, glucocorticoids , dexamethasone, white blood cell, neutrophils.

How does the side-effect information in patient information leaflets influence peoples' side-effect expectations? A cross-sectional national survey of 18- to 65-year-olds in England.

ObjectivesTo establish how the terms recommended by the European Commission to describe side‐effect risk in patient information leaflets (PILs) influences expectations of side‐effects and to identify factors associated with these side‐effect expectations.DesignA cross‐sectional online survey was carried out by a market research company.SettingData were collected in England between 18th March and 1st April 2016.ParticipantsA total of 1003 adults aged between 18 and 65. Main outcome measures: Self‐reported expectation that the described side‐effects would affect participants if they took the medicine, measured on a likelihood scale from 1 (very unlikely) to 5 (very likely).ResultsParticipants formed high expectations of side‐effects for “very common” and “common” side‐effects, with 51.9% and 45.0% of participants rating these as “very likely” or “likely” to happen to them, respectively. This fell to 8.1% for “uncommon,” 5.8% for “rare” and 4.1% for “very rare.” For each descriptor, higher expectations of side‐effects were more associated with women or being from an ethnic minority, or having less education, a household illness, high perceived sensitivity to medicines or negative beliefs about medicines.DiscussionThe current use of verbal descriptors to communicate side‐effect risk in PILs leads to high side‐effect expectations. These expectations could contribute to nocebo‐induced medication side‐effects experienced by patients. Additional work is required to identify ways to improve the way risk information is conveyed in PILs.

Lipophilicity estimation of statins as a decisive physicochemical parameter for their hepato-selectivity using reversed-phase thin layer chromatography

Lipophilicity plays a crucial role in determining the hepato-selectivity and hence, the biological activity and the associated side effects of statins. Herein, the employment of RP-TLC for estimation of lipophilicity of six statins namely; atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin and fluvastatin is examined. A very good correlation between the chromatographically-determined retention parameters (relative lipophilicity (RM0) or lipophilic parameter (C0)) and both experimental and computed log P values were obtained. However, the results indicate that the type of organic modifier in the mobile phase system (methanol, acetonitrile and acetone) has a small influence on RM0 or C0 values. Higher values of RM0 or C0 are ascribed to lipophilic statins and lower values of RM0 or C0 are attributed to hydrophilic ones. Therefore, RM0 or C0 could be effectively used as simple practical predictors of extra-hepatic distributions of statins and thus their expected side effects. Furthermore, three QSPR (quantitative structure-property relationship) models were constructed to describe the relationship between RM0 with log P and log D of the statins under investigation. These models can be very useful to predict the lipophilicity of other members of statin drugs and might be expanded to newly synthesized compounds with the same structural features.

Pretreatment expectations of side effects from endocrine therapy found to influence occurrence

Key Points A higher expectation of side effects from adjuvant endocrine therapy increased the risk of actual side effects experienced. Adherence was worse in patients with higher expectations of side effects from adjuvant endocrine therapy, and health‐related quality of life was lower.

Is it best to expect the worst? Influence of patients' side-effect expectations on endocrine treatment outcome in a 2-year prospective clinical cohort study

This study aims to determine the role of patient expectations as potentially modifiable factor of side-effects, quality of life, and adherence to endocrine treatment of breast cancer. A 2-year prospective clinical cohort study was conducted in routine primary care with postoperative patients with hormone-receptor-positive breast cancer, scheduled to start adjuvant endocrine treatment. Structured patient-reported assessments of side-effects, side-effect expectations, quality of life, and adherence took place during the first week post-surgery and after 3 and 24 months of endocrine treatment. Of 111 enrolled patients, at 3 and 24 months, 107 and 88 patients, respectively, were assessed. After 2 years of endocrine treatment, patients reported high rates of side-effects (arthralgia: 71.3%, weight gain: 53.4%, hot flashes: 46.5%), including symptoms not directly attributable to the medication (breathing problems: 28.1%, dizziness: 25.6%). Pre-treatment expectations significantly predicted patient-reported long-term side-effects and quality of life in multivariate models controlling for relevant medical and psychological variables. Relative risk of side-effects after 2 years of endocrine treatment was higher in patients with high negative expectations at baseline than in those with low negative expectations (RR = 1.833, CI 95%, 1.032-3.256). A significant interaction confirmed this expectation effect to be particularly evident in patients with high side-effects at 3 months. Furthermore, baseline expectations were associated with adherence at 24 months (r = -0.25, P = 0.006). Expectations are a genuine factor of clinical outcome from endocrine treatment for breast cancer. Negative expectations increase the risk of treatment-specific side-effects, nocebo side-effects, and non-adherence. Yet, controlled studies are needed to analyze potential causal relationships. Optimizing individual expectations might be a promising strategy to improve side-effect burden, quality of life, and adherence during longer-term drug intake. ClinicalTrials.gov Identifier: NCT02088710.

What do women with breast cancer expect from their treatment? Correlates of negative treatment expectations about endocrine therapy.

Patients' negative treatment expectations can lead to nocebo-related side effects and non-initiation of treatment. This study aims to identify correlates of treatment expectations in patients with breast cancer before the start of endocrine therapy. Expectations were assessed in a cross-sectional sample of 166 patients with breast cancer after receiving treatment information. Side effect expectations (one item) and treatment necessity-concern balance (Beliefs about Medicines Questionnaire) were assessed. Correlates were analyzed using regression analyses. The structure of treatment expectations was investigated using a network analysis. About 25% of patients expressed negative expectations. Higher side effect expectations were associated with lower treatment efficacy expectations (ß = -0.20, p = 0.01), higher medication overuse beliefs (ß = 0.17, p = 0.01), and a negative treatment appraisal before study treatment information (ß = -0.17, p = 0.02). A negative necessity-concern balance was associated with lower treatment efficacy expectations (ß = 0.36, p < 0.001), lower adherence intention (ß = 0.21, p < 0.001), and no knowledge of tumor's receptor status (ß = 0.21, p < 0.001); furthermore, it was associated with higher medication harmfulness beliefs (ß = -0.16, p = 0.02), negative treatment pre-appraisal (ß = 0.15, p = 0.01), higher somatosensory amplification (ß = -0.14, p = 0.02), and higher education (ß = -0.12, p = 0.02). The most important network node was the concern that endocrine therapy disrupts life. Negative treatment expectations before treatment start are mainly associated with psychological variables. These results are relevant for patient education in clinical settings. To improve expectations, clinicians might emphasize treatment efficacy and discuss general and specific medication concerns. Improving treatment knowledge could also be beneficial. Copyright © 2016 John Wiley & Sons, Ltd.

Extrapyramidal Symptoms as a Result of Risperidone Discontinuation During Combination Therapy with Methylphenidate in a Pediatric Patient

[Author Affiliation]Carlos A. Perez. 1 Division of Child and Adolescent Neurology, University of Texas Health Science Center at Houston, Houston, Texas.Sean S. Garcia. 2 Department of Pharmacy, Clear Lake Regional Medical Center, Webster, Texas.Regina D. Yu. 3 Division of Community and General Pediatrics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, Texas.Address correspondence to: Carlos A. Perez, MD, University of Texas Health Science Center at Houston, 2600 Gramercy St. #327, Houston, TX 77030, E-mail: Carlos.A.Perez@uth.tmc.eduTo The Editor:Risperidone is a second-generation antipsychotic used in the treatment of schizophrenia and disruptive behaviors in adolescents and young adults. Although extrapyramidal symptoms (EPS) are a known complication of psychotropic use, they are not an expected side effect of psychotropic discontinuation. To our knowledge, this is the first case that describes the acute onset of EPS as a result of discontinuation of risperidone during combination therapy with methylphenidate in a pediatric patient.Case ReportC.G. was a 13-year-old boy with a psychiatric history of schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD), and autism who was responsive to risperidone, oxcarbazepine, and methylphenidate. His medical and family histories were noncontributory. Risperidone was started at age 4 for aggressive behavior and titrated to 1.5 mg b.i.d.A few months prior to presentation, he experienced significant weight gain and a decision was made to taper risperidone and start quetiapine instead. When risperidone was at a dose of 0.5 mg b.i.d., the patient developed a severe, painful cervical dystonia and dyskinesia consisting of intense, repetitive, involuntary movements of the upper extremities, as well as an uncontrollable sense of restlessness and agitation. The patient had never had any symptoms of dystonia, akathisia, or tardive dyskinesia.Quetiapine was increased to 300 mg t.i.d. with minimal improvement after 3 weeks. The patient was also treated with diphenhydramine 50 mg t.i.d., benztropine 2 mg t.i.d., clonidine 0.2 mg b.i.d., and lorazepam 2 mg t.i.d., but his symptoms continued to worsen. Risperidone was reinstated at a dose of 0.5 mg b.i.d. and increased to his previous dose of 1.5 mg b.i.d. within 3 days, after which the dystonia, akathisia, and tardive dyskinesia resolved. …

Persistence and compliance with medication management in the treatment of overactive bladder.

Overactive bladder (OAB) is a common and chronic condition that impacts patients' daily activities and quality of life. Pharmaco-therapy for OAB is a mainstay of treatment. Antimuscarinics and β3-adrenoceptor agonists are the two major classes of oral pharmacotherapy and have similar efficacy for treating the symptoms of OAB. Owing to the chronic nature of OAB, long-term use of medication is essential for OAB symptom control and positive health outcomes. However, many patients elect to stop their medications during the treatment period. Unmet expectations of treatment and side effects seem to be the major factors for discontinuing OAB pharmacotherapy. Furthermore, the short- and long-term persistence and compliance with medication management are markedly worse in OAB than in other chronic medical conditions. Improvement in persistence and compliance with OAB pharmacotherapy is a hot topic in OAB treatment and should be an important goal in the treatment of OAB. Effective strategies should be identified to improve persistence and compliance. In this review, we outline what is known about persistence and compliance and the factors affecting persistence with pharmacotherapy in patients with OAB.

Incidence of atazanavir- associated adverse drug reactions in second -line drugs treated south Indian HIV-1 infected patients.

Background:Ritonavir-boosted atazanavir (ATV/r) is the preferred second-line protease inhibitor (PI) option for HIV patients in resource-limited settings; its pattern of adverse drug reactions (ADRs) has not been much reported from India; hence, in this study, we have analyzed the incidence of ATV/r-associated ADRs in Southern Indian HIV-1-infected patients.Methods:In this prospective study, 111 HIV patients treated with ATV/r were included with at least 2 years follow-up visits for the emergence of hyperbilirubinemia, hypertransaminasemia, and serum creatinine elevation. The causality assessment was done based on the WHO scale for the causality assessment of suspected ADR.Results:The incidence of severe hyperbilirubinemia, hypertransaminasemia, and creatinine elevation was 28.6, 0.76, and 1.62 cases/100 person years, respectively. 3TC/FTC + TDF (odds ratio [OR]: 6.07, confidence interval [CI]: 1.31–27.98, P = 0.015) nucleos (t) ide reverse transcriptase inhibitor backbone and male sex (OR: 18.64, CI: 2.13–162.93, P = 0.0082) were found to be significantly associated with hypertransaminasemia and creatinine elevation, respectively. The causality assessment of ADR was “possible” for all the participants. Kaplan–Meier analysis showed hyperbilirubinemia to emerge earlier (mean duration: 32.18 months, CI: 24.9–39.4 months) followed by hypertransaminasemia and creatinine elevation. Hyperbilirubinemia is an expected side effect associated with ATV/r which is benign, transient, and does not predispose to hypertransaminasemia.Conclusion:Our study results show that patients starting ATV/r should be counseled for a good adherence in spite of the emergence of hyperbilirubinemia which generally reverts to normal range.

Framing and personalizing informed consent to prevent negative expectations: An experimental pilot study.

Informing patients about medical treatments and their possible side effects is ethically and legally obligatory but may trigger negative expectations and nocebo-related side effects. This pilot study aims to investigate the effect of different informed consent procedures on treatment expectations for adjuvant breast cancer treatments (Study 1: endocrine therapy; Study 2: chemotherapy). Using an experimental 2-factorial design, healthy women were informed about endocrine therapy (n = 60) or chemotherapy (n = 64) within a hypothetical scenario. Information was framed with or without treatment benefit information and delivered in a personalized or standardized interaction. Primary outcomes were necessity-concern beliefs about the treatment and side-effect expectations, secondary outcomes were decisional conflicts. In Study 1, side-effect expectations (η²p= .08) and decisional conflicts (η²p = .07) were lower when framed treatment information was given. Providing personalized information resulted in more functional necessity-concern beliefs (η²p = .06) and lower decisional conflicts (η²p = .07). Personalizing and framing of information resulted in more functional necessity-concern beliefs (η²p = .10) and lower decisional conflicts. In Study 2, necessity-concern beliefs were more functional with framing (η²p = .06). Participants in the personalized groups reported lower decisional conflicts (η²p = .06). No differences in side-effect expectations were revealed. This is the first study to provide evidence for optimized treatment expectations through altered informed consent strategies. The results emphasize that framing and personalizing informed consent can positively influence treatment expectations and reduce decisional conflicts. However, generalizations are impaired by the study's pilot character. The potential to prevent nocebo responses in clinical practice should be analyzed. (PsycINFO Database Record

P251 Treatment dilemma of chlamydia in pregnancy

<h3>Background</h3> Drug hypersensitivity reactions are immunological responses to medications. An accurate understanding of the type of antibiotic hypersensitivity reactions is crucial in the decision making process of alternative antibiotic usage versus desensitisation. <h3>Clinical presentation</h3> A 25-year old female, twenty-four weeks pregnant, with dysuria was diagnosed with Chlamydia. She had asthma, which was treated with inhalers. She gave a history of reaction to penicillin and an episode of collapse and rash to erythromycin. Effective treatments for Chlamydia are azithromycin, erythromycin, amoxicillin and doxycycline. The latter is contraindicated in pregnancy and erythromycin and amoxicillin were contraindicated because of this patient’s history. There is small risk of cross reactivity between azithromycin and erythromycin, so a desensitisation protocol was drawn up by the immunologist. The patient was counselled regarding the possibility of a reaction even to small doses of azithromycin and the possibility of an anaphylactic reaction needing adrenaline, which could precipitate preterm labour. She was admitted on the ward and given azithromycin in titrating doses, which was tolerated well without any problems. The repeat chlamydia test following treatment was negative. <h3>Discussion</h3> There are limited therapeutic choices for treatment of various sexually transmitted infections in patients with allergies particularly in pregnancy. These patients will need desensitisation under an immunologist with careful monitoring. If a patient with a reported allergy is deemed not allergic or if the allergy is simply an expected side effect, the medical record should be updated to reflect this change along with educating the patient.

Efficacy of topical azathioprine and betamethasone versus betamethasone-only emollient cream in 2-18 years old patients with moderate-to-severe atopic dermatitis: A randomized controlled trial.

Background:Atopic dermatitis is a chronic skin disease with increasing prevalence worldwide and a considerable burden especially among children. To circumvent the problems related to oral azathioprine (AZT) we aimed to evaluate its topical variant and assess its efficacy in patients aged 2–18.Materials and Methods:In a single-blind trial, we randomized the patients into two groups, one treated with topical emollient containing AZT and betamethasone (BM), and the other treated solely with topical emollient of BM. The treatments were administered twice a day for 8 weeks in both groups. The efficacy, recurrence, and the presence of side effects were evaluated using SPSS 20.Results:The amount of reduction in severity scoring for atopic dermatitis (SCORAD) score was significantly greater in the group treated with the topical AZT (P = 0.024). Incidentally, there were no difference between two treatments in difference in proportions of recurrence and adverse effects as well as SCORAD reduction in subgroups of sex and age (all P > 0.05).Conclusions:Our results showed the superiority of topical AZT over BM with a low recurrence and adverse effects. No expectation of severe side effects, like those of oral AZT, is the major advantage of topical AZT. The sample size was an issue in uncovering the value of AZT in the subgroups. Conducting prolonged studies of quality-of-life and comparing the topical AZT potency relative to the common alternatives are recommended areas of future work.

P47: Methemoglobinemia following Dapsone poisoning (DDS)

Introduction Methemoglobinemia is a side effect of Dapsone (4, 4 diaminodiphenylsulfone or DDS) observed following therapeutic dose administration or after an accidental overdose incidentally with hemolysis causing suffering hypoxic. About an observation, we recall the main clinical, toxicological and therapeutic characteristics of overdose with Dapsone. Observation An elderly man of 30 years, without significant medical history, was hospitalized in the department of dermatology for extensive bullous dermatosis. The patient was treated orally with 2mg/kg daily (150mg per day) of DDS. Accidentally, he took 450mg, 3 times per day for 5 days. On the sixth day, the patient presented a mucocutaneous pallor, cyanosis of the extremities and lips and tachycardia of 160 beat / min. The dosage of methemoglobinemia by spectrophotometry objectified a value of 26%. Medical decision was to stop the DDS and put the patient on oxygen therapy and in vitamin C orally with 3 g per day. Methemoglobinemia analysis performed 2 days after was 19% with regression of clinical signs. Regular monitoring of methemoglobinemia showed degression values ranging from 11.8% to 3.3% at tenth day after accidental overdose. The outcome was favorable and the patient was supported in dermatological consultation. Conclusion Methemoglobinemia is an expected side effect of Dapsone. Its reduction by the methylene blue is indicated for levels above 30% or when it is poorly tolerated. Its evolution is extended due to the long half- life of the toxicant.

Deslorelin Implants in Pre‐pubertal Female Dogs: Short‐ and Long‐Term Effects on the Genital Tract

Deslorelin acetate is a GnRH agonist used for contraception in dogs. This study aimed to evaluate the treatment of pre-pubertal female dogs with deslorelin acetate implants, to better investigate the primary stimulatory effect of the drug and the long-term effects on the genital tract, throughout repeated treatments. Sicilian hound female dogs (24) were randomly assigned to treated group, control group 1 and control group 2. First group bitches were implanted at 4.5, 9.0 and 13.5 months and monitored clinically, ultrasonographically and endocrinologically, throughout the study period (13.5 months). Control group 1 bitches were not implanted and clinically monitored for the same period. At 18 months, the animals underwent ovariohysterectomy, thus allowing evaluation of the internal genitalia. Control group 2 bitches were ovariohysterectomized at the age of 4.5 months. The suppression of oestrus was obtained in the treated group despite the fact that the first implant caused a modest increase in plasmatic levels of 17-beta estradiol and an evident cornification of the vaginal mucosa cells (50-80%). Estradiol and progesterone were at baseline levels for the remaining study period, in which no other oestrous manifestations were observed. The external genitalia maintained a juvenile appearance. The ovaries, ultrasonographically, showed no follicular structures and stayed the same size. At 18 months, the genital tract was still juvenile with inactive small ovaries and a thin filiform uterus. Deslorelin suppressed ovarian activity in pre-pubertal bitches, and oestrous induction was not observed despite the presence of the primary stimulatory effect of the drug. Juvenile genitalia were an expected side effect of the treatment.

A Rare Presentation of Severe Colitis with Ipilimumab Therapy

Introduction: Diarrhea is a commonly encountered problem in the inpatient hospital and the outpatient setting as well. We present an interesting case of a female patient whose diarrhea demonstrated GI (Gastrointestinal) toxicity in a setting of immunotherapy. Case: A 67-year-old Caucasian female with malignant melanoma of the right index finger, status post resection, developed recurrence with axillary involvement. She was undergoing systemic chemotherapy with ipilimumab. She presented with severe, non-bloody diarrhea (> 10 times a day) associated with abdominal pain. She did not have any recent hospitalizations, infections, antibiotics, or known gastrointestinal disorders. Initially, she was afebrile without leukocytosis, and negative Clostridium difficile toxin. Stool culture and fecal leukocytes were unremarkable. Despite anti-motility agents, her diarrhea persisted, and she underwent a flexible sigmoidoscopy, which revealed non-specific active transmural colitis with ulceration and necrosis involving the distal ileum, cecum, and descending colon. Given recent treatment with ipilimumab, immune-related enterocolitis was highly suspected. The patient was treated with IV (intravenous) high-dose prednisone, mesalamine, and ioperamide. She continued to have progressively worsening diarrhea, despite therapy. Her clinical condition rapidly declined, requiring surgery for bowel perforation. Recovery was complicated and prolonged, and she decided to forego any further medical treatment, and subsequently died. Discussion: Ipilimumab has recently been found to be an efficacious treatment of malignant melanoma. However, it does present with an array of adverse effects, including enterocolitis in 1% of patients. If suspected, early immune-mediated enterocolitis responds well to systemic steroids, as per recently documented case reports. Other studies concluded that surgery in steroid-resistant cases maybe necessary in order to prevent progression of colitis to intestinal perforation. Although our patient's presentation of diarrhea and colitis was an expected side effect of Ipilimumab, she failed to respond to systemic steroids; this resulted in bowel perforation, rapid decline, and ultimately death. In conclusion, this case report should raise the awareness of ipilimumab GI-related side effects among gastroenterologists. Moreover, steroid therapy, as suggested by our reference studies, may not be sufficient in such severe enterocolitis. Other treatment options should be considered.

Therapeutic Potential of JAK2 Inhibitors

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.

Abstract A86: Inactivation of p110delta PI3K releases potent antitumor immunity.

Abstract In cancer the tumor suppressive potential of the immune system is limited by the induction of self-tolerance and chronic inflammation promoted through the activity of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) respectively. The phosphoinositide-3-kinase (PI3K) pathway is very frequently activated in cancer cells, and clinical trials with PI3K inhibitors are ongoing. The p110delta isoform of PI3K is highly enriched in leukocytes in which it regulates various immune functions. p110delta is involved in both the adaptive and innate immune system and p110delta inhibitors may be used to treat a broad range of immune disorders including T cell mediated auto-immune disorders. An expected side effect of long-term p110delta inhibition is, immune suppression, which could pre-dispose to cancer. We now show that paradoxically, genetic or pharmacologic inactivation of p110delta protects mice against tumor growth and metastasis. Blockade of p110delta; inhibits the activation of Treg cells and the accumulation of MDSCs, thus allowing the development of an effective CD8+ T cell-dependent anti-tumor response. These data provide a rationale for the use of p110delta inhibitors as adjuvants to boost anti-tumor immune responses in cancer. Note: This abstract was not presented at the conference. Citation Format: Khaled Ali, Dalya Soond, Roberto Pinero, Wayne Pearce, Cheryl Scudamore, Lori Friedman, Martin Turner, Klaus Okkenhaug, Bart Vanhaesebroeck. Inactivation of p110delta PI3K releases potent antitumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A86.

Final Results of a Phase I/II Trial of the Combination of Concurrent Lenalidomide, Thalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Myeloma

AbstractAbstract 75 Background:The combination of lenalidomide (Len) and dexamethasone (Dex) has demonstrated overall response rates (ORR) of 60% in relapsed and/or refractory multiple myeloma (RRMM). Preclinical studies have demonstrated Len resistance is mediated via the Wnt/β-catenin pathway, which can be reversed by thalidomide (Thal). The concurrent administration of Len, Thal and Dex has not previously been evaluated in RRMM. Our hypothesis proposed that the concurrent administration of Len, Thal and Dex may overcome Len resistance and improve response rates in patients with relapsed and/or refractory myeloma. The aim of this study was to determine the maximum tolerated dose (MTD) of the combination of Len/Thal/Dex and evaluate efficacy of the combination. Methods:The primary objective of the phase 1 portion was to determine the MTD, and the primary objective of the phase 2 was to determine the overall response rate. Patients (pts) with relapsed and/or refractory myeloma with ≥1 line of therapy were eligible, and received dexamethasone in pulse dose fashion in cycles 1–2, and weekly Dex in cycles 3 and beyond. The protocol was amended to enroll an additional 10 patient cohort who were Len refractory and received Dex on days 1, 8, 15 and 22 starting with cycle 1. All patients received anticoagulation with warfarin or low molecular weight heparin. Phase 1 data has been previously presented, and herein we present the final data from the phase 1/2. Adverse events (AEs) were graded by NCI-CTCAE v4, and responses were assessed by the modified International Uniform Response Criteria. Results:64 patients were enrolled who had a median of 4 prior lines of therapy (range: 1–12), a median age of 65 (range: 36–86), and 40/64 (63%) were males. 60/64 patients had available cytogenetic data; and 52% (31/60) had high risk cytogenetics, including 40% (24/60) with deletion 13; 13% (8/60) with deletion 17p; 5% (3/60) with t(4:14); and 12% (7/60) with t(11:14). These patients were heavily pretreated, with 66% (42/64) having Len refractory disease; 56% (36/64) had prior Thal; and 77% (49/64) had prior autologous transplantation. The maximum tolerated dose used for phase 2 was Len 25 mg/Thal 100 mg/Dex 40 mg. Among the 64 patients, 59/64 patients were evaluable for efficacy, excluding 5 who withdrew consent during cycle 1. Among the 59 evaluable patients, 56% (34/59) had a partial remission (PR) or greater, and 73% (43/59) had at least a minor response (MR). 13% (8/60) achieved a complete remission (CR/near CR (nCR)), 7% (4/60) had a very good partial remission (VGPR), 37% (22/60) had a PR, 15% (9/60) had MR, 15% had stable disease (SD), and 12% (7/60) had progressive disease (PD).Among the 42 patients who were Len refractory, 38 were efficacy evaluable. The ORR (≥MR) was 63% (24/38) and ≥PR was 39% (15/38), and achieved at least a minor response. 2/38 had a CR/nCR, 1/38 a VGPR, 12/38 a PR, 9/38 a, MR, 8/38 had SD, and 6/38 had PD.Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (26/56), thrombocytopenia (29/56), neutropenia (21/56), diarrhea (24/56), constipation (32/56), nausea (15/56), dizziness (32/56), memory changes (21/56), blurred vision (24/56), fatigue (41/56), elevated creatinine (16/56), dyspnea (32/56), transaminitis (11/56), pneumonia (14/56), upper respiratory infection (16/56), hyperglycemia (18/56), hypomagnesemia (23/56), hypokalemia (16/56), hyponatermia (14/56), and hypophosphatemia (15/56). Grade ≥3 AEs regardless of causality included anemia (10/56), thrombocytopenia (12/56), neutropenia (15/56), diarrhea (2/56), dizziness (5/56), fatigue (17/56), elevated creatinine (5/56), and pneumonia (10/56).One venous thromboembolic (VTE) event was observed. No treatment emergent G3/4 peripheral neuropathy was seen. 1 patient died on study with cardiac arrest at home. Conclusions:The recommended dose for this regimen is Len 25 mg/Thal 100 mg/Dex 40 mg. The combination is well tolerated with an expected side effect profile and, importantly, limited incidence of VTE and treatment emergent neuropathy. The ORR of 73% was higher than would be expected of the two-drug regimen of Len/Dex. The preserved activity in Len-refractory disease, with a response rate of 63%, supports the hypothesis that the combination of Len and Thal can overcome lenalidomide resistance, and provides a new treatment option for patients with Len-refractory disease. Disclosures:Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Orlowski:Celgene: Honoraria, Research Funding. Thomas:celgene: Research Funding.

The Use of Pegylated G-CSF in Chronic Neutropaenia of Childhood. A Single Centre Experience

AbstractAbstract ▪3268▪This icon denotes a clinically relevant abstractChronic Neutropenia of Childhood (CNC) is defined as an absolute neutrophil count that is persistently below 0.5×109/L and leaves patients at risk of severe, systemic bacterial and fungal infections. The standard treatment to raise the neutrophil count is daily injections of recombinant G-CSF to maintain the neutrophil count above 1.0 × 109/L and the child infection free.A long acting Pegylated G-CSF (PEG G-CSF) is available but is unlicensed for use in chronic neutropenia and in children. Concern has been expressed regarding long term exposure to PEG G-CSF and the potential for neutralising antibodies; there is a lack of clinical evidence and experience in its use for CNC. Potential advantages exist in its use including a more stable and sustained neutrophil count and fewer subcutaneous injections; the latter an important consideration in a paediatric population.We report a single centre experience of seven consecutive cases using PEG G-CSF in CNC. Five boys and two girls age range five months to six years had a total of thirty four presentations in Accident and Emergency for bacterial infection; eleven episodes required hospital admission and intravenous antibiotics. All had a history of persistent neutropenia ranging from one to thirty two months. Prophylactic oral anti-infectives; ciprofloxacin and itraconazole were prescribed and once bone marrow examination had excluded evidence for other causes of persistent neutropenia standard G-CSF was commenced.All seven patients were responsive to G-CSF and so following two – four weeks of treatment a switch to PEG G-CSF was made. Neutrophil response kinetics was monitored to tailor individual dose and frequency of injections.In all cases there was an increased longevity of neutrophil response over time. Treatment with PEG G-CSF was required initially every seven days, but the neutrophil count was ultimately sustained by one injection every three to four weeks. We hypothesise that this is due to gradual recruitment of immature precursors and stem cells towards the neutrophil lineage; whereas the initial neutrophil responses are the result of more mature committed precursors.Once on PEG G-CSF there was a marked reduction in serious bacterial infections with a total of only six urgent medical assessments sought. This resulted in one admission each for three of the children. Four children had no further hospital admissions.The neutrophil count responded and was maintained in all seven cases. Prophylactic anti-infectives were discontinued once a stable neutrophil count was achieved. Six patients continued the PEG G-CSF successfully whilst one discontinued its use due to maternal concerns of an associated behaviour change and sleep disturbance, not an expected side effect of PEG G-CSF.These cases demonstrate the effective, safe use of PEG G-CSF in chronic neutropenia of childhood, with a more sustained neutrophil count and thus reduced risk of infection. There was no evidence of a reduced response to PEG C-CSF suggesting no development of neutralising antibodies.The decreased frequency of injections has led to an improved quality of life for these children and their families, with fewer hospital visits for treatment, blood sampling and review. Disclosures:Off Label Use: PEGylated G-CSF used in chronic neutropaenia of childhood.