Flare Reaction Research Articles

Inhibition of allergen‐induced wheal and flare reactions by levocetirizine and desloratadine

The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action. Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet. The time-response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial. This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine. In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity. This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation. To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations. A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time-response of the wheal and flare reaction areas under the curve (AUC) were compared by anova. Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean +/- SEM wheal AUC(0-24 h) was 506.4 +/- 81.0 with levocetirizine and 995.5 +/- 81.0 mm(2) h with desloratadine as compared with placebo (1318.5 +/- 361.0 mm(2) h). Flare AUC(0-24 h) was 5927.3 +/- 1686.5 and 15838.2 +/- 1686.5 mm(2) h, respectively [P < 0.001 for both compared with placebo (22508.2 +/- 7437.1 mm(2) h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P <or= 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 +/- 13.4 and 20.0 +/- 8.1 ng ml(-1), respectively) as compared with desloratadine (0.82 +/- 0.24 and 0.45 +/- 0.16 ng ml(-1)). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g(-1)) than for desloratadine (0.07 ng g(-1)). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h. Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency.

The development of sarcoidosis with the use of alemtuzumab – clues to T‐cell immune reconstitution

The development of sarcoidosis with the use of alemtuzumab – clues to T‐cell immune reconstitution

Praktische Tipps für die Betreuung von Patienten mit Urtikaria

Urticaria (hives), one of the most common inflammatory skin conditions, is relatively easy to diagnose because of its characteristic skin symptoms, i.e. wheal and flare type skin reactions and/or angioedema. Urticaria, however, actually comprises 12 distinct conditions and it is important and often difficult, to determine which urticaria subform(s) individual patients are afflicted with. The most challenging task in diagnosing urticaria is to identify the underlying causes in chronic urticaria. Yet, this is important as many patients with chronic urticaria can be successfully treated by eliminating the reason for their condition. In contrast, the treatment of virtually all other urticarias is primarily aimed at achieving symptom control, e.g. by avoiding accountable triggers and/or by using symptomatic treatment.

A Small Animal Positron Emission Tomography Study of the Effect of Chemotherapy and Hormonal Therapy on the Uptake of 2-Deoxy-2-[F-18]fluoro-d-glucose in Murine Models of Breast Cancer

We used small animal positron emission tomography (PET) imaging to monitor the time-course of tumor metabolic response to hormone and chemotherapy in a murine model of hormone-sensitive breast cancer. Estrogen receptor positive murine mammary carcinomas were inoculated in Balb/c mice. Small animal PET imaging using 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) was used to assess tumor metabolic activity. Imaging was done before and at days 1, 7, and 14 after the administration of doxorubicin, methotrexate, letrozole, or placebo. The tumor uptake of FDG was calculated from a region-of-interest drawn around the tumor. All treatments resulted in a decrease in tumor growth rate and end volume compared to untreated control. FDG uptake was also markedly decreased after treatment although a flare reaction was observed on PET at day 7, the intensity of which varied according to the treatment modality. PET imaging is sensitive to detect early changes associated with therapy in murine breast cancer models. A flare reaction was observed 7 days after the initiation of therapy.

Recurrent Pregnancy Loss and Inappropriate Local Immune Response to Sex Hormones

The cause of recurrent miscarriage is often unknown. Recurrent miscarriage may be associated with inappropriate responses to progesterone and estrogen. We examined whether the condition may be diagnosed by skin testing. In a longitudinal prospective study, the weal and flare reaction after intradermal injection of estradiol and progesterone was compared in 29 women with recurrent miscarriage to the response in 10 healthy women. Reactions were evaluated after 20 min, 24, and 48 hr and 5 days later. Estrogen hypersensitivity was found in 23 patients, and progesterone hypersensitivity in 20 patients. No patient in the control group demonstrated sex hormone hypersensitivity. Recurrent pregnancy loss may be associated with inappropriate local immune responses to sex hormones. Further research is necessary into the mechanisms of hypersensitivity to estrogen and progesterone and their interactions with other systems.

Assessment of Immunologic Mechanisms for Flare Reactions to Synvisc®

Assessment of Immunologic Mechanisms for Flare Reactions to Synvisc®

Safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution in cataract surgery patients

To determine the safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution (Vigamox) in patients having cataract surgery. American Eye Center, Manila, Philippines. Preoperative and 1-month postoperative anterior chamber reaction, corneal endothelial cell density, and corneal thickness were assessed in 65 eyes that had cataract surgery with intracameral moxifloxacin. All eyes received 0.1 mL intracameral moxifloxacin 0.5% ophthalmic solution containing 500 mug of moxifloxacin as the last step of phacoemulsification. Different ophthalmologists conducted the postoperative evaluation in an observer-masked fashion. A P value less than 0.05 was considered significant. All 65 eyes completed the study. The mean age was 69.5 years +/- 9.13 (SD) (range 48 to 84 years). All eyes had a postoperative best corrected visual acuity of 20/30 or better. All eyes had trace to +2 cells and flare anterior chamber reaction only on the first day after surgery. The mean endothelial cell count was 2491.52 cells/mm(2) preoperatively and 2421.58 cells/mm(2) postoperatively. The mean difference was 70 cells/mm(2), which not statistically significant (P = .737). The increase of 17.80 microm in postoperative pachymetry 1 month after surgery was not statistically significant (P>.65). Intracameral Vigamox 0.5 mg/mL appeared to be nontoxic in terms of visual rehabilitation, anterior chamber reaction, pachymetry, and corneal endothelial cell density.

Infective Endocarditis: A Multidisciplinary Interactive Team-Based Learning Exercise

OPEN ACCESSNovember 20, 2006Infective Endocarditis: A Multidisciplinary Interactive Team-Based Learning Exercise Stuart Nelson, PhD Stuart Nelson, PhD Wright State University Boonshoft School of Medicine Google Scholar More articles by this author https://doi.org/10.15766/mep_2374-8265.330 SectionsAbout ToolsDownload Citations ShareFacebookTwitterEmail Abstract Introduction: This educational resource is a team-based exercise centering on a case of infective endocarditis due to viridans streptococci. These bacteria gained access to the patient's blood following trauma to the mouth and teeth inflicted by a baseball bat during a barroom brawl. The patient presents with a fever, facial bruise, heart murmur, subungual splinter hemorrhages, Roth spots, and splenomegaly. Methods: The exercise is a PowerPoint presentation organized as an unfolding case history. Presenting the slides in sequence allows the case to unfold over time. Eight multiple-choice questions are inserted at strategic points in the exercise. Medical students may answer these questions in teams or as individuals. In attempting to answer these questions, the student or teams of students should have access to reference books, a medicine textbook, and a medical dictionary. The exercise works best if it is not distributed to medical students in paper form at the beginning of class or ahead of time. Instead, the PowerPoint presentation should be projected on a screen and allowed to unfold one slide at a time. This exercise typically requires 75–90 minutes. Results: We have field-tested this exercise for 3 years (in 2003, 2004, and 2005) as part of a module in the second-year curriculum's cardiovascular course at the Wright State University Boonshoft School of Medicine. Suggestions for improvement from students and faculty have been incorporated to enhance the exercise's quality. Discussion: Use of this exercise encourages collegial interaction, peer-to-peer clarification of knowledge, and dynamic sharing to arrive at consensus choices. The slide-by-slide presentation mimics real life, and our experience has confirmed the effectiveness of this strategy. When presenting the case to students, it is important to use a title that does not reveal which disease(s) the patient has. The case is suited for use as a team-based learning application exercise in which students reach consensus and then vote as a team. Use of timers and audience response technology may enhance the administration of this resource. Educational Objectives By the end of this session, learners will be able to: Recognize the clinical signs of infective endocarditis.Describe antimicrobial agents' mechanisms of action.Identify the adverse effects of antimicrobial agents.Explain the mechanisms involved in Type I hypersensitivity.Explain a Type I allergic skin test and describe a wheal and flare reaction on the skin.Recognize various microorganisms observed in gram stains.List the most common causes of native valve endocarditis, prosthetic valve endocarditis, and endocarditis involving previously damaged heart valves.Identify risk factors that contribute to infective endocarditis. Sign up for the latest publications from MedEdPORTAL Add your email below FILES INCLUDEDReferencesRelatedDetails FILES INCLUDED Included in this publication: Infective Endocarditis.ppt To view all publication components, extract (i.e., unzip) them from the downloaded .zip file. Download editor’s noteThis publication may contain technology or a display format that is no longer in use. CitationNelson S. Infective Endocarditis: A Multidisciplinary Interactive Team-Based Learning Exercise. MedEdPORTAL. 2006;2:330. https://doi.org/10.15766/mep_2374-8265.330 Copyright & Permissions© 2006 Nelson. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives license.KeywordsTBLType I HypersensitivityNative ValveEndocarditisAllergic Skin TestTeam-based LearningAntimicrobial AgentsProsthetic ValveViridans StreptococciWheal and Flare Disclosures None to report. Funding/Support None to report. Loading ...

Clinical Efficacy and Safety of Combined Thalidomide and Fludarabine Therapy in B-Cell Chronic Lymphocytic Leukemia Patients.

Background: Targeting the tumor microenvironment through modulation of cytokines is a potential way to treat B-CLL. Thalidomide (THAL) is an immunomodulatory agent with pleiotropic activities, reported to exert antitumor activity through downregulation of cytokines. THAL may enhance proapoptotic activity of fludarabine (F) with resultant improvement of clinical responses. This preliminary study assesses the efficacy and safety of THAL+F combined therapy in B-CLL patients with focus on immune responses.Patients and methods: Twelve patients (pts) were included in this study. Seven of them (5M, 2F) were newly diagnosed and 5 (2M, 3F) pts were refractory (ref) or relapsed (rel). The median age was 59, range 50–72 yrs. The increased Zap70/CD38 expression had 7/3 pts respectively. All pretreated pts had short lymphocyte doubling time < 6 months. Median prior lines of therapy were 3, range 2–4.THAL 100 mg po, alone was given for the first 7 days of cycle 1 and continued a la longue for 6 months, F 25 mg/m2 iv, was given for 5 days every 28 days for up to 6 cycles, starting on the seventh day after initiating THAL. Acetylsalicylic acid 75 mg was used to prevent venous thromboembolism. Cytokine levels of TNF, IL-2, IL-4 and IL-10 were assessed before, after THAL and after F treatment (D0, D7 and D12) using ELISA test. T regulatory cells were identified as CD4+CD25highFOXP3+ and assessed by FACS analysis.Results:. Median duration of follow-up was 5.5, range 2–7 months. Pts completed 1–5 cycles (mean: 3). In 3 heavily pretreated pts we stopped therapy due to disease progression. Other 9 pts achieved partial remission (7 pts) or stabilization of disease (2 pts). Directly after 1 cycle of therapy 11 pts showed reduction in WBC (Fig. 1). One patient with anemia was transfusion dependent and after 6 weeks of THAL became transfusion free. Interestingly, we have observed increasing levels of TNF during the treatment. Additionally increase in IL-2, IL-4 and IL-10 was observed. We noted significant reduction in absolute count of Treg cells after treatment with THAL (in 9 evaluated patients), that was enhanced in 7 by addition of F to the treatment (mean cells/mL: 315 before treatment, 100 after THAL and 81 after F).Toxicity: A flare reaction with tenderness and rash of involved lymph nodes was observed during the first cycle in 3 pts. Moderate side effects including constipation and fatigue were noted in all patients. No of them required the additional therapy or discontinuation of THAL+F regimen. Granulocytopenia with WHO grade 4 after the first 2 cycles was noted in 1 patient. Inflammatory complications of respiratory tract with WHO grade 2/3 occured in 3 pts following the first courses of THAL+F.Conclusions: Results of our study suggests that THAL combined with F demonstrated significant efficacy in B-CLL patients not only as a first line treatment but also as a salvage therapy with good safety profile. THAL+F regimen should be tested on a larger group of patients. [Display omitted]

Clinical Efficacy of Lenalidomide {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase II Clinical Trial.

Introduction: Lenalidomide (L) is an immunomodulatory agent (IMiD®), recently approved for treatment of patients (pts) with previously treated multiple myeloma and del 5q- MDS. Its antitumor effects are reported to be mediated at least in part through modulation of both the cytokine and the immune cellular tumor microenvironment. Clinical efficacy of L in pts with B-CLL has not been investigated previously. In a phase II clinical study, we examined the antileukemic effects of L in pts with relapse (rel) or refractory (ref) B-CLL.Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD from days 1–21 of 28-day cycle. Response was assessed every month using the NCI-WG 1996 criteria. Treatment with L was continued until progressive disease (PD) or molecular complete response (CR). Pts with PD received rituximab (R) (375mg/m2) with L. Target enrollment was 45 patients.Results: Forty-five pts, median age of 64 years (range: 42–75) were enrolled. Advance stage disease was noted in 64%, elevated B2M in 24% and fludarabine refractory disease in 51% of the pts. Pts had a median of 3 prior therapies (range 1–10). All pts are evaluable for toxicity. Thrombocytopenia and neutropenia were the most common hematologic toxicity while fatigue and flare reaction (sudden, tender enlargement of lymph node, liver and/or spleen, with or without rash, low grade fever and/or increase in white blood counts) were the most common non-hematologic complications. Two patients experience reversible tumor lysis syndrome. On an intent-to-treat analysis, overall response rate was 42% with complete remission in 9% (n=4) and partial remission in 33% (n=15) of the pts. Molecular complete response (determined by PCR) was noted in 3 pts. Twelve pts were inevaluable (unable to complete 2 treatment cycles; either for toxicity or consent withdrawal) 4 are too early for response evaluation. Response rate among evaluable patients was 65.5% (19/29). To date only 2 pts have required the addition of R to L due to PD. Both have achieved a PR with combination therapy.Correlative studies: we evaluated baseline T and NK cell repertoire, modulation of cytokines (VEGF, IL-10, IL-6, TNF-alpha) as well as modulation of gene expression profiles before and after treatment with L, this data will be presented at the meeting.Conclusion: L is clinically active in pts with rel/ref CLL. CR's, as well as, molecular CR determined by PCR were achieved with single agent L. Interestingly, in pts who developed resistance to L alone, addition of R resulted in a clinical response. These results are exciting and warrant further investigation of L in CLL pts. Final results of this study will be presented at the meeting.

Lenalidomide Induces Complete and Partial Responses in Patients with Relapsed and Treatment-Refractory Chronic Lymphocytic Leukemia (CLL).

Lenalidomide is an immunomodulatory drug indicated as treatment for 5q-MDS and previously treated MM. Several of its properties, i.e. inhibition of TNF-α and VEGF, modulation of T-cell activity and impact on the microenvironment suggest that lenalidomide may play a role in the treatment of CLL. A pilot study by Chanan-Khan et al. has shown clinical activity in this disease (Blood 106: 447a). To further investigate the activity of lenalidomide in CLL, we conducted a phase II study. Patients (pts) were eligible if they had received at least one purine analog-based regimen. All pts received lenalidomide at 10 mg daily for 28 days followed by titration upward by 5 mg increments every 28 days to a maximum dose of 25 mg daily. De-escalation to 5 mg daily was allowed. The planned 35 pts have been enrolled. Twenty-two pts have received treatment for at least 3 months and are therefore evaluable for response. The median daily dose of lenalidomide at three months was 10 mg. The median age was 64 yrs (range 49–82), the median number of prior treatments was 4 (1–15), and the median β2M was 4.1 mg/dL (1.6–10.1). Twelve pts (55%) had Rai stage III or IV disease. Eight pts (36%) were refractory to fludarabine and 7 pts (32%) to alkylating agents. Responses according to NCI-WG criteria assessed after 3 months of treatment showed that 7 pts (32%) achieved a response [1 CR (5%), 1 nodular PR (5%), 5 PR (23%)]. Nine pts (41%) attained stable disease or clinical improvement and are continuing on treatment, and 6 pts (27%) progressed, including one early death that occurred on day 22 secondary to mucormycosis. A tumor flare reaction was observed in 6 pts (27%), fatigue was reported in 59% (G3 in 5%), nausea in 45%, pruritus in 31% and diarrhea in 22% (G 3 in 5%). Myelosuppression occurred in 55% of the pts (32% ≥G3 neutropenia and/or thrombocytopenia). Infectious complications were observed in 6 pts: 2 cases of neutropenic fever and 4 episodes of pneumonia. To decipher lenalidomide's mechanism of action we measured plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor 1 (TNF-R1), interferon (IFN)-γ, VEGF, bFGF, interleukin (IL)-1β, -2, -6, -8, -10, -12, IL-1 receptor antagonist (IL-1RA), and soluble IL-2 receptor (IL-2R) in 19 pts pre-treatment, on day 28, and after 3 months of therapy. We found a significant reduction in plasma VEGF level on day 28 in 4 pts that achieved a response [mean reduction of 55.6 (± 15.3) pg/mL, p = 0.036] and on day 90 in 4 pts with stable disease or clinical improvement [mean reduction of 50.9 (± 3.3) pg/mL, p = 0.003]. There were no changes in the levels of the other cytokines, including TNF-α. Further correlative studies include measurement of marrow vascularity, number of circulating T regulatory cells and CLL apoptotic rate. In conclusion, we found that lenalidomide is active in heavily pre-treated pts with relapsed CLL. Myelosuppression has been the most significant toxicity. Results of ongoing correlative studies will be presented.

The autologous serum skin test in a cohort of chronic idiopathic urticaria patients compared to respiratory allergy patients and healthy individuals

A positive autologous serum skin test (ASST) is considered to reflect the presence of anti-FceRI and/or anti-IgE autoantibodies that are capable of activating mast and basophil cell degranulation. The ASST is regarded as a reliable in vivo test in chronic idiopathic urticaria (CIU) patients, with diagnostic, therapeutic and prognostic implications. However, positive ASST results have also occasionally been demonstrated in patients with other diseases and in healthy subjects. To evaluate the specificity and sensitivity of the ASST in a cohort of CIU patients compared to a cohort of respiratory-allergic patients and a group of normal individuals. ASST was performed in a cohort of 116 subjects, 47 subjects with seasonal allergic rhinitis, 32 respiratory-symptom-free CIU patients, and 37 healthy individuals. The results were compared statistically to those of the CIU patients. The intradermal injection of autologous serum induced a weal and flare reaction in 17/32 (53.1%) CIU patients; 14/47 (29.8%) patients with seasonal allergic rhinitis (P=0.06) and in 15/37 (40.5%) of the healthy controls (P=0.34). The sensitivity and specificity of the ASST in the CIU patients and the seasonal allergic rhinitis patients was 53 and 28%, respectively. When comparing the CIU patients with the healthy controls the sensitivity and specificity was 55 and 31%, respectively. The positive and negative predictive values of the ASST when comparing CIU patients with healthy controls were 53 and 59.5%, respectively. The positive and negative predictive values of the ASST in the CIU patients compared to seasonal allergic rhinitis patients were 53 and 70%, respectively. The relatively low sensitivity and specificity of the ASST in the CIU patients compared to the seasonal allergic rhinitis patients and healthy controls warrants a more critical interpretation of the ASST in chronic idiopathic urticaria.

First Clinical Evidence of In Vivo Natural Killer (NK) Cell Modulation in Chronic Lymphocytic Leukemia (CLL) Patients (pts) Treated with Lenalidomide (L).

Introduction: Pts with Chronic Lymphocytic Leukemia (CLL) are reported to have quantitative and qualitative T and NK cell dysfunction. While NK cells act through non-specific killing, T-cells are more specific. The 2 types of T-lymphocytes, CD4+ (Th; helper) and CD8+ (Ts; cytotolytic/suppressor) are subcategorized based on cytokine secretion profile upon activation. Release of different cytokines from these immune cells modulates the host response. T1 cells (Th1, Ts1) secrete IL-2 and interferon-g which initiate the Th1 response- mainly CD4+ activation along with B and T cells, leading to proliferation and differentiation of these cells. T2 (Th2, Ts2) cells initiate the Th2 response (release of TNF-a, IL-10) resulting in direct lysis of the target cell by production of cytokines such as IL-4, IL-5 and IL-10.Hypothesis: To decipher this antitumor mechanism of L in CLL pts we investigated its effect on the efferent arm of immune response by evaluating the T cell population and the afferent response by change in expression of co-stimulatory molecules on B-CLL cells and cytokine profile in these pts treated on a phase II clinical study.Methods: CLL pts treated with L were evaluated for absolute number of T (CD4+, CD8+) and NK (CD56+) cells by flow cytometry on day before (day0) start and on Day 8 of treatment with L. Peripheral blood was collected and ficolled to obtain enriched mononuclear cells. The serum was used to study the cytokines. Activation status was determined by co-expression of CD45+. Serum cytokine profile was measured by Flow cytometry using the Luminex system. B-CLL surface co-stimulatory molecules were detected by flow cytometry and analyzed by FACS. These responses were correlated with the tumor flare (TF) reaction that the patients developed during the first week of treatment with L.Results: Eighteen out of 45 pts have so far been evaluated for immunomodulatory activity of L. There were 2 complete responders (CRs) and 6 partial responders (PRs); while 4 had stable disease (SD), 4 were clinically unevaluable and 2 were too early for response in this group. Mean baseline (bl) NK cell count pretreatment was 251 (range 31–1510) vs. post treatment was 193 (range 6–13,482). Six out of 18 patients showed an increase, ranging from 20 −199% in the absolute NK (CD16+/CD56+/CD45+). While there was no appreciable change in CD4+ numbers there was a general trend in increase of CD8+ cells. No change in monocyte population was noted. Concurrent increase in the expression of co-stimulatory molecules such as CD95 and CD80 was noted. This response in co-stimulation was confirmed by in vitro experiments done on isolated B-CLL cells (n=4)treated with L. An increase in Th-2 cytokines such as IL-4, IL-5, IL-6 and IL-10 was noted in all eight responders, while VEGF levels were decreased in 6/18 patients. 99% of patients had a TF and the grade of TF correlated with the changes in T cells and cytokine profile.Conclusion: It appears that in vivo L is able to orchestrate an anti-tumor response in CLL by modulating the NK cells, changing the cytokine profile and up-regulating co-stimulatory molecules. This change in the immune effector cell repertoire and the Th2 skewing may explain the initial flare reaction noted in these L treated pts. Data from these correlative studies is being evaluated in the context of the phase II clinical trial to be reported at the 48th ASH annual meeting.

Prednisone (P) prophylaxis decreases incidence and severity of lenalidomide (L) induced flare reaction (flr) in patients with relapse (rel) or refractory (ref) chronic lymphocytic leukemia

18512 Background: Flare reaction (flr) is a new side effect unique to CLL pts treated with immunomodulating agents both thalidomide (T) and L. It is characterized by tender swelling of disease involved lymph nodes (LN), spleen, rash, low-grade fever and/or increase in absolute lymphocyte counts (ALC). Underlying biologic process remains unknown though it is postulated to be mediated through activation of immune effector cells and/or change in serum concentration of pro-inflammatory cytokines. In a phase II clinical trial of L in rel/ref CLL pts we noted a high incidence of flr. Here we report treatment schema for flr and a new preventive approach employed in this study. Methods: A total of 35 pts are enrolled. No prophylaxis given to initial cohort (A). Pts were treated at onset of symptoms with (1) ibuprofen (Ib) 600 mg po q6 hours (2) oxycodone (oxy) 5–10 mg po prn q 6 hours. In subsequent cohort (B) we are investigating prophylactic use of P 20 mg PO QD starting day −1 × 5 days followed by 10 mg QD × 5 days. Results: All pts had rel or ref disease. Median age 63 (range 48–76) year. In cohort A (n = 29) overall incidence of flr was 79% (n = 23). Of these the severity was graded as I, II and III in 48%, 24%, and 7% respectively. There was no grade IV flr. Symptoms initiated within hours of intake of the 1st dose of L lasting for a median of 14 days (cycle 1 only). Pts were adequately managed with symptom resolution using Ib/oxy. Recurrence in cycle 2 was noted in 1 pt. Pain in LN was the most common complaint. Increase ALC noted in 2 pts. Serum cytokine analysis (n = 5) pre and post 7-days of L treatment showed significant increase in TNF-α, IL-10 and MIG. In cohort B (n = 6) 2 pts had flr (grade I) lasting ≤ 10 days. Conclusions: Prophylactic use of P results in decrease incidence, severity and duration of flr. There was no correlation with clinical response. Elevation of ALC can be part of the flr, pts response should be interpreted cautiously for disease progression. Our findings suggest that use of P may be an effective prophylactic maneuver for prevention of L induced flr. Updated results of cohort B will be presented at this meeting. [Table: see text]

Infarctus dorsal du bulbe dans les suites d’une piqûre de guêpe

Although wasp stings can cause local reactions such as pain, flare, edema, swelling and severe reactions, including anaphylaxis; neurological vascular complications are rare. We report a case of a 36-year-old male who developed focal neurological symptoms after a wasp sting. The brain MRI showed an infarct in the left dorsal medulla. The blood test has showed an elevated level of venom-specific IgE antibodies and the skin test with wasp venom was highly positive. Improvement occurred rapidly after treatment with methylprednisone. The postulated mechanisms include vasoconstriction and platelet aggregation secondary to an injection of distinct allergens contained in wasp venom. It would thus be important to ask patients about any recent wasp sting, in order to provide appropriate treatment.

Efalizumab: a review of events reported during clinical trials and side effects

Efalizumab is a recombinant humanised IgG1 kappa isotype monoclonal antibody against the CD11a molecule. Efalizumab is approved for the treatment of moderate-to-severe psoriasis and is currently administered as a weekly subcutaneous injection. Throughout October 2005, 19,000 patients were treated with efalizumab. According to the package insert that is based on 2762 subjects, the most common adverse reactions associated with efalizumab are a first dose reaction complex that includes headache, chills, fever, nausea and myalgia within two days following the first two injections. These reactions are dose-level-related in incidence and severity and were largely mild-to-moderate in severity when a conditioning dose of 0.7 mg/kg was used as the first dose. Adverse events occurring at a rate between 1 and 2% greater in the efalizumab group compared with placebo were arthralgia, asthenia, peripheral oedema and psoriasis. Efalizumab is associated with a rebound flare reaction in ∼ 5% of patients when therapy is ceased. Antiefalizumab antibodies develop in ∼ 5% of the subjects who were treated with efalizumab, but the clinical significance of these antibodies is unclear. Efalizumab has rare but serious haematological side effects. Immune-mediated thrombocytopenia platelet counts at or below 52,000 cells/µl have been observed in 0.3% of cases and monitoring of platelet counts monthly for the first 3 months of use and each 3 months thereafter. Reports of four cases of haemolytic anaemia diagnosed four to six months after patients started on the monoclonal antibody exist. Infrequent new onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing surveillance. Symptoms associated with a hypersensitivity reaction (e.g., dyspnoea, asthma, urticaria, angioedema, maculopapular rash) were rarely noted in the first 12 weeks of the controlled clinical studies. The overall incidence of malignancies of any kind was 1.8 per 100 patient-years for efalizumab-treated patients compared with 1.6 per 100 patient-years for placebo-treated patients. One case each of the following serious adverse reactions was observed: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, sialedenitis and sensorineural hearing loss. In the complete safety data from both controlled and uncontrolled studies, the overall incidence of hospitalis ation for infections was 1.6 per 100 patient-years for efalizumab-treated patients compared with 1.2 per 100 patient-years for placebo-treated patients. The rate of infection was 26% in the control group and 29% in treated cases. The most common findings on laboratory assessments in patients using efalizumab were reversible increases in lymphocyte count and total white blood cell. Efalizumab is a safe, effective, but expensive treatment for psoriasis.

A 12-Month Clinical Study of LA-2585 (45.0 MG): A New 6-Month Subcutaneous Delivery System for Leuprolide Acetate for the Treatment of Prostate Cancer

The safety, efficacy and pharmacokinetics of LA-2585, a new 6-month subcutaneous depot of leuprolide acetate (Atrix Laboratories, Fort Collins, Colorado) were investigated in patients with prostate cancer. In this 12-month, open label, multicenter study 111 patients with adenocarcinoma of the prostate were administered 45.0 mg LA-2585 subcutaneously once every 6 months. The primary efficacy parameter was serum testosterone 50 ng/dl or less. Leuprolide acetate pharmacokinetics were analyzed in a subset of 28 patients. Of the 111 enrolled patients 103 (93%) completed the 12-month study. Eight patients withdrew due to nonmedical reasons in 1, disease progression in 5 and cardiovascular disease in 2. By day 28, 108 of the 109 remaining patients (99%) achieved testosterone suppression, while 1 who never attained suppression was withdrawn at day 85. Mean time to castrate suppression was 21.2 days (median 21). At study completion 102 of 103 patients (99%) were below medical castrate testosterone levels of 50 ng/dl (mean +/- SE 12.3 +/- 2.1 ng/dl) with 91 of 103 (88%) at less than 20 ng/dl. Mean luteinizing hormone decreased from 6.98 +/- 0.48 mIU/ml at baseline to 0.23 +/- 0.14 mIU/ml at month 12. Luteinizing hormone was consistently below 1 mIU/ml. Mean prostate specific antigen decreased 97% from 39.8 +/- 21.5 ng/ml at baseline to 1.2 +/- 0.3 ng/ml at 12 months. No clinically significant flare reactions were observed. The most common treatment related adverse event was mild to moderate hot flashes. LA-2585 (45.0 mg depot) consistently produced and maintained safe and effective serum testosterone suppression with total serum testosterone well below the medical castrate level of less than 50 ng/dl.

Assessment of Immunologic Mechanisms for Flare Reactions to Synvisc®

Intraarticular injection of Synvisc for treatment of knee pain sometimes results in an acute local reaction (flare). We tested the hypothesis that the flare was a Type-1 hypersensitivity reaction as manifested by the presence of Synvisc antibodies in the synovial fluid and serum and by an increase in the concentration of the mast-cell enzyme tryptase in the synovial fluid. Our second objective was to determine whether the ratio of CD4+ to CD8+ lymphocytes in the synovial fluid was increased, as would be expected in a Type-4 hypersensitivity reaction. The study population was a prospective, consecutive series of 16 patients who had a flare, and 20 control patients. We found no differences in product-specific antibodies in the synovial fluid or serum between patients with flares and patients without flares. The mean tryptase level in the synovial fluid of patients with flares, 3.8 +/- 0.8 microg/L, was not different from the corresponding level in the control patients. The CD4+/CD8+ ratio in the synovial fluid was more than eight times greater in patients with flares. Flares that sometimes occur after treatment with Synvisc are probably not Type-1 (antibody-mediated) hypersensitivity reactions, but may be Type-4 (cell-mediated) hypersensitivity reactions.

Characterization of IMiDs (Immunomodulating Agents) Induced “Flare Reaction” in Patients with Chronic Lymphocytic Leukemia (CLL) and Correlation with Changes in Serum Cytokine Levels.

Introduction: Several cytokines (including TNF-alpha, IL-6 and VEGF) are reported to play a critical role in the pathogenesis of CLL cells. Targeting the tumor microenvironment through modulation of the cytokine milieu thus is a potential way to treat CLL. In 2 separate clinical studies we investigated the role of IMiDs (thalidomide and lenalidomide) either in combination with standard chemotherapy (thalidomide + fludarabine, FT) or single agent (lenalidomide, L) in pts with previously untreated or relapsed/refractory CLL, respectively. In these studies we observed tumor flare reaction not previously reported. In this report we describe the clinical characteristics of this side effect, its management and correlation with changes in serum cytokine levels. Flare Reaction (FR): CLL pts treated with IMiDs were noted to have tender increase in lymph nodes size starting within 24–48 hours of initiating therapy with or without erythema and rash. Some patients also increased their total white cell as well as absolute lymphocyte count (ALC).Results: A total of 48 pts (20 on FT and 28 on lenalidomide) are collectively treated on 2 clinical trials. Median age was------, -----had limited stage (0-II) and ----- has advance Rai stage (III, IV). ------(%) on the FT and 22 (78.5%) on the L developed a FR, which was noted as early as 24 hours after initiation of therapy (median 48 hours). Most pts resolved FR by day 14. A comparison of serum cytokine level at day 0 and 7 was done in 10 pts (9 with FR) treated with L. An increase in TNF-a (n=4), MIG (n=6), IP-10 (n=8), IL-8 (n=7) and IL-10 (n=6) was noted at day 7.Management: FR was treated with ibuprofen 400 mg q 6 hr with addition of oral morphine (or agents of equivalent potency) for improved pain control.Conclusion: FR is a new side effect noted in CLL pts treated with IMiDs that is fairly well managed by anti-inflammatory agent along with aggressive pain control. Higher incidence is noted with L. There seems to be no correlation of FR with clinical response to therapy. Identification of the FR is important to avoid confusion with disease progression. An increase in levels of inflammatory cytokine was noted in all pts treated with L which may explain the underlying mechanism of this phenomenon.

Results of Phase II Study of Lenalidomide (L) {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).

Introduction: Lenalidomide (L) is a compound in a new group of drugs called ImiDs® which have Immunomodulatory properties and with anti-tumor activity reported in multiple myeloma and MDS. Although the exact mechanism of action of L is unknown, they are reported to affect the tumor microenvironment through modulation of critical cytokines such as TNF-a, VEGF and IL-6. These cytokines also play an important role in pathogenesis of CLL. Based on these properties we have investigated and previously reported on the anti-leukemic activity of thalidomide in CLL. We subsequently conducted a phase II study with L, to evaluate its clinical activity in pts with relapse (rel) or refractory (ref) CLL. Here we present the results of this study.Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD x 21 days followed by 7 days rest on a 28 day cycle. Absolute lymphocyte counts (ALC) were measured at Day 0, 7 and 30. Response was assessed at day 30 and monthly thereafter using the NCI-WG 1996 criteria. Pts with stable disease (SD) or better response were continued on therapy for a maximum of 12 months while those with progressive disease (PD) were to receive rituximab (R) (375mg/m2) added to L. Pts were considered evaluable for response if they completed at least 2 months of treatment. Target enrollment is 29 patients.Results: Twenty nine pts, median age of 64 years (range: 47–75) were enrolled. All pts are available for toxicity and 17 out of 29 pts available for response evaluation. Three pts on treatment are too early for response assessment while 9 pts are off study (2 withdrew consent and 5 got < 2 months of therapy due to toxicity). Response is reported based on evaluable pts. Complete remission (CR) was noted in 2/17 (11.7%) pts while partial remission (PR) was noted in 9/17 (52.9%) pts. Additional 5/17 (29.4%) pts, currently on treatment, achieved stable disease (SD). ORR (CR+PR) in the intent to treat population is 42.3% (11/26, excluding pts currently too early for response assessment). To date only 1 pt has PD after 3 months of L and is on LR per protocol. Toxicity: Flare reaction (tender swelling of lymph nodes and/or rash) was the most common SE noted in almost all pts. Other important SE were tumor lysis syndrome (n=2); grade 3/4 hematologic toxicities (n=7) and febrile neutropenia (n=3).Conclusion: This is the first study to report the clinical activity of L in pts with CLL. Our findings are encouraging and provide evidence of the anti-CLL activity of L. Although some of the pts did achieve a CR, longer follow-up will determine the durability of responses noted to date. Update results of this study along with toxicity profile of L in CLL will be presented at the meeting.