Concomitant Cyclophosphamide Use Research Articles

Rationale of concomitant cyclophosphamide for remission-induction in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A propensity score-matched analysis of two nationwide prospective cohort studies

Objectives We evaluated the effectiveness of cyclophosphamide for patients with microscopic polyangiitis and granulomatosis with polyangiitis. Methods Patients treated with cyclophosphamide and glucocorticoid (cyclophosphamide group) or glucocorticoid alone (non-cyclophosphamide group) for remission-induction were enrolled from two Japanese nationwide prospective inception cohort studies. The effectiveness and safety outcomes were compared before and after propensity score (PS)- matching. Results Proportion of patients achieving Birmingham Vasculitis Activity Score (BVAS)-remission and BVAS-remission plus a daily prednisolone dosage of ≤10 mg (GC-remission) by Month 6 were not significantly different between cyclophosphamide and non-cyclophosphamide groups before (n = 144 and 155) and after (n = 94 for each group) PS-matching. In myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive PS-matched patients, GC-remission by Month 6 was superior in CYC group (n = 82) than in non-CYC group (n = 91) (49 vs. 31%, p = .020). Overall, end-stage renal disease-free and relapse-free survival rates, Vasculitis Damage Index score, and proportions of serious infection were comparable between the two groups both in the unmatched and PS-matched patients. Prednisolone doses at any point after treatment initiation in the PS-matched patients were lower in the cyclophosphamide group than in a non-cyclophosphamide group. Conclusions Concomitant cyclophosphamide use may improve GC-remission by Month 6 in MPO-ANCA-positive patients and could exert glucocorticoid sparing effect.

Current status of eye disorders caused by docetaxel administration every 3 weeks: A case-control study in Japanese patients.

Docetaxel is known to cause eye disorders. In this study, current status of eye disorders caused by docetaxel administration every 3 weeks in Japanese patients was examined. This case-control study targeted patients who were newly administered docetaxel at the Kyoto Okamoto Memorial Hospital between 1 July 2015 and 30 June 2018. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. Of the 89 subjects, 7 (7.9%) had eye disorders. The symptoms were watering eyes (7.9%), a stye and eye discharge (2.2% each), corneal and conjunctival disorder, visual acuity reduction, and blepharedema (1.1% each). Four patients who presented with watering eyes, eye discharge, or corneal and conjunctival disorder showed improvement with the use of eye drops such as artificial tears. Two patients who presented with a stye showed improvement with the use of oral cefcapene. One patient with mild symptoms showed spontaneous improvement. However, one patient had irreversible visual acuity reduction. The multivariate logistic regression analysis revealed that a cumulative docetaxel dose of ≥300 mg/m2 (odds ratio: 15.50, 95% confidence interval: 1.37-175.00, p = 0.027) and concomitant cyclophosphamide use (odds ratio: 13.20, 95% confidence interval: 1.13-153.00, p = 0.039) were significant risk factors associated with eye disorders. In conclusion, it was determined that docetaxel-related eye disorders might be influenced by the cumulative dose of docetaxel and concomitant cyclophosphamide use. In addition, relatively mild symptoms improved with medication.

Immunoglobulin levels and infection risk with rituximab induction for anti-neutrophil cytoplasmic antibody-associated vasculitis.

BackgroundRituximab (RTX), a B cell–depleting anti-CD20 monoclonal antibody, is approved for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Low immunoglobulin (Ig) levels have been observed surrounding RTX treatment. The association between the degree of Ig deficiency and infection risk is unclear in AAV patients.MethodsAAV patients treated with RTX for remission induction at a single center (2005–15) with serum Ig measurements were included. Patient characteristics; serum IgG, IgM and IgA levels and occurrence of infections were collected retrospectively. Low IgG was defined as mild (376–749 mg/dL) or severe (>375 mg/dL). Logistic regression models were adjusted for age at RTX administration, estimated glomerular filtration rate (eGFR) and race to examine the association of degree and type of Ig deficiency and infection risk.ResultsOur cohort of 30 patients had a mean age of 63 (SD 7) years, 23 were women, 16 had granulomatosis with polyangiitis and 13 were PR3 ANCA positive. Nine patients received concomitant cyclophosphamide. The mean IgG level was 625 mg/dL (SD 289), mean IgM level was 55 mg/dL (SD 41) and mean IgA level was 133 mg/dL (SD 79). In this cohort, 20 patients had low serum IgG levels (<750 mg/dL) following RTX treatment. During the follow-up period, four individuals developed infections requiring hospitalization. In unadjusted logistic regression analysis, an IgG level ≤ 375 mg/dL was associated with 23 times higher odds of hospitalized infection [95% confidence interval (CI) 1.8–298.4; P = 0.02]. After adjustment for age, race and eGFR, results were similar [odds ratio (OR) 21.1 (95% CI 1.1–404.1) P = 0.04]. Low IgA was also associated with an increased risk of infections requiring hospitalization after adjusting for age, race and eGFR [OR 24.6 (95% CI 1.5–799.5) P = 0.03]. Low IgM was not associated with a higher risk of infections requiring hospitalization.ConclusionsSevere hypogammaglobulinemia was associated with increased odds of infection requiring hospitalization in this cohort. Further investigation is warranted given our study is limited by small sample size, concomitant cyclophosphamide use and variable timing of Ig measurement.

Current status of the treatment of microscopic polyangiitis and granulomatosis with polyangiitis in Japan.

BackgroundThis study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan.MethodsWe used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset.ResultsThe mean ages of the MPA and GPA patients were 69.4 ± 0.4 and 58.4 ± 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA.ConclusionA dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function.

Doxorubicin-induced cardiotoxicity in adult Indian patients on chemotherapy

Background:Doxorubicin-induced cardiotoxicity is widely known to occur at cumulative doses exceeding 450 mg/m2. However, very few studies have reported incidence of cardiac dysfunction in patients on chemotherapy with lower cumulative doses. To the best of our knowledge, there is no study carried out so far that has reported the incidence of cardiac dysfunction in adult Indian patients receiving doxorubicin. This study was undertaken to determine the incidence of doxorubicin-induced cardiotoxicity by serial resting echocardiography in patients on chemotherapy and identify risk factors associated with cardiotoxicity.Materials and Methods:Patients that were started on doxorubicin-based chemotherapy in the period from January 2000 to June 2001 and had completed at least 300 mg/m2 cumulative dose were taken in the study. Electrocardiography, chest X-ray and echocardiography were done at baseline, at 300 mg/m2 and at 450 mg/m2 cumulative doses of doxorubicin. All patients were evaluated for the presence of the following risk factors: Age>70 years, female sex, preexisting cardiac disease, hypertension, chest wall irradiation, body mass index (BMI)<20 kg/m2 , Karnofsky performance status, combination chemotherapy with cyclophosphamide and presence of liver disease. Subclinical cardiac dysfunction was defined as ejection fraction fall greater than 10% on follow-up echocardiography.Results:Thirty patients satisfied the criterion for being considered for evaluation. One (3%) patient developed congestive cardiac failure, while 8 (27%) patients developed subclinical cardiac dysfunction. Concomitant use of cyclophosphamide significantly increased the risk of cardiac dysfunction (P = 0.048), while low BMI (<20 kg/m2) and preexisting cardiac disease showed a trend towards increased risk of cardiac dysfunction (P = 0.07 for both).Conclusion:Twenty-seven percent of the patients developed subclinical cardiac dysfunction in the cumulative dose range of 300-450 mg/m2 . This entails regular monitoring for cardiac dysfunction by echocardiography during treatment.

B-Cell-Targeted Therapy for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage. B cells play a key role in the pathogenesis; therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE. In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide. Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE. Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients. All these therapies are well tolerated, but accompanying infectious complications have been observed. Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (e.g. ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials.

Cyclophosphamide and Immunoadsorption Apheresis Treatment of Lupus Nephritis Nonresponsive to Drug Therapy Alone

In this report we present a 28-year-old male patient with systemic lupus erythematosus (SLE) that was treated with immunoadsorption apheresis (IA) and cyclophosphamide for lupus nephritis (proliferative glomerulonephritis, class IV-B) after proving nonresponsive to drug therapy alone. Before starting the therapeutic cycle with IA, the patient was administered prednisone 25 mg/d, hydroxychloroquine 200mg twice/d, ACE inhibitors 5 mg/d, aspirin 100 mg/d, furosemide 50 mg/d, and intravenous (IV) albumin (20%) 50 mL. Deteriorating clinical conditions necessitated a renal biopsy, and thereafter an increase in medication. The patient was given a bolus of IV cyclophosphamide 1 g/d for 1 day and IV methylprednisone 500 mg/d for 3 days. This was not followed by any improvement and the renal functions worsened. Thus, 3 weeks after the more aggressive pharmacologic treatment with cyclophosphamide, which had been prescribed to improve renal function, and given the young age of the patient, the decision was made to administer IA (Selesorb). IA selectively removes IgG and IgM immune complexes from the plasma, thereby reducing the complications induced by the pathogenic autoimmune reaction. The treatment was administrated twice a week for the first 15 days, once a week for a further 5 weeks, and biweekly in the last month with a bolus of cyclophosphamide (average 250-100 mg) after each session. After twelve sessions of IA over 3 months, renal function was completely restored and the patient discharged. Although it is not proven, the concomitant use of cyclophosphamide could presumably improve the final clinical outcome.

Failure to detect toxicity with the concomitant use of cyclophosphamide and halothane in humans.

Failure to detect toxicity with the concomitant use of cyclophosphamide and halothane in humans.

Antilymphocytic leukemic serum and chemotherapy in the treatment of murine leukemia.

Antiserum against L 1210 murine leukemia was prepared in rabbits and goats. Murine antibody titers against such antisera were lower than against normal foreign serum, suggesting an immunosuppressive effect. Additional suppression of antibody formation was obtained by the concomitant use of cyclophosphamide. The antiserum had an equally cytotoxic effect against normal and leukemic lymphocytes in vitro. The antileukemic effect in vivo was demonstrated by a statistically significant but slight prolongation of survival time of leukemia-bearing mice. The results of therapy with the antileukemic serum were enhanced in some experiments by the incorporation of cyclophoshamide and 6-mercaptopurine into the treatment schedule.