Cyclophosphamide Therapy In Patients Research Articles

Phase II study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer

BackgroundS-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m2/day for S-1 and 100 mg/m2/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen.MethodsThis was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2×/day for 14 consecutive days, and then CPA was administered orally 2×/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety.ResultsThirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8–12.6 months). The median OS was 20.2 months (95%CI: 15.0–25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality.ConclusionThe combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy.Trial registrationJRCT, JRCTs031180296. Registered 2 December 2019 – Retrospectively registered.

Nuclear magnetic resonance-based targeted profiling of urinary acetate and citrate following cyclophosphamide therapy in patients with lupus nephritis.

Metabolomics, the study of global alterations in small metabolites, is a useful tool to look for novel biomarkers. Recently, we reported a reprogramming of the serum metabolomic profile by nuclear magnetic resonance (NMR) spectroscopy following treatment in lupus nephritis (LN). This study aimed to compare the urine excretory levels of citrate and acetate in patients with biopsy-proven LN before and six months after cyclophosphamide induction therapy and to evaluate their correlation with the Systemic Lupus Erythematosus Disease Activity Index 2K (SLEDAI 2K) and renal SLEDAI. Urine obtained from LN patients (N = 18, 16 female) at diagnosis and six months following induction therapy with cyclophosphamide and healthy controls (HC; N = 18, median age = 35 years, all female) were stored at -80°C. Metabolomic profiling was done using high resolution 800 MHz 1D 1H NMR spectroscopy. The urinary ratio of metabolites was calculated as (metabolite×1000)/creatinine. Disease activity was measured using the SLEDAI. Metabolomic profiles were compared between groups and correlated with clinical parameters. Compared to HC, LN patients had significantly lower median urinary citrate/creatinine levels (LN = 18.26, range 12.80-27.62; HC = 107.7, range 65.39-138.4; p < 0.0001) which significantly increased after six months of cyclophosphamide treatment (51.05, range 11.51-170.2; p = 0.03). LN patients also differed from HC by having a higher mean urinary acetate/creatinine ratio (LN = 17.44, range 11.6-32.7; HC = 9.61, range 7.97-13.71; p = 0.054) with a non-significant fall in values after six months of treatment. The Area under curve for differentiating LN from HC for urinary citrate was 0.9136, and urinary acetate was 0.6883. The urinary acetate levels correlated with SLEDAI (r = 0.337, p = 0.048). Urinary citrate levels correlated positively with C3 (r = 0.362, p = 0.03) and negatively with urine protein/creatinine (r = -0.346, p = 0.039). Urinary citrate, which reflects dampened aerobic glycolysis and oxidative phosphorylation, improved significantly and is a potential non-invasive biomarker for diagnosis and monitoring treatment response in LN.

Use of Oral Low-dose Cyclophosphamide Therapy in Patients With Refractory Extensive Crohnʼs Disease

Introduction Cyclophosphamide (CPM) is one of the oldest chemotherapeutic agents available, which also has immunosuppressive properties. It was first used for inflammatory bowel disease (IBD) in 1985, when given to 4 patients who developed pancreatitis on azathioprine. The first case series using pulse IV CPM for steroid-refractory IBD was described in 2003. Case presentation We describe a case of a 23-year-old Caucasian male diagnosed with Crohn's disease (CD) at 14 years of age (Montreal Classification A1L1L4B1p). He was initially treated with infliximab but developed an anaphylactic reaction prompting a transition to adalimumab combined with methotrexate. His disease, however, remained active involving the entire small bowel. He was started on vedolizumab with methotrexate but did not achieve remission. A subsequent transition to ustekinumab allowed tapering off prednisone, but 1 month later, he developed symptoms, which persisted despite dose escalation. A short course of mycophenolate mofetil was attempted but it was unsuccessful.By the end of 2016, he developed arthralgias and osteoporosis, both attributed to steroid use. Given the persistence of inflammation despite conventional medical therapy, he was started on oral CPM (1.5 mg/kg/day), alongside prednisone. At 10 days follow-up, the patient reported significant improvement in his energy levels and abdominal pain. His symptoms continued improving, and he was able to taper prednisone to 15 mg daily at 5 weeks from starting CMP, and achieve clinical remission. Two months into starting therapy, he noted worsening of his symptoms with loose stools, nausea and weight loss. However, CRP (C reactive protein) was trending down. Discontinuation of abaloparatide, which was taken concomitantly, lead to symptom resolution. At his most recent follow-up visit, at 24 weeks from starting CPM, the patient was in clinical remission, on CMP and prednisone 7.5 mg/day. Discussion: The use of oral low-dose CPM offers an improvement in efficacy but also a mild increase in the rate of leukopenia. We chose the oral regimen for its rapid onset, efficacy and steroid-sparing properties, with the convenience of avoiding IV administration. A lower dose was selected to reduce the risk of leukopenia. Besides the 4 cases described in 1985, this is the first description of oral CPM use for induction of remission in a patient with CD. This case highlights another treatment option for highly refractory IBD patients.

Influence of Dexamethasone Dose on Skin Toxicity Caused by Docetaxel plus Cyclophosphamide Therapy in Patients with Breast Cancer

Influence of Dexamethasone Dose on Skin Toxicity Caused by Docetaxel plus Cyclophosphamide Therapy in Patients with Breast Cancer

Clinical evaluation of cyclophosphamide therapy in patients with myasthenia gravis and thymoma

Objective To evaluate the efficacy and safety of cyclophosphamide in the treatment of patients with myasthenia gravis (MG) and thymoma. Methods Ninety-five MG patients with thymoma were selected, and 60 of them were finally involved in the study. Patients were given low or median dose of cyclophosphamide (0.20 g intravenously per day, twice a week), and the dose was gradually increased to 0.80 g intravenously per week. When the total dose of cyclophosphamide reached 6 and 10 g, the drug efficacy was respectively assessed by Clinical Absolute Score (CAS) and Clinical Relative Score (CRS). Adverse events were also recorded. Results Compared with the score before treatment (19.65 ± 8.90), the CAS after 6 g (13.73 ± 8.63) and 10 g (10.58 ± 8.11) cyclophosphamide treatment were significantly lower than that of before treatment ( P < 0.05, for all). The drug efficacy of the treatment was 73.33% (44/60) and 81.67% (49/60) when the total dose reached 6 and 10 g, respectively. No serious adverse reactions occurred. Conclusions Cyclophosphamide is an effective and safe treatment for post-thymectomized patients with myasthenia gravis and thymoma. Further follow-up and study is still needed to evaluate the long-term outcome. doi: 10.3969/j.issn.1672-6731.2014.10.010

Exhaled NO predicts cyclophosphamide response in scleroderma-related lung disease

Cyclophosphamide (CYC) is not always effective in patients with scleroderma-related interstitial lung disease (SSc-ILD), hence the need for biomarkers able to predict beneficial responses to CYC therapy. We therefore assessed whether baseline alveolar concentration of nitric oxide (CANO) could predict the favourable response to CYC therapy in patients with SSc-ILD.Nineteen non-smoker patients with SSc-ILD, were enrolled and treated with 6 courses of CYC (0.75g/m2/monthly) for lung function decline the year before inclusion, and followed-up for 2years period. We assessed the proportion of favourable response to CYC, defined as improvement of forced vital capacity (FVC) or total pulmonary capacity (TLC) more than 10% between the inclusion and each following visit, according to the validated cut-off of CANO at 8.5ppb identifying progressive SSc-ILD subset.At inclusion, 7 patients out of 19 had CANO >8.5ppb. Clinical parameters were comparable between patients with high (>8.5ppb) and low level of CANO (≤8.5ppb). After CYC therapy, and during the follow-up, 9 out of 19 patients had favourable response to CYC therapy, 10 did not meet responder’s criteria, from whom 4 patients died from respiratory failure. Six out of 7 patients with CANO >8.5ppb at inclusion had favourable response to CYC therapy, while only 3 out of 12 patients with CANO ≤8.5ppb responded favourably to CYC therapy (p=0.001).High level of CANO >8.5ppb reflecting alveolar inflammation identify SSc patients with a greater chance to benefit from CYC treatment with a significant lung function improvement.

Pulse cyclophosphamide therapy in refractory warm autoimmune hemolytic anemia: a new perspective.

Treatment of steroid refractory autoimmune hemolytic anemia (AIHA) is challenging especially with no evidence based consensus guide lines and limited resources. The aim of this study was to evaluate the efficacy of pulse cyclophosphamide therapy in patients with severe refractory warm AIHA. The prospective study was designed to evaluate the efficacy of pulse cyclophosphamide-1g/month for four consecutive months-in 17 patients (10 males and 7 females) with severe refractory warm AIHA [13 primary AIHA and 4 (females) secondary to SLE], all studied patients failed to respond to high dose of steroid therapy±azathioprine±intravenous immunoglobulin±oral cyclophosphamide. Mean hemoglobin level, reticulocytic count and direct antiglobulin test were assessed before and after cyclophosphamide treatment every month. After the 4th cycle of cyclophosphamide (82%, 14 patients) achieved partial response while the remaining (17%, 3 patients) showed no response, while after 6months follow up 47% (8 patients) show complete response, while 53% (9 patients) showed partial response. The mean hemoglobin levels were significantly increased after the 1st, 2nd, 3rd and 4th months of pulse cyclophosphamide therapy when compared to before treatment (P<0.01, P<0.001, P<0.001 and P<0.001) respectively, and the mean reticulocyte (%) were significantly decreased after the 2nd, 3rd and 4th months (P<0.05, P<0.01 and P<0.001) respectively. We conclude that pulse cyclophosphamide therapy is well tolerated and induces good response in patients with severe refractory warm AIHA.

Relationship of glutathione S‐transferase genotypes with side‐effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus

Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE. DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile-->Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay. Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients. The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.

Infection in children with lupus nephritis receiving pulse and oral cyclophosphamide therapy

Infection is the major complication of cyclophosphamide therapy in patients with lupus nephritis. The objectives of this study were to report and compare the rate of infection between children with lupus nephritis who had received intravenous pulse cyclophosphamide (IVCY) and those who had received oral cyclophosphamide (OCY) and to determine the risk factors for infection during treatment with cyclophosphamide in these groups. Records of nine patients who had received IVCY from the beginning [pure intravenous cyclophosphamide (PIVCY) group], 11 patients who had received prior oral cyclophosphamide and later switched to IVCY [combined intravenous cyclophosphamide (CIVCY) group] and 41 patients who had received OCY were reviewed. Infection occurred in 21 of 61 patients (34%). In the PIVCY group, four episodes of infection occurred in three of nine patients (33%). In the CIVCY group, six episodes of infection occurred in four of 11 patients (36%). In the OCY group, 18 episodes of infection occurred in 14 of 41 patients (34%). The rate of infection between these groups was not different (P=0.99). None of the following parameters were risk factors for infection: cumulative dose of cyclophosphamide, leukopenia and neutropenia. On the contrary, white blood cell (WBC) count and polymorphonuclear cell (PMN) count were significantly less in the no-infection group (P=<0.001, P<0.001, respectively), with odds ratios for leukopenia (WBCs <4,000 mm(3)) and neutropenia (PMNs <1,500 mm(3)) between the infection and the no-infection group equal to 0.18 (95%CI 0.05-0.63) and 0 (95%CI 0-0.19), respectively. Most of the patients who had infection received prednisolone at a dosage of more than 0.5 mg/kg per day (67% of the PIVCY group, 50% of the CIVCY group and 83% of the OCY group). Fatal infections occurred in two patients who had concomitant active systemic lupus erythematosus (SLE). Although lymphopenia (lymphocyte count <1,500/mm(3)) was not the risk factor for infection, it was observed that six of seven patients with herpes zoster had lymphopenia. Herpes zoster seemed to occur more frequently in the OCY group (15%) than in the whole IVCY group (5%), but there was no statistical difference (P=0.41). We conclude that the rate of infection in the IVCY and OCY group was not different. Infection is likely to occur in patients receiving a concomitant high dose of prednisolone. The occurrence of fatal infection in patients with active disease should be noted. No single risk factor was detected in this study.

Pharmacogenetic determinant of cyclophosphamide therapy in patients with lupus nephritis

Clinical Pharmacology &amp; Therapeutics (2003) 73, P97–P97; doi:

Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with Wegener's granulomatosis.

To assess the effectiveness of pulse cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG) and to identify the patients who are responsive to the treatment. The prospective study included 43 patients with biopsy-proven WG. Clinical, radiographic, laboratory, and immunologic data were evaluated for predictive values regarding the outcome of pulse CYC therapy. Only 42% of the patients showed complete or partial remission that lasted at least 6 months after cessation of pulse CYC therapy. These responders had a higher frequency of disease activity limited to the upper and lower respiratory tract (39%, versus 8% in the nonresponder group; P < 0.05) and had lower titers of classic antineutrophil cytoplasmic antibody (cANCA) prior to treatment (< 1:64 42%, versus 6% in the nonresponder group; P < 0.05). In the 58% of patients who did not respond to pulse CYC treatment, there was both systemic disease involving more than 4 organ systems (mainly, the heart, nervous system, eye, and skin) and constitutional symptoms. Serious side effects induced by pulse CYC occurred in only 1 patient. Based on these findings, pulse CYC therapy appears to be effective in WG patients with moderate disease activity and low titers of cANCA, but of little benefit in patients with severe WG. Pulse CYC should therefore not be used as first-line therapy in patients with severe and rapidly progressing forms of WG associated with high titers of cANCA.

Inverse relationship between serum cholinesterase activity and the administration of cyclophosphamide: an Index of cyclophosphamide therapy

To determine whether serum cholinesterase activity can be a monitoring index of cyclophosphamide therapy in patients with steroid-resistant glomerulopathy, we compared the cholinesterase activity of 37 patients who received a combined therapy that included the use of cyclophosphamide, prednisolone, antiplatelet drugs, and anticoagulant drugs, with the cholinesterase activity of 25 patients who received prednisolone therapy that excluded cyclophosphamide from the combined therapy. In the prednisolone and the combined groups, cholinesterase activity declined as shown in the following formula: Y = 371-26.4 x log(X): (r2 = 0.28), Y = 444-147.7 x log(X): (r2 = 0.95), respectively. (Y: cholinesterase activity, X: the day after treatment). In the combined therapy group, the prevalence of adverse reactions following treatment in the subgroup below 200 U/l of cholinesterase activity was significantly greater (P < 0.01) than that in the subgroup above 200 U/l of cholinesterase activity. However, there was no significant difference (P < 0.25) in the prevalence of adverse reactions between the subgroups with more or less than 184 U/l of cholinesterase activity following treatment. These results suggest the importance of not going below 200 U/l of cholinesterase activity after treatment when the normal cholinesterase activity range is between 300 and 760 U/l (e.g. less than 65% of the lowest value of the normal range of other hospitals) in order to eliminate the hazards of cyclophosphamide to the patients with steroid-resistant glomerulopathy.

Immunosuppressive treatment in multifocal motor neuropathy

We report the results of immunosuppressive treatments of 13 patients with multifocal motor neuropathy and elevated titers of serum antibodies to the GM1 ganglioside. All patients failed to respond to oral prednisone. There was no clinical response in 4 patients treated with plasma exchange. Nine patients received cyclophosphamide, with clinical improvement and fall in antibody titers in 8. In 3 patients, cyclophosphamide was discontinued with ensuing clinical relapse and rise in the titers of serum anti-GM1 antibodies. These patients provide further evidence for the efficacy of cyclophosphamide therapy in patients with multifocal motor neuropathy.

Intravenous cyclophosphamide therapy in patients with steroid-resistant lupus nephritis

We evaluated short term clinical effects of intravenous cyclophosphamide (iv CyP) therapy performed by every three month in 7 patients with steroid-resistant lupus nephritis. Significant improvements were observed in daily urinary protein excretion (3.1 to 0.83 g/day), creatinine clearance (65.4 to 95.3 ml/min), CH 50 levels (20.8 to 37.4 U/ml), and anti-DNA antibody titer (26.6 to 7.0 U/ml). In addition, the mean daily dose of prednisolone (PSL) could be markedly reduced from 38.6 mg to 13.9 mg at the final observation. Two patients suffered from Herpes Zoster infection at a few months after ivCyP therapy, however this incidence were not considered as critical side effect which reached to the discontinuation of this therapy. We concluded that ivCyP therapy by every three months were safety and achieved beneficial clinical effects on steroid-resistant lupus nephritis as far as short observation. On the contrary, the long term effect of this mode of therapy is to be defined.

Response to Cyclophosphamide Therapy in Saudi Children with Idiopathic Nephrotic Syndrome

Thirty-three children with idiopathic nephrotic syndrome received an eight-week course of 2.5 to 3.0 mg/kg of body weight of cyclophosphamide. Twenty-five (76%) were in remission 12 to 28 months la...

Intermittent Cyclophosphamide for the Treatment of Autoimmune Thrombocytopenia in Systemic Lupus Erythematosus

To determine the effect of monthly intravenous cyclophosphamide therapy in patients with systemic lupus erythematosus and autoimmune thrombocytopenia. Uncontrolled, retrospective clinical study. Government referral-based research hospital. Seven patients with systemic lupus erythematosus and 2 or more months of thrombocytopenia refractory to or requiring excessive doses of corticosteroids. Two patients had also failed to respond to splenectomy and repeated intravenous methylprednisolone infusions. Six patients had severe active renal disease at the time of treatment. Cyclophosphamide, 0.75 to 1.0 g/m2 body surface area, was given intravenously every month for at least 4 months. Prednisone dose ranged between 0.5 to 1.0 mg/kg.d. All seven patients had normal platelet counts within 2 to 18 weeks after cyclophosphamide treatment (one to four doses). Prednisone was tapered to 0.25 mg/kg on alternate days in all patients. All six patients had significant improvement in their renal disease and lupus serologies. Cyclophosphamide was discontinued after four to six doses in five patients. Four patients maintained normal platelet counts on low dose, alternate-day prednisone for a mean of 5.6 years of follow-up. Two patients had recurrence of thrombocytopenia 1 to 3 years after discontinuing cyclophosphamide. Monthly intravenous cyclophosphamide is potentially useful for the management of autoimmune thrombocytopenia in patients with systemic lupus erythematosus who are refractory to or dependent on unacceptably high doses of corticosteroids, or are experiencing side effects of conventional medical or surgical treatment.

Gonadal function, testicular histology, and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome

Gonadal function, histology, and meiosis were studied in patients after puberty who had received cyclophosphamide in the treatment of nephrotic syndrome. Four males with minimal lesion nephrotic syndrome received cyclophosphamide, 2 to 4 mg/kg/24 hr, during periods ranging from 49 to 60 days and had normal semen at 15 3/12 to 22 3/12 years of age. Four males who received cyclophosphamide, 2 to 5 mg/kg/24 hr, during 89 to 489 days were azoospermic at 15 6/12 to 21 11/12 years of age. Plasma testosterone levels were normal in both groups. LH and FSH levels were elevated in the azoospermicgroup. Light and electron microscopy and meiotic analysis of testicular tissue were normal in two normospermic patients tested. Germinal cells were absent but Leydig and Sertoli cells were present in three azoospermic patients tested. No neoplasia was observed. Two preadolescent and two postadolescent males received 64 to 129 mg/kg of cyclophosphamide during 14 to 45 days and have since fathered normal children. One preadolescent female received 182 mg/kg of cyclophosphamide during 49 days and later bore a normal child. Two preadolescent females who died of complications of their nephrotic syndrome during childhood after courses of cyclophosphamide had normal preadolescent ovaries.

Cyclophosphamide therapy in patients with advancing breast cancer following adrenalectomy and 5-fluorouracil.

Seven of 21 patients with advanced breast cancer previously treated with a combination of adrenalectomy and 5-fluorouracil responded to cyclophosphamide administered when disease relapsed after response to the combination. Four women who failed to benefit from adrenalectomy and 5-fluorouracil also did not respond to cyclophosphamide. Neither time from primary therapy to appearance of first metastases (free interval) nor time from adrenalectomy to cyclophosphamide therapy predicted response. Patients with dominant soft tissue disease appeared to have a greater chance of response than those with predominantly visceral or bony disease. Mild-to-moderate gastrointestinal and hematologic toxicity was seen in the majority of patients, but transient adrenal insufficiency was noted in only two women. There were no deaths due to toxicity, and increased maintenance corticoid dosage was not required. Cyclophosphamide is a useful palliative agent in advanced breast cancer patients who have relapsed after response to adrenalectomy, even when 5-fluorouracil was combined with the procedure.