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PubMed2002

High-dose cyclophosphamide for aplastic anemia and autoimmunity.

High-dose cyclophosphamide was developed as a conditioning regimen for allogeneic bone marrow transplantation. Later, it was discovered that high-dose cyclophosphamide spares early hematopoietic stem cells because of their relatively high levels of the enzyme aldehyde dehydrogenase; thus, high-dose cyclophosphamide is a potent immunosuppressive agent, but nonmyeloablative. Recent reports demonstrate that high-dose cyclophosphamide without bone marrow transplantation induces durable treatment-free remissions in severe aplastic anemia and a variety of other autoimmune disorders; however, there is lingering concern about the safety of this approach.

Anemia, Aplastic↗

PubMed1995

The pattern of emesis following high-dose cyclophosphamide and the anti-emetic efficacy of ondansetron.

Two randomized, double-blind placebo-controlled ondansetron dose ranging studies in patients receiving high-dose cyclophosphamide (with or without doxorubicin) were completed in the US. These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has a long latency of onset (8-13 h) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors.

Antiemetics↗

PubMed1995

Alpha-tocopherol ameliorates cyclophosphamide-induced hyperlipidemia in fibrosarcoma-bearing rats.

Cyclophosphamide, an alkylating agent, is currently being used for the treatment of various types of cancer, either alone or in combination with other cytostatic drugs. However, cyclophosphamide has a detrimental effect on lipid metabolism and causes hyperlipidemia in patients. Since alpha-tocopherol is known to reduce hyperlipidemia, we have investigated the effects of adding alpha-tocopherol to the cyclophosphamide treatment. Our study, carried out on fibrosarcoma-bearing rats, shows that alpha-tocopherol markedly reduces cyclophosphamide-induced hyperlipidemia and brings lipid metabolism down to values observed in untreated controls.

Animals↗

PubMed2000

Prolongation of xenograft survival using monoclonal antibody CD45RB and cyclophosphamide in rat-to-mouse kidney and heart transplant models.

BACKGROUND: Intrigued by the finding that a monoclonal antibody (mAb) directed against the B exon of restricted CD45 (CD45RB mAb) induced renal allograft tolerance in the mouse model, we hypothesized that CD45RB mAb may prevent xenograft rejection. We explored the role of CD45RB mAb in preventing xenograft rejection in rat-to-mouse kidney and heart transplant models. METHODS: Mice with rat kidney and heart xenografts were treated with a short course of mAb, cyclosporine, cyclophosphamide, or mAb + cyclophosphamide combination therapy. Untreated heart and kidney xenografts served as controls. RESULTS: Untreated controls developed acute vascular and cellular rejection rapidly with a median survival time of only 6 days. Long-term kidney (median survival time = 70 days) and heart xenograft survival (median survival time = 65 days) was achieved using the combination therapy of mAb + cyclophosphamide. One-third of the kidney recipients with combination therapy survived 100 days. Immunohistochemistry and xenospecific-antibody analysis demonstrated that combination therapy remarkably reduced IgG and IgM deposition and also inhibited CD4+, CD8+, and Mac-1+ cell infiltration at early stages. This therapy, however, did not induce tolerance in this model as evoked xenoreactive antibodies and cellular responses may be the cause of late xenograft failure. CONCLUSION: A short course of CD45RB mAb combined with cyclophosphamide effectively inhibits cellular and humoral immunoresponses and remarkably prolongs xenograft survival in rat-to-mouse heart and kidney transplant models.

Animals↗

PubMed1990

Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation.

A 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure was treated with high-dose cyclophosphamide, busulfan, and antithymocyte globulin followed by an infusion of human leukocyte antigen-identical, mixed lymphocyte culture (MLC) non-reactive sibling bone marrow. He developed cardiac arrhythmias and intractable hypotension and died on day 23 posttransplant. Autopsy findings were consistent with cyclophosphamide-induced pancarditis. The bone marrow showed signs of early engraftment. Allogeneic bone marrow transplantation may be a treatment alternative for Shwachman-Diamond syndrome with severe bone marrow failure. However, fatal posttransplant pancarditis due to doses of cyclophosphamide not usually associated with cardiac death may be an unanticipated problem. Further trials of bone marrow transplantation as therapy for this syndrome may be warranted, perhaps using lower doses of cyclophosphamide or substituting for it other immunosuppressive and myelosuppressive agents.

Bone Marrow Diseases↗

PubMed2005

Sparse sampling design for therapeutic drug monitoring of sequentially administered cyclophosphamide, thiotepa, and carboplatin (CTC).

The alkylating agents cyclophosphamide, thiotepa, and carboplatin (CTC) are administered simultaneously in high-dose chemotherapy regimens. This regimen is sometimes complicated by severe organ toxicities, which may be caused by interindividual variability in the pharmacokinetics of the agents. Monitoring plasma levels and adapting doses may reduce variability in exposure to the compounds and their metabolites. The aim of this study was to develop and validate a sparse sampling design for routine dose individualization of cyclophosphamide, thiotepa, and carboplatin both during and between courses in the CTC regimen. Models describing the population pharmacokinetics of the prodrug cyclophosphamide (4000 or 6000 mg/m) and its activated metabolite 4-hydroxycylophosphamide, thiotepa (320 or 480 mg/m), and its equipotent metabolite tepa, and carboplatin (1067 or 1600 mg/m) in the 4-day CTC regimen have been developed previously using the program NONMEM. Based on these models, plasma concentrations were calculated in 20 groups of 50 simulated patients in each group during multiple courses of therapy, and the exposure, expressed as area under the plasma concentration-versus-time curve (AUC), was calculated. Subsequently, individual model-predicted AUCs were calculated for all courses, based on selected simulated plasma concentrations during the first course of therapy. Strategies were compared by assessment of their predictive performance of the AUC and their applicability in clinical practice. Withdrawal of 3 samples on the first day of the course at 190, 290, and 400 minutes after start of cyclophosphamide infusion resulted in unbiased and precise first course AUC predictions of 4-hydroxycylophosphamide, thiotepa and tepa, and carboplatin (precision [root mean squared relative prediction error, %RMSE] 20%, 16%, 8.8%, respectively). Applying this same strategy at day 3 (or 4) of the course, with an additional sample at 600 minutes on both days, resulted in unbiased and precise predictions of the AUC of a following course (%RMSE 21%, 18%, 17%, respectively). Prospective validation of the strategies in 23 additional patients yielded comparable results. It can be concluded that a good and useful sparse sampling design was developed for precise and accurate estimation of the AUCs of 4-hydroxycyclophosphamide, thiotepa and tepa, and carboplatin in the CTC regimen. This method is valuable in pharmacokinetically guided dose adaptation both during and between CTC courses.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma.

Both single and tandem cycles of high dose therapy and autologous peripheral blood stem cell transplantation (ASCT) have been shown to improve survival in multiple myeloma (MM) patients. We report outcomes in 104 MM patients undergoing a single transplant after conditioning with a conventional myeloablative regimen, busulphan and cyclophosphamide. The patients were either in a first (71%), or subsequent remission (29%). Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony stimulating factor. The conditioning regimen consisted of busulphan 0.85 mg/kg given orally every 6 h (16 doses) and cyclophosphamide 60 mg/kg/d given intravenously for 2 d. The entire conditioning, transplant and post-transplant course were in the outpatient setting for 45% patients. At a median follow-up of 26 months (range 2-98 months), the median overall and progression-free survival were 57 months [95% confidence interval (CI) 47-68] and 26 months (95% CI 20-32) respectively. Younger age and higher CD34+ cell dose infused were independently predictive of improved overall and progression-free survival. Busulphan and cyclophosphamide is an effective and well-tolerated preparative regimen for ASCT that can be given to MM patients in the outpatient setting.

Adult↗

PubMed1995

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer.

BACKGROUND: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. AIMS: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. METHODS: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m2) and cyclophosphamide 600 mg/m2. The dose of epirubicin was to be escalated or reduced depending on toxicity. RESULTS: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. CONCLUSIONS: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90 mg/m2 of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy.

Adenocarcinoma↗

PubMed1984

The effect of cyclophosphamide on T lymphocytes and T lymphocyte subsets in patients with chronic progressive multiple sclerosis.

The lymphocytes in peripheral blood and cerebrospinal fluid of patients with chronic progressive multiple sclerosis (MS) were characterized with monoclonal antibodies to surface antigens of T cells, helper/inducer T cells and suppressor/cytotoxic T cells. The influence of cyclophosphamide treatment on these immune parameters was investigated. Compared to healthy persons, the mononuclear cell fraction of the peripheral blood of patients with chronic progressive MS consisted of normal %s of T cells and helper/inducer T cells, but decreased %s of suppressor/cytotoxic T lymphocytes. Intensive as well as chronic treatment of MS patients with cyclophosphamide resulted in a decline in the %s of T cells and helper/inducer T cells, whereas the %s of suppressor/cytotoxic T cells returned to normal. In cerebrospinal fluid, cyclophosphamide also induced a relative decrease in the % of helper/inducer T cells and an increase in the % of suppressor/cytotoxic T cells compared to untreated MS patients. Intensive as well as chronic therapy with cyclophosphamide both led to a significant decrease in the absolute number of T cells and T cell subsets in the blood of the patients.

Adult↗

PubMed1975

The effect of cyclophosphamide, methotrexate and X-irradiation on the ultrastructure and endocytic capacity of murine peritoneal macrophages.

100 mg/kg cyclophosphamide given subcutaneously daily for 5 days and whole-body X-irradiation (500 r) had an appreciable effect on the phagocytosis of E. coli by mouse peritoneal macrophages. Less bacteria were ingested by cells from the treated mice as compared with control cells. In contrast, whole-body X-irradiation had a stimulatory effect on pinocytosis as compared with cells from cyclophosphamide treated mice or control mice. Morphological changes in the cells from animals treated with cyclophosphamide or X-rays were evident. The cells were larger than normal macrophages and contained large amounts of lipid and phagolysosomes and had more vacuoles as compared with control cells. Many giant cells were present in the treated mice. Treatment of mice with methotrexate for 5 days, although affecting the cells morphologically in that they were larger than normal cells and had many vacuoles did not appear to have any effect on either phagocytosis or pinocytosis. Cells from methotrexate treated animals did not contain the large quantities of lipid seen in cells from the cyclophosphamide treated and X-irradiated mice.

Animals↗

PubMedDate not supplied

Cyclophosphamide exerts no beneficial effect over prednisone alone in the initial treatment of acute immune-mediated hemolytic anemia in dogs: a randomized controlled clinical trial.

Cyclophosphamide is commonly used with prednisone in the initial treatment of severe idiopathic immune-mediated hemolytic anemia (IMHA) in dogs because retrospective reports suggest its benefit. This randomized controlled prospective clinicaltrial evaluated whether combined cyclophosphamide and prednisone therapy is more efficacious than prednisone therapy alone in the initial treatment of IMHA. Eighteen dogs with acute, severe idiopathic IMHA were randomly assigned to 1 of 2 treatment groups. The P group received prednisone therapy alone (1-2 mg/kg PO q12h), and the PC group received prednisone (1-2 mg/kg PO q12h) and cyclophosphamide (50 mg/m2 PO q24h for 4 consecutive days a week) for 4 weeks. The mortality rate in the P group was 20% (2 of 10), and in the PC group, the mortality rate was 38% (3 of 8). There was no difference in sequential CBC evaluations between the 2 groups. However, whereas dogs in the P group showed increases in reticulocyte count, reticulocytosis was suppressed in dogs in the PC group during the 1st week of therapy. Spherocytosis resolved more quickly in the P group (day 21) than in the PC group (day 28), but the time taken to achieve a negative Coombs' test result was comparable between groups. No difference was observed in the volume of packed red blood cells (pRBCs) given per transfusion between treatment groups, but more dogs in the PC group required a 2nd transfusion. The results of this limited study suggest that cyclophosphamide plus prednisone has no benefit over prednisone alone in the initial treatment of acute, severe idiopathic IMHA indogs.

Acute Disease↗

PubMed1988

The role of the abdominal visceral innervation and 5-hydroxytryptamine M-receptors in vomiting induced by the cytotoxic drugs cyclophosphamide and cis-platin in the ferret.

We have used the ferret as an animal model to investigate the emetic action of the cytotoxic drugs cyclophosphamide and cis-platin. Using selective nerve lesions, a crucial role for the abdominal innervation in the genesis of retching and vomiting in response to these agents has been demonstrated. A combination of bilateral abdominal vagotomy and greater splanchnic nerve section can totally abolish retching and vomiting in response to intraperitoneal cis-platin or intravenous cyclophosphamide. Intraperitoneal cyclophosphamide still produced retching but vomiting was markedly reduced, demonstrating complex and probably separate control mechanisms for retching and vomiting. The effect of a widely used anti-emetic, metoclopramide, was compared to that of nerve lesions. While effective this compound did not totally control retching or vomiting to either drug. Recent studies have attributed metoclopramide's action to its ability to antagonize 5-HT M-receptors (5-HT-3 receptors). Therefore we investigated BRL 24924, a gastro-kinetic agent with more specific 5-HT M-receptor antagonist properties. This agent was extremely potent in almost totally abolishing retching and vomiting in response to cyclophosphamide, given by either an intravenous or intraperitoneal route, and totally abolished cis-platin-induced vomiting for at least 4 h. Clearly the abdominal visceral innervation plays a complex and major role in the emesis produced by these two cytotoxic drugs; circumstantial evidence suggests that 5-HT M-receptors on visceral afferent nerves mediate this action, but other possibly central sites of action of the 5-HT M-receptor antagonists cannot be excluded.

Animals↗

PubMed1988

Effects of cyclophosphamide and a metabolite, acrolein, on Naegleria fowleri in vitro and in vivo.

Mice challenged intranasally with Naegleria fowleri died of primary amoebic meningoencephalitis. Mice given 30 mg of cyclophosphamide per kg of body weight daily for 10 days starting 2 days before challenge were protected. Neither cyclophosphamide nor serum from cyclophosphamide-treated mice inhibited N. fowleri in vitro. A metabolic product of cyclophosphamide, acrolein, inhibited growth and enflagellation of N. fowleri. Acrolein at 40 microM was amoebicidal. Acrolein injured starved cells and amoebae at 5 degrees C and growing N. fowleri.

Acrolein↗

PubMed1982

Increased severity of urinary tract infection and bacteremia in mice with urinary bladder injury induced by cyclophosphamide.

The effect of cyclophosphamide on urinary tract infection was studied, using Pseudomonas aeruginosa in a murine model. Urinary tract infections were produced by injecting P. aeruginosa through a urethral catheter into the bladders of mice. The number of P. aeruginosa organisms in the bladder tissue and kidneys, histopathology, peripheral leukocyte count, and antibody response to P. aeruginosa was measured. The local effect of cyclophosphamide on the bladder was determined by measuring the bladder tissue water and examining the histopathology. Cyclophosphamide increased the susceptibility of mice to P. aeruginosa urinary tract infection, resulting in marked cystitis and an increase in renal infection, bacteremia, and mortality. These changes correlated with the toxic effect of cyclophosphamide on the wall of the bladder rather than with peripheral leukopenia or failure of antibody response.

Animals↗

PubMed1987

Characterization of cyclophosphamide-rat model of cryptosporidiosis.

A cyclophosphamide-treated-rat model for cryptosporidiosis is described. The optimal conditions for inducing a cryptosporidial infection in rats were a 50 mg/kg dose of cyclophosphamide per day in the drinking water for a minimum of 14 days before inoculation with 10(4) or more infectious oocysts. Eighteen days after inoculation, 80% or more of the animals were infected. Cryptosporidia were attached to the terminal 24 cm of the small intestine, and the immunosuppressed animals remained infected as long as they received cyclophosphamide. However, the intestinal infection cleared within 7 to 10 days after cyclophosphamide was withdrawn. Oocysts continued to be detected in the feces for an additional 5 to 7 days after cryptosporidia were no longer visibly attached to the ideal enterocytes. This study characterized an animal model that can be used to investigate the pathogenesis of and evaluate therapeutic regimens for cryptosporidiosis in the immunocompromised host.

Age Factors↗

PubMed2005

Cyclophosphamide reduces neutrophilic alveolitis in patients with scleroderma lung disease: a retrospective analysis of serial bronchoalveolar lavage investigations.

OBJECTIVES: To determine whether cyclophosphamide is beneficial for patients with scleroderma lung disease (SLD). METHODS: The effect of 6 months' treatment with intravenous cyclophosphamide on the functional capacity of patients, lung function tests, high resolution computed tomography of the lungs, and cytology of bronchoalveolar lavage was evaluated in 21 patients with SLD. RESULTS: The treatment was well tolerated and all patients completed 6 months' treatment. Intravenous cyclophosphamide stabilised or improved the patients' functional status and lung function tests. The extent of the lungs affected remained unchanged, as assessed with HRCT of the lungs. Patients with SLD and neutrophilic alveolitis (NA) showed greater improvement than patients with normal levels of granulocytes in the bronchoalveolar lavage fluid (BALF). Significant reduction of neutrophils was also seen in the patients with SLD and NA, whereas no significant change was seen in the level of granulocytes in patients with SLD and an initially normal percentage of granulocytes. CONCLUSIONS: Previous reports that patients with SLD with increased levels of granulocytes in BALF are more likely to benefit from treatment with intravenous cyclophosphamide are confirmed. Additionally, clinical improvement in this group of patients is accompanied by a significant decrease in the percentage of granulocytes in BALF.

Adult↗

PubMed1997

Immunosuppressive treatment in severe connective tissue diseases: effects of low dose intravenous cyclophosphamide.

OBJECTIVE: To review our experience with low dose intravenous pulse cyclophosphamide in the treatment of patients with severe connective tissue diseases. PATIENTS: Ninety patients (68F:22M) with severe connective tissue diseases received a total of 883 cyclophosphamide pulses with 78 of 90 patients initially having weekly 500 mg pulses for a median of three (2-10) weeks. Diagnoses included: systemic lupus erythematosus (SLE) (n = 43); systemic vasculitides (n = 42); idiopathic inflammatory myopathies (n = 4); mixed essential cryoglobulinaemic vasculitis (n = 1). The median age was 48 (range 22-76) years with a median disease duration of 94 (18-250) months. RESULTS: Complete or partial remission was noted in 68 of 90 patients (75.5%) after a median follow up of 56 (5-213) months. At follow up significant median changes were noted in SLE patients: erythrocyte sedimentation rate (ESR) from 44 to 22 mm 1st hour; anti-dsDNA antibody concentrations from 81 to 48 IU/ml; proteinuria from 2.5 to 1.5 g/day; serum albumin from 36 to 40 g/l; complement C3 from 0.88 to 0.90 g/l, and C4 from 0.18 to 0.22 g/l. In the vasculitis patients significant median changes were seen in: ESR from 44 to 15 mm 1st hour; C reactive protein (CRP) from 16 to 5 g/dl; neutrophils from 8.55 to 4.3 x 10(9)/l; platelets from 340 to 261 x 10(3)/l, and haemoglobin from 12.6 to 13.2 g/dl. Patients with Churg-Strauss syndrome, Wegener's granulomatosis, and neuropsychiatric lupus showed the best initial response but 58% of Wegener's patients relapsed. Median corticosteroid doses were significantly reduced from 15 (5-60) mg to 10 (3-35) mg daily. Adverse events: infections (7 patients), neutropenia (5), lymphopenia (18), and haemorrhagic cystitis (1 intravenous and 2 oral cyclophosphamide), allergies to mesna (2). None of the women at risk had prolonged amenorrhoea. Five patients doubled their serum creatinine and five died from sepsis (2) or severe disease (3). CONCLUSION: Treatment of severe connective tissue diseases with 'low dose' intravenous cyclophosphamide pulses compares in efficacy with the higher monthly doses previously advocated. Treatment was well tolerated with fewer adverse effects and most significantly, there were no cases of premature ovarian failure.

Adult↗

PubMed1969

Cyclophosphamide therapy in the nephrotic syndrome in childhood.

Forty-six children with the nephrotic syndrome whose renal biopsy specimens showed minimal changes and whose response to corticosteroid therapy was unsatisfactory were treated with cyclophosphamide. Three patients were completely steroid-resistant from the outset and the remainder were steroid-dependent. In several patients steroids controlled the condition less effectively with time. Most patients showed signs of steroid toxicity, and growth retardation was striking.A moderate leucopenia was induced with cyclophosphamide, and treatment was maintained for three to four months in the majority of cases. Thirty-eight children (83%) have remained in complete remission off all treatment for periods of 3 to 23 months, 33 after one course of cyclophosphamide and five after a second course. Two other patients who remitted but relapsed later are still on treatment. In only six patients was full remission not obtained, and three of these were steroid-resistant from the start. Two died from pneumonia and adrenal failure and four continued to have proteinuria, though in one an impressive reduction occurred.The results indicate that cyclophosphamide therapy is an effective alternative for nephrotic children with normal glomeruli on light microscopy who develop steroid dependence or resistance, and who exhibit toxic effects of steroid therapy.

Adolescent↗