General toxicity of cyclophosphamide in rheumatic diseases

INTRODUCTION — Cyclophosphamide (CYC) is an alkylating agent that was introduced into clinical practice as a chemotherapeutic agent but has also been used to treat a number of systemic autoimmune diseases. It is generally used in cases of life- or organ-threatening rheumatic diseases, such as antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis or systemic lupus erythematosus (SLE) with renal or central nervous system involvement.

CYC is also associated with a variety of toxicities that should lead clinicians to consider less toxic alternative medications whenever possible. While much of our knowledge about the toxicity of CYC has been extrapolated from its use in oncology and historical studies, contemporary use of CYC often results in a lower cumulative dose, making toxicity likely lower than prior reports.

Historically, patients were often treated with daily oral CYC for several years at a time. This type of oral CYC dosing could result in exposure to more than 36 g of CYC over a year of therapy and 50 to 150 g over a lifetime of vasculitis management [1]. Contemporary regimens are more likely to include intermittent intravenous dosing of CYC for a three- to six-month period, followed by a less-toxic immunosuppressant. Typical intravenous dosing of 0.75 to 1 g/m² over a six-month course results in 4.5 to 9 g, depending on the size of the patient [2]. Alternatively, the Euro-Lupus protocol for lupus nephritis results in just 3 g of CYC dosed over a three-month period [3]. Nonetheless, patients who require multiple courses of therapy, particularly with oral CYC, may ultimately reach cumulative doses associated with significant, long-term toxicity. Administration to a female patient of several pulse CYC regimens over the course of her illness (eg, for recurrent lupus nephritis) poses a risk of premature ovarian insufficiency particularly for women in their 30s and 40s, even if the risk from a single treatment is relatively small.

This topic will provide an overview of the mechanism of action and major toxicities associated with CYC use for the treatment of systemic rheumatic diseases. General principles of the use of CYC for rheumatic diseases as well as the pharmacology of the drug are discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

MECHANISM OF ACTION — Alkylating agents exert their biologic activity via covalent binding and crosslinking of a variety of macromolecules including deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. DNA crosslinking, probably the most important biologic action of these drugs, impairs DNA replication and transcription, ultimately leading either to cell death or to altered cellular function [4].

The degree of inhibition of immune function is dependent upon the dose and duration of therapy. Alkylating agents are cytotoxic. Absolute lymphopenia is frequently seen following their administration, with reductions in the number of B cells and T cells of both CD4+ and CD8+ types [5,6]. The ratio of circulating T cells and B cells may also be affected [7]. Repeated pulses of CYC may be associated with B cell depletion to <5 CD20 cells/mm³ [6].

TOXICITY — The alkylating agents share a number of potentially severe side effects including bone marrow suppression, increased susceptibility to infection, gonadal toxicity, teratogenicity, bladder toxicity, hyponatremia, and an increased risk of malignancy.

The cumulative dose of cyclophosphamide (CYC) is a major risk factor for toxicity. Thus, strategies that reduce the cumulative dose and duration of exposure can minimize long-term risks. One such strategy is to use intermittent pulse CYC regimens rather than daily oral therapy, which can result in a 60 percent or greater decrease in the cumulative dose. Also, changing CYC for another less toxic medication after remission induction is achieved is another strategy to limit exposure. The following examples are illustrative:

●In a trial of sequential therapy for lupus nephritis, patients began with pulse CYC for six months, followed by random assignment to one of three different regimens: continued CYC, mycophenolate mofetil, or azathioprine [8]. By switching from CYC to another drug, the risk for infection decreased from 77 percent to 29 to 32 percent. Prolonged amenorrhea decreased from 32 percent to 6 to 8 percent. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

●In the CYCAZAREM trial, a study of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), orally administered CYC (plus glucocorticoids) was given for three to six months for remission induction, and then patients were randomly assigned to discontinue CYC in favor of the less toxic azathioprine or to continue CYC [9]. At 18 months, the numbers of disease flares in the two treatment groups did not differ, but those patients in the azathioprine group were spared months of CYC exposure, presumably incurring lower long-term risks of cancer, infertility, and other side effects. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Choice of maintenance therapy'.)

Because the daily and intermittent intravenous administrations of CYC are not therapeutically equivalent in some settings, the decision about the route of administration and duration of therapy, whenever possible, should be based upon data available for a specific disease.

In addition to the cumulative dose, the toxicity of CYC is also affected by genetic polymorphisms of the cytochrome P450 enzyme system [10]. As an example, in one study of 62 patients with lupus nephritis, those treated with CYC who were either homozygous or heterozygous for the cytochrome P450 variant 2C19*2 demonstrated a significantly lower risk of ovarian failure (from 80 to 35 percent) [11] (see 'Gonadal toxicity' below). However, the genotypes resulting in lower exposure also correlated with an increased risk of progression to end-stage kidney disease. Another study of 196 people with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis found a higher frequency of leukopenia if a variant CYP2C9 was present (odds ratio [OR] 2.09) [12]. Assessment of cytochrome P450 variants is not performed routinely in clinical practice. These findings, however, emphasize the variability in susceptibility to the effects of alkylating agent therapy. They also underscore the importance of careful monitoring for adverse effects. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide'.)

Hematologic toxicity — One of the most serious short-term side effects of CYC relates to the induction of cytopenias. Hematologic toxicity becomes more common with increasing doses and is also more likely to occur with a longer duration of use. In a meta-analysis of trials of CYC for idiopathic membranous nephropathy and lupus nephritis, leukopenia was reported in 46 out of 276 (17 percent) and 12 out of 90 (13 percent) patients, respectively [13,14]. Granulocytes and lymphocytes are most likely to be affected first (sometimes within days to a few weeks of treatment), followed by the platelet count and hematocrit. The total white blood cell count, as well as either the absolute neutrophil or the lymphocyte lines, can be affected. The tendency of CYC to cause lymphopenia is enhanced by the concomitant use of high doses of glucocorticoids. In view of the demargination of neutrophils that occurs with high-dose glucocorticoids, a white blood cell count below 4000/mm³ in this situation has been reported to be associated with substantial immunosuppression even if the absolute neutrophil count remains >1500/mm³.

In order to detect impending and potentially dangerous bone marrow toxicity, patients treated with daily oral CYC should have complete blood counts checked approximately every two weeks for as long as they receive this medication. Suppression of the total white blood cell count is not an aim of treatment with daily oral CYC and should be avoided, with dose adjustments as the total white blood count begins to fall. Patients receiving intravenous pulse CYC, usually administered on a monthly basis, develop leukopenic nadirs in a predictable fashion 7 to 14 days after administration, with the nadir of the lymphocyte count occurring approximately day 7 and that of the granulocyte count approximately day 14 [6].

Titrating the dose of monthly (but not biweekly) infusions of CYC to achieve a nadir of approximately 3000 to 3500 white blood cells per mm³ with an absolute neutrophil count of greater than 1000 to 1500 has been used as a method of dose adjustment. Bone marrow recovery is usually evident by 21 days. Monitoring of blood counts during treatment with CYC is discussed in detail separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of intermittent CYC dosing'.)

Although it is easier in clinical practice to monitor white cell counts with intravenous administration of CYC given the predictable nadir, there does not seem to be a significant difference in the frequency of severe leukopenic events with oral versus intravenous administration. As an example, in a review of 212 systemic lupus erythematosus (SLE) patients with diffuse proliferative lupus nephritis treated with CYC, there was no significant difference in the number of severe leukopenic events (defined as white blood cell counts <2000/mm³) among patients treated with oral versus intravenous CYC (5 versus 7 percent, respectively) [15]. The CYCLOPS study, which compared oral with intravenous CYC for the treatment of ANCA-associated vasculitis, found fewer episodes of neutropenia in the intravenous CYC arm [2]. However, this lower rate of neutropenic events was not associated with fewer infectious complications of treatment.

Infection — CYC can predispose to bacterial, opportunistic, and viral infections [16-22]. CYC increases the risk of infection by inducing bone marrow depression, resulting in neutropenia and/or lymphopenia, and by interfering with normal neutrophil and lymphocyte function even in the absence of count reductions.

Patients receiving CYC who become neutropenic (absolute neutrophil count less than 1500/microL), especially those who are treated concomitantly with high doses of glucocorticoids, are at particular risk for infection [16,22]. As an example, a study including 143 patients with SLE found that infection occurred in 45 percent of CYC-treated patients compared with 12 percent of those treated with glucocorticoids alone [22]. Bacterial infections were the most common, followed by opportunistic infections and herpes zoster. Multiple meta-analyses suggest the risk for infection during CYC therapy with glucocorticoids is between 20 and 40 percent [13,14,23].

The effect of obesity on the safety of calculating bolus CYC dose according to total versus ideal body weight remains controversial, but the weight of the evidence from the cancer literature suggests that dose reduction may not be necessary to reduce the risk of neutropenia and/or infection. In several studies, the incidence of febrile neutropenia was not higher in patients with obesity treated according to total body weight [24], and reviews and guidelines suggest for cancer treatment that doses calculated according to full body weight or partially adjusted toward lean body weight should be used [25,26].

Major bacterial or fungal infections can occur in the absence of neutropenia. This has been estimated to occur in 5 to 21 percent of patients treated with CYC for GPA or lupus nephritis [15,16,19,27]. Concomitant use of glucocorticoids is thought to be a major risk factor for fungal infection, as well [16].

Infection with Pneumocystis jirovecii is a known complication of treatment with CYC, particularly when administered in combination with glucocorticoids [28]. As a result, prophylaxis is indicated for almost all patients on CYC. Prophylactic therapy for Pneumocystis pneumonia is discussed elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prophylaxis for Pneumocystis jirovecii pneumonia infection' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

There is also substantially increased risk for herpes zoster infection with CYC treatment. The incidence of zoster in different trials of vasculitis and lupus has ranged from 8 to 33 percent [16,19,27]. In one large trial of GPA, most zoster events did not occur during the periods of most intensive immunosuppression but rather occurred after patients had discontinued CYC and prednisone, suggesting the possibility of an immune reconstitution syndrome [29]. The increased risk of herpes zoster has also been demonstrated in patients with SLE treated with CYC. A population-based study using medical records found an adjusted OR for developing zoster of 3.76 to 4.64 for oral and intravenous CYC, respectively [30]. In a study of childhood SLE, CYC increased the risk of herpes zoster with an adjusted OR of 4.1 [31]. In both of these studies, prednisone use was also an independent predictor of herpes zoster with an OR between 6.3 and 6.7. Immunization with recombinant adjuvanted zoster vaccine would optimally be accomplished prior to CYC administration, although this may not be practical. This is discussed in detail separately. (See "Vaccination for the prevention of shingles (herpes zoster)".)

CYC therapy is associated with increased susceptibility to infection with or reactivation of human papilloma virus (HPV) based on the observed incidence of cervical intraepithelial neoplasia in women treated with CYC [32]. Age-appropriate screening for cervical cancer and HPV infection in women is discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Laboratory and clinical testing' and "Screening for cervical cancer in resource-rich settings".)

Gonadal toxicity — CYC is toxic to both ovaries and testes. The incidence of gonadal dysfunction is dependent upon age, sex, and cumulative CYC dose [33,34]. (See "Effects of cytotoxic agents on gonadal function in adult men".)

Female gonadal toxicity — In women, CYC may lead to infertility and premature menopause (premature ovarian failure [POF]). Treatment-induced damage includes depletion of ovarian follicles and shrinkage and fibrosis of the ovaries. Some patients who develop amenorrhea during treatment may subsequently recover ovarian function. Conversely, some women with apparent preservation of ovarian function during and after treatment may develop premature ovarian insufficiency years later. Women treated before the age of 25 are at lower risk of infertility than those treated after the age of 30 [18,33,35-39]. The cumulative total CYC dose is an independent risk factor for ovarian toxicity, regardless of how the medication is administered.

The following data illustrate these points:

●A meta-analysis including 1388 women (mean age 27.7) receiving intravenous CYC for systemic rheumatic diseases found that sustained amenorrhea occurred in 273 women (19.7 percent) [40]. The rate of sustained amenorrhea was positively correlated with increasing cumulative CYC and was unlikely in patients with a cumulative CYC dose <5 g.

●A report of 84 women who were menstruating prior to intravenous CYC administration for SLE or vasculitis also demonstrated the importance of age [37]. Chronic amenorrhea did not develop in any of the 22 women younger than 26 years of age but occurred 14 of the 20 women (70 percent) older than age 35.

●A study of women receiving the lower-dose regimen of CYC used for SLE (of six 500 mg intravenous pulses every two weeks) did not reveal changes in ovarian function as assessed by anti-Müllerian hormone (AMH) levels compared with never-treated patients [41].

Some women who are treated successfully with CYC are able to conceive and deliver healthy children [36,37,42]. In a study of 85 women treated with intravenous CYC for rheumatologic diseases, 16 women became pregnant after completing treatment [37]. The outcomes of 16 pregnancies in these women included 10 healthy babies, three spontaneous miscarriages, and three pregnancy terminations (two for anomalies and one for an SLE flare). In another study of women with SLE, 80 percent of those who tried to conceive were pregnant after 12 months, regardless of whether they had received CYC or not; the authors estimated that <10 percent of study participants had received gonadotropin-releasing hormone (GnRH)-agonist cotherapy with CYC [43].

Another study evaluated the impact of prior intravenous CYC exposure on pregnancy outcomes in 535 women with SLE in Saudi Arabia, and found that the rate of live birth was not significantly different among women with and without prior CYC exposure (68 percent and 71 percent, respectively) [44]. Despite having the same rate of active lupus nephritis during pregnancy in each group (around 30 percent), significantly more pregnancies were delivered preterm to women with prior CYC exposure (41 percent) than to women without prior CYC exposure (23 percent).

Because women may remain fertile during therapy with CYC, steps to avoid pregnancy during treatment are essential. Counseling about the need for effective contraception during CYC administration is discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Contraception' and "Contraception: Counseling and selection", section on 'Special populations'.)

Male gonadal toxicity — CYC causes a decrease in sperm count and with higher doses and treatment duration can lead to irreversible azoospermia [45,46]. Testicular injury is reported to occur in boys and men after 7 to 9 g of CYC and to occur more often with comparable doses of intravenous versus oral CYC; recovery is documented in some patients [47]. As an example, the reproductive function was studied in 31 male patients with Behçet syndrome during treatment with CYC and/or colchicine [48]. Severe oligospermia or azoospermia occurred in 13 of 17 men treated with CYC but occurred in none of the patients treated with colchicine alone [48]. Nevertheless, many men have fathered children after alkylating agent therapy [49,50].

Men with SLE appear to have diminished sperm quality compared with healthy controls [51]. A study of 35 men with SLE found that 86 percent of those with prior CYC treatment had very poor sperm quality, compared with 45 percent of the men without prior CYC [51]. The average duration between CYC and sperm analysis was five years and all CYC was given after the first ejaculation.

The effects of CYC on gonadal function in men as well as the prevention of gonadal toxicity are discussed in detail separately. (See "Effects of cytotoxic agents on gonadal function in adult men", section on 'Cyclophosphamide' and "Effects of cytotoxic agents on gonadal function in adult men" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in males with rheumatic diseases", section on 'Cyclophosphamide' and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Infertility risk'.)

Teratogenicity — CYC is associated with congenital (or fetal) malformations and should be avoided during the first 10 weeks of gestation, when the fetus is most susceptible to teratogens (figure 1). However, CYC has been used in life-threatening circumstances in the mother, especially in the second and third trimesters [52-55]. The frequency of congenital anomalies is difficult to estimate, as many conceptions exposed to CYC result in a pregnancy loss. In two cohorts totaling 86 live births with CYC exposure, 23 (26.7 percent) were born with a congenital malformation [56].

The risk of congenital anomaly is greatest with exposure during the first trimester. Eleven case reports of women who received CYC for cancer or lupus therapy during the first trimester showed a pattern of anomalies labeled "cyclophosphamide embryopathy" [57-60]. These infants had multiple abnormalities, including growth restriction, ear and facial abnormalities, absence of digits, and hypoplastic limbs. Of the six pregnancies that resulted in surviving children, at least three had severe developmental delay. One twin pregnancy with CYC exposure for acute lymphocytic leukemia resulted in two live infants who were small for dates and who required intubation after delivery. One of these infants recovered fully and developed normally. The other had significant congenital abnormalities, had developmental and cognitive problems, and developed both papillary thyroid cancer and neuroblastoma by the age of 14 [61].

Exposure to CYC during the second and third trimester may be associated with low birthweight and with neonatal pancytopenia. In a study of women diagnosed with breast cancer during pregnancy, all 24 pregnancies with second- and third-trimester exposure to CYC resulted in live births [62]. A study of fetal brain growth after second and third trimester dosing of chemotherapy (anthracyclines and CYC-based regimens) did not reveal smaller brain size in infants, nor developmental changes at 18 months of age compared with infants born to healthy women [63].

When CYC is required mid-pregnancy to treat a life-threatening lupus flare, however, the survival of the fetus is less likely [55,64] (see "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'). The increasing availability of alternative therapies has reduced the need for this approach.

Men should also practice effective birth control to avoid conception during CYC treatment. Although there are no established human data, exposure of male rats to CYC is associated with increased rates of fetal loss and malformations [65]. If sperm are to be collected for cryopreservation, they should be obtained prior to the first dose of CYC, as genetic damage from CYC can occur in sperm anywhere along the developmental pathway, especially those near maturity [66]. (See "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in males with rheumatic diseases", section on 'Cyclophosphamide'.)

As noted above, men previously treated with CYC have fathered successful pregnancies. Chromosomal abnormalities have been noted in patients after CYC exposure, but it is unclear if similar changes occur in eggs or sperm [67]. One man with prior CYC therapy fathered an infant with tetralogy of Fallot and syndactyly of the toes [68]. Four pregnancies after CYC therapy for SLE resulted in four live births. One baby was delivered preterm, and another was small for gestational age [42]. The risk of congenital anomalies in offspring to parents previously treated with these agents is unknown.

Malignancy — Patients with rheumatoid arthritis (RA), SLE, and other systemic autoimmune diseases are at increased risk of developing lymphoma independent of treatment. However, the administration of CYC enhances this risk, and an increased risk of leukemia, skin cancer, cervical cancer, and other malignancies has been reported [16,69-72]. Mechanisms of alkylating agent-induced malignancy include direct chromosomal damage and decreased immune surveillance. The duration of therapy is an important risk factor, with the incidence being greatest in patients treated for more than two to three years [71].

A population-based cohort study found that 195 patients with CYC therapy for ANCA-associated vasculitis had higher than expected rates of malignancy in long-term follow-up (median 8 years, interquartile range [IQR] 4.0 to 11.9 years) [73]. The risk was highest for patients with a cumulative dose of CYC over 36 g with an age- and sex-standardized incidence ratio of 3.4 (95% CI 1.5-6.4) for all malignancies other than squamous cell carcinomas. Patients with a cumulative dose of CYC below 10 g had a higher risk for squamous cell carcinomas, but not other malignancies.

Patients with previous exposure to CYC are at increased risk for hematologic malignancies. Myelodysplastic syndrome may occur in up to 8 percent of patients with GPA after CYC and in 13 percent of such patients with a cumulative dose over 100 g [74]. Myeloproliferative disease, including acute leukemia, non-Hodgkin lymphoma (NHL), and multiple myeloma, occurred in 5 of 119 patients within the first decade after treatment with CYC, compared with one case of chronic lymphocytic leukemia in 119 RA patients without a history of use of CYC [71]. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Bladder toxicity — Both hemorrhagic cystitis and bladder cancer are associated with CYC therapy because of exposure of the bladder to the acrolein, a toxic metabolite of CYC (see "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Cyclophosphamide' and "Clinical presentation, diagnosis, and staging of bladder cancer"). Prevention of bladder toxicity associated with CYC use for systemic rheumatic diseases is discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis'.)

Hemorrhagic cystitis — The risk of hemorrhagic cystitis in patients receiving CYC as an immunosuppressive agent for rheumatologic disease varies according to the route of administration. It is highest with continuous daily oral administration because the duration of treatment and total cumulative exposure are higher as compared with intermittent intravenous dosing regimens [75]. In three large cohort studies including patients with GPA, the incidence of hemorrhagic cystitis ranged from 12 to 41 percent [74,76,77]. The patients included in these studies were exposed to cumulative doses ranging from 50 to 100 g.

By contrast, newer CYC regimens of intravenous CYC have markedly reduced the cumulative exposure to CYC, resulting in lower rates of hemorrhagic cystitis [75].

Few cases of hemorrhagic cystitis have been reported from clinical trials and case reports of patients treated with intermittent intravenous CYC for rheumatic diseases [75]. In a retrospective analysis of 1018 patients treated for autoimmune disease and vasculitis from 13 rheumatology centers, the median CYC dose was 9 g (range 1.5 to 180), and CYC was administered exclusively intravenously in 91 percent, exclusively orally in 5 percent, and by both routes in 4 percent [78]. Overall, only 17 patients were identified with hemorrhagic cystitis (1.67 percent), and the incidence was similar in patients treated with and without mesna (9 of 585 versus 8 of 424, 1.5 versus 1.9 percent). Cumulative dose was associated with hemorrhagic cystitis (hazard ratio [HR] for each 10 g increment 1.24, 95% CI 1.12-1.38). The use of mesna in patients receiving intermittent intravenous CYC for rheumatologic disorders is discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis'.)

Another potential contributory factor for hemorrhagic cystitis in these patients may be BK virus (human polyomavirus 1). BK virus has been recognized in renal transplant populations as playing a role as a cofactor in cases of drug-induced cystitis [79]. This virus is present in its latent form in the majority of adults and can be reactivated, usually in the urogenital tract, during immunosuppression (see "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections"). While the risk of BK infection in nontransplanted immunosuppressed patients has not been well-described, there is reasonable concern for an increased risk of infection among patients with rheumatic diseases treated with CYC [80,81].

Bladder cancer — Treatment with oral CYC confers an increased, and likely dose-dependent, risk of bladder cancer that may be sustained for years after discontinuation. As an example, a retrospective study of 145 GPA patients treated with oral CYC for at least one year found a 4.8 and 16 percent incidence of bladder cancer after a median follow-up period of 8.5 and 15 years, respectively [76]. Approximately 65 percent of these patients received total doses of more than 50 g. All of the patients who developed bladder cancer had had one or more episodes of microscopic or macroscopic nonglomerular hematuria, and all had been treated for at least 2.7 years.

In a population based cohort study, after a median of 8 years of follow-up, of 195 patients with history of CYC therapy for ANCA-associated vasculitis, it was reported that 5 patients developed bladder cancer, 3 with a cumulative CYC dose over 10 g and 2 with less than 10 g, leading to an overall sex- and age-adjusted standardized incidence ratio of 4.30 (95% CI 1.40–10.04) over the expected rate [73].

The risk of secondary bladder cancer increases markedly after an episode of hemorrhagic cystitis. The risk of bladder cancer is also dose related and approaches 5 to 10 percent by five years in patients receiving cumulative doses of CYC ≥30 g, with new cases occurring for up to 20 years [82]. Bladder cancer has developed as little as seven months after starting CYC therapy and as many as 15 or more years after discontinuing the medication [16,71,76].

Bladder tumors induced by CYC can be particularly aggressive biologically. As an example, a study of 12 cases, found that all of the tumors were grade 3 or 4 transitional cell carcinomas at presentation [83].

Our approach to surveillance for bladder cancer in patients who have received CYC is discussed separately. (See "Screening for bladder cancer".)

Hyponatremia due to SIADH — Intravenous pulse CYC can induce hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Marked water retention and potentially fatal hyponatremia can occur, because patients receiving this regimen are treated with intravenous fluids to prevent drug-induced cystitis [84]. SIADH has been described primarily with doses in the range of 30 to 50 mg/kg, typical of those used to treat cancer. SIADH can also occur with the somewhat lower doses (10 to 15 mg/kg) used to treat inflammatory disorders [84-87]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)

Hyponatremia can be minimized in this setting by using isotonic saline (or half normal saline in patients with edema) rather than free water to maintain a high urine output [87]. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Therapies to raise the serum sodium'.)

Miscellaneous — Several other side effects can also be induced by alkylating agent therapy:

●Nausea is common, especially with intravenous CYC [88]. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide'.)

●Hair loss may occur, although it is generally not as severe as that seen with cancer chemotherapy. The most common pattern is diffuse thinning, which is generally reversible upon discontinuation of the drug. Patients can be told that, although they may note hair thinning that ranges from mild to substantial, all of their hair will not fall out (in contrast to patients treated with cancer chemotherapy doses of CYC). This is particularly true if circumscribed courses (three to six months) of CYC are used. Among patients receiving CYC for membranous nephropathy, 10 percent reported alopecia [13].

●Pulmonary fibrosis is a rare complication of CYC. (See "Cyclophosphamide pulmonary toxicity".)

●Cardiac toxicity is a major problem in oncology patients treated with higher dose regimens (see "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Cyclophosphamide'). For patients with systemic rheumatic diseases treated with CYC, doses may need to be attenuated, and heart function may need to be followed closely if there is decreased myocardial contractility at baseline.

●Both hepatotoxicity [89] and anaphylaxis [90] due to CYC are rare. (See "Hepatotoxicity of chemotherapy and other cytotoxic agents", section on 'Cyclophosphamide'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY

●The alkylating agent cyclophosphamide (CYC) exerts its biologic activity via covalent binding and crosslinking of a variety of macromolecules including DNA, RNA, and proteins. (See 'Mechanism of action' above.)

●The major risk of toxicity from CYC is related to the cumulative dose of the medication. Therefore, strategies that reduce the duration of exposure can minimize the long-term risks. The standard of care for most inflammatory diseases is to induce remission with courses of CYC lasting not longer than six months and then to switch to a less toxic medication for remission maintenance. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

●The principal toxicities of CYC relate to its effects on bone marrow, reproductive organs, and bladder. Long-term concerns relate to the induction of malignancy of many different types. (See 'Toxicity' above.)

●Specific forms of CYC toxicity include:

•Hematologic toxicity (see 'Hematologic toxicity' above)

•Infection (see 'Infection' above)

•Infertility (see 'Female gonadal toxicity' above and 'Male gonadal toxicity' above)

•Adverse effects on pregnancy (see 'Teratogenicity' above and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide')

•Malignancy induction (see 'Malignancy' above)

•Bladder toxicity (see 'Bladder toxicity' above)

•Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (see 'Hyponatremia due to SIADH' above)

•Several other side effects such as nausea, hair loss, pulmonary fibrosis, cardiac toxicity, and hepatotoxicity (see 'Miscellaneous' above)