Version July 2025
INTRODUCTION —
Cyclophosphamide (CYC) is an alkylating agent that is one of the most potent immunosuppressive therapies available. Historically, both oral and intravenous forms of CYC have been used to treat a variety of rheumatic diseases, including systemic lupus erythematosus (SLE) and various vasculitides (eg, antineutrophil cytoplasmic autoantibody [ANCA]-associated vasculitis). However, due to the serious adverse effects associated with CYC therapy and the increasing availability of more targeted, less toxic immunosuppressive agents, intravenous CYC is typically reserved for patients with severe disease manifestations who need rapid disease control and patients who are refractory to other therapies.
This topic discusses the principles of use, pharmacology, adverse effects, dosing, and monitoring of CYC in the setting of rheumatic diseases. The indications for use of CYC to treat specific rheumatic diseases as well as other conditions (eg, malignancy) and supportive evidence are discussed in the respective disease treatment topics.
PRINCIPLES OF USE —
Two major aims govern the use of cyclophosphamide (CYC):
●Achieving prompt control of the underlying disease – CYC is very effective and has a relatively quick onset of action, which can allow for rapid control of a variety of rheumatic diseases. It is generally reserved for patients with severe disease manifestations (eg, kidney or central nervous system involvement in systemic lupus erythematosus [SLE]) or patients who are either resistant to or intolerant of less toxic immunosuppressive medications.
●Minimizing cumulative CYC exposure – It is important to minimize exposure to CYC since higher cumulative doses are associated with a greater risk of potentially devastating short- and long-term toxicities (eg, malignancy, infertility), even after the medication is stopped. (See 'Adverse effects' below.)
Strategies to reduce cumulative CYC exposure and minimize the risk of toxicity include the following:
•Using intermittent (pulse) CYC – Using intermittent intravenous (pulse) CYC rather than daily oral therapy reduces the cumulative dose by 60 percent or more. Historic daily CYC regimens exposed patients to more than 36 g of CYC over a year of therapy and 50 to 150 g over a lifetime of disease management [1]. By contrast, contemporary regimens of intermittent CYC require much lower cumulative CYC doses; the Euro-Lupus protocol for lupus nephritis (LN) exposes patients to just 3 g of CYC over a three-month period [2], while other intermittent regimens for rheumatic diseases (eg, 750 to 1000 mg/m2 every two to four weeks for six months) expose patients to 4.5 to 9 g of CYC depending on the patient's weight [3]. This likely decreases the risks of long-term complications.
•Transitioning to alternative immunosuppressive therapy – When CYC is used to treat rheumatic disease, the standard of care is generally to use CYC to induce remission (typically over the course of ≤6 months) and then transition to an alternative, less toxic therapy to maintain remission. The optimal duration of CYC for induction and type of immunosuppression to transition to will depend on the specific condition being treated.
The potential to spare patients from adverse effects by transitioning to alternative maintenance therapy is illustrated by a trial of sequential therapy for LN, where patients began with intermittent CYC for six months, followed by random assignment to one of three different regimens: continued CYC, mycophenolate mofetil, or azathioprine [4]. Patients who switched to alternative therapies had better disease outcomes and fewer adverse effects; as examples, when comparing patients who transitioned therapy with those who continued CYC, the risk of infection was 29 to 32 percent versus 77 percent, and the risk of amenorrhea was 6 to 8 percent versus 32 percent, respectively. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'.)
Despite efforts to minimize CYC exposure, some patients (especially those with refractory LN) may require multiple courses of CYC and ultimately reach cumulative doses associated with significant, long-term toxicity. This underscores the importance of careful long-term monitoring for adverse effects. (See 'Monitoring' below.)
MECHANISM OF ACTION —
Cyclophosphamide (CYC) is an alkylating agent that covalently binds and crosslinks a variety of macromolecules (eg, deoxyribonucleic acid [DNA], ribonucleic acid [RNA], and proteins). The most important biologic action of CYC is DNA crosslinking, which impairs DNA replication and transcription; this can be cytotoxic or alter function of affected cells [5].
The degree of inhibition of immune function depends on the dose and duration of CYC therapy. Absolute lymphopenia is frequently seen following CYC administration, with reductions in the number of B cells and CD4+ and CD8+ T cells [6,7]. Repeated pulses of CYC may be associated with B-cell depletion to <5 CD20 cells/mm3 [7]. The ratio of circulating T cells and B cells may also be affected [8].
PHARMACOLOGY —
It is important to understand the metabolism and excretion of cyclophosphamide (CYC) in order to minimize its toxicity.
●Metabolism – CYC is primarily metabolized in the liver to 4-hydroxy CYC and aldophosphamide (figure 1). Aldophosphamide is then converted to the active metabolite phosphoramide mustard and the highly reactive aldehyde, acrolein, which is primarily responsible for bladder and cardiac toxicity (see 'Bladder toxicity' below and 'Other adverse effects' below). The appearance of these metabolites is delayed after CYC administration, with acrolein appearing in the urine up to 24 hours later.
Several cytochrome P450 enzymes in the liver are responsible for the conversion of CYC to its active form, especially cytochrome P450 2B6 (CYP2B6). CYP2B6 is highly polymorphic, which may account for some of the pharmacokinetic variability seen among patients [9]. Other genetic polymorphisms in the cytochrome P450 enzyme system will similarly influence CYC metabolism and subsequent toxicity [10]. As an example, in a study of 62 patients with lupus nephritis (LN) who were treated with CYC, those who were homozygous or heterozygous for the CYP2C19*2 had a lower risk of ovarian failure [11]. 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]. While testing for cytochrome P450 variants is not routinely performed in clinical practice, we do recognize this potential variability and monitor patients carefully for adverse effects.
●Distribution – Active CYC metabolites are highly protein-bound and are distributed to all tissues, including brain and cerebrospinal fluid. The active metabolites are assumed to cross the placenta and are known to be present in breast milk in small amounts [13]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)
●Elimination – Both active and inactive metabolites are primarily excreted unchanged in the urine, with elimination complete by 48 hours. Consequently, the dose of CYC should be adjusted according to the degree of kidney dysfunction [14,15]. (See 'Factors requiring dose adjustment' below.)
RELATIVE CONTRAINDICATIONS —
The following conditions represent relative contraindications to the use of cyclophosphamide (CYC):
●Active infection – Since CYC can cause neutropenia, we avoid using it in patients with active systemic or potentially life-threatening infections. We also carefully assess the advisability of treating patients with high risk due to latent infections (eg, tuberculosis, hepatitis B or C virus). (See 'Infection' below.)
●Neutropenia – We avoid CYC use in neutropenic patients due to the risk of worsening the neutropenia. An exception is when the neutropenia is immune-mediated (eg, from systemic lupus erythematosus [SLE]), in which case using CYC to control the underlying autoimmune disease may improve neutropenia. (See 'Cytopenias' below.)
●Severe hepatic impairment – Since CYC is metabolized by the liver to its active form, we avoid giving CYC to patients with severe hepatic impairment (eg, serum bilirubin >5 mg/dL).
●Prior history of hemorrhagic cystitis – CYC is associated with an increased risk of both hemorrhagic cystitis and bladder cancer (see 'Bladder toxicity' below). The risk of bladder cancer is even higher for patients with a history of hemorrhagic cystitis. Thus, we generally avoid additional doses of CYC in patients with a history of hemorrhagic cystitis. However, this common practice is based on a theoretical risk and has not been well studied. There may be certain scenarios in which it is appropriate to still administer pulse intravenous (but not daily oral) CYC, especially when patients with severe acute disease lack equally effective therapeutic options and have a remote or poorly documented history of hemorrhagic cystitis.
●Inadequate contraception – Due to the teratogenicity of CYC, it is critically important to avoid conception during therapy. This is especially true for female patients, who can often still conceive despite active rheumatic disease. Patients must therefore receive adequate counseling and ideally start an effective form of contraception prior to initiating CYC. If patients are too ill to start contraception at the time of initial CYC administration, we address the issue as soon as their clinical status allows. (See 'Contraception' below.)
●Pregnancy and lactation – In pregnant females, CYC is teratogenic and is contraindicated in the first trimester (see 'Teratogenicity' below). CYC may be appropriate to administer during the second or third trimesters in rare clinical scenarios when pregnant patients have severe, life-threatening rheumatic disease and safe, effective alternatives are unavailable [16,17]. In the postpartum period, CYC therapy is not compatible with breastfeeding since active and/or toxic CYC metabolites can be excreted in breastmilk. More information on the use of CYC during pregnancy and lactation is provided elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)
ADVERSE EFFECTS —
The principal short-term adverse effects associated with cyclophosphamide (CYC) use include cytopenias, infections, teratogenicity, hemorrhagic cystitis, and hyponatremia. Long-term concerns include gonadal toxicity and induction of various types of malignancy, including bladder cancer.
Cytopenias — One of the most serious short-term side effects of CYC is hematologic toxicity and subsequent cytopenias. Patients may develop leukopenia, lymphopenia, neutropenia, anemia, and/or thrombocytopenia. Typically after intravenous CYC, granulocytes reach a nadir on day 14 and lymphocytes on day 7, while reduction of red blood cells and platelets is less frequent and occurs later. In a meta-analyses of CYC trials for idiopathic membranous nephropathy and lupus nephritis (LN), 13 to 17 percent of patients experienced leukopenia [18,19]. The monitoring of and response to CYC-induced cytopenias is discussed below. (See 'Monitoring' below.)
The hazard of having CYC-induced lymphopenia is enhanced by the concomitant use of high doses of glucocorticoids, which can cause substantial immunosuppression. (See 'Infection' below.)
Infection — Multiple types of viral, bacterial, and opportunistic infections are more common in patients taking CYC [20-26]. Infections affect an estimated 5 to 21 percent of patients treated with CYC for granulomatosis with polyangiitis (GPA) or LN [20,23,27,28]. They may result from neutropenia (ie, an absolute neutrophil count [ANC] <1500/microL) and/or lymphopenia, or from interference with normal neutrophil and lymphocyte function in the absence of neutropenia.
Patients who require both CYC and high-dose glucocorticoids have an even higher risk of infection [20,26], including fungal infections and herpes zoster [20,29,30]. Multiple meta-analyses suggest the risk for infection during CYC therapy with glucocorticoids is between 20 and 40 percent [18,19,31]. As an example, a study including 143 patients with systemic lupus erythematosus (SLE) found that infection occurred in 45 percent of CYC-treated patients compared with 12 percent of those treated with glucocorticoids alone [26]. Bacterial infections were the most common, followed by opportunistic infections and herpes zoster. These patients may experience substantial immunosuppression at relatively higher white blood cell (WBC) counts (eg, 1500 to 4000/mm3), since glucocorticoids cause demargination of neutrophils and elevate the WBC count.
More information on specific types of infections related to CYC is provided below:
●Pneumocystis jirovecii – Infection with P. jirovecii is a known complication of CYC treatment, particularly when patients are taking concomitant glucocorticoids [32]. As a result, prophylaxis is indicated for almost all patients on CYC. Prophylactic therapy for Pneumocystis pneumonia is discussed elsewhere. (See 'Prophylaxis for Pneumocystis jirovecii pneumonia' below and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
●Herpes zoster – There is also a higher incidence of herpes zoster infections in patients taking CYC, with rates ranging from 8 to 33 percent in various trials of CYC for vasculitis and SLE [20,23,28]. Among patients with SLE, the adjusted odds ratio (OR) for developing zoster in adults is approximately 4.6 for intravenous CYC [29]; in children, it is 4.1 [30]. Concomitant use of prednisone further increases the OR to between 6.3 and 6.7. In one large trial of GPA, most zoster events occurred after patients had discontinued CYC and prednisone and were relatively less immunosuppressed, suggesting the possibility of an immune reconstitution syndrome [33]. When feasible, we consider vaccination for herpes zoster prior to starting CYC. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Immunocompromised patients' and 'Preventive vaccinations' below.)
●Human papilloma virus (HPV) – CYC therapy is associated with increased susceptibility to infection with or reactivation of HPV based on the observed incidence of cervical intraepithelial neoplasia in women treated with CYC [34]. Age-appropriate screening for cervical cancer and HPV infection in women is discussed separately. (See 'Pretreatment testing' below and "Screening for cervical cancer in resource-rich settings".)
The administration of prophylactic vaccinations for patients who are receiving CYC is discussed below. (See 'Preventive vaccinations' below.)
Gonadal dysfunction — CYC is toxic to both ovaries and testes and can therefore lead to gonadal dysfunction and infertility in both females and males. The incidence of gonadal dysfunction is dependent upon age, sex, and cumulative CYC dose [35,36].
The importance of addressing reproductive health as part of the pretreatment evaluation for CYC, including fertility preservation and implementation of effective contraception during CYC administration, is discussed below.
●Female gonadal dysfunction – In females, treatment-induced damage includes ovarian follicle depletion and ovarian shrinkage and fibrosis. This may lead to infertility and premature ovarian insufficiency (POI, formerly called premature ovarian failure [POF]). The onset of symptoms related to gonadal dysfunction is variable. Some patients may develop amenorrhea during CYC treatment and subsequently recover ovarian function. Others may have apparently normal ovarian function during and after CYC administration but go on to develop POI years later. In a meta-analysis of over 1300 females (mean age 27.7 years) receiving intravenous CYC for systemic rheumatic diseases, 20 percent experienced sustained amenorrhea [37].
•Risk factors – The likelihood of ovarian toxicity rises with increasing age of the patient and the cumulative dose of CYC received [35,38]. As an example, in a study of patients with breast cancer, a 50 percent risk of POI was associated with cumulative CYC doses of approximately 20 g for females in their twenties, 10 g for females in their thirties, and 5 g for females in their forties [39]. Other studies illustrating the impact of CYC dose and patient age include the following:
-Cumulative CYC dose – In the meta-analysis of females receiving CYC for systemic rheumatic diseases described above, sustained amenorrhea was unlikely to occur in patients with a cumulative CYC dose <5 g; however, the rate of sustained amenorrhea correlated positively with increasing cumulative CYC [37]. In another observational study of females with SLE, ovarian function (as measured by anti-Müllerian hormone [AMH] levels) was similar between the group that did not receive CYC and the group that received the lower-dose Euro-Lupus CYC protocol (six 500 mg intravenous pulses every two weeks) [40]. Patients who received higher doses of intravenous CYC (cumulative dose >6 g) did have lower levels of ovarian function compared with patients who did not receive CYC.
It is important to note that some patients may require several courses of pulse CYC over time (eg, for recurrent LN). This poses a risk of POI particularly for women in their 30s and 40s, even if the risk from a single treatment is relatively small.
-Patient age – Females treated before the age of 25 are at lower risk of infertility than those treated after the age of 30 [22,35,41-45]. Similarly, among females who were menstruating prior to the administration of CYC for SLE or vasculitis, the rate of chronic amenorrhea was lower in younger patients, affecting none of those under the age of 26 and 70 percent of those over the age of 35 [43].
•Impact on fertility – It is important to recognize that despite the risk of gonadal dysfunction, females who are receiving CYC may still become pregnant [43]. Given the teratogenicity of CYC, it is critically important to counsel patients about the need to use reliable contraception. (See 'Contraception' below.)
Some females who have been successfully treated with CYC in the past are able to conceive and deliver healthy children [42,43,46]. In a study of 56 females 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 [47]. In another study of 85 patients with rheumatic diseases who had received CYC in the past, 16 became pregnant after completing treatment, ultimately leading to the delivery of 10 healthy babies, three spontaneous miscarriages, and three pregnancy terminations (two for fetal anomalies and one for an SLE flare) [43]. Finally, in a larger study of 535 pregnant females with SLE in Saudi Arabia, the rate of live birth was similar between those with and without prior CYC exposure (68 percent and 71 percent, respectively) [48]. However, the rate of preterm delivery was higher among those with prior exposure to CYC than those without (41 and 23 percent, respectively), despite both groups having a similar rate of active LN (approximately 30 percent).
Fertility preservation in patients taking CYC is discussed separately. (See 'Fertility preservation for adults' below.)
●Male gonadal dysfunction – In males, CYC is associated with genetic changes in sperm, decreased sperm count, and potentially irreversible azoospermia. The risk of testicular dysfunction is higher with larger cumulative CYC doses and also appears more common with intravenous versus oral CYC administration [49,50]. The effects of CYC on gonadal function in males is discussed in detail separately. (See "Effects of cytotoxic agents on gonadal function in adult men", section on 'Cyclophosphamide'.)
While data describing the effects of CYC in males with rheumatic disease are limited, in a study of 27 male patients with Behçet syndrome, severe oligospermia or azoospermia occurred in 13 of the 17 patients taking CYC and none of those taking colchicine alone or neither drug [51]. Likewise, in another study of 35 males with SLE, multiple measures of sperm number and quality were lower in the 14 patients with prior CYC exposure compared with the 21 without prior CYC exposure [52].
Despite these risks, recovery of testicular function is documented in some patients [53], and many males have successfully had children after alkylating agent therapy [54,55]. Counseling males about fertility preservation is discussed separately. (See 'Fertility preservation for adults' below.)
Teratogenicity — CYC is associated with fetal and congenital malformations and should be avoided in pregnant females during the first 12 weeks of gestation, when the fetus is most susceptible to teratogens [56,57]. Rarely, CYC may still be given to pregnant females in life-threatening circumstances in the mother, though this should be reserved for the second or third trimesters. The use of CYC in pregnant females is discussed in more detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)
Males taking CYC may also have abnormal sperm that theoretically may increase the risk of fetal anomalies. Although there are no established human data, exposure of male rats to CYC is associated with increased rates of fetal malformations and loss [58]. As noted above, males previously treated with CYC have fathered successful pregnancies; however, there are also case reports of congenital abnormalities, including one male with prior CYC therapy who fathered an infant with tetralogy of Fallot and syndactyly of the toes [59].
Due to the risk of teratogenicity, we counsel all patients who are taking CYC on the importance of using reliable contraception. (See 'Contraception' below.)
Bladder toxicity — CYC therapy is associated with both hemorrhagic cystitis and bladder cancer. The major cause of bladder toxicity is the exposure to the metabolite acrolein, which can appear in the urine for up to 24 hours after CYC administration. (See 'Pharmacology' above.)
Hemorrhagic cystitis — The risk of hemorrhagic cystitis in patients receiving CYC for rheumatologic disease increases with larger cumulative doses of CYC. Therefore, the risk is higher with continuous daily oral administration as compared with intermittent intravenous dosing regimens [60]. In three large cohort studies of patients with GPA who were exposed to a high cumulative CYC doses (50 to 100 g), the incidence of hemorrhagic cystitis ranged from 12 to 41 percent [61-63].
By contrast, few cases of hemorrhagic cystitis have been reported from clinical trials and case reports of patients treated with intermittent intravenous CYC for rheumatic diseases [60]. In a retrospective analysis of over 1000 patients treated with CYC (median dose 9 g, range 1.5 to 180) for autoimmune disease and vasculitis, CYC was administered exclusively intravenously in 91 percent, exclusively orally in 5 percent, and by both routes in 4 percent [64]. Hemorrhagic cystitis was associated with the cumulative CYC dose (hazard ratio [HR] 1.24 for each 10 g CYC increment, 95% CI 1.12-1.38). However, it only affected 17 patients (1.7 percent), and the incidence was similar in patients treated with and without mesna. Prevention of drug-induced cystitis in patients with systemic rheumatic diseases is discussed separately. (See 'Prevention of drug-induced cystitis' below.)
Another potential contributory factor for hemorrhagic cystitis in these patients may be BK polyomavirus (BKPyV), which is a common latent infection that may reactivate during immunosuppression, usually in the urogenital tract. In patients who have received a kidney transplant, BK virus is recognized as a cofactor in cases of drug-induced cystitis [65]. 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 [66,67]. The relationship between BKPyV and hemorrhagic cystitis is described in more detail elsewhere. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections", section on 'Hemorrhagic cystitis'.)
The incidence and prevention of hemorrhagic cystitis related to CYC in patients with cancer is described separately. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Cyclophosphamide'.)
Bladder cancer — Treatment with CYC confers an increased risk of developing secondary urothelial carcinoma of the bladder. As an example, in a retrospective study of 195 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who had previously received CYC, five patients (2.6 percent) developed bladder cancer over a median of eight years of follow-up, leading to a sex- and age-adjusted standardized incidence ratio of 4.3 (95% CI 1.4-10) over the expected rate [68]. In another study of 145 patients with GPA who received oral CYC for ≥1 year and who were followed for a median of 8.5 years, seven patients (5 percent) developed bladder cancer [62]. (See "Epidemiology and risk factors of urothelial carcinoma of the bladder", section on 'Cyclophosphamide'.)
Risk factors for the development of secondary bladder cancer in patients who receive CYC include the following:
●Cumulative CYC dose – The risk of bladder cancer is dose-related and approaches 5 to 10 percent by five years in patients receiving cumulative doses of CYC ≥30 g [69]. In the same cohort study of patients with ANCA-associated vasculitis described above, the risk of bladder cancer was not elevated in patients who received <10 g of CYC [68].
●Prior hemorrhagic cystitis – The risk of secondary bladder cancer also increases markedly after an episode of hemorrhagic cystitis [60]. In the study of patients with GPA described above, all patients who developed bladder cancer had previously experienced at least one episode of microscopic or macroscopic, nonglomerular hematuria [62].
The time from CYC exposure to diagnosis of bladder cancer is variable, with cases reported after as few as seven months after starting CYC therapy and as many as 15 or more years after discontinuing the medication [20,62,70]. In addition, urothelial carcinoma of the bladder related to CYC can be particularly aggressive [71]; in a study of 12 such cases, all tumors were grade 3 or 4 transitional cell carcinomas at presentation [71]. It is therefore important to consider regular surveillance for bladder cancer in patients who have received higher doses of CYC, which is discussed separately. (See "Screening for bladder cancer".)
Other malignancies — In addition to bladder cancer, patients with rheumatic diseases who use CYC also appear to have an increased risk of other malignancies, including leukemia, skin cancer, and cervical cancer [20,70,72-74]. While patients with rheumatic diseases may have an increased risk of certain malignancies due to the underlying disease itself, this risk appears to be compounded by the use of CYC. As an example, while all females with SLE are at high risk for developing cervical dysplasia, the risk is even higher for those with prior CYC therapy [34,75,76].
Patients who have used CYC may have a higher risk of malignancy due a combination of direct chromosomal damage from CYC and decreased immune surveillance in the setting of immunosuppression. The duration of CYC therapy is an important risk factor, with the incidence being greatest in patients treated for more than two to three years [70]. Key studies include the following:
●A population-based cohort study of 195 patients with ANCA-associated vasculitis who had received CYC therapy found higher than expected rates of malignancy over a median of eight years of follow-up [68]. The risk was highest for patients with a cumulative CYC dose of >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.
●In a cohort study that included 142 patients with GPA who had previously received CYC, 11 patients (7.7 percent) developed a myelodysplastic syndrome; the risk of developing a myelodysplastic syndrome was two times higher among patients who received a cumulative CYC dose of ≥100 g [61].
●Another study compared the incidence of myeloproliferative disease between a group of 119 patients with refractory rheumatoid arthritis who received oral CYC and a group of matched control patients with rheumatoid arthritis [70]. Various myeloproliferative diseases (eg, acute leukemia, non-Hodgkin lymphoma, and multiple myeloma) occurred in five patients who had received CYC within the first decade after treatment, compared with one case of chronic lymphocytic leukemia in the control group.
More information on therapy-related myeloid neoplasms and monitoring patients for malignancy is provided elsewhere. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and 'Monitoring' below.)
Hyponatremia due to SIADH — Intravenous pulse CYC can induce hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Since patients treated with intravenous CYC standardly receive intravenous fluids to prevent drug-induced cystitis, marked water retention and potentially fatal hyponatremia can occur [77]. SIADH has been described primarily with CYC doses in the range of 30 to 50 mg/kg, typical of those used to treat cancer; however, it can also occur with the somewhat lower doses (10 to 15 mg/kg) used to treat inflammatory disorders [77-80]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)
For patients who develop SIADH while taking CYC, hyponatremia can be minimized by using normal saline (or half normal saline in patients with edema) rather than free water to maintain a high urine output [80]. The management of SIADH is discussed in more detail elsewhere. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Therapies to raise the serum sodium'.)
Other adverse effects — Several other adverse drug effects can also be induced by CYC, including the following:
●Nausea – Nausea is common, especially with intravenous CYC [81]. Strategies to prevent this are discussed below. (See 'Prevention of nausea and vomiting' below.)
●Hair loss – Hair loss may occur with CYC, most commonly with a pattern of diffuse hair loss that is reversible upon drug discontinuation. In a systematic review of 21 trials of patients with idiopathic membranous nephropathy, 10 percent of patients who received CYC reported alopecia [18].
While hair loss from CYC ranges in severity from mild to substantial, the complete alopecia seen with higher doses of CYC used for chemotherapy is rare with the lower doses of CYC used to treat rheumatic diseases, especially when CYC is given for a circumscribed course (eg, three to six months). The prevention of alopecia related to high doses of CYC used for chemotherapy is discussed separately. (See "Alopecia related to systemic cancer therapy", section on 'Prevention of alopecia'.)
●Pulmonary fibrosis – Pulmonary fibrosis is a rare complication of CYC which is discussed in more detail elsewhere. (See "Cyclophosphamide pulmonary toxicity".)
●Cardiac toxicity – CYC can cause cardiac toxicity when used at higher doses to treat malignancy (see "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Cyclophosphamide'). Thus, for patients with rheumatic disease who require CYC and who have decreased myocardial contractility at baseline, we consider reducing the dose and carefully monitor cardiac function.
●Other rare adverse effects – Rarely, patients taking CYC may develop hepatotoxicity [82] and anaphylaxis [83]. (See "Hepatotoxicity of chemotherapy and other cytotoxic agents", section on 'Cyclophosphamide'.)
PRETREATMENT CONSIDERATIONS —
Our approach to the pretreatment evaluation and management of patients who anticipate beginning therapy with cyclophosphamide (CYC) is summarized in the algorithm (algorithm 1) and described in detail below.
Pretreatment testing — We typically perform the following studies prior to CYC therapy:
●Complete blood count (CBC) with differential.
●Serum creatinine and urinalysis.
●Liver function tests, including albumin.
●In females, a pregnancy test, preferably serum human chorionic gonadotropin (hCG) to increase the ability to identify a very early pregnancy.
●Serologic testing for hepatitis B and C infection. (See "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection".)
●Screening for latent tuberculosis with tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
●Screening for cervical cancer and human papilloma virus (HPV) infection in females. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states", section on 'Immunosuppressed patients without HIV'.)
Baseline testing can help identify relative contraindications to starting CYC therapy, such as significant neutropenia, severe hepatic dysfunction, and untreated latent infections. (See 'Relative contraindications' above.)
Reproductive health management
Fertility preservation for adults — The use of CYC is associated with a risk of gonadal dysfunction (see 'Gonadal dysfunction' above). Prior to treatment with CYC, we counsel patients with childbearing potential about the risks of infertility and, in females, premature menopause (primary ovarian insufficiency [POI]). Whenever possible, we also refer patients interested in having children to a reproductive endocrine and infertility specialist. Our approach to fertility preservation is outlined below:
●Males – Cryopreservation of ejaculated semen is usually the preferred fertility-preserving measure in males who require CYC, which is discussed in detail elsewhere and briefly summarized below. (See "Effects of cytotoxic agents on gonadal function in adult men", section on 'Semen cryopreservation'.)
We generally refer patients to a reproductive endocrinologist or urologist to help identify a sperm bank; often samples can be collected by appointment prior to the formal consultation. When feasible, we collect as many semen samples as possible (typically one to six) prior to the initiation of CYC. If the samples are not collected prior to CYC treatment, some experts recommend delaying sample collection to 6 to 12 months following CYC completion, since the risk of genetic anomalies in sperm is highest in the one to two weeks following CYC administration [84,85]. If the patient is not able to ejaculate, urologists can offer various procedures to extract sperm. Even limited sperm numbers with poor morphology can often be used to fertilize an egg with advanced reproductive health technology.
More information on assisted reproductive technologies involving cryopreserved semen is provided elsewhere. (See "Treatments for male infertility", section on 'Assisted reproductive technologies'.)
●Females – We discuss potential fertility preservation for all females receiving CYC, although the risk of POI varies based on the protocol used as summarized in the table (table 1) and explained in detail below.
•When to pursue fertility preservation – When deciding whether to recommend gonadotropin-releasing hormone (GnRH)-agonist therapy, we take into consideration the expected cumulative dose of CYC and the patient's age and future pregnancy goals. As an example, the cumulative dose (3 g) of CYC received in Euro-Lupus protocol does not appear to cause long-term ovarian damage in females with SLE [2,40]; thus, we typically counsel patients to pursue fertility preservation only if we expect that they will require multiple rounds of CYC over time or if they are over age 30 and therefore at higher risk for ovarian dysfunction. However, it is important to recognize that it is not possible to predict who may require additional courses of CYC therapy in the future and that individuals for whom intravenous CYC is chosen may be at particular risk for recurrent disease.
•Types of fertility preservation – Approaches to fertility preservation in females with rheumatic disease who require CYC include the following:
-Cryopreservation (preferred, but often not possible) – The optimal method for fertility preservation in females is cryopreservation of either ovarian tissue or of oocytes or embryos through ovarian stimulation, which is described elsewhere (see "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Cryopreservation'). However, these procedures are often not possible in seriously ill patients with rheumatic disease who require urgent initiation of CYC.
-GnRH agonist therapy (leuprolide) – When patients desire fertility preservation or wish to avoid POI from CYC but are acutely ill and cannot access, afford, and/or medically tolerate cryopreservation, the authors of this topic often use a GnRH agonist (ie, leuprolide) as an attempt to preserve fertility through ovarian suppression.
The dose and frequency of leuprolide varies based on which CYC protocol is being used. We use either 3.75 mg of leuprolide every 4 weeks or 11.25 mg of leuprolide dosed every 12 weeks, depending on insurance coverage and availability. For those receiving the three-month Euro-Lupus protocol, we administer 11.25 mg of leuprolide as a single dose, which will be effective for three months. We consider additional treatment if CYC is prolonged beyond the expected timeframe. Practice patterns vary for patients who do not have SLE.
Although it is ideal to give the initial GnRH-agonist dose 10 to 14 days prior to the initial CYC dose, most patients in this clinical scenario require urgent CYC administration; therefore, the GnRH agonist is often started 10 to 14 days before the second CYC dose. We avoid giving GnRH agonists and CYC on the same day, since the initial dose of GnRH typically overstimulates ovarian follicles and may therefore increase the degree of ovarian damage from CYC.
Limited data support the use of GnRH agonists in patients with rheumatic disease who require CYC. A meta-analysis indicated that patients who received GnRH with CYC were more likely to have preservation of ovarian function (94.6 versus 58 percent, odds ratio [OR] 10.3, 95% CI 4.8-36.3) [86]. Pregnancy rates also appeared higher with GnRH agonist use (22 in 103 patients versus 6 in 75 patients). However, the quality of these data is low and thus the efficacy of GnRH agonists remains controversial [87]. Other experts, including other UpToDate contributors, do not use GnRH agonists for fertility preservation. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Role of GnRH agonist'.)
Contraception — CYC is associated with teratogenicity, and patients taking CYC may still conceive a pregnancy despite the risk of CYC-induced gonadal dysfunction (see 'Teratogenicity' above). We therefore counsel patients with rheumatic diseases who require CYC therapy about these risks and how to practice reliable methods of contraception. Counseling patients on contraceptive options in the context of CYC therapy is summarized below and discussed in detail elsewhere (see "Contraception: Counseling and selection"):
●Males – Since CYC can cause genetic changes in sperm, several groups recommend that males taking CYC avoid conceiving a pregnancy while taking the medication and in the 90 days following treatment.
●Females – We carefully, clearly, and repeatedly counsel female patients of childbearing potential about the potential to become pregnant while taking CYC, even in the absence of menses, and the potential teratogenicity of CYC. We document these discussions appropriately in the medical record.
We advise patients to use reliable forms of contraception for three to six months after cessation of CYC administration. In addition, we encourage patients who require >3 months of CYC infusions to choose a type of long-acting reversible contraceptive (LARC; eg, an intrauterine devices [IUD] or implantable progesterone), as these are more effective than other types of contraception. Some patients may be too ill to institute contraception at the time of initial drug administration, in which case the issue must be addressed as soon as possible.
The approach to contraception in females with systemic lupus erythematosus (SLE) is presented separately. (See "Approach to contraception in women with systemic lupus erythematosus", section on 'Long-acting reversible contraception'.)
Preventive vaccinations — Prior to the institution of CYC, we advise that all patients receive appropriate immunizations as outlined in the table (table 2) and discussed in detail elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Prophylaxis for Pneumocystis jirovecii pneumonia — Patients who are receiving CYC have an increased risk of opportunistic infections, particularly Pneumocystis jirovecii (carinii) pneumonia (PCP) (See 'Infection' above.) The authors provide P. jirovecii prophylaxis to all patients with rheumatic diseases who require CYC; however, this practice is best supported in individuals with leukopenia, ANCA-associated vasculitis, and/or concomitant, prolonged use of glucocorticoids (equivalent to ≥20 mg of prednisone daily for one month or longer) [88-90]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)
Options for PCP prophylaxis are outlined in the table (table 3). While trimethoprim-sulfamethoxazole (TMP/SMX) is commonly used, alternative options may be preferable for patients with SLE who have not previously demonstrated tolerance of TMP/SMX given a higher risk of adverse reactions to sulfonamides in this population. More information on choice, dosing, and efficacy of prophylactic therapy is provided elsewhere. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
INTERMITTENT (PULSE) CYCLOPHOSPHAMIDE (MOST COMMON) —
Intermittent (pulse) cyclophosphamide (CYC) therapy is given intravenously at specified intervals (eg, every two to four weeks). This approach is favored over daily CYC dosing for most patients with rheumatic disease since it offers several notable advantages, including a comparatively lower cumulative CYC dose and therefore a lower risk of potential drug toxicities. (See 'Principles of use' above.)
Choice of care setting — Stable patients may be able to receive intermittent intravenous CYC safely in the outpatient setting. However, we favor inpatient administration for patients with comorbid conditions that may limit their tolerance of the typical protocol for intermittent CYC administration, including the following:
●Heart failure and/or severe pulmonary hypertension that limit the ability to tolerate required pretreatment hydration
●Severe nephrotic syndrome or lower urine output (ie, <100 mL/hour) that limits the ability to protect the bladder through brisk urine output
●Frailty or other conditions that limit the ability to tolerate moderate nausea
Continuous bladder irrigation through a three-way Foley catheter may be required for bladder protection in patients with inadequate urine output (see 'Prevention of drug-induced cystitis' below). The use of such catheters, as well as aggressive use of diuretics, is more feasible in the inpatient setting.
Critically ill patients in the intensive care unit who have a decreased level of consciousness and/or who require mechanical ventilation are still candidates for intermittent CYC. However, particular attention should be given to measures for bladder protection in such cases. (See 'Prevention of drug-induced cystitis' below.)
Dosing — The dosing and frequency of intermittent intravenous CYC can vary depending on the specific disease as well as provider experience and practice style. Below, we present general principles regarding dosing of intravenous CYC for systemic rheumatic diseases. A detailed discussion of the dosing regimens for intravenous CYC in several specific diseases are presented separately. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Cyclophosphamide' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'.)
Euro-Lupus protocol — The Euro-Lupus protocol is a lower-dose CYC regimen that results in similar efficacy to higher-dose protocols for the treatment of lupus nephritis (LN) with fewer adverse effects. CYC is given intravenously at a dose of 500 mg every two weeks for six doses. The dose may be reduced by approximately 25 percent for patients with significant kidney insufficiency and/or a very low white blood cell count (WBC). The approach to prevention of adverse effects during the infusion and laboratory monitoring is summarized in the table (table 1) and discussed in detail below. (See 'Prevention of adverse effects' below and 'Laboratory monitoring during cyclophosphamide therapy' below.)
NIH protocol — A higher-dose CYC regimen was initially published by the National Institute of Health (NIH) to treat granulomatosis with polyangiitis [91]. The authors reserve this NIH protocol for patients with severe, life-threatening disease.
●Initial dose – In patients with normal kidney function, the recommended initial dose of intermittent CYC is typically in the range of 750 to 1000 mg/m2 of estimated total body surface area (BSA). The initial CYC dose may need to be adjusted for various factors (eg, kidney function, drug interactions, concern for infection). (See 'Factors requiring dose adjustment' below.)
The approach to prevention of adverse effects during the CYC infusion and laboratory monitoring is summarized in the table (table 1) and discussed in detail below. (See 'Prevention of adverse effects' below and 'Laboratory monitoring during cyclophosphamide therapy' below.)
●Subsequent doses – We adjust subsequent CYC doses based upon the patient's response to therapy and the nadir of the WBC count. The nadir of the absolute lymphocyte count (ALC) typically occurs around day 7, followed by a nadir of the absolute neutrophil count (ANC) at day 14 [7]. Thus, for patients who receive CYC every four weeks, we typically check a complete blood count (CBC) around 10 to 14 days after the previous infusion to facilitate any necessary dose adjustments, and again on the day of infusion to ensure that there is not any significant residual bone marrow suppression from the previous dose. (See 'Laboratory monitoring during cyclophosphamide therapy' below.)
Dose adjustment for subsequent CYC doses based on the WBC are as follows:
•ALC <3500/mm3 and/or ANC <1500/mm3 – For such patients, we reduce the subsequent CYC dose by 20 to 25 percent.
•WBC >4000/mm3 and no significant toxicity – For such patients, the subsequent CYC dose may be increased by 20 to 25 percent. Some experts recommend a maximum CYC dose of 1 g/m2 BSA; however, this dose limit may be too low, particularly if calculations are based on lean body weight.
In addition, patients may need adjustment of subsequent doses based on changes in kidney function and/or new drug interactions, as is done for the initial dose.
Most patients receive intermittent CYC to induce remission and transition after three to six months to an alternative, less toxic immunosuppressive agent to maintain remission (see 'Principles of use' above). However, historically, the NIH protocol included monthly CYC pulses for six months followed by pulses every three months for an additional 18 months [91].
Factors requiring dose adjustment — The CYC dose may need to be adjusted for multiple factors including impaired kidney function, drug interactions, obesity, and advanced age:
●Impaired kidney function – CYC dosing should be adjusted for kidney function (as estimated by a calculated creatinine clearance). Recommendations for dose adjustment in patients with more severe kidney dysfunction are varied and not evidence-based. In the setting of kidney failure, the extent of dose reduction may also be influenced by the acuteness and severity of the rheumatic disease.
●Drug interactions – Before starting patients on CYC therapy, we carefully analyze their medication regimen for potential drug interactions, especially when initiating and adjusting therapy. This can be done using the drug interactions program included within UpToDate.
Examples of potentially significant CYC drug interactions include:
•Drugs that alter P450 enzyme activity – CYC must be converted to its active form (4-hydroxycyclophosphamide) by several cytochrome P450 enzymes in the liver, including CYP2B6 (see 'Pharmacology' above). These hepatic microsomal enzymes may be induced by certain medications (eg, carbamazepine, barbiturates, phenytoin, rifampin), leading to accelerated CYC metabolism and a subsequent increase in both the pharmacologic and toxic effects of CYC [92,93]. Conversely, these enzymes may be inhibited by other drugs (eg, clopidogrel, desipramine, paroxetine, sertraline), causing delayed CYC metabolism with a decrease in both therapeutic and adverse effects.
•Anticholinergic agents – Tricyclic antidepressants and other anticholinergic agents delay bladder emptying and may lead to prolonged bladder exposure to toxic CYC metabolites.
•Allopurinol – Allopurinol appears to increase systemic exposure of CYC's toxic metabolites by altering liver metabolism or renal excretion; however, studies of this interaction have yielded inconsistent results [94-96].
•Succinylcholine – CYC reduces plasma pseudocholinesterase activity; thus, coadministration or subsequent use of succinylcholine may lead to prolonged neuromuscular blockade [97-99]. Anesthesiologists should be aware of recent CYC treatment prior to administering succinylcholine.
●Obesity – For patients with obesity (defined as a body mass index [BMI] ≥30 kg/m2), there is controversy over whether intermittent CYC dosing should be calculated on total versus ideal body weight, as theoretically the former approach may expose patients to a greater risk of toxicity. The authors use total rather than ideal body weight for patients with obesity; however, they do not include body weight related to fluid retention.
Studies of patients with malignancy who require CYC suggest that the use of total body weight to calculate intermittent CYC dosing is not associated with an increased risk of febrile neutropenia [100]. Our approach is consistent with reviews and guidelines for the use of CYC to treat malignancy, which outline the use of total body weight or partially adjusted toward lean body weight [101,102].
●Advanced age – Some older adults (≥70 years) who are taking intermittent CYC may benefit from dose reduction to decrease their risk for infection.
Prevention of adverse effects — Patients who receive intermittent CYC therapy are typically given hydration, antiemetics, and sometimes mesna around the CYC infusions.
Prevention of drug-induced cystitis — In order to minimize the time that the bladder is exposed to the toxic CYC metabolite acrolein, we hydrate patients, carefully monitor urine output and bladder emptying, and, for selected patients, administer mesna. This approach is summarized in the table (table 1) and explained in more detail below.
●Maintain adequate hydration – For most patients receiving CYC, we give 1 to 2 liters of half-normal to normal saline, preferably starting approximately 30 minutes prior to infusion. The type and volume of intravenous fluid should be adjusted based on the individual patient’s comorbidities. As examples, we may use a reduced volume and lower salt concentration for patients with heart failure or kidney insufficiency, and a higher salt concentration for those who develop syndrome of inappropriate antidiuretic hormone secretion (SIADH) from the CYC (see 'Hyponatremia due to SIADH' above). When CYC is given in the outpatient setting, we also encourage oral hydration for 24 hours before the infusion and then consumption of at least 1 liter of fluid every six to eight hours for the subsequent 24 hours.
Although vigorous hydration is regarded as a standard of care for bladder protection, it has never been formally evaluated in studies using CYC for the treatment of rheumatic diseases.
●Ensure adequate urine output and bladder emptying – Some patients may be unable to make sufficient urine to maintain an adequate output (>100 mL/hour) despite ensuring adequate hydration. Diuretic therapy (eg, furosemide) may be required, especially in patients with cardiopulmonary disease or kidney dysfunction who develop volume overload related to hydration.
If patients are unable to make sufficient urine, they should be evaluated for possible urinary retention, which would require the placement of a foley catheter. More rarely, patients may require continuous bladder irrigation through a three-way foley catheter if they are simply unable to produce adequate urine. The diagnosis of acute urinary retention and placement of urinary catheters are discussed in more detail elsewhere. (See "Acute urinary retention" and "Placement and management of urinary catheters in adults".)
●Use mesna – Mesna (2-mercaptoethane sodium sulphonate) is a thiol compound that inactivates acrolein in the urine to minimize the risk of bladder toxicity from alkylating agents like CYC (see "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Mesna'). For patients receiving intermittent CYC, we also give mesna during their CYC infusion. The dose of mesna is equal to 20 percent of the CYC dose and is administered intravenously twice: 15 to 30 minutes prior to the CYC infusion, and then several hours after the CYC infusion. For patients receiving the Euro-Lupus protocol, mesna is reserved for patients at risk of poor hydration or bladder emptying.
Occasionally, patients develop allergic rashes after mesna [103]; in our experience, this is most often a reaction to mesna rather than CYC, although allergic reactions to CYC have been reported [104].
There is a lack of direct evidence to support the efficacy of mesna to prevent cystitis in patients receiving CYC for rheumatic diseases and practice patterns vary. A retrospective study with over 1000 patients treated with CYC for rheumatic diseases found a similar incidence rate of 1 to 2 percent of hemorrhagic cystitis in patient groups concomitantly treated with or without mesna [64]. However, randomized trials have demonstrated the efficacy of mesna in reducing the risk of bladder injury in cancer patients receiving high-dose CYC and other alkylating agents [105-107]. Since it is not possible to prospectively identify patients who will require repeated CYC treatments and ultimately have a high cumulative exposure to CYC, we often favor using mesna based on its favorable safety profile and potentially protective effect.
Prevention of nausea and vomiting — We typically give a dose of an antiemetic (eg, ondansetron 8 mg disintegrating tablets) approximately 30 minutes before the dose of CYC to prevent nausea and repeat after the infusion as needed for nausea and/or vomiting. The NIH CYC protocol is moderately emetogenic, whereas the Euro-Lupus protocol is much less so. Prevention of nausea and vomiting during and for the first 48 hours after the initial dose of CYC helps prevent anticipatory emesis, which is a conditioned response of nausea during chemotherapy that can persist with subsequent treatments.
Monitoring
Laboratory monitoring during cyclophosphamide therapy — For patients who are actively taking CYC, we regularly obtain the following laboratory testing to monitor for development of various drug-related toxicities, as outlined in the table (table 1) and summarized below:
●Complete blood count (CBC) and differential – We check a CBC with differential on the day of drug administration. For patients receiving the NIH protocol, we check another CBC with differential approximately 10 to 14 days after the infusion to facilitate adjustment of subsequent doses. (See 'NIH protocol' above.)
●Kidney and liver function – We check serum creatinine, urea nitrogen, electrolytes, and serum aminotransferases every month. Changes in kidney function may necessitate adjustment of the CYC dose. (See 'Factors requiring dose adjustment' above.)
●Urinalysis – We check urinalyses every month.
●Serum human chorionic gonadotropin (hCG) – In females of childbearing potential, we check a serum hCG prior to every CYC infusion; we hold the infusion if the test is positive.
Patients with hematuria require further evaluation; the presence of blood on dipstick should prompt a microscopic examination of the urine sediment. If the presence of hematuria is confirmed and there are not clinical findings that strongly suggest glomerulonephritis, then most patients require prompt cystoscopy to evaluate for alternative etiologies including drug-induced cystitis, premalignant changes in the bladder epithelium, and development of frank bladder cancer. More information on the evaluation of hematuria and diagnosis of bladder cancer is provided separately. (See "Evaluation of hematuria in adults" and "Clinical presentation, diagnosis, and staging of bladder cancer".)
It is important to note that some patients may have baseline hematuria related to their underlying rheumatic disease (eg, kidney involvement from vasculitis or systemic lupus erythematosus [SLE]). In such cases, an increase in hematuria is more likely to reflect bladder toxicity when there is no other evidence of increased activity of the underlying disease (ie, no worsening in kidney function, no cellular casts or dysmorphic cells on urinalysis, and no signs or symptoms of active systemic disease). More information on monitoring kidney disease for patients with LN is provided elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Monitoring response to therapy'.)
Screening for malignancy — Once patients have discontinued CYC therapy, we continue to check a urinalysis annually and obtain urine cytology if hematuria is present. However, there is inadequate evidence to determine the optimal approach to screening for bladder toxicity after CYC use, and we typically do not obtain these tests for patients who received a single round of the Euro-Lupus CYC protocol. (See "Screening for bladder cancer".)
Given the increased risk of various types of malignancy in patients who have received CYC, we encourage patients to obtain regular, routine cancer screening, as outlined elsewhere. (See "Overview of preventive care in adults", section on 'Cancer screening'.)
DAILY CYCLOPHOSPHAMIDE (UNCOMMONLY USED) —
Historically, daily oral cyclophosphamide (CYC) was used to treat severe rheumatic disease prior to the advent of intravenous, pulse-dosing CYC regimens and newer, safer, immunosuppressive agents. Daily oral dosing results in cumulative doses that are approximately three times higher than intravenous regimens, with patients receiving 30 to 150 g of CYC over their lifetime. This frequently causes significant long-term adverse effects, including infertility, hemorrhagic cystitis, and bladder and hematologic malignancies.
When oral CYC was used more commonly, it was typically started at a dose of 1 to 1.5 mg/kg per day and increased to 2 mg/kg per day, up to a maximum dose of 200 mg per day. The dose was then adjusted down if the white blood cell (WBC) or neutrophil counts dropped significantly. Aggressive oral hydration was encouraged to decrease the risk for bladder toxicity. Laboratory monitoring was essential with frequent assessments of complete blood count (CBC) and differential, kidney function, and urinalysis. Annual urine cytology was recommended to monitor for bladder cancer.
SUMMARY AND RECOMMENDATIONS
●Principles of use – Cyclophosphamide (CYC) can rapidly control a variety of rheumatic diseases. However, due to drug-related toxicities, it is generally reserved for patients with severe disease manifestations and/or resistance to less toxic immunosuppressive medications. Strategies to reduce cumulative CYC exposure and minimize the risk of toxicity include using intermittent intravenous CYC, rather than daily oral therapy, and transitioning to alternative immunosuppressive agents once the patient has achieved remission. (See 'Principles of use' above.)
●Relative contraindications – Relative contraindications to the use of CYC include active infection, neutropenia, severe hepatic impairment, history of hemorrhagic cystitis, inadequate contraception, and pregnancy or lactation. (See 'Relative contraindications' above.)
●Adverse effects – The principal short-term adverse effects associated with CYC use include cytopenias, infections, teratogenicity, hemorrhagic cystitis, and hyponatremia. Long-term concerns include gonadal dysfunction and induction of various types of malignancy, including bladder cancer. (See 'Adverse effects' above.)
●Pretreatment considerations – Our approach to the pretreatment evaluation and management of patients who anticipate CYC therapy is summarized in the algorithm (algorithm 1). (See 'Pretreatment considerations' above.)
•Fertility preservation – We counsel patients about their risk of gonadal dysfunction based on their anticipated cumulative dose of CYC and age. For adults who desire fertility preservation, cryopreservation is the standard approach. For adult females who cannot use cryopreservation (eg, due to critical illness), we use a gonadotropin-releasing hormone (GnRH) agonist (ie, leuprolide), although opinions on the efficacy of this approach vary. (See 'Fertility preservation for adults' above and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
•Contraception – Patients taking CYC, even amenorrheic females, may still conceive. We therefore advise all patients to use reliable forms of contraception. (See 'Contraception' above.)
•Preventing infections – When possible, we advise that all patients receive appropriate immunizations prior to the institution of CYC (table 2) and provide Pneumocystis jirovecii prophylaxis. (See 'Preventive vaccinations' above and 'Prophylaxis for Pneumocystis jirovecii pneumonia' above.)
●Intermittent (pulse) CYC – Giving CYC intravenously at specified intervals exposes patients to a lower cumulative dose compared with daily oral therapy. (See 'Intermittent (pulse) cyclophosphamide (most common)' above.)
•Dosing – Dosing varies by specific disease as well as provider experience and practice style. The two most common regimens are the Euro-Lupus protocol and the National Institute of Health (NIH) protocol (table 1); the Euro-Lupus protocol involves a relatively lower cumulative dose of CYC. Dosing may need to be adjusted for multiple factors including impaired kidney function, drug interactions, obesity, and advanced age. (See 'Dosing' above.)
•Prevention of adverse effects and drug monitoring – Intravenous fluids, mesna, and antiemetics can prevent hemorrhagic cystitis and nausea, and we routinely obtain laboratory testing to monitor for various drug-related toxicities (table 1). (See 'Prevention of adverse effects' above.)
●Daily CYC – While daily oral CYC was used historically, it has largely been replaced by intermittent CYC regimens and alternative immunosuppressive agents. (See 'Daily cyclophosphamide (uncommonly used)' above.)
