|Ahead of print publication
Safety of Cyclophosphamide Therapy in Autoimmune Rheumatic Diseases
Ramaswamy Subramanian1, Himanshu Pathak2, Vinod Ravindran3
1 Department of Rheumatology and Immunology, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
2 Department of Rheumatology, Tricolour Hospitals, Vadodara, Gujarat, India
3 Centre for Rheumatology, Calicut, Kerala, India
Centre for Rheumatology, Calicut, Kerala
Source of Support: None, Conflict of Interest: None
Cyclophosphamide (CYC) is one of the most potent antineoplastic and immunosuppressant agents. It is used as a drug of choice in many organ-threatening manifestations of systemic autoimmune rheumatic diseases (AIRDs) such as lupus nephritis, antineutrophil cytoplasmic antibody-associated vasculitis, classical polyarteritis nodosa, and myositis. It is also used in connective tissue disease-related interstitial lung disease and Behcet's disease. However, its use may be limited by the toxicities including its adverse effects on gonads in the childbearing age group, severe infections, hemorrhagic cystitis, and malignancies associated with prolonged usage. As a result, mycophenolate, azathioprine, and rituximab have gained popularity over CYC as an induction and maintenance agent in many AIRDs. However, in the event of failure of aforementioned agents in aggressive rheumatic diseases or in a resource-limited setting, the usage of CYC continues to be a useful therapeutic strategy. In this review, we have appraised the adverse effects of CYC therapy in AIRDs which would help clinicians in taking informed decisions regarding CYC usage.
Keywords: Cyclophosphamide, gonadal failure, hemorrhagic cystitis, immunosuppressants, lupus nephritis
| Introduction|| |
Cyclophosphamide (CYC) is now an established drug for major organ dysfunction in many autoimmune rheumatic diseases (AIRDs) and has been recommended in many treatment guidelines.,,, It is an alkylating agent which has an effective antineoplastic activity and strong and sustained immunosuppressive effect. As a prodrug, CYC gets converted into aldophosphamide by several P450 enzymes in the liver. Aldophosphamide transports freely into the somatic and germ cells where it is converted into active phosphoramide mustard and acrolein by the process of beta-elimination. Phosphoramide mustard is the main cytotoxic metabolite which works by introducing alkyl radicals into DNA strands leading to interference in DNA replication by forming DNA cross-linkage. Cellular concentrations of aldehyde dehydrogenase (ALDH); an enzyme causing detoxification of CYC is responsible for many of the differential activities of CYC in the cell. ALDH1A1 is a major isoform of ALDH, responsible for detoxification of CYC, and cells with a higher concentration of ALDH1H1 (liver, intestinal mucosa, and hematopoietic stem cells) are relatively resistant to CYC toxicity. CYC depletes lymphocytic activity in both peripheral and central lymphoid tissues and diminishes macrophage response because of limited formation of monocyte precursors., It is capable of inhibiting both, humoral and cell-mediated immune response. Through the actions on rapidly diving somatic cells, germ cells, immune cells, and hematopoietic cells, CYC has the potential to cause multiple systemic side effects [Table 1]. Both intravenous and oral CYC get absorbed rapidly, and with many studies demonstrating similar efficacy of both intermittent pulse intravenous CYC and oral therapy, oral CYC therapy in rheumatic diseases is now almost redundant.
To appraise the documented toxicities of CYC therapy in systemic AIRDs, we searched the available literature by the screening of primary sources MEDLINE (1966 to date) and Old MEDLINE (1949–1965) using the PubMed interface, as well as secondary sources, the Embase and Cochrane library without any time limits. Appropriate combinations of search terms including “rheumatic” “autoimmune,” “CYC,” “adverse effects,” “toxicities,” and the names of individual known side effects of CYC were used with limits”(English, Human, Animal).” Relevant keyword variations for different databases were used. This was supplemented by a manual search of bibliographies of these articles and of previously published reviews and animal studies. However, the focus was on articles published since 1980, but commonly cited and highly regarded older publications were not excluded.
In view of variable reporting, design and scope of the studies and reports found in the literature, we did not formally evaluate the quality of the studies and chose to present our findings by way of a narrative review. [Table 2] provides information relevant extracted from all available randomized controlled trials (RCTs) and retrospective case series, which highlights the aforementioned tremendous heterogeneity. These studies confirm variable safety profile of CYC therapy [Table 2]. Although in these studies, CYC adverse effects were quite widespread, affecting almost all major organs, there were multiple confounding factors associated with them such as total dosages of CYC, concomitant immunosuppressive therapies, mode of administration (IV or oral), duration of administration, and type of autoimmune rheumatic disorder. It must be appreciated that not all studies addressed CYC-related gastrointestinal toxicity, cardiac toxicity, urogenital toxicity, and pregnancy outcomes, which may be of relevance in daily clinical practice. Although, overall, based on the available studies, it can be concluded that CYC is generally well tolerated and side effects can be adequately managed by following available guidelines[Table 3], we provide more detailed analysis of key adverse events below.
|Table 2: Randomized controlled trial and retrospective studies in autoimmune rheumatic diseases with cyclophosphamide safety data|
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|Table 3: Measures to reduce toxicity and enhance safety of cyclophosphamide therapy|
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| Adverse Effects on the Reproductive System|| |
Animal studies have shown clear evidence that CYC causes injury to germ cells and induction of transmissible genetic damage. In addition to premature menopause and sterility, CYC usage in pregnancy increases frequency of abortions, birth defects, genetic, and neoplastic diseases in the offspring.
The number of germ cells is limited, fixed since the fetal life, and cannot be regenerated. Cytotoxicity of CYC is cell cycle nonspecific and affects mostly mitotically active cells. CYC-induced infertility and premature menopause depends on the age of start of therapy and cumulative doses of CYC received. The incidence of gonadal failure in CYC-treated groups for systemic lupus erythematosus (SLE) patients ranges from 19% to 45%. CYC use can lead to premature ovarian failure (POF). Antiovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role remain questionable., The follicular pool reserve, which diminishes as age advances, the degree of neutropenia, and the cumulative dose of CYC, all tend to correlate with CYC-induced infertility. Recommencement of menstrual cycle alone may not corroborate to the return of fertility in CYC-treated female patients. However, prolonged duration of amenorrhea seemed to correlate with POF.
In a retrospective study involving 274 patients of SLE by Mok et al., logistic regression analysis showed that age of initiation and cumulative dosages of CYC were independent risk factors for CYC-induced ovarian failure. Anti-Mullerian hormone (AMH) is shown to sustain the ovarian reserves by its effects on the size of primordial follicle pool and transition of primordial follicles to growing follicle. Low AMH levels before CYC treatment may suggest high possibility of CYC-induced ovarian toxicity. A recent research showed no changes in AMH levels in lupus nephritis patients when treated with low-dose Euro-Lupus protocol with IV CYC cumulative dose <3 g (500 mg every 2 weeks for 3 months) when compared with high-dose National Institute of Health protocol with IV CYC cumulative dose >3 g (0.5 mg – 1 g/m2 monthly for 6 months). The cumulative dose up to 6 g was shown to be gonadal safe (normal AMH levels). The mean ± standard deviation time interval between the last IV CYC treatment and measurement of serum levels of AMH was 7 ± 5 years. The possibility of pretreatment with gonadotrophin (GnRH) analogs to preserve the gonadal function during cytotoxic therapy is also been explored. GnRH analogs have been shown to be of some benefit in smaller studies, but long-term randomized control trials are lacking. Studies in prepubertal patients receiving CYC have shown protection of gonadal functions with adjuvant testosterone therapy in males and triptorelin (GnRH analogue) in females. In the absence of proven alternatives, GnRH analogs (depot leuprolide acetate 3.75 mg once a month 10 day before CYC bolus with transdermal estrogen patch every 4 weeks and quarterly doses of depomedroxyprogesterone acetate) has been tried with some success, and current EULAR guidelines advice this to be considered for ovarian function preservation. Generally, GnRH analogs are advised to be started before or concomitantly with CYC therapy. A recent RCT in young females with lupus suggested starting GnRH injections 22 days before the start of IV CYC or about 4–6 days after CYC infusion during ongoing monthly cycles. The rationale behind it is that GnRH injection requires 22 days to completely suppress ovarian functions thus providing protection against CYC toxicity.
Although far fewer studies have been conducted on men receiving CYC, men also seem to experience a high risk of infertility. In a study of 30 men treated with CyC, 4 developed azoospermia and 9 oligospermia after a mean follow-up of 12. 8 years. There is a paucity of literature regarding the usage of GnRH analogs in males for fertility preservation. Testicular tissue banking or testicular tissue cryopreservation can be considered if sperm banking is not available, but this technique still requires the development of standardized protocols.
CYC causes teratogenicity and should be avoided in the first trimester of pregnancy. Congenital deformities noted are multiple skeletal deformities, low set ears, cleft palate, and eye abnormalities. Use during second and third trimester is associated intrauterine growth retardation, small for gestational age, hearing defects, neonatal pancytopenia, and craniofacial deformities.
| Malignancies|| |
The risk of malignancies in rheumatic diseases is compounded by factors such as tissue alteration, chronic lymphocytic stimulation, and the effect of other immunosuppressive drugs. A prospective study of idiopathic membranous nephropathy treated with oral CYC showed a three-fold increase in the risk of cancer during period of 10–15 years follow-up; however, average treatment duration and total accumulative CYC dosages were not clearly mentioned. Leukemias, solid organ malignancies (lung, colon, rectal, and renal), and skin cancers have been described along with bladder cancers and acute leukemias; skin cancers being the most common among all.,, Development of malignancies following CYC use is based on the duration of exposure and the cumulative doses of CYC. A longitudinal cohort study done on patients with refractory rheumatoid arthritis, who were given oral CYC, has shown that bladder malignancies occur more with a higher cumulative dose (>80 gm), and malignancy rates were similar in cases and controls roughly till 6 years of follow-up; after that, CYC group had higher rate of cancers. A study linking Danish cancer registry to 293 granulomatosis with polyangiitis patients from 1973 to 1999 and followed through 2010, showed an increased incidence of nonmelanoma skin malignancy, bladder cancer, and myeloid malignancy in CYC-treated cohort. CYC cumulative dose more than 36 g was associated with more malignancy while cumulative dosages <36 g were associated with only nonmelanoma skin malignancy. The malignancy risk remained high in the follow-up period of more than 10 years in comparison to CYC-naïve patients. In antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, as the cumulative CYC dosages used for remission induction is in the range of 10–25 gm, there may not be a significantly higher risk of future malignancy except nonmelanoma skin malignancy, as suggested by above observations.,
Acrolein, the inactive metabolite of CYC, is postulated to be the cause of cystitis and bladder cancer with CYC usage. Both squamous cell carcinomas and transitional cell carcinomas can occur and later being more common. The cumulative oral dosages, erratic bladder evacuation, and inadequate hydration add to the risk of CYC-induced bladder toxicity. Age and background history of smoking are additional confounders for the development of bladder cancers., The patients having documented hemorrhagic cystitis have higher risk of bladder cancer; however, the association is not reported to be strong in the published literature. Intermittent pulse intravenous use of CYC with lesser cumulative dose has shown lesser incidence of hemorrhagic cystitis and bladder cancer.,
Mesna decreases the incidence of cystitis and bladder cancer by counteracting the toxic effects of acrolein. It combines directly with the double bond of acrolein as well as other urotoxic 4-hydroxyoxazaphosphorine metabolites. Mesna does not protect against nonurologic toxicities associated with the oxazaphosphorines (CYC and ifosfamide). The recommended dosing of IV mesna is a total dose equal to 20% (weight/weight) of the total CYC dose, in the form of 3 equal doses of mesna, with the first dose administered 15–30 min before CYC infusion and the others administered 4 h and 8 h following CYC. The dosages of mesna needed to be increased to 40% of the total CYC dose if given orally. However, it is interesting to note that the American Society of Clinical Oncology does not recommend the routine use of mesna for patients receiving CYC and states that mesna should be used only in conjunction with the administration of high-dose CYC, typically defined as 50 mg/kg or 2 g/m2. Such high doses of CYC are not used in rheumatology practice.
| Infections|| |
Infection is known to alter the course of many AIRDs and is a major concern with the use of any type of immunosuppressive therapy. The incidence of bacterial and nonbacterial infections across CYC studies varies and is confounded by age, the extent of organ involvement, demographics, and concomitant drug usage. The cumulative doses of steroids and prior nadir white blood cell (WBC) counts are also significantly associated with an increased risk of infection in SLE patients.,
With CYC usage, infections reported are bacterial infections, herpes zoster, fungal, and some opportunistic infections., Oral and IV CYC appears to pose a similar risk for infections. Both sequential IV and oral CYC substantially increase the risk of infections. Multiple organ involvement of rheumatic disease, cumulative corticosteroid dose at the time of infection rather than the point dosage of the steroids at the time of infection, and prior WBC nadir (<3000) are significantly associated with an increased risk of infection in a multivariate analysis of patients with lupus nephritis. CYC has revolutionized the outcome of systemic necrotizing vasculitis with increased rates of complete remission of up to >80%, compared to a 5-year survival of 48% with steroid usage alone., Intravenous or oral CYC use increases Pneumocystis jiroveci infection risk and guidelines advice prophylaxis use of trimethoprim-sulfamethoxazole one double-strength tablet thrice a week., The infection may not be related to the dosage or the total duration of CYC therapy, and the “threshold” neutrophil count for development of infection remains unclear.
In a longitudinal study of SLE patients, the rates of serious infection and mortality did not differ among new users of MMF, AZA, or CYC. In Scleroderma Lung study 1, 145 patients were given daily oral CYC (1–2 mg/kg) for 6 months at least. At 2-year follow-up, the incidence of pneumonia was higher in CYC arm than placebo arm, but it was not statistically significant. Scleroderma Lung study 2 compared 2 years of MMF with 1 year of oral CYC. At the end of study period, the infection rates (pneumonia) were comparable in MMF and CYC treatment arms. Long-term follow-up (18 months) of CYCLOPS study comparing oral and IV CYC in ANCA vasculitis did not show much difference in the occurrence of severe infection rate (25% vs. 28%) in both treatment arms.
| Hematotoxicity|| |
CYC can induce bone marrow suppression resulting in neutropenia, lymphopenia, thrombocytopenia, and anemia. Hematotoxicity is generally dose dependent and requires close monitoring. As hematopoietic stem cells have high levels enzyme ALDH1A1 which is a key intracellular enzyme responsible for CYC inactivation as described above, hematopoietic stem cells are relatively resistant to side effects of CYC. On the contrary, mature progenitor blood cells and lymphocyte subsets are very sensitive to CYC toxicity as they have low levels of ALDH1A1. A randomized control trial of maintenance therapy in ANCA vasculitis comparing CYC and AZA therapy did not show a significant difference in hematotoxicity between two therapies. A systematic review of CYC and MMF in lupus nephritis showed less leukopenia with MMF, but risk of infections and renal dysfunctions were not significantly different. Elderly age group and renal impairment increase CYC-associated hematotoxicity. Amifostine has been used concurrently with CYC to prevent marrow suppression with some success in oncology practice.
| Other Toxicities|| |
Cardiac toxicity associated with CYC is widely reported in oncology and considered to be dose related. It is not frequently seen with CYC treatment protocols used in AIRDs. Direct damage to the capillaries and endothelial stress-related mechanisms together with the formation of hyaline thrombi has been implicated in the pathogenesis of CYC-induced cardiac toxicity. Common manifestations include tachyarrhythmias, hypotension, heart failure, myocarditis, and perimyocarditis. The incidence of acute heart failure has been reported between 7% and 33% of patients receiving a total dose of more than 150 mg/kg CYC. Goldberg et al. showed that CYC dose per body surface area of more than or equal to 1.55 g/m2 produces significant cardiac toxicity. Diuretics, ACE inhibitors, extracorporeal membrane oxygenation, and mechanical circulatory support have been used in severe cases.Hepatotoxicity following low-dose CYC therapy has been rarely reported, and induction of sinusoidal obstruction syndrome has been postulated. The liver injury often spontaneously recovers.
Nausea and vomiting are dose related and usually occur 6–10 h after IV CYC therapy. CYC causes 4-fold more risk of alopecia in comparison to MMF, but nausea and hyperglycemia risk are similar. Prophylactic antiemetics may help in nausea symptoms. Alopecia is usually diffuse pattern and starts 3–6 weeks after the start of therapy. It is usually reversible and stops after completion of CYC therapy with regrowth of normal hair. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion can occur during excessive fluid intake with IV CYC therapy. Mucositis, stomatitis, and sore lips can be associated with significant distress although improve with completion of therapy. Paradoxically, there are few reports in oncology available of high CYC dosages for the prolonged time being associated with interstitial pulmonary fibrosis.
| Conclusion|| |
CYC is routinely used as a first line or a rescue therapy in organ-threatening AIRDs. However, due to concerns of CYC-related toxicities, there is a current shift toward a widespread usage of MMF and Rituximab. This review highlights the toxicities of CYC with respect to the reproductive system, malignancies, infection risk, and other miscellaneous conditions. CYC has established efficacy with several validated induction protocols used in AIRDs. It is a cheaper and affordable option than several other currently available agents. As most of the CYC associated adverse events are dose dependent and occur with oral regimes having higher cumulative doses, treatment protocols using pulse low-dose IV regimens have repeatedly shown better tolerance and significantly improved toxicity profile. When used in correct clinical context with validated treatment protocols and orderly monitoring to reduce toxicity and enhance safety, CYC is generally well tolerated and remains a very effective drug for remission induction and maintenance of life-threating and organ-damaging complications of AIRDs. Although newer effective and less toxic immunosuppressants are available now, CYC remains the preferred drug, especially in the resource-limited settings.
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[Table 1], [Table 2], [Table 3]