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Keywords:

  • cyclophosphamide;
  • microscopic polyangiitis;
  • treatment;
  • vasculitis;
  • Wegener's granulomatosis

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

The introduction of cyclophosphamide (CyP) as a treatment for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) has been among the most significant contributions in vasculitis. Prior to the introduction of CyP, WG was a uniformly fatal disease, with mortality occurring within 5–12 months from pulmonary or renal failure or from infection due to glucocorticoids. In 1973 Fauci and Wolff, at the National Institutes of Health, published their experience with a regimen that combined CyP and prednisone in which disease remission was seen in 12 of 14 patients. Long-term experience with CyP provided even greater evidence for its efficacy in which an 80% survival rate was seen, with 91% of patients having significant improvement and 75% achieving complete remission. However, extended follow-up also demonstrated that disease relapse occurred in at least 50% of patients and that 42% experienced morbidity solely as a result of treatment. These observations showed that while CyP was life-saving, it did not prevent relapse and was associated with significant toxicity such that safer means to induce remission needed to be pursued. Strategies aimed at reducing exposure to CyP have included intermittent administration, induction–maintenance regimens and avoidance of CyP for non-severe disease. Recently, the introduction of rituximab has raised important questions regarding the place of CyP in the treatment of WG/MPA. This paper examines the past, present and future of CyP through a review of its efficacy and safety.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

The introduction of cyclophosphamide (CyP) as a treatment for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) has been among the most significant contributions in vasculitis. While, importantly, CyP induced remission and prolonged patient survival, it also allowed physicians the opportunity to understand more clearly the spectrum of these diseases and their potential pathogenesis. While CyP has been life-saving, it does not prevent relapse and is associated with significant toxicity. Strategies aimed at reducing exposure to CyP have included intermittent administration, induction–maintenance regimens and avoidance of CyP for non-severe disease. Most recently, the introduction of rituximab (RTX) has questioned the place of CyP in the treatment of WG/MPA. This paper examines the past, present and future of CyP through a review of its efficacy and safety.

Historical perspective

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

Prior to the introduction of CyP, WG was a uniformly fatal disease, with mortality occurring within 5–12 months from pulmonary or renal failure or from infection due to glucocorticoids. In 1973 Fauci and Wolff, at the National Institutes of Health (NIH), published their experience with a regimen that combined CyP 2 mg/kg/day and prednisone, in which disease remission was seen in 12 of 14 patients [1]. Long-term experience with CyP provided even greater evidence for its efficacy in which an 80% survival rate was seen, with 91% of patients having significant improvement and 75% achieving complete remission [2,3]. However, extended follow-up also demonstrated that disease relapse occurred in at least 50% of patients and that 42% experienced morbidity solely as a result of treatment. In addition to the substantial side effects of glucocorticoids, CyP was associated with acute toxicities including infection, cytopenias and cystitis, as well as long-term complications with infertility, myelodysplasia and bladder cancer. This experience showed that while CyP was effective, safer means to induce remission needed to be pursued.

Daily versus intermittent administration

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

Concurrent with the investigation of daily CyP in WG, intermittent intravenous (i.v.) CyP was being studied in systemic lupus erythematosus. Although i.v. CyP remains associated with infection, cytopenia and infertility, it provides less exposure to the bladder urothelium and reduction of cumulative CyP dose over time. With these potential advantages, the question arose as to whether i.v. CyP was also effective in WG/MPA. Small studies of monthly i.v. CyP suggested that a higher rate of relapse occurred [4], and although the rate of remission induction appeared comparable in one randomized trial, this was insufficiently powered to prove efficacy [5]. Additionally, concern has remained about patients who did not improve with i.v. CyP for whom daily administration has been effective [6].

A randomized trial conducted by the European Vasculitis Study Group (EUVAS) compared CyP 2 mg/kg/day to i.v. CyP given as 15 mg/kg every 2 weeks for three doses and every 3 weeks thereafter. After remission was achieved, patients received an additional 3 months of CyP in a consolidation phase, after which CyP was stopped and switched to azathioprine (AZA), as discussed below [7]. In this trial, i.v. and daily CyP did not differ in the primary end-point of time to remission or in the proportion of patients who achieved remission at 9 months (88·1% versus 87·7%, respectively). While patients in the i.v. group received a lower cumulative dose of CyP, this would have been less pronounced had CyP been limited to the duration of time required to achieve remission, which was 3 months in each arm. Leucopenia was seen in both groups, and although this occurred less frequently in those who received i.v. CyP, comparable rates of serious infection were seen. The complete blood count (CBC) monitoring schedule for daily CyP, which was weekly for the first month, every other week for the second month and monthly thereafter, may have also influenced the rate of leucopenia, as suggested by the first episode occurring at median time of 68 days (range 8–318 days). Nineteen per cent of patients in the i.v. CyP arm experienced a relapse compared with 9% of those who received daily CyP, and while this difference was not statistically significant the trial was not powered to test the effect of the intervention on relapse rate.

This trial showed that IV CyP is efficacious for remission induction, but as it was not superior the use of daily CyP remains a valid and appropriate option for remission induction in severe WG/MPA. For both routes, this study provided valuable information in guiding how CyP should be used in practice. For physicians who prefer to use i.v. CyP, it is important to emphasize that the doses and frequency investigated in this trial remains the only schedule for which efficacy has been proven in WG/MPA and should be the regimen that is used. For physicians who prefer daily CyP, these results support that the duration of therapy should be limited to 3–4 months and that CBC monitoring should be performed every 1–2 weeks throughout the course of treatment to detect and prevent leucopenia.

Induction–maintenance regimens

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

Recognizing the efficacy of CyP to induce remission of severe WG/MPA, the question arose as to whether CyP could be given for 3–6 months to induce remission, after which time it would be stopped and replaced by a less toxic agent for remission maintenance. This staged induction–maintenance approach was examined at the NIH using methotrexate (MTX) as the maintenance agent. In this standardized open-label trial the median time to remission was 3 months, and as CyP was stopped at remission this was a vastly shorter duration of CyP exposure than had previously been possible [8]. Serious treatment-related toxicity was 10%, which was also lower than had been seen with long-term CyP. A main concern, however, was whether shortening the CyP duration would increase the frequency of relapse, and while the rate of 52% was similar to previous studies, comparability could not be concluded from a single-arm trial.

An important randomized study conducted by EUVAS investigated whether exposure to CyP in patients with generalized WG or MPA could be reduced by substitution of AZA at remission [9]. In this trial, all patients received at least 3 months of CyP 2 mg/kg/day and prednisolone, and after remission were assigned randomly to continue CyP 1·5 mg/kg/day for a total of 12 months or be switched to AZA 2 mg/kg/day. During the induction phase, 96% of these 155 patients survived and 93% achieved remission, again demonstrating the efficacy of CyP in severe disease. The relapse rate of those in the AZA arm was statistically no different to those who received CyP (15·7% versus 13·7%, P = 0·65). This trial therefore provided evidence that the withdrawal of CyP and the substitution of AZA after remission did not increase the rate of relapse, and thus allowed the duration of CyP exposure to be markedly reduced.

Other induction–maintenance trials have been performed. These have included an open-label study of MTX after daily CyP induction in which a 3·7% mortality rate was seen, in which sustained remission occurred in 78% of patients and serious infections in 17% [10]. A randomized trial comparing AZA to MTX for remission maintenance showed that these agents had a comparable rate of toxicity and relapse in eligible patients without contraindications to these agents [11]. In another randomized trial, mycophenolate mofteil (MMF) was less effective than AZA for maintaining disease remission after CyP induction but had a similar adverse event rate [12]. While a detailed review of these agents is beyond the scope of this paper, these data support that AZA and MTX have emerged as the main maintenance options following induction with CyP, with MMF being a consideration in patients who have relapsed through, or who are unable to take, these other choices. As AZA and MTX do not appear to have distinct advantages over each other, selection of a maintenance option becomes individual for each patient, being influenced by relative and absolute contraindications and past disease history.

This collective experience provides abundant evidence to support that when CyP is given for severe active WG/MPA, its use should be limited strictly to the duration necessary to bring about significant disease improvement or remission, which is typically 3 months to no longer than 6 months. After this time, CyP should be stopped and switched to a maintenance agent, which includes primarily MTX or AZA. When using CyP in WG/MPA the use of an induction–maintenance approach should be considered the standard of care, as longer durations of CyP offer no advantage and are associated with enhanced potential for toxicity.

Toxicity, monitoring and prevention

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

As CyP has significant toxicity, strategies to monitor for and prevent side effects play an important role in minimizing the risk of treatment-related morbidity or mortality (Table 1). Infection is the most common cause of death in patients treated with CyP and glucocorticoids, particularly including risk from bacterial and opportunistic pathogens [13]. Infection with Pneumocystis jiroveci pneumonia (PJP) has occurred in up to 10% of WG patients receiving induction therapy. As PJP has a high mortality rate, prophylaxis is important in all patients receiving CyP induction [14].

Table 1.  Cyclophosphamide (CyP) toxicity and monitoring recommendations.
Adverse effectsMonitoring and prevention recommendations
  1. CBC: complete blood count; WBC: white blood cells.

• Infection • Bone marrow toxicity • Cystitis • Transitional cell carcinoma • Myelodysplasia • Infertility • Pulmonary fibrosis (rare) • Teratogenicity• CBC once a week • Adjust dose to keep WBC count > 3500/mm3 • Daily CyP: advise patient to take in the morning • Intermittent CyP: 2-mercaptoethanesulphonate sodium • Drink a large amount of fluid to maintain a dilute urine • Urinalysis every 1–4 weeks • Urine cytology every 6–12 months • Cystoscopy for non-glomerular haematuria or abnormal cytology • For people who desire future childbearing: consideration of testosterone for males, gonadotrophin-releasing hormone analogues for females • Effective contraception

Neutropenia enhances the risk of infection, particularly with fungal organisms, and as CyP is bone marrow-suppressive for all cell lines, close monitoring of the CBC is essential in maintaining an absolute neutrophil count of >1500/mm3. As blood counts obtained today reflect the CyP dose taken a week ago, attention must be paid not only to absolute numbers but also declining trends. For patients treated with daily CyP, CBCs should be obtained every 1–2 weeks, while with i.v. CyP CBCs have been performed on days 10 and 14 after each pulse and immediately before the next pulse. Even when counts have been stable, this frequency should be continued, as counts tend to decline over time as a result of glucocorticoid-tapered and cumulative impact on the bone marrow.

Bladder toxicity with CyP, which includes cystitis and risk of transitional cell carcinoma (TCCA), is due to toxic effects of the CyP metabolite acrolein on the urothelium. For patients treated with i.v. CyP, the risk can be lessened with hydration and the use of 2-mercaptoethanesulphonate sodium (MESNA), which binds to acrolein. With daily administration, it is critical that CyP be taken all at once in the morning and that fluid be consumed throughout the day to maintain dilute and frequently voided urine. Monitoring for bladder toxicity should include urinalysis for detection of non-glomerular haematuria with cystoscopy, should this be found. Urine cytology performed every 6–12 months is a useful monitoring technique, although it is insensitive to detect low-grade lesions [15]. All CyP-treated patients should be educated that the risk of TCCA, and thus the need for monitoring, is life-long.

Infertility represents among the greatest concerns with CyP use for people who desire future childbearing. Although this is linked to treatment duration and cumulative dose, counselling regarding infertility should be given to all patients treated for any duration. In males, limited data have suggested that supplemental testosterone may offer protection, although use must be weighed against its side effects [16]. In women, approaches have included hormonal manipulation through the use of oral contraceptives and gonadotrophin-releasing hormone analogues [17]. Cryopreservation of ova or sperm is not usually possible because of the urgent need to initiate CyP immediately in the setting of severe vasculitis.

The future of CyP

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References

The demonstration that RTX is as effective as CyP to induce remission of severe active WG/MPA, as discussed elsewhere in this journal, raises questions about where CyP fits into our current treatment approach [18,19]. As outlined in this review, despite its respected drawbacks, CyP is an extremely effective and well-understood therapy which must be weighed when examining alternative choices. Will CyP be replaced in the future? Unquestionably, the answer to this is ‘yes’. In the pursuit of better therapies, it is a happy reality that trusted treatments will be replaced by new approaches that will improve the lives of our patients. Has CyP already been replaced for WG/MPA? This remains a matter of opinion. While the data for RTX are important and exciting, there remains knowledge yet to be learned about this therapy with regard to relapse rate, frequency of administration, use with maintenance agents and efficacy in the most fulminantly ill patients. While these answers will be gained from further study, at the current time the risks and benefits, knowledge and uncertainty of these therapies must be weighed with each patient in making decisions that are most appropriate for them.

CyP has been an important part of the treatment armamentarium for WG/MPA for almost 40 years, and it remains essential in many forms of vasculitis for which alternative agents have not, as yet, been identified. CyP will always hold a place of ground-breaking importance in the history of vasculitis and it will remain so until equally effective agents exist for all vasculitic diseases.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Historical perspective
  5. Daily versus intermittent administration
  6. Induction–maintenance regimens
  7. Toxicity, monitoring and prevention
  8. The future of CyP
  9. Disclosure
  10. References