Chapter 46 Cytotoxic Drug Treatment
Cytotoxic agents were initially introduced for their ability to interrupt nucleic acid and protein synthesis in malignant cells. The realization that these agents may also suppress the immune system led to their use in immune-mediated diseases including systemic lupus erythematosus (SLE). Ever since their introduction, management of the disease has dramatically changed and its prognosis has greatly improved. Because of their significant side effects, cytotoxic therapy in lupus is reserved only for patients with moderate to severe disease (Box 46.1).
To date, most experts agree that the treatment of moderate to severe lupus consists of a period of intensive immunosuppressive therapy (induction therapy) followed by a longer period of less-intensive therapy (maintenance therapy). The primary objective of the induction therapy is to halt injury, recover function, and induce remission by controlling immunologic activity. On the other hand, maintenance therapy is used to consolidate remission and prevent flares with agents (or schedules) that are associated with a lower risk for complications and are more convenient to the patient.
In this chapter, we discuss the use of cytotoxic/immunosuppressive drug therapy in SLE. For each drug under discussion, we provide background information on the mode of action, pharmacokinetics, clinical use in lupus, and side effects. We also discuss monitoring for side effects and strategies to minimize them. Because azathioprine, cyclophosphamide, and mycophenolate mofetil are the most widely used cytotoxic drugs, we review these drugs in more detail.
Azathioprine is a cycle-specific antimetabolite that is commonly included in maintenance regimens for lupus nephritis and in regimens against SLE. Azathioprine and its metabolite, 6-mercaptopurine, are believed to affect cell-mediated and humoral immune responses. These effects include decreasing circulating lymphocytes, inhibiting lymphocyte proliferation, reducing antibody production, and suppressing natural killer (NK) cell activity.1
Azathioprine is rapidly converted to 6-mercaptopurine through enzymatic and nonenzymatic mechanisms. 6-mercaptopurine is then converted (1) to active analogues such as thiopurine via hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT), and (2) inactive analogues such as 6-methylmercaptopurine (via thiopurine methyltransferase) and 6-methylthiouric acid (via xanthine oxidase) metabolites.2
One daily dose is sufficient for therapeutic purposes. Measurement of neither azathioprine nor 6-mercaptopurine (6-MP) plasma levels is helpful in predicting the drug’s therapeutic or toxic effects. Approximately 1% of 6-MP is excreted in the urine; dose modification helps in reducing toxicity in the case of renal impairment (25% reduction of the dose if creatinine clearance [CrCl] occurs; 50% reduction if CrCl is below 10 mL/min). The drug is slightly dialyzable (5 to 20%) and is administered post-hemodialysis.
Concurrent administration of allopurinol should be avoided since the combination of the two drugs may dramatically increase the toxicity of azathioprine.3 Resistance to warfarin has been associated with the administration of azathioprine.4
Gastrointestinal complaints such as nausea, vomiting, and diarrhea are the most common side effects of azathioprine, leading approximately 15 to 30% of patients to discontinuation of the drug within 6 months.5 Mild increases in liver-associated enzymes are not uncommon, but severe liver injury is uncommon. Reversible dose-related myelosuppression is not uncommon; leucopenia occurs in approximately 4.5% and thrombocytopenia in 2% of patients receiving low-dose azathioprine.6
Notably, azathioprine toxicity is highly idiosyncratic, and has been associated with genetic polymorphisms leading to decreased thiopurine methyltransferase (TPMT) activity, and thus, to impaired ability to detoxify 6-MP. Subjects with low or absent TPMT activity seem to be at increased risk of developing severe azathioprine-induced myelotoxicity, which when occurring, has a delayed (between 4 and 10 weeks after initiation of the treatment) but acute onset.6 Genetic testing for TPMT polymorphisms represents an option for identifying patients with impaired TPMT activity. Alternatively, TPMT activity can now be measured directly in red cell membranes using commercially available kits. In the case that neither of the above-mentioned options are available, a low initial dose of azathioprine with frequent monitoring of the white blood cell count (WBC) every 1 to 2 weeks for the first 3 months of treatment and every 1 to 3 months thereafter. Less common side effects include acute hypersensitivity syndromes (usually within the first 2 weeks of the treatment), infection (albeit less common than with cyclophosphamide), and perhaps an increased risk for lymphoproliferative malignancies.5,7,8
The starting dose is 1 mg/kg/d with the usual dose at 2 to 3 mg/kg/d in one to three doses taken with food. Monitoring includes complete blood cell count (CBC) with platelets, creatinine, and AST or ALT. Liver enzyme activity should be measured every 3 to 4 months (Table 46.1). The drug should be used cautiously in patients with renal or liver disease or in patients who use allopurinol. Controlled randomized studies in lupus nephritis have not shown superiority for azathioprine when compared to high-dose corticosteroids, and the drug is used as a corticosteroid-sparing agent in various manifestations of lupus. In moderate to severe lupus, azathioprine has been used as a maintenance therapy at doses ranging from 1 to 3 mg/kg/d, especially in women of reproductive age, because of its acceptable safety profile during pregnancy. Although discontinuation of the drug due to side effects is not uncommon, more often the drug is discontinued for lack of efficacy.
Cyclophosphamide (CY) is an alkylating agent whose administration results in cell death, which can occur at any stage during the cell cycle. CY depletes both T and B cells, and reduces the production of pathogenic autoantibodies.9
Cyclophosphamide, an inactive merchlorethamine derivative, is rapidly metabolized to a variety of active metabolites, such as 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein, by cytochrome P-450 in the liver or other tissues such as transitional epithelial cells of the bladder or lymphocytes. Oral and intravenous administrations of CY result in similar plasma concentrations.10 Plasma concentrations of CY are not used as clinical predictors of either efficacy or toxicity.
Approximately 20% of the drug is exerted by the kidney, whereas 80% is processed by the liver. A dose modification is necessary for patients with renal impairment (25% reduction in patients with creatinine clearance 25 to 50 mL/min; 30 to 50% reduction if creatinine clearance is below 25 mL/min). CY may be administered in patients with end-stage renal disease on dialysis with dialysis performed 8 to 12 hours later. No dose modification is usually required for patients with liver disease. Concurrent administration of other drugs such as allopurinol, carbamazepine, phenytoin, and succinylcholine may increase the toxicity of CY.
Because of a better efficacy-to-toxicity ratio, intermittent intravenous pulse therapy (IV-CY) has replaced daily oral use in lupus in most places (see Box 46.2 for protocols). Reversible myelotoxicity is a common dose-related, adverse effect of CY. After pulse therapy, the nadir of lymphocyte count occurs on approximately day 7 to 10 and that of granulocyte count on approximately day 10 to 14. The WBC nadir is about 3000 cells/mm3 after a dose of 1 g/m2 and 1500 cells/mm3 after a dose of 1.5 g/m2.11 Because the risk of infection increases substantially with WBCs below 3000 cells/mm3, the dose is adjusted to keep it above this level. A prompt recovery from granulocytopenia usually occurs after 21 to 28 days. On the other hand, thrombocytopenia is extremely rare in monotherapy with CY.
Repeat CY doses monthly (every 3 weeks in patients with extremely aggressive disease) for 6 months (7 pulses), then quarterly for 1 year after remission is achieved (inactive urine sediment, proteinuria <1 gram/d, normalization of complement [and ideally anti-DNA], and minimal or no extrarenal lupus activity). Alternative maintenance therapy: azathioprine or MMF for 1–2 years.
Diuresis with 5% dextrose and 0.45% saline (e.g., 2 L at 250 mL/hr). Frequent voiding; continue high-dose oral fluids for 24 hours. Patients return to clinic if they cannot sustain adequate fluid intake.
Consider Mesna (each dose 20% of total CY dose) intravenously or orally at 0, 2, 4, and 6 hours after CY dosing. Sustained diuresis may be difficult to achieve, or if pulse CY is administered in outpatient setting.
If difficulty is anticipated with sustaining diuresis (e.g., severe nephrotic syndrome) or with voiding (e.g. neurogenic bladder), insert a three-way urinary catheter with continuous bladder flushing with standard antibiotic irrigating solution (e.g., 3 L) or normal saline for 24 hours to minimize risk of hemorrhagic cystitis.
Dexamethasone 10 mg in single dose plus the following: Serotonin receptor antagonists: Granisetron (Kytril) 1 mg with CY dose (usually repeat dose in 12 hours); Ondasetrone (Zofran) 8 mg tid for 1–2 days.
Common: significant infection diathesis only if leukopenia not carefully controlled; modest increase in herpes zoster (very low risk of dissemination); infertility (male and female); amenorrhea proportional to age of the patient during treatment and to the cumulative dose of CY. In females at high risk for persistent amenorrhea, may consider using leuprolide 3.75 mg subcutaneously 2 weeks prior to each dose of cyclophosphamide. In males, may use testosterone 100 mg intramuscularly every 2 weeks.
Monitoring for daily oral administration includes CBC with differential and platelet count every 1 to 2 weeks initially, and then every 1 to 3 months thereafter, along with urinalysis, creatinine, and AST or ALT. Total WBC counts of less than 3500/mm3 should lead to dose reductions, because lower counts are associated with a markedly increased risk of opportunistic infection. Urinalysis is performed every 6 to 12 months after cessation (Table 46.1).
Reversible alopecia and nausea are the most commonly observed side effects of CY, whereas myelotoxicity, gonadal toxicity, and malignancy represent less frequent, although much more serious, adverse effects.
A variety of different infections can occur, including bacterial infections, opportunistic infections (pneumocystitis carinii, fungal infections, and nocardia) and reactivation of latent Herpes zoster, Mycobacterium tuberculosis, and human papilloma virus. An increased rate of Herpes zoster and bacterial infections has been documented in patients receiving CY, and has been associated with higher doses of corticosteroids and a nadir of WBC less than 3000 cells/mm3 at some point during treatment.12 Oral CY regimens also may pose a greater risk of infection compared with intravenous pulse regimens.13 Opportunistic infections such as candidiasis or Pneumonocystis carinii pneumonia may be seen in patients on concomitant high-dose corticosteroid therapy. In this regard, recent studies have shown by multivariate analysis that the dosage of corticosteroids is the overriding independent determinant of the risk of infection among patients with SLE patients receiving CY with concomitant high doses of corticosteroids.14
Premature ovarian failure represents a well-documented side effect of CY. Several mechanisms have been implicated in its pathogenesis including marked acceleration in follicular maturation, depletion, and eventually exhaustion, and direct toxicity of the drug and its metabolites to gonadal cells. The risk of developing premature ovarian failure depends on the age of patient at the initiation of treatment and the cumulative dose of the drug as we first reported in 1993.15 In our study, the rates of sustained amenorrhea after a short course (seven or fewer pulses) of CY were 0% for patients aged under 25 years, 12% for those aged 26 to 30, and 25% for patients aged 30 and older. On the other hand, a long course (15 or more pulses) of CY induced sustained amenorrhea in 17% of patients under age 25, 43% of patients aged 26 to 30, and 100% of patients 30 and older.
A number of strategies to preserve fertility in patients with SLE taking CY have been tried with encouraging initial results. Some authors have suggested that the co-administration of GnRH antagonists confers protection against premature ovarian failure, and therefore recommend a GnRH antagonist–based protocol in CY-treated female patients17–19 (Box 46.2). Other strategies for preserving fertility, such as cryopreservation of unfertilized ova and ovarian tissue germ cell transplantation, are currently under investigation, and should be considered experimental at best at the present time. In male patients receiving CY for malignancies, the frequency of azoospermia ranges from 50 to 90%.20,21 The administration of testosterone and sperm banking represent valid strategies for preservation of testicular function and fertility (Box 46.2).21,22
Patients with systemic lupus erythematosus are at increased risk of developing lymphoma independent of treatment. However, the administration of alkylating agents enhances this risk and also probably that of leukemia, skin cancer, and other malignancies as well. Mechanisms of alkylating agent–induced malignancy include direct chromosomal damage and decreased immune surveillance. The duration of therapy is an important risk factor; the incidence is greatest in patients treated for more than 2 to 3 years or patients with a cumulative dose over 100 g.23 Patients with previous exposure to cyclophosphamide are at increased risk for hematologic malignancies including myelodysplastic syndrome, and myeloproliferative disease including acute leukemia and multiple myeloma.
The appearance of hemorrhagic cystitis and bladder carcinoma has been well documented in patients receiving long-term oral CY.24 The role of BK virus, present in the majority of adults in latent form in the urogenital tract, and its reactivation following CY therapy are currently been explored. In these patients, nonglomerular microscopic or gross hematuria represents the most common manifestation of CY-induced hemorrhagic cystitis. The value of urine cytology has been questioned. In our opinion, this does not represent a useful test to monitor for bladder cancer.24,25 The risk for bladder malignancy is life-long after CY therapy, and patients with nonglomerular hematuria should undergo cystoscopy no matter how late hematuria occurs. Although the absolute risk of bladder cancer is largely unknown, an up to 30-fold increase in the risk of developing bladder cancer has been documented in large trials. Among patients receiving CY, a cumulative dose of above 100 g of CY and smoking are well-documented risk factors for bladder cancer.25
The use of intermittent pulse CY, together with adequate hydration, has practically eliminated the cases of bladder carcinoma, although hemorrhagic cystitis may be seen in cases of inability to empty the bladder (i.e., neurogenic bladder in patients with transverse myelitis) or in cases where the practice of adequate hydration and frequent emptying of the bladder are not followed meticulously (Box 46.2). We use routinely sodium 2-mercaptoethane sulfonate (mesna)—an agent that has been advocated to reduce the concentration of acrolein and probably other toxic metabolites in the bladder—although controlled studies demonstrating its efficacy in lupus are not available.
Although some centers still employ daily oral CY regimens for short periods of time (2 mg/kg/d every morning in a single dose for 3 to 12 months until remission), the National Institutes of Health (NIH) protocol has become the protocol of choice for most physicians (Box 46.2). Randomized controlled studies (RCTs) are available only for lupus nephritis; recommendations for other indications are based on extrapolation from those data.
RCTs with long-term follow-up have shown that IV-CY is effective for moderate to severe proliferative lupus nephritis, with a better toxicity profile than daily oral CY.27 Following induction therapy, a maintenance regimen is essential to decrease the risk of flares.28 Subsequent studies from the NIH have demonstrated that combination pulse therapy with CY and methylprednisolone (IV-MP) improves renal outcomes without increasing toxicity.29,30 Based on these studies, the NIH group has proposed seven monthly pulses of IV-CY (0.5 to 1 g/m2) followed by quarterly pulses for at least 1 year beyond remission. For patients with moderate to severe disease, monthly pulses of IV-MP are added during the induction period. Ovarian toxicity (found to be both age and dose related), infections (especially with herpes zoster), flares (observed in approximately one-third of patients), incomplete response, and in rare cases, refractoriness to treatment, have emerged from these studies as significant limitations of current cytotoxic therapy.
Because of concerns about toxicity, together with the appreciation that the disease may be less severe in whites, European investigators sought alternative protocols to administer the drug (Euro-Lupus Nephritis Trial [ELNT]).31,32 In studies involving for the most part patients with milder forms of disease, less intensive regimens of CY (six fortnightly pulses at a fixed dose of 500 mg each in combination with three daily doses of 750 mg of IV-MP) followed by azathioprine as maintenance, had comparable efficacy but less toxicity than a short course of high-dose IV-CY (eight pulses).32 By multivariate analysis, early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/d) was the best predictor of good long-term renal outcome. In addition to demonstrating that in patients with milder forms of lupus nephritis less intensive regimens of IV-CY may be involved, this study demonstrated that sequential therapy with a short course of IV-CY followed by azathioprine is a valid approach in lupus.
In addition to proliferative and membranous lupus nephritis, case reports, case series, and uncontrolled clinical studies support the efficacy of IV-CY in severe thrombocytopenia, neurologic disease (myelitis, encephalitis, psychosis, mononeuritis multiplex, and polyneuropathy), abdominal vasculitis, acute pneumonitis/alveolar hemorrhage, dermatologic disease, and other severe manifestations of lupus.34–36 A randomized controlled trail in neuropsychiatric lupus has confirmed its efficacy in severe neuropsychiatric lupus.36