Chapter 46 Cytotoxic Drug Treatment
INTRODUCTION
BOX 46-1 GENERAL INDICATIONS FOR CYTOTOXIC DRUG USE IN SYSTEMIC LUPUS ERYTHEMATOSUS
General
AZATHIOPRINE
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
Pharmacokinetics
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.
Drug Interactions
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
Adverse Effects
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
CYCLOPHOSPHAMIDE
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
Pharmacokinetics
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.
Modes of Administration and Monitoring
Pulse Cyclophosphamide Therapy
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.
Adverse Effects
Infections
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
Gonadal Toxicity
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.
In males, gonadal toxicity may be observed with as little as a 7-gm cumulative dose corresponding to an approximately 2-month daily oral therapy.16
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
Malignancy
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.
Bladder Toxicity Including Bladder Carcinoma
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
Clinical Use
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