This study will test the safety and effectiveness of combination therapy with
cyclophosphamide (Cytoxan) and fludarabine in treating lupus nephritis (kidney
inflammation). This condition, common in patients with systemic lupus erythematosus, is
caused by abnormal action of immune cells called lymphocytes against the kidneys. Left
untreated, severe cases can result in loss of kidney function. The current treatment of
choice-intermittent high doses (pulses) of cyclophosphamide-does not work in all patients
and causes infertility in many women. The rate of infertility in men is not known. This
study will examine whether fludarabine can safely be given with significantly lower doses of
cyclophosphamide, and if this combination controls kidney inflammation.
Patients 18 years of age and older with severe lupus nephritis (called proliferative lupus
nephritis) may be eligible for this study. Candidates will have a history and physical
examination; blood and urine tests; chest X-ray; electrocardiogram; cancer screening that
may include a Pap smear, mammogram, rectal examination, PSA testing, and sigmoidoscopy.
Participants will be divided into one of the following treatment groups:
Group 1-Patients undergo three treatment cycles of cyclophosphamide, taken by mouth, and
fludarabine, injected subcutaneously (under the skin). Patients receive both drugs on day 1
of the cycle, and fludarabine alone on days 2 and 3. This regimen is repeated once every 5
weeks for three cycles.
Group 2-Same as for Group 1, except fludarabine injections are given intravenously (through
a vein) for the second treatment cycle. Patients in this group have frequent blood sampling
during the first and second treatment cycles to monitor blood levels of the drug. Samples
are collected before the first injection is given and at 0.5, 1, 1.5, 2, 4, 8, 24 and 48
hours after the third injection. A total 12 tablespoons of blood is drawn over a 2-month
All patients will have blood drawn once or twice a week during the first two cycles and then
less frequently to monitor blood counts. Some patients will have the following additional
procedures to test the effects of treatment on lymphocytes:
1. Blood sample collection
2. Bone marrow aspiration-The skin over the hip bone is cleaned and a local anesthetic is
injected into the outer covering of the bone. Bone marrow is suctioned through the
needle into an attached syringe. The procedure is done before treatment begins, at the
end of treatment, and 6 months after treatment.
3. Tonsillar biopsy-The tonsils are numbed with a local anesthetic and 1 to 4 pieces of
tissue are removed using special forceps. The procedure is done before treatment
begins, at the end of treatment, and 6 months after treatment.
4. Magnetic resonance imaging (MRI) of the abdomen-The patients lies on a table in a
narrow cylinder (the MRI scanner) containing a strong magnetic field, which is used to
create images of parts of the body in small section views.
Patients will be followed for at least 24 months to monitor late side effects and the
response to treatment.
Studies at the NIH Clinical Center have shown that intermittent pulse cyclophosphamide
therapy is effective for treating patients with severe lupus nephritis, but may result in
substantial rates of sustained amenorrhea. Initial studies in patients with autoimmune
rheumatic diseases have also suggested a beneficial effect from the lymphocyte-specific
nucleoside analogs chlorodeoxyadenosine and fludarabine. Cyclophosphamide induces DNA
cross-links whereas, nucleoside analogs inhibits DNA repair indicating complementary and
partially synergistic modes of action. Whether combination of lower doses of
cyclophosphamide with nucleoside analogs will increase efficacy while at the same time
minimize toxicity from higher-cumulative doses of cyclophosphamide has not been determined.
In this phase I/II study, 15 patients with proliferative lupus nephritis will be treated as
outpatients with a combination of oral cyclophosphamide (500 mg/m(2)) on day 1 followed by
fludarabine (30 mg/m(2)) subcutaneously on days 1, 2 and 3 every month for 3 cycles. The
cumulative dose of cyclophosphamide in this regimen is approximately 2.5g as compared to
greater than or equal to 30g in the standard NIH cyclophosphamide regimen. In this study
the tolerance and toxicity of this combination will be studied. Regeneration of T and B
cells following depletion including analysis of antigen-repertoire and function will also be
examined. Preliminary efficacy information, including rates and time to renal remission and
rates of preservation of renal function, will be analyzed to be used for future controlled
studies. Pharmacokinetic analysis will be performed on a subset of patients to determine
the bioavailability and pharmacokinetic parameters of subcutaneous fludarabine.
Patients must be 18 years of age or older and able to provide informed consent.
Patients must have at least 4 criteria for SLE as defined by the American Rheumatism
Active glomerulonephritis with:
Renal biopsy within 1 year with class III or class IV active lupus nephritis, AND;
Abnormal urine analysis:
Greater than 10 RBC/hpf and cellular (RBC, WBC or mixed) casts, OR;
Greater than 10 RBC/hpf and proteinuria greater than 2 g/day, OR;
Proteinuria greater than 3.5 g/day.
No patients with severe proliferative lupus nephritis: a. very active renal histology
with crescents or necrosis in more than 25% of glomeruli; or b. rapidly progressive
glomerulonephritis (doubling of serum creatinine in less than or equal to 3 months); or c.
severe impairment of renal function Cr greater than 2.5 mg/dL or GFR less than 50 mL/min
measured by inulin clearance.
Patient has not had previous immunosuppressive therapy:
Patients must not be receiving azathioprine, cyclosporine, methotrexate. Patients
receiving these drugs will be eligible only if these drugs are discontinued and after a
waiting period of greater than or equal to 4 weeks;
Patients must not be receiving cyclophosphamide:
Greater than 3 pulses (maximum 1 g/m(2)/pulse) within the last 12 months or since last
renal biopsy showing active disease; OR
greater than 6 pulses ever.
Patients must not have had pulse therapy with glucocorticoids or any experimental therapy
during the 4 weeks before study entry.
Patients who need at study entry oral corticosteroids in dosages greater than 0.5
mg/kg/day of predisone to control extrarenal disease are not eligible.
Patients with active or chronic infection are not eligible.
Patients who are pregnant, breast-feeding or using inadequate birth control are not
Patients who have poorly controlled diabetes mellitus or with evidence of end-organ damage
are not eligible.
No history of cerebrovascular accident, seizures within the last 5 years or chronic
No history of malignancy other than squamous cell and/or basal carcinoma of the skin.
No confounding medical illness that in the judgment of investigators would pose added risk
for study participants such as:
Unstable coronary artery disease, cardiomyopathy or dysrhythmia requiring therapy;
Pulmonary disease (PFTs less 70% of predicted value or DLCO less than 60%), or;
Hematologic disease (Hb less than 8 mg/dL, platelets less than 100,000 micro liters or WBC
less than 2,500/micro liters.