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Reversible Neurologic Toxicity in Patients Treated with Standard-Dose Fludarabine Phosphate for Mycosis Fungoides and Chronic Lymphocytic Leukemia

High doses of fludarabine (Fludara; Berlex, Alameda, California) (> 40 to 125 mg/m2 per day for 5 to 7 days) in patients with acute leukemia have caused life-threatening neurotoxicity that occurs 3 to 8 weeks after discontinuation of treatment, with optic neuritis, cortical blindness, altered mental status, seizures, and paralysis. Neurologic deterioration was often progressive and fatal. Autopsies showed severe demyelination and vacuolar changes of white matter throughout the central nervous system [1-4]. Neurotoxicity is unusual, however, in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia receiving lower doses (18 to 25 mg/m2 per day for 5 days) [5-9]. In patients with non-Hodgkin lymphoma, reversible grade III visual changes, auditory hallucinations, confusion, and lethargy have been noted in some [5] but not all studies [6]. Severe neurologic symptoms occurred in a single patient with mycosis fungoides treated with fludarabine at 25 mg/m2 per day for 5 days, but he had central nervous system lymphoma at post-mortem examination [7]. No serious neurotoxicity has been reported in patients with chronic lymphocytic leukemia [8, 9]. Case Reports Patient 1 A 46-year-old white man with a 3-year history of mycosis fungoides (Stage IVA: T3LN3N0M0; erythematous plaques and nodules) received eight courses of fludarabine (25 mg/m2 daily for 5 days) and -interferon (5 million units/m2 subcutaneously three times weekly) between February and December 1991, achieving complete remission after three cycles. After six cycles a new subcutaneous nodule in the right external auditory canal was biopsied, showing mycosis fungoides. Computed tomography showed no brain involvement. Radiation therapy (consisting of 800 cGy [9 MeV electron beam] to the nodule and an additional 2200 cGy [6 MV photon beam] to a depth of 4 cm to the middle ear and mastoid) was begun on 1 November and was completed 24 days later. Two further courses of fludarabine and -interferon were given per protocol because the single nodule represented less than 25% disease progression. One month after the last treatment the patient had a right-sided focal motor seizure with generalization and loss of consciousness. A neurologic evaluation showed a right foot drop. The results of electroencephalographic and cerebrospinal fluid examinations were normal. A magnetic resonance imaging [MRI] scan (Figure 1, top left) showed a left temporoparietal white-matter abnormality. Diphenylhydantoin was given. One month later the patient developed progressive right leg weakness. A repeat MRI showed marked subcortical white-matter abnormalities on the left with new right-sided lesions (Figure 1, top right). A lumbar puncture was normal. Neurologic findings improved rapidly over the next week and a repeat MRI showed improvement with a residual high left parietal lobe abnormality (Figure 1, bottom left). After 6 weeks the results of a neurologic examination and MRI scan were normal (Figure 1, bottom right). Figure 1. Serial magnetic resonance T2-weighted spin echo scans of brain in Patient 1. (top left) (top right) (bottom left) (bottom right) Patient 2 A 64-year-old white woman with an 18-year history of chronic lymphocytic leukemia (Rai stage IV) received fludarabine after failing local radiation therapy, chlorambucil, and radiolabeled anti-T101 monoclonal antibody. Six cycles of fludarabine were given between January and November 1991 at a dose of 20 mg/m2 per day intravenously for 5 days except for cycle two when she received 25 mg/m2 per day. One month after cycle six and the achievement of partial remission, she had uncomplicated bilateral endoscopic ethmoidectomies and antrostomies under general anesthesia for treatment of pansinusitis. The next day she noted difficulty walking and visual blurring that worsened over the next 2 weeks. Neurologic examination was normal except for a wide-based, lurching, unsteady gait. Magnetic resonance imaging scans showed an increased signal on T2-weighted images within deep white-matter structures. Over the next 6 months her blurred vision resolved and her gait improved. Repeat MRI scans were unchanged. No interval treatment for her leukemia was required. Discussion We describe disabling, but reversible, neurologic syndromes in two patients treated with the recommended dose and schedule of fludarabine. The reversibility of toxicity with cessation of treatment contrasts with the experience in patients with acute leukemia in whom there was generally inexorable progression to blindness, encephalopathy, and death [2-4]. Reported neurologic toxicities in patients with chronic lymphocytic leukemia treated with the recommended doses of fludarabine have been mostly grade I [8, 9]. Rarely, grade III visual and auditory changes have occurred in patients with non-Hodgkin lymphoma [5]. Our two patients represent the first reports of grades III to IV neurotoxicity in patients with chronic lymphocytic leukemia and lymphoma treated at standard or low dose fludarabine, in whom coexistent central nervous system involvement with tumor was not a confounding factor [7]. In both cases neurologic symptoms and findings were seen several weeks after the treatment, fitting the previously described pattern. The MRI scans of both patients showed hyperintense T2-weighted signals compatible with demyelination as reported previously in patients with overwhelming neurotoxicity [2, 4]. Radiation and -interferon (Patient 1) and general anesthesia (Patient 2) may have potentiated fludarabine toxicity. It is unlikely, however, that the low dose of radiation to ipsilateral brain in Patient 1 can account for the extensive lesions that began on the contralateral side (Figure 1, top left, right, and bottom left). Outpatient surgery in Patient 2 was brief, limited in scope, and uncomplicated, and because her symptoms progressed for weeks postoperatively, an ischemic event was unlikely. Nevertheless, general anesthesia may have enhanced this patient's vulnerability to fludarabine neurotoxicity. Caution is warranted when fludarabine is used even at low doses, particularly when it is combined with other treatments such as -interferon, radiation, cytosine arabinoside, and intrathecal methotrexate, which may allow for greater drug penetration into the central nervous system. At the earliest indication of neurotoxicity (such as visual blurring, auditory hallucinations, gait disorder, lethargy, tremor), a full neurologic examination, including a lumbar puncture, MRI scan, and possibly evoked potentials, should be done and treatment with fludarabine discontinued.