a) In clinical trials, cough occurred in 10% to 44% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) INCIDENCE: In clinical trials, pneumonia occurred in 16% to 22% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).
b) CASE REPORT: A 53-year-old woman with a history of severe rheumatoid aortic valve stenosis developed acute eosinophilic pneumonia two weeks after receiving fludarabine phosphate (25 mg/m(2) for 5 days) for the treatment of stage IVB follicular non-Hodgkin's lymphoma. Laboratory data showed thrombocytopenia 62,000/mcL (greater than 143,000), lymphopenia 8.1%, but markedly elevated peripheral eosinophils 39% (less than 7) or 1.44 xs 10(3)/mcL in absolute counts, and a normochromic, normocytic anemia. Bronchoalveolar lavage cell differentials showed mostly eosinophilic granulocytes, suggesting an allergic drug-induced eosinophilic pneumonia. Her condition was complicated by cardiac failure due to a pre-existing aortic valve stenosis. Following supportive therapy, the patient recovered rapidly and was extubated after 4 days (Trojan et al, 2002).

a) In clinical trials, dyspnea occurred in 9% to 22% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, sinusitis occurred in up to 5% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, pharyngitis occurred in up to 9% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, upper respiratory infection occurred in 2% to 16% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Pulmonary hypersensitivity reactions to fludarabine characterized by dyspnea, cough and interstitial pulmonary infiltrates have been reported. There are post-marketing reports of acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis and respiratory failure associated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Pulmonary dysfunction, including bilateral pneumonia, and interstitial pneumonitis, has been associated with fludarabine use (Tobinai et al, 2006; Levin et al, 1997; Pillay et al, 1996; Hurst et al, 1987).
b) CASE REPORT: A 71-year-old man with chronic lymphocytic leukemia received 5 courses of fludarabine 50 milligrams for 5 days every 4 weeks after which he developed interstitial pneumonitis. The patient had cough and low-grade fever with radiologic evidence of bilateral asymmetric pulmonary infiltrates. His condition did not respond to oral antibiotics but resolved one week after initiation of chlorambucil and prednisone. Following retreatment with fludarabine for CLL relapse over a year later, the patient again developed symptoms and within 7 days required intubation. Intravenous prednisolone reversed the patient's circulatory collapse and he was discharged with a tracheostomy and positive pressure ventilation, but he died 2 weeks later. Lymphocytic infiltrate without infectious etiology was noted on postmortem needle biopsy (Levin et al, 1997).
c) CASE REPORT: A 61-year-old man had diffuse interstitial pneumonitis 2 weeks after the third course of fludarabine (20 milligrams/square meter daily for 5 days every 4 weeks). The patient presented with fever, dyspnea, and nonproductive cough. Chest radiograph demonstrated bilateral pleural effusions, and open-lung biopsy revealed a fibrosing interstitial pneumonitis with a mononuclear cell infiltrate and fibrosing alveolitis. Infectious etiology was excluded and the patient responded to prednisone therapy over the ensuing week. However, symptoms and infiltrates returned upon tapering of prednisone. The patient developed fever with each administration of fludarabine, and the authors suggest that fludarabine-induced pneumonitis may be preceded by a febrile reaction during daily doses (Hurst et al, 1987).

a) Fatigue has been reported in patients treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014; Keating et al, 1989; Leiby et al, 1988; Harvey et al, 1987; Balducci et al, 1987; Harvey et al, 1987a; Warrell & Berman, 1986).
b) INCIDENCE: In clinical trials, fatigue occurred in 10% to 38% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) INCIDENCE: In clinical trials, paresthesia occurred in 4% to 12% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) INCIDENCE: In clinical trials, malaise occurred in 6% to 8% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) INCIDENCE: In clinical trials, weakness occurred in 9% to 65% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).
b) CHILDREN: In childhood malignancy studies (n=62), asthenia developed following fludarabine therapy (an intravenous loading dose of 10.3 mg/m(2) followed by a continuous infusion of 30.5 mg/m(2)/day for 5 days) (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, agitation has been reported in chronic lymphocytic leukemia patients treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, confusion has been reported in chronic lymphocytic leukemia patients treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Peripheral neuropathy and a single case of wrist-drop have been reported in patients who received fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, coma has been reported in chronic lymphocytic leukemia patients treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Irreversible central nervous system toxicity (blindness, coma and death) has resulted from high dose fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014; Prod Info FLUDARA(R) injection, 2003).

a) Somnolence has been reported in some patients treated with fludarabine (Harvey et al, 1987; Balducci et al, 1987; Harvey et al, 1987a; Warrell & Berman, 1986; Leiby et al, 1988).

a) A severe neurotoxicity of delayed onset has been reported following initiation of therapy with fludarabine in higher doses (100 to 150 mg/m(2)/day for 5 to 7 days). Neurotoxic effects have been observed 21 to 60 days after receiving at least one course of fludarabine (either a 5- to 7-day course of short daily infusion or by continuous infusion) and are characterized by visual deficits, dysarthria, paresthesias, weakness, and seizures progressing to bilateral cortical blindness, confusion, spastic paralysis, and coma. Progressive demyelination in the central nervous system appears to be responsible for the neurotoxic syndrome (Warrell & Berman, 1986; Chun et al, 1986).
b) There is evidence that central nervous system (CNS) toxicity is dose-related, being relatively infrequent with doses of equal to or less than 125 mg/m(2) per course of treatment (Chun et al, 1986; Warrell & Berman, 1986). However, there are now numerous reports of a similar neurotoxic syndrome occurring in patients treated with low doses of fludarabine (18 to 22.5 mg/m(2) for 5 days) (Merkel et al, 1986; Weiss et al, 1986; Rainey et al, 1988; Chun et al, 1986).
c) Delayed neurotoxicity was associated with fludarabine therapy in a phase I and II trial in 25 patients with acute leukemia. Seventeen patients received doses of equal to or less than 125 mg/m(2)/day for 5 days (21 infusions), whereas 9 were treated with 150 mg/m(2)/day for 5 days (5 patients) or 125 mg/m(2)/day for 7 days (4 patients). Although remissions were observed at the 2 highest dosage levels, 4 of the 9 patients treated with these doses developed severe and delayed neurotoxicity. Symptoms were observed 21 to 43 days after initiation of treatment, and were characterized by altered mental status, blurred vision, amaurosis, and generalized seizures, followed by progression to blindness, spastic or flaccid paralysis, quadriparesis, and coma. Four of the patients experienced progressive deterioration and died, 3 of whom had achieved complete remission; only 1 patient regained visual and neurologic function. Clinicopathologic evaluation suggested widespread and severe demyelination as the etiology of neurotoxic reactions (Warrell & Berman, 1986).
d) No neurotoxicity occurred in 34 of 70 patients treated with fludarabine at daily doses of equal to or less than 80 mg/m(2) for 5 days. However, of 36 patients who received at least 1 course of equal to or less than 96 mg/m(2)/day for 5 to 7 days, 13 (36%) experienced severe central nervous system toxicity. Previous therapy with high-dose cytarabine or intrathecal chemotherapy were not considered predisposing factors to the development of neurotoxicity in these patients. Visual symptoms were the most frequent presenting symptom, and vision loss occurred in 11 patients. Mental status deterioration and progressive encephalopathy were also observed, leading to a vegetative state in 11 patients. All 13 patients died, with postmortem examinations revealing various degrees of demyelination in the brain and spinal cord (frequently cortical or diffuse) in 5 patients; a diagnosis of multifocal leukoencephalopathy was reported in 2 patients. A review of phase II solid tumor trials by the authors, involving 443 patients, revealed only 1 case (0.2%) of neurotoxicity with fludarabine therapy in low doses (equal to or less than 125 mg/m(2) per course), suggesting the dose-related nature of the syndrome (Chun et al, 1986).

a) Irreversible central nervous system toxicity (blindness, coma and death) has resulted from high dose fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Two suspected cases and one confirmed case of progressive multifocal leukoencephalitis (PML) among 60 standard-dose fludarabine recipients with refractory or relapsed chronic lymphocytic leukemia denote a 5% institutional incidence rate. Common presenting symptoms were unilateral hemiparesis and ataxia, with an onset ranging from 4 to 8 months after the last fludarabine cycle. Diffuse white-matter abnormalities indicative of demyelination appeared on magnetic resonance imaging of the brain. Two patients developed progressive neurologic deterioration and died 3 months later. Despite a partial neurologic recovery, the remaining patient died 28 months later (Gonzalez et al, 1999).

a) In clinical trials, nausea/vomiting occurred in 31% to 36% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014). In another study (n=52), nausea and vomiting (mostly grade 1 or 2) occurred in 50% of patients (Tobinai et al, 2006).
b) CHILDREN: In childhood malignancy studies (n=62), nausea and vomiting developed following fludarabine therapy (an intravenous loading dose of 10.3 mg/m(2) followed by a continuous infusion of 30.5 mg/m(2)/day for 5 days) (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, diarrhea occurred in 13% to 15% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014). In another study (n=52), diarrhea (mostly grade 1 or 2) occurred in 37% of patients (Tobinai et al, 2006)
b) CHILDREN: In childhood malignancy studies (n=62), diarrhea developed following fludarabine therapy (an intravenous loading dose of 10.3 mg/m(2) followed by a continuous infusion of 30.5 mg/m(2)/day for 5 days) (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, anorexia occurred in 7% to 34% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, stomatitis occurred in up to 9% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, gastrointestinal bleeding occurred in 3% to 13% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) A case of intestinal PSEUDO-OBSTRUCTION was attributed to fludarabine therapy of non-Hodgkin's lymphoma in a 67-year-old male. Initial symptoms of abdominal distension with pain and nausea emerged 36 hours after the first fludarabine infusion, with radiologic evidence of a dilated right hemicolon. Two days later, the pseudo-obstruction resolved with conservative management, only to reappear after fludarabine rechallenge. The same sequence of events happened with a third fludarabine dose. After ruling out other etiologies, clinicians administered two intravenous doses of neostigmine 1 milligram 30 minutes apart, resulting in only temporary improvement. The pseudo-obstruction was finally cleared via mechanical decompression (Campbell et al, 2000).

a) In clinical trials, dysuria occurred in 3% to 4% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, urinary infection occurred in 2% to 15% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) There have been reports of pancytopenia in both previously treated and untreated patients; cytopenia has lasted from 2 months to 1 year and has sometimes resulted in death (Prod Info fludarabine phosphate intravenous injection, 2014).
b) Neutropenia and thrombocytopenia are the most common adverse effects of fludarabine therapy and are dose-limiting (Tobinai et al, 2006; Ogawa et al, 2006; Trojan et al, 2002; Pillay et al, 1996; Keating et al, 1989; Shevrin et al, 1989; Leiby et al, 1988; Ajani et al, 1988; Leiby et al, 1987a; Harvey et al, 1987; Balducci et al, 1987; Harvey et al, 1987a; Hersh et al, 1986a; Warrell & Berman, 1986).
c) Lymphopenia and anemia have also been reported, albeit less frequently (Ogawa et al, 2006; Trojan et al, 2002; Ajani et al, 1988; Balducci et al, 1987; Weiss et al, 1987).
d) Septicemia and other infections have been common (Keating et al, 1989) and fatalities have been reported in association with neutropenia and thrombocytopenia (Balducci et al, 1987).
e) INCIDENCE: Of 133 patients treated for chronic lymphocytic leukemia, absolute neutrophil counts fell to less than 500/cubic millimeter in 59% of those receiving fludarabine. In addition, hemoglobin (decreased by at least 2 grams) and platelets (50% decrease) both declined in 60% and 55%, respectively, of those treated after initiation of therapy (Prod Info FLUDARA(R) injection, 2003).
f) There is some evidence that a continuous infusion of fludarabine is more myelosuppressive than daily bolus injections (Leiby et al, 1988); however, this must be confirmed in further studies.
g) Neutropenia has occurred more frequently and has been more severe than thrombocytopenia in some studies (Keating et al, 1989; Shevrin et al, 1989; Leiby et al, 1988; Weiss et al, 1987; Harvey et al, 1987).
h) In a study involving 68 patients with chronic lymphocytic leukemia, neutropenia and thrombocytopenia were observed in 56% and 25% of evaluable treatment courses, respectively. Myelosuppression was not cumulative; the incidence of both neutropenia and thrombocytopenia was lower in cycles 4 to 6 as compared to cycles 1 to 3 (with doses of 25 to 30 mg/m(2)/day for 5 days every 3 to 4 weeks). Myelosuppression also appeared to correlate with the patient's response to therapy; minimal myelosuppression was observed in patients achieving a complete response or nodular partial response, whereas significantly more myelosuppression and morbidity and mortality from infection was seen in patients achieving only a partial response or no response at all to fludarabine (Keating et al, 1989).
i) NADIR: Median white blood cell count nadir was reported on day 8 of therapy with fludarabine in a loading dose of 20 mg/m(2) intravenously initially followed by continuous infusion of 30 mg/m(2)/24 hours for 48 hours. The median platelet count nadir was observed on day 15. Leukopenia was more severe than thrombocytopenia in this study (Leiby et al, 1988). The manufacturer cites median nadir intervals of 13 days (range 3 to 25) for granulocytes and 16 days (range 2 to 32) for platelets (Prod Info FLUDARA(R) injection, 2003).
j) CHILDREN: In childhood malignancy studies, 12 children with solid tumors developed dose-limiting myelosuppression following fludarabine therapy (an intravenous loading dose of 8 mg/m(2) followed by a continuous infusion of 23.5 mg/m(2)/day for 5 days) (Prod Info FLUDARA(R) injection, 2003).

a) Severe myelosuppression (thrombocytopenia, neutropenia and anemia) has been reported with high doses of fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Autoimmune hemolytic anemia, sometimes fatal, has been reported; hemolysis has recurred in the majority of patients rechallenged (Prod Info fludarabine phosphate intravenous injection, 2014).
b) Twenty-four chronic lymphocytic leukemia patients experienced hemolytic anemia that was temporally related to fludarabine therapy. The age range of this group of patients was 33 to 78 years (median, 68 years). Fludarabine doses ranged from 20 to 30 mg/m(2) daily for 5 days, repeated monthly. The majority of patients (17/71%) developed hemolytic anemia after either the first, second, or third cycle of therapy. The remaining patients (29%) developed it after the fourth, fifth, or sixth cycle of fludarabine. Hematocrit values dropped by median of 14.1% (range, 8% to 29.8%). Seven patients (29%) died as a result of complications secondary to the anemia or recurrent hemolysis upon rechallenge with fludarabine (Weiss et al, 1998).
c) INCIDENCE: Autoimmune hemolytic anemia (AIHA) has developed in about 20% of patients receiving conventional doses of fludarabine, typically occurring after 1 to 6 treatment cycles (Taha et al, 1998; Gonzalez et al, 1998). Treatment with prednisone has not been uniformly successful. The overall response to chemotherapy does not appear to be affected by development of hemolysis, but patients without hemolysis had a better median survival time after fludarabine therapy (612 days versus 506 days in patients with hemolysis; p=0.005) (Gonzalez et al, 1998).
d) Twelve of 52 chronic lymphocytic leukemia patients treated with fludarabine developed severe autoimmune hemolysis. Three patients had a prior history of hemolytic anemia. Exacerbation of hemolytic anemia occurred in 6 of 8 patients retreated with fludarabine after control of fludarabine-induced hemolytic anemia (Myint et al, 1995).

a) Fludarabine was associated with eosinophilia in two patients undergoing therapy for chronic lymphocytic leukemia. After two fludarabine-cyclophosphamide cycles, a 67-year-old patient developed asymptomatic peripheral blood eosinophilia with a peak count of 7.9 x 109/liter and bone marrow eosinophil infiltration of 50%. Counts normalized spontaneously 33 days later. Eosinophilia did not recur with fludarabine-cyclophosphamide rechallenge. Fludarabine was the likely culprit, as previous cyclophosphamide administration caused no such effect. Isolated bone marrow eosinophilia of 20% was discovered by chance in an asymptomatic 53-year-old patient after four cycles of fludarabine; the chemotherapy regimen was not changed (Sezer et al, 1999).
b) Two patients who received fludarabine for follicular lymphoma developed eosinophilia after courses 3 and 6, respectively. The eosinophil count returned to normal within 14 days in the first patient; this patient received no further treatment. In the second patient, eosinophilia developed about 10 days after the third course. She received 7 additional courses of fludarabine but had only mild eosinophilia after course 9. Neither patient received other drugs or had other conditions which could cause eosinophilia. In this series 2 of 11 (18%) patients developed eosinophilia after treatment with fludarabine. Although uncertain of the mechanism, the authors provided the following possible explanations: (1) Due to pancytopenia and immunosuppression, cytokine levels are increased which may increase eosinophil counts or (2) Eosinophilia could be caused by an allergic reaction to the drug, but this is improbable in the second patient as she continued to receive the drug (Larfars et al, 1996).

a) CASE REPORT: A 64-year-old woman developed Evans's syndrome (combined autoimmune hemolytic anemia and immune thrombocytopenia) 10 days after her second cycle of fludarabine (25 mg/m(2) for 5 days every 4 weeks) to treat chronic lymphocytic leukemia (CLL). Presenting signs and symptoms included severe fatigue, shortness of breath, skin and mucous membrane purpura, severe pallor, mild scleral icterus, and moderate hepatosplenomegaly. Platelet count was 5000/microliter (mcL) and hemoglobin was 5.5 grams/deciliter (g/dL) with microspherocytosis, polychromasia, and rare nucleated red blood cells on peripheral smear. Erythroid and megakaryocytic hyperplasia was found on bone marrow aspirate and direct Coomb's test was positive for panagglutinin, IgG, and complements. The patient improved with a 2-week course of prednisone (1 mg/kg) but relapsed with prednisone tapering. Splenectomy provided a durable remission and prednisone was successfully withdrawn. In the authors' opinion, this case of Evan's syndrome was clearly precipitated by fludarabine in a patient with no history of autoimmune hemolytic anemia or immune thrombocytopenia (Sen & Kalaycio, 1999).
b) CASE REPORT: A 49-year-old male developed Evans syndrome after receiving fludarabine for chronic lymphocytic leukemia. The patient had received 6 cycles of fludarabine 50 mg/day for 5 days in 1993, followed by 2 cycles in 1996, 6 weeks before presenting with hematologic symptoms. Clinical presentation included severe gingival bleeding, purpura, and subicterus, as well as decreased hemoglobin, lymphocyte, and platelet counts, a positive Coombs' test, and platelet antibodies. Bone marrow examination revealed diffuse lymphocytosis, normoblastosis, and immature megakaryocytes, and the patient was diagnosed with acute Evans syndrome. Treatment with prednisone and vincristine resolved the hematologic abnormalities, and cyclosporine/prednisone therapy for 3 months resulted in recovery. However, the Coombs test remained positive without active hemolysis. The investigators attribute this adverse event to fludarabine's induction of dysregulation in T-cell function and the production of autoantibodies against red cells and platelet antigens (Shvidel et al, 1997).

a) CASE REPORT: While in chronic remission after receiving fludarabine for non-Hodgkin's lymphoma, a 31-year-old female developed a fatal hemophagocytic syndrome in association with miliary tuberculosis and a decreased number of CD4 T-cells. The patient had received two courses of fludarabine 25 milligrams/square meter (mg/m(2)) daily for 5 days for persistent splenomegaly after receiving chemotherapy, cranial irradiation, and intrathecal methotrexate. Subsequently, a splenectomy was performed and fludarabine 25 mg/m(2)/day was continued with alternating courses of chlorambucil 0.2 mg/kilogram (kg) per day and prednisone 60 mg/kg/day for 5 days every 28 days. After 4 cycles of this regimen, the patient developed pancytopenia, massive cervical lymphadenopathy, and retroperitoneal necrotizing lymphadenopathy. Bone marrow aspirate demonstrated panhemophagocytosis by cytologically benign histiocytes. Bone marrow and the cervical lymph node was positive for M tuberculosis, but the chest X-ray was normal. Rifampicin, isoniazid, and pyrazinamide were started for the tuberculosis, but resulted in peripheral neuropathy and fulminant hepatic failure leading to profound coma 2 days later. Liver failure resolved with the change in therapy; however, the peripheral neuropathy and pancytopenia persisted and the patient died 4 weeks after the hepatic failure had begun (Ruiz-Arguelles et al, 1998).

a) CASE REPORT: Fulminant myelofibrosis was observed in a 62-year-old man patient who had received fludarabine to treat grade 2 non-Hodgkin's lymphoma. Fludarabine 25 mg/m(2)/day was given for 5 days, and after the second cycle pancytopenia was evident on laboratory analysis. Bone marrow biopsy revealed diffuse fibrotic and sclerotic reactions. Despite treatment with hemopoietic growth factor, blood/platelet support, and antibiotics, the patient died of pneumonia. The causal relationship of fludarabine with this adverse event was not definitively determined (Palomera, 1998).

a) Two cases of autoimmune thrombocytopenia due to fludarabine therapy have been published. A 44-year-old man with autoimmune hemolytic anemia and stage B chronic lymphocytic leukemia (CLL) received 12 uneventful courses of fludarabine before developing signs and symptoms of severe autoimmune thrombocytopenia (platelet nadir: 3 x 10(9)/liter). The patient required transfusions, high-dose steroids and a course of intravenous immunoglobulin (IVIG) before platelets recovered 10 weeks later. He was rechallenged with fludarabine 12 and 18 months later because of progressive disease, causing precipitous declines in platelet counts both times, finally resulting in fatal gastrointestinal hemorrhage. A 72-year-old male with stage C CLL responded clinically to 5 courses of fludarabine, but 8 weeks later had a platelet count of 7 x 109/liter. He recovered with steroids and IVIG and was not rechallenged with fludarabine. These two cases occurred out of 45 fludarabine-treated patients for a 4.4% institutional incidence rate (Leach et al, 2000).

a) Investigators reported the first known case of autoimmune neutropenia caused by fludarabine therapy of chronic lymphocytic leukemia in a 60-year-old male. Approximately 3 weeks after his second 5-day course of fludarabine 25 milligrams/square meter/day plus prednisolone, the patient presented with fever of 40.8 degrees Celsius and zero neutrophils. Although anti-neutrophil antibodies were not detected, the bone marrow aspirate was consistent with autoimmune neutropenia. With broad spectrum antibiotic and filgrastim therapy, the patient recovered without sequelae and did not undergo fludarabine rechallenge. He was subsequently treated successfully with the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen (Stern et al, 1999)

a) In clinical trials, rash occurred in 15% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014; Harvey et al, 1987; Harvey et al, 1987a; Weiss et al, 1986).
b) CHILDREN: In childhood malignancy studies (n=62), rash developed following fludarabine therapy (an intravenous loading dose of 10.3 mg/m(2) followed by a continuous infusion of 30.5 mg/m(2)/day for 5 days) (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, diaphoresis occurred in 1% to 13% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) Three adult male patients treated for chronic lymphocytic leukemia with 5-day courses of intravenous fludarabine 25 mg/m(2) developed paraneoplastic pemphigus marked by conjunctivitis, edema, and cutaneous blistering of the extremities, facial area, and/or trunk. Withdrawal of fludarabine and treatment with steroids and cyclophosphamide or cyclosporine produced mucocutaneous improvement in all 3 patients, suggesting a possible causative link between fludarabine and the autoimmune reactions (Gooptu et al, 2001).

a) Muscular weakness has been reported in some fludarabine patients (Keating et al, 1989; Shevrin et al, 1989; Harvey et al, 1987a; Weiss et al, 1987; Von Hoff et al, 1988).

a) In clinical trials, myalgia occurred in 4% to 16% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, edema occurred in 8% to 19% of chronic lymphocytic leukemia (CLL) patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).

a) In clinical trials, angina occurred in up to 6% of chronic lymphocytic leukemia patients (n=133) treated with fludarabine (Prod Info fludarabine phosphate intravenous injection, 2014).