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Case Report
A 57-year-old man was referred for treatment of advanced, refractory CLL. A diagnosis of typical B-cell CLL 6 1/2 years previously was followed by the administration of several chemotherapeutic regimens, including chlorambucil and prednisone; cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone; and etoposide -- all of which elicited a partial, transient response. Most recently the patient had received three cycles of fludarabine, with only a minor response and a rapid relapse. On admission he was afebrile, with bulky generalized lymphadenopathy and marked hepatosplenomegaly. The white-cell count was 208,000 per cubic millimeter, the hemoglobin level was 8.6 g per deciliter (5.34 mmol per liter), and the platelet count was 25,000 per cubic millimeter. Creatinine clearance was 108 ml per minute. Other laboratory values were normal, including serum calcium, uric acid, and lactate dehydrogenase concentrations. The patient was treated with the usual dose of 0.1 mg of 2-chlorodeoxyadenosine per kilogram of body weight per day for seven days, administered as a continuous intravenous infusion, together with allopurinol. By the fourth day of treatment, there was a notable reduction in the degree of lymphadenopathy, whereas the white-cell count and biochemical values remained unchanged. The patient was discharged on completion of treatment.
He felt entirely well until seven days after treatment, when he was admitted with a temperature of 39 °C. Physical examination revealed a 50 percent reduction in the bulky lymphadenopathy, but the degree of hepatosplenomegaly was unchanged. No source of infection was found. The initial white-cell count was 189,000 per cubic millimeter, with over 99 percent lymphocytes and fewer than 500 granulocytes per cubic millimeter. The platelet count was 16,000 per cubic millimeter. Azotemia was noted, with an increase in the serum urea concentration from 16.8 to 32 mg per deciliter (6.0 to 11.6 µmol per liter), but the serum creatinine concentration was unchanged at 1.4 mg per deciliter (124 µmol per liter). The serum lactate dehydrogenase level was substantially elevated from 478 to 1855 U per liter (normal, <620). The serum uric acid level had risen slightly from 6.2 to 7.2 mg per deciliter (369 to 428 µmol per liter) and the serum potassium concentration had increased from 3.2 to 4.8 mmol per liter, whereas the serum calcium concentration had decreased from 8.5 to 7.9 mg per deciliter (2.1 to 2.0 mmol per liter). Empirical treatment with a combination of antibiotics was begun, along with vigorous hydration and allopurinol therapy.
Over the next three days, signs of massive tumor lysis developed. The serum lactate dehydrogenase level increased to 4484 U per liter, the serum uric acid level increased to 12.6 mg per deciliter (749 µmol per liter), and the serum creatinine concentration rose daily until it peaked at a level of 5.75 mg per deciliter (508 µmol per liter). The serum urea concentration increased to 78 mg per deciliter (28 mmol per liter), the serum phosphorus concentration rose from 4.0 to 8.4 mg per deciliter (1.3 to 2.7 mmol per liter), and the serum potassium concentration peaked at a level of 5.4 mmol per liter, whereas serum calcium levels dropped to a low of 5.76 mg per deciliter (1.44 mmol per liter), with a serum albumin concentration of 2.8 g per deciliter. In parallel, the white-cell count fell precipitously to 7000 per cubic millimeter on the eighth day after admission, accompanied by persistent granulocytopenia. Despite a urine output of 3 liters per day, renal function continued to deteriorate, and on the third hospital day, peritoneal dialysis was instituted. The fever, which had initially responded to a combination of antibiotics, rose again, accompanied by hypotension and, finally, septic shock due to Pseudomonas aeruginosa. The patient died on the 10th day of hospitalization.
A postmortem examination revealed generalized lymphadenopathy and hepatosplenomegaly. The liver weighed 3400 g; the spleen, 1290 g. Histologic examination revealed widespread, extensive infiltrates of CLL in bone marrow, spleen, lymph nodes, liver, and kidneys, with massive necrosis due to tumor lysis (Figure 1).
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Massive tumor lysis is an unusual event that is generally confined to histologically aggressive neoplasms and is very rare in CLL. Tumor lysis developed in four patients with CLL after high doses of cytarabine, cisplatin, and etoposide,6 and one of these patients died. Isolated instances of tumor lysis in CLL after fludarabine therapy have also been reported7,8,9. 2-Chlorodeoxyadenosine has been considered a relatively nontoxic agent that was developed after the observation that adenosine deaminase deficiency, a cause of combined immunodeficiency in humans, results in lymphopenia due to the accumulation of toxic levels of deoxyadenosine. The drug can cause a rapid reduction in the white-cell count of patients with susceptible hematologic neoplasms. Carson et al.3 monitored drug levels in two patients, one with chronic myeloid leukemia in blast crisis and another with T-cell leukemia-lymphoma, both of whom were treated with continuous infusions of 2-chlorodeoxyadenosine at a dose of 0.2 mg per kilogram per day -- twice the dose that our patient received. In these patients, a dramatic decline in the white-cell count coincided with an abrupt elevation of the drug levels to more than five times those generally measured during continuous infusions, due to the release of 2-chlorodeoxyadenosine from lysed cells. These two patients with documented toxic 2-chlorodeoxyadenosine levels had prolonged suppression of bone marrow, and both died of opportunistic infections3. However, neither had documented tumor lysis.
In our patient, tumor lysis started insidiously after the completion of therapy and was indicated by a substantial reduction in the palpable tumor mass, as well as by elevated serum lactate dehydrogenase and urea levels on readmission. The process peaked 11 days after the infusion of 2-chlorodeoxyadenosine was completed. Delayed lysis of CLL lymphocytes may have resulted in a sustained elevation of serum 2-chlorodeoxyadenosine levels, compounded by decreased excretion due to acute renal failure.
Pretreatment evaluation of renal function is important, since 2-chlorodeoxyadenosine is probably excreted by the kidneys, and impaired clearance may enhance the risk of tumor lysis. However, even the presence of normal renal function does not eliminate the risk of acute renal failure, as illustrated by this case report. Prophylactic allopurinol therapy, adequate hydration, and close monitoring of renal function are essential, particularly in patients with a large tumor burden.
We are indebted to Dr. E. Beutler for his help in obtaining 2-chlorodeoxyadenosine and to Dr. P. Drakos for his clinical insights in caring for the patient.
Source Information
From the Departments of Hematology (E.J.D., S.G., A.P., D.R., E.A.R.) and Pathology (E.O.), Hadassah University Hospital, Ein Kerem, Jerusalem, Israel.
Address reprint requests to Dr. Dann at Hadassah University Hospital, Kiryat Hadassah, P.O. Box 12000, il-91 120 Jerusalem, Israel.
References
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Related Letters:
Tumor Lysis Syndrome after Treatment of Chronic Lymphocytic Leukemia with Cladribine
Trendle M. C., Tefferi A., Dann E. J., Rachmilewitz E. A., Rund D.
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Full Text
N Engl J Med 1994;
330:1090, Apr 14, 1994.
Correspondence
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