Leukemia and Lymphoma, Vol. 22, pp. 361-363 Reprints available directly from the publisher Photocopying permitted by license only

Acute Tumor Lysis Intrathecal

0 1996 OPA (Overseas Publishers Association) Amsterdam B.V. Published in The Netherlands by Harwood Academic Publishers GmbH

Printed in Singapore

Syndrome Following Methotrexate

MUSTAFA BENEKLI, IBRAHIM H. @LU, M. CEM~L SAVAS, ASPURRAHMAN KADAYIFCI, M. KADRI ALTUNDAG, GULTEN TEKUZMAN and DINCER FIRAT

Department of Internal Medicine, Hacenepe University, Faculty of Medicine, Ankara, Turkey

(Received infinal form October 22, 1995)

We report a 17-year-old boy with meningeal involvement of lymphoblastic lymphoma who experi- enced acute tumor lysis syndrome following intrathecal administration of methotrexate. Intrathecally injected methotrexate provides a slow- release reservoir of methotrexate into the bloodstream with prolonged cytotoxic levels. To the best of our knowledge, this is the second case of tumor lysis syn- drome to be described after intrathecal methotrexate injection. The pathogenesis of this unusual com- plication of intrathecal chemotherapy is discussed.

KEY WORDS: Lymphoblastic lymphoma meningeal involvement intrathecal methotrexate tumor lysis syndrome

INTRODUCTION

Tumor lysis syndrome is described in patients with rapidly proliferating lymphoid neoplasms such as acute lym- phoblastic leukemia and high grade lymphomas follow- ing cytoreductive chemotherapy.1-3 The rapid lysis of large numbers of highly susceptible tumor cells leads to severe metabolic alterations resulting from the inability to handle the excessive load of released intracellular con- stituents, primarily uric acid, phosphorus and potassium.’ The typical metabolic consequences are hyperuricemia, hyperkalemia, hyperphosphatemia with concomitant hypocalcemia and acute renal failure.

We report here a case of tumor lysis syndrome follow- ing intrathecal methotrexate in a patient with meningeal involvement of lymphoblastic lymphoma. This case is the second report in the literature of tumor lysis syndrome following intrathecal methotrexate which illustrates an unusual, potentially life-threatening complication of in- trathecal methotrexate administration.4

Address for correspondence: Mustafa Benekli, M.D., 14. Sokak. 43/3, Bahqelievler, Ankara, TURKEY

CASE REPORT

A 17-year-old boy was readmitted in August 1993 to our hospital with fever, malaise and headache. In his medical history, a lymphoblastic lymphoma diagnosed 8 months earlier had been induced into complete remission follow- ing the administration of a chemotherapeutic regimen which included alternating cycles of vincristine- bleomycin and cyclophosphamide-doxorubicin-etopo- side-prednisolone (VB-CHEP). The planned cranial prophylactic radiotherapy was refused by the patient. On this current admission, he had generalised lym- phadenopathy, hepatosplenomegaly and nuchal rigidity. The white blood cell (WBC) count was 214 x lOVl, con- sisting of 90% lymphoblasts on the peripheral smear. A cranial computerised tomography showed meningeal in- volvement by the lymphoma. A lumbar puncture con- firmed the lymphoblastic infiltration. The bone marrow was infiltrated with lymphoblasts of B-cell type, which were CD19+, CD20+, HLA-DR+ and Ig h+. Qn labora- tory analysis, blood urea nitrogen (BUN) was 27 mg/dl, serum creatinine 1.8 mg/dl, LDH 1 166 IUA, potassium 3.8 tnEqA, uric acid 7.9 mg/dl, albumin 3.6 g/dl, &alcium 1 1.1 mg/dl and phosphorus 1.9 mg/dl. Immediately after admission, the patient was started on intravenous hydra- tion with saline and dextrose 5%, sodium bicarbonate in-

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362 M . BENEKLI ETAL.

fusion and allopurinol 300 mg/day. Urine output was 2.5 liters on the first day of admission. Amikacin and cef- tazidime were begun because of persistant fever with neu- tropenia despite to negative blood and urine cultures.

Starting from the second day of hospitalisation, 15 mg of preservative-free methotrexate were administered in- trathecally, 3 times weekly, for 6 doses for the treatment of CNS relapse. Systemic chemotherapy was postponed a few days until the results of the immunophenotypic analy- sis were available. Throughout this time, the patient re- ceived no steroid medication. After 30 mg of methotrexate given over 4 days, the WBC fell to 2.6 x l09A; this was followed by a rise in serum creatinine and urea nitrogen to 3.8 mg/dl and 84 mg/dl, respectively (Fig I). Uric acid rose to 13.6 mg/dl, serum phosphorus increased to 9.2 mg/dl with a concomitant fall in serum calcium to 4.4 mg/dl. A renal ultrasound revealed an increase in parenchymal echo pattern and a urinary tract obstruction was excluded. The patient was treated with vigorous hy- dration and sodium bicarbonate infusion to force alkaline diuresis and aluminum hydroxide gel. Allopurinol was in- creased to 900 mg/day. Over the next 2 days, the serum biochemistry profile returned to normal levels without the need of hemodialysis. The patient received cranial radio- therapy and subsequent systemic chemotherapy consist- ing of vincristine, mitoxantrone and prednisolone with close monitoring and no further complication. He is cur- rently alive and in remission.

DISCUSSION

Tumor lysis syndrome following intrathecal methotrexate is very rare and to the best of our knowledge, there has only been a single report until now in the l i t e r a t~ re .~ Methotrexate is employed intrathecally for cranial pro- phylaxis of leukemia and in situations of carcinomatous or leukemic meningitis. Methotrexate is negatively charged at neutral pH as a weak organic acid, and there- fore has limited lipid solubility and diffuses slowly across physiologic membranous barriers.5 During systemic chemotherapy for leukemia, the blood-brain barrier greatly prevents the entry of chemotherapeutic drugs into the brain, thus creating a “sanctuary” site for leukemic cells. This reduced rate of absorption slows the egress of methotrexate from CSF and has become the basis for di- rect intracavitary therapy.6 Since duration of exposure is important, short exposure periods are less effective than longer periods in producing cell kill.7 Intrathecally in- jected methotrexate provides a slow-release reservoir of methotrexate into the blood stream with prolonged cyto- toxic levels and may cause tumor lysis syndrome. CSF

.. 80

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Figure 1 days of intrathecal methotrexate administration.

Changes in serum biochemical values. Arrows indicate the

clearance of the drug may further be prolonged in patients with active meningeal disease as in our case.&

Methotrexate is loosely bound to serum albumin with approximately 60% binding rates and can be displaced easily resulting in increased serum free-methotrexate concentration^.^ Unfortunately, simultaneous serum methotrexate levels were not obtained during the tumor

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TUMOR LYSIS WITH IT MTX 363

period. Thepatientwas givenprophylacticamikacinandcef- tazidime both of which bind to plasma proteins in very low amounts and do not alter methotrexate-protein binding. Free- methotrexate levels are also increased in hypoalbuminemia, but the serum albumin level was normal in our patient.

Tumor lysis syndrome has been reported most commonly after systemic combination chemotherapy of rapidly prolif- erating neoplasms. Although single agent induced acute tumor lysis has previously been identified in lymphomas and leukemias,23 the occurrence of massive tumor lysis follow- ing intrathecal administration of methotrexate is not a well recognised clinical entity. For prophylactic treatment, vig- orous hydration, urine alkalinisation with sodium bicarbon- ate and allopurinol should be initiated once intrathecal methotrexate is planned. Close monitoring of renal func- tions, serum electrolytes and urine output is essential, par- ticularly in patients with high serum LDH levels reflecting large tumor burden. However, renal failure may ensue de- spite adequate pretreatment preventive supportive measures. Prompt institution of appropriate treatment upon diagnosis of tumor lysis can be life-saving.

REFERENCES

1. Arrambide, K. andToto, R. D. (1993)Tumor lysis syndrome. Semin. Nephrol., 309, 1094-1104.

2. Benekli, M., Savas,, M. C., Giillii, I. H., KadayifGi, A., Akpek, G., Kars, A., Giiler, N., Kansu, E., Tekuzman, G. and Firat, D. (1995) Tumor lysis syndrome following single dose mitoxantrone. Chemotherapy, 41,470472.

3. Sparano, J., Ramirez, M. and Wiemik, P. H. (1990) Increased recog- nition of corticosteroid induced tumor lysis syndrome in non- Hodgkin’s lymphoma. Cancer, 65,1072-1073.

4. Simmons, E. D. and Somberg, K. A. (1991) Acute tumor lysis syn- drome after intrathecal methotrexate administration. Cancer, 67, 2062-2065.

5. Shapiro, W. R., Young, D. R. and Mehta, B. M. (1975) Distribution in cerebrospinal fluid after intravenous, ventricular and lumbar in- jectjons. N. Engl. J. Med, 293, 161-166.

6. Bode, U., Magrath, I. T., Bleyer, W. A,, Poplack, D. G. and Glaubiger, D. L. (1980) Active transport of methotrexate from cere- brospinal fluid in humans. Cancer Res., 40,2184-2187.

7. Jolivet, J.,Cowan, K. H., Curt,G. A.,Cleadeninn,N. J. andchabner, B. A. (1983) The pharmacology and clinical use of methotrexate. N. Engl. J. Med., 309,10941104.

8. Bleyer, W. A., Drake, J. C. and Chabner, B. A. (1973) Neurotoxicity and elevated cerebrospinal fluid methotrexate concentration in meningeal leukemia. N. Engl. J. Med, 289,770-773.

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