Acute Tumor Lysis Syndrome Following Intrathecal ...

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

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

Acute Tumor Lysis Syndrome Following Intrathecal Methotrexate MUSTAFA BENEKLI, IBRAHIM H. @LU, M.C E M ~ LSAVAS, ASPURRAHMAN KADAYIFCI, M. KADRI ALTUNDAG, GULTEN TEKUZMAN and DINCER FIRAT Department of Internal Medicine, Hacenepe University, Faculty of Medicine, Ankara, Turkey

Leuk Lymphoma Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.

(Received infinal form October 22, 1995)

We report a 17-year-old boy with meningeal involvement of lymphoblastic lymphoma who experienced acute tumor lysis syndrome following intrathecaladministration 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 syndrome to be described after intrathecal methotrexate injection. The pathogenesis of this unusual complication of intrathecal chemotherapy is discussed.

KEY WORDS: Lymphoblastic lymphoma methotrexate tumor lysis syndrome

meningeal involvement

intrathecal

INTRODUCTION

CASE REPORT

Tumor lysis syndrome is described in patients with rapidly proliferating lymphoid neoplasms such as acute lymphoblastic leukemia and high grade lymphomas following 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 constituents, 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 following intrathecal methotrexate in a patient with meningeal involvement of lymphoblasticlymphoma. 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 intrathecal methotrexate administration.4

A 17-year-oldboy 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 following the administration of a chemotherapeutic regimen which included alternating cycles of vincristinebleomycin and cyclophosphamide-doxorubicin-etoposide-prednisolone (VB-CHEP). The planned cranial prophylactic radiotherapy was refused by the patient. On this current admission, he had generalised lymphadenopathy, hepatosplenomegaly and nuchal rigidity. The white blood cell (WBC) count was 214 x lOVl, consisting of 90% lymphoblasts on the peripheral smear. A cranial computerised tomography showed meningeal involvement by the lymphoma. A lumbar puncture confirmed the lymphoblastic infiltration. The bone marrow was infiltrated with lymphoblasts of B-cell type, which were CD19+, CD20+, HLA-DR+ and Ig h+. Qn laboratory analysis, blood urea nitrogen (BUN) was 27 mg/dl, serum creatinine 1.8 mg/dl, LDH 1166 IUA, potassium 3.8 tnEqA, uric acid 7.9 mg/dl, albumin 3.6 g/dl, &alcium 11.1 mg/dl and phosphorus 1.9 mg/dl. Immediately after admission, the patient was started on intravenous hydration with saline and dextrose 5 % , sodium bicarbonate in-

Address for correspondence: Mustafa Benekli, M.D., 14. Sokak. 43/3, Bahqelievler, Ankara, TURKEY 361

Leuk Lymphoma Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.

362

M . BENEKLI ETAL.

fusion and allopurinol 300 mg/day. Urine output was 2.5 liters on the first day of admission. Amikacin and ceftazidime were begun because of persistant fever with neutropenia despite to negative blood and urine cultures. Starting from the second day of hospitalisation, 15 mg of preservative-free methotrexate were administered intrathecally, 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 analysis were available. Throughout this time, the patient received 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 hydration and sodium bicarbonate infusion to force alkaline diuresis and aluminum hydroxide gel. Allopurinol was increased 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 radiotherapy and subsequent systemic chemotherapy consisting of vincristine, mitoxantrone and prednisolone with close monitoring and no further complication. He is currently alive and in remission.

.. 80

-.70 --

80

-I

--

50

40

.-30 --

20

.- 10

10

--

I

--

4

.-

0

4

:

:

:

:

:

:

:

:

!

: 4 0

-1

0

1

2

3

4

6

6

1

8

:

:

:

:

2

3

4

5

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 ~ r e . ~ Methotrexate is employed intrathecally for cranial prophylaxis of leukemia and in situations of carcinomatous or leukemic meningitis. Methotrexate is negatively charged at neutral pH as a weak organic acid, and therefore 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 direct intracavitary therapy.6 Since duration of exposure is important, short exposure periods are less effective than longer periods in producing cell kill.7 Intrathecally injected methotrexate provides a slow-release reservoir of methotrexate into the blood stream with prolonged cytotoxic levels and may cause tumor lysis syndrome. CSF

2

0

: -t

: 0

: 1

:

6

:

t

7

o

8

time in days Figure 1 Changes in serum biochemical values. Arrows indicate the days of intrathecal methotrexate administration.

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

Leuk Lymphoma Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.

TUMOR LYSIS WITH IT MTX

period. Thepatientwasgivenprophylacticamikacinandceftazidime both of which bind to plasma proteins in very low amountsand do not alter methotrexate-proteinbinding. Freemethotrexatelevels are also increased in hypoalbuminemia, but the serum albumin level was normal in our patient. Tumor lysis syndromehas been reported most commonly after systemic combinationchemotherapy of rapidly proliferating neoplasms. Although single agent induced acute tumor lysis has previouslybeen identifiedin lymphomasand leukemias,23the occurrence of massive tumor lysis following intrathecal administrationof methotrexate is not a well recognised clinical entity. For prophylactic treatment, vigorous hydration, urine alkalinisationwith sodiumbicarbonate and allopurinol should be initiated once intrathecal methotrexate is planned. Close monitoring of renal functions, serum electrolytes and urine output is essential, particularly in patients with high serum LDH levels reflecting large tumor burden. However, renal failure may ensue despite adequatepretreatmentpreventivesupportivemeasures. Prompt institution of appropriate treatment upon diagnosis of tumor lysis can be life-saving.

363

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) Increasedrecognition of corticosteroid induced tumor lysis syndrome in nonHodgkin’s lymphoma. Cancer, 65,1072-1073. 4. Simmons, E. D. and Somberg, K. A. (1991) Acute tumor lysis syndrome 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 injectjons. N. Engl. J. M e d , 293, 161-166. 6. Bode, U., Magrath, I. T., Bleyer, W. A,, Poplack, D. G. and Glaubiger, D. L. (1980) Active transportof methotrexatefrom cerebrospinal 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.