Diabetes Insipidus 9 Years after Cessation of Therapy for Acute Lymphoblastic Leukemia

Short Communication

DIABETES INSIPIDUS 9 YEARS AFTER CESSATION OF THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA

Salvatore P. Dibenedetto, MD, Research fellow, Giovanna Russo Mancuso, MD, Research fellow, Piera Samperi, MD, Research fellow, Andrea Di Cataldo, MD, Research fellow, Rosalia Ragusa, MD, Research fellow, and Manuela Caruso-Nicoletti, MD, Research fellow 0 Department of Hematology and Pediatrics, University Hospital, Wale A. Doria 6, 95125 Catania, Italy

0 A case o j a 16-year-old who developed diabetes insipidus (DI) 9 years afier cessation of therapy for A L L is reported. Because hereditary and traumatic factors are excluded as a cause of DI in this patient, possible explanations may be leukemic CNS relapse, secondary brain tumor, primitive idiopathic DI, and late sequelae o j CNS radiochemotherapy.

KEY WORDS: acute lymphoblastic leukemia, diabetes insipidus, d q therapy, radiotherapy.

INTRODUCTION

The neuroendocrine function of long-term survivors who received central nervous system (CNS) prophylaxis as part of their therapy for acute lympho- cytic leukemia (ALL) has been extensively studied. Most studies report conflict- ing data on the effects of CNS prophylaxis on growth-hormone secretion, and hypothalamus-pituitary-thyroid, hypothalamus-pituitary-gonadal, and hypothalamus-pituitary-adrenal axes. Clinical evidence of posterior pituitary dysfunction has not been previously described. We report the case of a 16-year- old girl who developed diabetes insipidus (DI) 9 years after cessation of therapy for ALL.

CASE REPORT

In 1977 a 3'/z-year-old girl was diagnosed as having ALL and considered at average risk of relapse because of her age, a WBC of <25,00O/mmc, and the absence of extramedullary leukemia. She was induced with prednisone (PDN; 40 mg/sqm) daily, five doses of vincristine (VCR; 1.5 mg/sqm) plus adriamy-

This work was supported by grant from Minister0 della Pubblica Istruzione [Ministry of Public Instruction]; quota 40%-60% 1988-1989.

Pediatric H c m a t o l o ~ and Oncolou, 8:231-233, 1991 Copyright @ 1991 by Hemisphere Publishing Corporation

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232 S. P. DIBENEDETTO ET A1

cine (15 mghqm) once a week, and nine doses of L-asparaginase (6000 Ulsqm). Complete remission was achieved. The regimen of CNS prophylaxis included cranial irradiation (2400 cGy orthovoltage) plus intrathecal methotrexate (1 2 mg X 7). Maintenance chemotherapy consisted of 6-mercaptopurine (50 mg/ sqm) daily and methotrexate (20 mghqm) administered intramuscularly every week. VCR and PDN reinduction therapy was given every 3 months. Treat- ment lasted 3.5 years and the course was uneventful. After cessation of therapy the patient was closely monitored: monthly for the first year, every 3 months during the second year, and then every 6 months. Physical, hematologic, and neurologic examinations (including fundus oculi) were performed at each follow-up. Endocrine studies showed normal results for linear growth, the ACTH test, and levels of thyroid-stimulating hormone, T4, follicle-stimulating hormone, and luteinizing hormone. The patient had menarche at the age of 13 and has had regular menstrual cycles up to now.

In May 1989, 12 years after diagnosis, she presented polyuria (7 herdday) and polydipsia. Routine hematologic examination and urine analysis were all normal except for urine concentration. A water deprivation test showed the inability to concentrate urine and satisfactory responsiveness to 1 -deamino-8- arginine vasopressin (DDAVP). DI was diagnosed and DDAVP treatment was started successfully. Lumbar puncture was refused by the patient. Cranial nu- clear magnetic resonance (NMR) imaging, performed at onset of DI and 6 and 14 months later, revealed normal findings.

DISCUSSION

Hereditary and traumatic factors were excluded in our patient. Other possi- ble explanations could be leukemic CNS relapse, secondary brain tumor, primi- tive idiopathic DI, and the late sequelae of CNS radiochemotherapy.

The long interval between cessation of treatment and onset of DI makes CNS relapse unlikely even though a spinal fluid analysis has not been per- formed.6 Three negative NMRs and an accurate clinical and hematologic follow-up carried out until October 1990 tend to exclude brain tumor.

A relationship between CNS preventive therapy and brain damage should be taken into account before labeling this case as primarily idiopathic DI. Many reports suggest that cranial irradiation and intrathecal chemotherapy encom- pass a broad spectrum of

Neuroendocrine abnormalities have been mainly related to cranial irradia- tion. Low doses seem to affect the hypothalamus (including supraoptic and paraventricular nuclei), whereas high doses (over 3000 rads)* impair pituitary gland function. In this light it is surprising that DI is not seen as consequence of irradiati~n.~ A possible explanation can be that the detrimental effects of CNS prophylaxis tend to be delayed. In fact, interruption of approximately 50% of

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DIABETES INSIPIDUS AFTER ALL 233

the supraoptic-hypothalamic tract fibers or near-total destruction of the poste- rior lobe is required before clinical DI develops.’ These processes may take time and clinical manifestations may only be observed in very long-term survivors.

Neurologic consequences in long-term survivors are still unknown; the cost of CNS prophylaxis in terms of late-appearing toxicities is now being borne.

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2. Packer RJ, Meadows AT, Rorke LB, Goldwein JL, D’Angio G. Long-term sequelae of cancer treat- ment on the central nervous system in childhood. Med Pediatr Oncol. 1987;15:241-253.

3. Russo A, Schilirb G. Some aspects of neurotoxicity associated with central nervous system prophylaxis in childhood leukemia. Acta H a m t o l . 1987;78(suppl 1): 139-141.

4. Poplak DG, Broweis P. Adverse sequelae of central nervous system. J Clin Oncol. 1985;4:263-285. 5. Kimmel DW, O’Neill BP. Systemic cancer presenting as diabetes insipidus. Cancer. 1983;52:2355-2358. 6 . Schweinle JE, Alperin JB. Central nervous system recurrence 10 years after remission of acute lympho-

7. Appleton RE, Farrell K , Zaide J , Rogers P. Decline in head growth and cognitive impairment in

8. Russo A, Tomarchio S, Pero G, et al. Abnormal visual evoked potentials in leukemic children after

9. Littley MD, Shalet SM, Beardwell CG. Radiation and hypothalamic-pituitary function. In: Shalet SM,

blastic leukemia. Cancer. 1980;45:16-18.

survivors of acute lymphoblastic leukaemia. Arch Dis Child. 1990;65:530-534,

cranial radiation. Med Pediafr Oncol. 1985;13:313-317.

ed. Bailli&e i Clinical Endocrinolou and Metabolism. London: Bailliire Tindall; 1990: 147-1 75.

Received Augusi 7, 1990 Accepted October 23, 1990

Address correspondence to S. P Dibenedetfo

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