Acute leukemia relapse presenting as central diabetes insipidus

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Acute Leukemia Relapse Presenting as Central Diabetes lnsipidus Pia Ra’anani, M.D.,* Ofer Shpilberg, M.D.,* Meir Berezin, M.D.,t and Isaac Ben-Bassat, M.D.*

Background, Diabetes insipidus due to leukemic involvement of the central nervous system has been described previously in several patients. Although the timing of the diabetes insipidus onset in relation to the leukemia is variable, it has not been described previously as the first manifestation of leukemia relapse. Methods. Two cases of leukemia relapse presenting as central diabetes insipidus are described and the literature is reviewed. Results. Clinical data of 29 of the 39 reported cases were available. The median age was 46 years, with no gender predominance. Seventy-three percent had acute nonlymphocytic leukemia, and deletion of chromosome 7 or monosomy 7 was the predominant cytogenetic abnormality. No temporal relation between the onset of diabetes insipidus and the leukemia was found. In none of the previously reported cases was diabetes insipidus the first manifestation of the leukemia recurrence. Conclusions. The temporal relationship between diabetes insipidus and leukemia is inconsistent. The former may precede, follow, or present concomitantly with the latter. Two cases of diabetes insipidus as the presenting sign of leukemia relapse are reported. Cancer 1994;73:2312-16.

Key words: acute leukemia, desamino-8-D-arginine vasopressin, diabetes insipidus, central nervous system.

Central nervous system (CNS) involvement in acute leukemia is not rare. Although more frequent in acute lymphocytic leukemia (ALL), it is also a well recognized entity in acute nonlymphocytic leukemia (ANLL),especially in the monocytic subtypes.’ Diabetes insipidus (DI) due to leukemic involvement of the hypothalamus or neurohypophysis is one of the clinical manifestations of CNS involvement and has been described previously From the Institutes of ‘Hematology and tEndocrinology, the Chairn Sheba Medical Center, Tel-Hashorner, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Address for reprints: Ofer Shpilberg, M.D., Institute of Hernatology, the Chaim Sheba Medical Center, Tel-Hashorner 52 621, Israel. Accepted for publication December 6, 1993.

in a few dozen patients.*-” The timing of the Dl onset in relation to the leukemia is variable, and it may precede, follow, or present concomitantly with the leukemia. In a literature search, we did not find cases in which DI was the first manifestation of the leukemia relapse. Hence, we report two such cases. Case Reports Case 1 In February 1991, a 46-year-old woman was admitted to our hospital with a history of polyuria and polydipsia for several days, compatible with recent-onset DI. The patient was diagnosed in March 1987 as having T-cell ALL according to immunophenotype analysis (CD2+, CD3+, CD5+, CD7+). Cytogenetic analysis was not available. Remission was achieved after aggressive chemotherapy according to the Berlin-Frankfurt-Munchen protocol for high-risk ALL, including daunorubicin, vincristine, L-asparginase, corticosteroids,cyclophosphamide, cytarabine, methotrexate, mercaptopurine, teniposide, and doxorubicin until 1 year before the present admission. At diagnosis, there was no CNS involvement by the leukemia, and the patient received prophylactic treatment consisting of 24 Gy cranial irradiation and intrathecal methotrexate injections. At admission, the physical examination was unremarkable except for pallor. Laboratory data revealed normal levels of sodium, creatinine, urea, and osmolality (136 mEq/l, 0.9 mg/dl, 18 mg/dl, and 289 mEq osm/kg water, respectively). Hematologic findings included hematocrit level, 34%; and leukocyte count, 23.9 times 109/1 with 56% myeloblasts, 2% myelocytes, 4% metamyelocytes, 3% bands, 17%neutrophils, 7% lymphocytes, and 11%monocytes. The platelet count was 90 times 109/l. Daily urine output averaged 14 1 with urine osmolality of 57 mOsm/kg water. Brain computed tomography scan was normal. Hormonal assays showed prolactin levels of 80 ng/ml (high); follicle stimulation hormone, 4.3 mIU/ ml (low); luteinizing hormone, 1.8 mIU/ml (low); thyroid stimulating hormone-immunoradiometric assay levels, undetectable; T4 radioimmunoassay, 5.3 mcg% (low); and free thyroxine index, 5.6 mcg/ml (low). All these levels were compatible with panhypopituitarism from hypothalamic origin. The cerebrospinal fluid analysis showed the presence of leukemic

Diabetes Insipidus in Leukemia/Ra’anani et al.

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::p: 16

URINE OUTPUT(Llter8)

10

1

6

11

16

21

26

31

DAYS Figure 1 . Patient 1’s daily urine output and response to DDAVP.

cells. Immunophenotyping of the peripheral blood leukemic cells, which were HLA-DR+, CD13+, and CD14+, was compatible with a transformation to secondary ANLL. The patient was treated with mitoxantrone, 12 mg/m2 for 3 days, and etoposide, 100 mg/m2 for 5 days. Intrathecal injections of methotrexate, cytarabine, and hydrocortisone were also given. A prolonged fluid restriction test could not be done because of her poor general condition and extreme thirst. Based on the clinical picture and laboratory data, a trial of intranasal desamino-8-D-arginine vasopressin (DDAVP), 0.05 ml (20 U) twice daily, was begun. Figures 1 and 2 show the patient‘s clinical course in terms of her daily urine output and urine osmolality. The patient was discharged with a dose of DDAVP of 0.05 ml(20 U) once daily, which controlled her DI. Unfortunately, she did not achieve a second remission and died a few months later. Permission for autopsy was denied.

Case 2 A 37-year-old man was hospitalized with diffuse musculoskeletal pain, purpura, polydipsia, and polyuria of recent onset. ANLL (French-American-British M2) had been diagnosed 1

URINE OSMOLALlTY(mOSMOL/L)

380 I

so0 260

I

I

/

i.4

Figure 3. Brain computed tomography scan of Patient 2 showing an infiltrative process in the suprasellar region.

year previously. At that time, the leukemic cells were positive on cytochemishy for myeloperoxidase and alpha-naphthyl-acetate esterase. Immunophenotyping was not performed. Cytogenetic analysis showed that the most prevalent clone was 45x; -y; t(8; 21) (q22; q22). Complete remission was achieved after induction treatment with daunorubicin, 45 mg/m2 for 3 days, plus cytarabine, 100 mg/m2 in continuous infusion for 7 days. Postremission consolidation consisted of intermediate-dose cytarabine (500 mg/m2 twice daily for 5 days) followed by a course of mitoxantrone (12 mg/m2 for 2 days) and etoposide (100 mg/ m2 for 5 days) until 8 months before the present admission. No prophylactic CNS treatment was given. Physical examination on admission revealed extensive purpura on all extremities and gingival bleeding. Laboratory data showed slightly elevated plasma osmolality (292 mOsm/kg water) but normal levels of sodium, creatinine, and urea (138 mEq/l, 1.1 m g / d and 32 mg/dl, respectively). Hematologic findings included hematocrit level, 40%; and leukocyte count, 3 X 109/1, with 65% myeloblasts, 4% segmented neutrophils, and 31% lymphocytes. The platelet count was 19 times 109/l. A bone marrow biopsy was compatible with ANLL. Cytochemical stains showed that the leukemic cells were positive for myeloperoxidase and negative for alphanaphthyl-acetate esterase. The average daily urine output was 10 1, with urine osmolality of 112 mOsm/kg water. Lumbar puncture was not performed due to the severe thrombocytopenia. Brain computed tomography scan demonstrated an infiltrative process in the suprasellar region (Fig. 3). Hormonal assays showed T4 radioimmunoassay values of 4.0 mcg/dl (low); free thyroxine index, 3.6 mcg/dl (low); and thyroid stimulating hormone-immunoradiometric assay, 0.5 U/ml (low), suggestive of panhypopituitarism from hypothalamic origin. A prolonged fluid restriction test was not done because of the patient’s poor general condition. Intranasal administration of DDAVP, 0.05 ml(20 U) twice daily, was initiated as a diagnostic and therapeutic trial of suspected central DI, and a prompt response was seen. Treatment with high-dose cytarabine, 3 g/m2 times 5 days, and amsacrine,

6

O1

6

10

16

20

PI

30

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DAYS Figure 2. Patient 1’s daily urine osmolality and response to DDAVP.

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Table 1. Clinical Characteristics of 29 Patients With Leukemia With DI Patient no.

Age (yr)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

35 69 52 57 51 53 26 55 22 69

44 79 8 56 10 3 46

Sex F M F M M F F M F M F F M F F

M M

46 37 16 24 10 22 59

M F F M F F F M M

53

M

Leukemia type ANLL ANLL (M5) ANLL (M2) ANLL (M2) ANLL (M2) ANLL (M2) ANLL (M7) ANLL ANLL ANLL ANLL ANLL (M4) ANLL ANLL ANLL ANLL ANLL ANLL (M4) ANLL ANLL ANLL ALL ALL ALL ALL CML-CP CML-BT CML-CP CLL

Previous hematologic abnormality

Dominant cytogenetic abnormality

DI onset in relation to leukemia -1 mo -4 mo

MDS MDS MDS MDS MDS

-7 -7 -7 -7 -7, -5

MDS MDS

+ I yr -2 mo AP +2 rno -4 mo AP AP AP +6 mo AP AP AP +3 mo AP +1 yr -2 rno

-7

ALL t(8;21)

lymphoma lymphoma

-7

On relapse On relapse +I2 yr -2 mo +4 mo AP +lOyr AP AP

Reference 2 3 4 4 4 4 5 6 6 6

6 7 8 9 10 11 12 13 14 Current case Current case 15 16 17 18 19 20 21 22

DI: diabetes insipidus; AP: at presentation; CP: chronic phase; BT: blastic transformation; ANLL acute nonlymphoblastic leukemia; ALL acute lymphoblastic leukemia; CML chronic mveloeenous leukemia.

200 mg/m2 times 3 days, was administered. The patient died on day 34 due to disseminated fungemia, and permission for autopsy was not granted.

Literature Review

A review of the literature by comprehensive search using the Medline data base showed that DI has been reported previously in association with leukemia in 39 patients. The main clinical characteristics of the 29 patients reported in the English literature (including the current 2 cases) are summarized in Table 1. The median age of the patients was 46 years (range, 3.5-79 years), and 14 of the 27 (52%) of known sex were females, The diagnostic subgroups included 2 1 (73%) patients with ANLL, 4 (14%) with ALL, 3 (10%) with chronic myelocytic leukemia (one in blastic crisis), and 1 patient (3%) with chronic lymphocytic leukemia. Seven of the 21 patients with ANLL had a myelodysplastic syndrome preceding the development of overt

leukemia. In two of the four patients with ALL, a lymphoma preceded the leukemic phase. In the remaining patients, a previous hematologic disorder either did not exist or was not mentioned. Chromosomal analysis was reported in eight of the patients and included monosomy 7 in six patients (including one patient with an additional deletion of chromosome 5), one patient with deletion of chromosome 7(q22), and one patient with translocation (8;21). In six patients, the DI preceded the leukemia at a median period of 2 months (range, 1-4 months). In 11 patients, DI and the leukemic process presented concomitantly, and in 8 patients, the leukemia preceded the DI at a median period of 9 months (range, 2 months-12 years). Only in the two current cases was DI the harbinger of the recurrence of leukemia. Discussion

DI is a rare complication of acute leukemia, although perihypophyseal leukemic infiltrates were found at au-

Diabetes Insipidus in Leukemia/Ra'anani et al.

topsy in 46% of the patient^.'^ Two types of histologic findings have been described as the pathogenesis of DI in patients with leukemia: diffuse leukemic infiltrates of the posterior pituitary gland and/or thrombosis of the small vessels in the hypothalamic nuclei and posterior lobe of the p i t ~ i t a r y . ~ , ~ , ~Unfortunately, -",'~ our cases lack documentation of the pathologic process and its anatomic location, because autopsy could not be obtained. However, based on the radiologic findings and the results of the hormonal assays, we assumed that the pathology was hypothalamic in origin. Several reports showed a failure of the antileukemic therapy to alleviate the symptoms of DI in patients with l e ~ k e m i aThe .~ failure to reverse DI may partly reflect the finding that clinical DI associated with leukemia results from destruction of cells rather than their dysfunction6 Thus, the most useful therapy is standard hormonal replacement, although 15% of the patients are resistant to DDAVP the rap^.^ We therefore assume that the correction of DI in both our patients cannot be attributed to the cytotoxic therapy but rather to DDAVP administration. The ratio of ANLL to ALL in patients with DI with leukemia is 5:l (73% versus 14%) and is significantly higher than the 1:1ratio in the general population.' This difference may be explained by the finding that CNS prophylaxis with CNS irradiation and intrathecal chemotherapy is administered routinely to patients with ALL but not to patients with ANLL. The possibility that ANLL developed secondary to treatment with epipodophyllotoxins (i-e., teniposide) could not be ruled out in Patient 1, especially because the T-cell immunophenotype has been associated with the development of secondary ANLL.24T25 However, because prolonged exposure to epipodophyllotoxins was associated with the development of secondary ANLL,24 it seems unlikely in our patient, because she was treated only three times with teniposide. A recent report by Tallman et al. pointed to an association between granulocytic sarcomas and ANLL with t(8; 21).26Several previous series reported the occurrence of granulocytic sarcomas in approximately 18% of this population, which is four times the expected incidence in ANLL. Although the possibility of a granulocytic sarcoma involving the hypothalamus in Patient 2 should be considered, we find it unlikely, because involvement of the suprasellar region has not been reported. Monosomy 7 is found in 7.4% of patients with de novo ANLL and in 28.6% of patients with secondary ANLL.27*28The fact that monosomy 7 or deletion 7q(22) was found in seven of eight patients with leukemia and DI suggests that this aberration may predispose to DI in patients with leukemia. The molecular mechanism triggered by this aberration and facilitating the development of DI is under study.4

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The data from the literature review showed that the temporal relationship between DI and leukemia is variable and inconsistent. Of note is the finding that in 6 of the 29 patients, DI preceded leukemia with a short interval of 1-4 months. This may reflect the minority of patients in whom CNS manifestations of the leukemic process precede the systemic ones. Our patients are unique, because DI was the first presentation of their leukemic relapse. Thus, the onset of DI in a patient with a history of acute leukemia in remission should alert the physician to the possibility of hematologic relapse. References 1. Henderson ES. Acute leukemia: general considerations. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA. Hematology. 4th ed. New York: McGraw-Hill, 1990936-50. 2. Miller VI, Campbell WG. Diabetes insipidus as a complication of leukemia. Cancer 1971; 28:666-73. 3. Foresti V, Casteli 0,Villa A, Lazzar A. Central diabetes insipidus due to acute monocytic leukemia: case report and review of the literature. ] Endocr Invest 1992; 15:127-30. 4. De-la-Chapelle A, Lahtinen R. Monosomy 7 predisposes to diabetes insipidus in leukemia and myelodysplastic syndrome. Eur ] Haematof 1987; 39:404-11. 5. Montecucco C, Cazzola M, Ascari E. Diabetes insipidus in the pre-leukemic phase of acute non-lymphocytic leukemia: a monosomy 7-associated condition [letter]? Scand ] Haematol 1984; 33:326-7. 6. Kimmel DW, O'Neil BP. Systemic cancer presenting as diabetes insipidus: clinical and radiographic features of 11 patients with a review of metastatic-induced diabetes insipidus. Cancer 1983; 15:2355-8. 7. Philippakos D, Kakouros S, Dervenoulas J, Pantidas E. Diabetes insipidus as a complication of acute myelomonocytic leukemia. PostgradMed] 1983; 59:93-4. 8. Newcomer LN. Diabetes insipidus associated with central nervous system leukemia. South M e d ] 1982; 75:1142-3. 9. Bergman GE, Baluarte HJ, Naiman JL. Diabetes insipidus as a presenting manifestation of acute myelogenous leukemia. ] Pediatr 1976; 88:355. 10. Rosenzweig Al, Kendall JW. Diabetes insipidus as a complication of acute leukemia. Arch Intern Med 1966; 117:397-400. 11. Joseph MC, Levin SE. Leukemia and diabetes insipidus: case report with unexpected effect of cortisone. Br M e d J 1956; 1:132831. 12. Roy S, Johnson WW. Diabetes insipidus in a child with erythromyelocytic leukemia. A m ]Dis Child 1970; 119:82-5. 13. Cumming WJK, Spiers ASD. Diabetes insipidus and marked elevation of foetal haemoglobin in a case of acute leukemia. Postgrad Med J 1974; 50:468-70. 14. Slater SE, Maccalum PK, Birjandi F, Gibbons B, Lister TA. Acute myelogenous leukemia and diabetes insipidus: further association with monosomy 7. Haematol Oncol 1992; 10:221-3. 15. Dibenedetto SP, Mancuso GR, Samperi P, Di-Castaldo A, Ragusa R, Caruso-Nicoletti M. Diabetes insipidus 9 years after cessation of therapy for acute lymphoblastic leukemia. Pediatr Hematof Oncof 1991; 8:231-3. 16. Kornberg A, Zimmerman J, Matzner Y, Polliak A. Acute lymphoblastic leukemia: association with vasopressin responsive diabetes insipidus. Arch Znterii Med 1980; 140:1236. 17. Maker IJ, Gross S, Teree TM. Diabetes insipidus complicating acute lymphocytic leukemia. A m J Dis Child 1969; 117228-30.

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18. Flynn JE, Bowers JM. Acute lymphatic leukemia with diabetes insipidus and uremia. J Urol 1947; 58:106-11. 19. Juan D, Hsu SD, Hunten J. Case report of vasopressin responsive diabetes insipidus associated with chronic myelogenous leukemia. Cancer 1985; 56:1468-9. 20. Sandullah S, Kruger AR, Barrington-Onslow S, Armitage M, Oscier DG. A patient with monosomy 7 and polyuria. Leuk Res 1992; 16:711-5. 21. Eichhorn P, Rhyner IL, Hallor D, Hammerli R, Steuli R, Furrer J. Diabetes insipidus in chronic myeloid leukemia: remission of hypophyseal infiltration during busulfan treatment. Schweiz Med Wochenschr 1988; 188:275-9. 22. Williams HM, Diamond HD, Craver LF. The pathogenesis and management of neurological complications in patients with malignant lymphomas and leukemias. Cancer 1958; 11:76-82. 23. Masse SR, Wolk RW, Conklin RH. Prepituitary gland involvement in acute leukemia in adults. Arch Pathol 1973; 96:141-2. 24. Pui CH, Ribeino RC, Hanoch ML, Rivena GK, Evans WE, Raime-

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ndi SC, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl ] Med 1991; 12:1682-7. Pui CH, Behm FG, Raimondi SC, Dodge RK, George SL, Rivera GK, et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl ]Med 1989; 321:136-42. Tallman MS, Hakimian D, Shaw JM, Lissner GS, Russel EJ, Vaniakojis D. Granulocytic sarcoma is associated with the 8; 21 translocation in acute myeloid leukemia. Clin Oncol 1993; 11: 690-7. Fourth International Workshop on Chromosomes in Leukemia, 1982. Abnormalities of chromosome 7 resulting in monosomy 7 or in deletion of the long arm (7q-): review of translocations, breakpoints and associated abnormalities. Cancer Genet Cytogenet 1984; 11:300-3. Fourth International Workshop on Chromosomes in Leukemia, 1979. Clinical significance of chromosomal abnormalities in acute nonlymphoblastic leukemia. Cancer Genet Cytogenet 1981; 2:108-11.