acute tumour lysis syndrome following a single-dose corticosteroid in children with acute...

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Case report Acute tumour lysis syndrome following a single-dose corticosteroid in children with acute lymphoblastic leukaemia Duzova A, C ¸ etin M, Gu ¨mru ¨ k F, Yetgin S. Acute tumour lysis syndrome following a single-dose corticosteroid in children with acute lymphoblastic leukaemia. Eur J Haematol 2001: 66: 404–407. # Munksgaard 2001. Abstract: Acute tumour lysis syndrome (ATLS) is a well recognised complication of treatment of a variety of malignant disorders. It commonly occurs in patients with non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukaemia (ALL) with the administration of combined cytotoxic chemotherapy. It is rarely reported after single-agent corticosteroid therapy. We present two children with acute lympho- blastic leukaemia of T-cell lineage who developed acute tumour lysis syndrome after a single dose of prednisolone, and methylprednisolone at the beginning of the induction chemotherapy. In the first case (an 11-yr- old) ATLS had occurred after an oral dose of prednisolone as small as 12 mg and within 18 h. The second case was a 14-yr-old boy with ALL who developed ATLS following a single dose of methylprednisolone. A few similar cases in the English literature are summarised in the report. These cases indicate that acute tumour lysis syndrome may occur after a single dose of corticosteroids. One should be aware of this potentially life-threatening complication especially while prescribing corticosteroids to patients with NHL and leukaemia. Ali Duzova 1 , Mualla C ¸ etin 2 , Fatma Gu ¨mru ¨k 2 , Sevgi Yetgin 2 1 Department of Pediatrics, Pediatric Nephrology and Rheumatology Unit and 2 Department of Pediatrics, Pediatric Hematology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey Key words: tumour lysis; acute lymphoblastic leukaemia; prednisolone; methylprednisolone Correspondence: Dr Ali Duzova, Department of Pediatrics, Pediatric Nephrology and Rheumatology Unit, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey Tel: +90-312-3051863 Fax: +90-312-3094232 e-mail: [email protected] Accepted for publication 21 March 2001 Acute tumour lysis syndrome (ATLS) typically accompanies treatment of lymphoproliferative dis- orders in which there is evidence of bulk disease and where the doubling time of the tumour cells is short. The syndrome consists of hyperuricemia, hyperka- lemia, hyperphosphatemia, hypocalcemia and acute renal failure. It commonly occurs in acute hemato- poietic neoplasms, particularly in non-Hodgkin’s lymphomas (NHL) and acute leukaemia (1, 2). It is rarely reported in association with non-hemato- poietic neoplasms such as breast cancer (3, 4), seminoma (4), or bronchogenic carcinoma (5). Patients with a high serum lactate dehydrogenase level or renal insufficiency are at increased risk (6). In this article two cases of ATLS in two children (aged 11 and 14 yr, respectively) with ALL at the beginning of the induction chemotherapy (the former secondary to a single dose of prednisolone, the latter secondary to methylprednisolone) are presented. The cases and the literature are dis- cussed. Case 1 An 11-yr-old boy was referred to Hacettepe University Children’s Hospital with a two-month history of malaise, loss of appetite and a weight loss of 4 kg. Physical examination revealed widespread lymphadenopathy with 1-cm firm lymph nodes palpable in the submental, cervical, axillary and inguinal regions; liver and spleen were extended below coastal margins 9 and 8 cm, respectively. Eur J Haematol 2001: 66: 404–407 Printed in UK. All rights reserved Copyright # Munksgaard 2001 EUROPEAN JOURNAL OF HAEMATOLOGY ISSN 0902-4441 404

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Case report

Acute tumour lysis syndrome following asingle-dose corticosteroid in children withacute lymphoblastic leukaemia

Duzova A, CË etin M, GuÈmruÈk F, Yetgin S. Acute tumour lysis syndromefollowing a single-dose corticosteroid in children with acutelymphoblastic leukaemia.Eur J Haematol 2001: 66: 404±407. # Munksgaard 2001.

Abstract: Acute tumour lysis syndrome (ATLS) is a well recognisedcomplication of treatment of a variety of malignant disorders. Itcommonly occurs in patients with non-Hodgkin's lymphoma (NHL) andacute lymphoblastic leukaemia (ALL) with the administration ofcombined cytotoxic chemotherapy. It is rarely reported after single-agentcorticosteroid therapy. We present two children with acute lympho-blastic leukaemia of T-cell lineage who developed acute tumour lysissyndrome after a single dose of prednisolone, and methylprednisolone atthe beginning of the induction chemotherapy. In the ®rst case (an 11-yr-old) ATLS had occurred after an oral dose of prednisolone as small as12 mg and within 18 h. The second case was a 14-yr-old boy with ALLwho developed ATLS following a single dose of methylprednisolone. Afew similar cases in the English literature are summarised in the report.These cases indicate that acute tumour lysis syndrome may occur after asingle dose of corticosteroids. One should be aware of this potentiallylife-threatening complication especially while prescribing corticosteroidsto patients with NHL and leukaemia.

Ali Duzova1, Mualla CË etin2,Fatma GuÈmruÈk2, Sevgi Yetgin2

1Department of Pediatrics, Pediatric Nephrology and

Rheumatology Unit and2Department of Pediatrics,

Pediatric Hematology Unit, Hacettepe University

Faculty of Medicine, Ankara, Turkey

Key words: tumour lysis; acute lymphoblastic

leukaemia; prednisolone; methylprednisolone

Correspondence: Dr Ali Duzova, Department of

Pediatrics, Pediatric Nephrology and Rheumatology

Unit, Hacettepe University, Faculty of Medicine, 06100

Ankara, Turkey

Tel: +90-312-3051863

Fax: +90-312-3094232

e-mail: [email protected]

Accepted for publication 21 March 2001

Acute tumour lysis syndrome (ATLS) typicallyaccompanies treatment of lymphoproliferative dis-orders in which there is evidence of bulk disease andwhere the doubling time of the tumour cells is short.The syndrome consists of hyperuricemia, hyperka-lemia, hyperphosphatemia, hypocalcemia and acuterenal failure. It commonly occurs in acute hemato-poietic neoplasms, particularly in non-Hodgkin'slymphomas (NHL) and acute leukaemia (1, 2). It israrely reported in association with non-hemato-poietic neoplasms such as breast cancer (3, 4),seminoma (4), or bronchogenic carcinoma (5).Patients with a high serum lactate dehydrogenaselevel or renal insuf®ciency are at increased risk (6).In this article two cases of ATLS in two children(aged 11 and 14 yr, respectively) with ALL at the

beginning of the induction chemotherapy (theformer secondary to a single dose of prednisolone,the latter secondary to methylprednisolone) arepresented. The cases and the literature are dis-cussed.

Case 1

An 11-yr-old boy was referred to HacettepeUniversity Children's Hospital with a two-monthhistory of malaise, loss of appetite and a weight lossof 4 kg. Physical examination revealed widespreadlymphadenopathy with 1-cm ®rm lymph nodespalpable in the submental, cervical, axillary andinguinal regions; liver and spleen were extendedbelow coastal margins 9 and 8 cm, respectively.

Eur J Haematol 2001: 66: 404±407Printed in UK. All rights reserved

Copyright # Munksgaard 2001

EUROPEANJOURNAL OF HAEMATOLOGY

ISSN 0902-4441

404

Laboratory examination revealed the following:haemoglobin 11.9 g/dL, WBC 345,000/mm3 (pre-dominantly blasts), platelet count 72,000/mm3,BUN 41 mg/dL, uric acid 10.2 mg/dL, creatinine2.0 mg/dL, albumin 4.5 g/dL, calcium 13.4 mg/dL,phosphorus 1.7 mg/dL, potassium 3.6 mEq/L,LDH 8817 U/L, AST 244 IU/L, ALT 142 IU/Land ALP 696 IU/L. Urinalysis was normal. Bonemarrow morphology, showing 100% blasts, wascompatible with an acute lymphoblastic leukaemia,FAB classi®cation L2. Fifty-eight percent of thebone marrow blasts were CD2 positive, and theywere CD10, CD33, CD13, CD3, CD19 and HLA-DR negative. Chest X-ray revealed a bilateral hilarmass. Ultrasonography revealed leukaemic in®ltra-tion in liver, spleen, kidney and parotis glands. Blastcells were found in the cerebrospinal ¯uid.

Following alkaline diuresis (3500 mL/m2/d; urinepH between 7.0 and 7.5) and allopurinol (7.5 mg/kg/d t.i.d.) a single dose of prednisolone (0.5 mg/kg,12 mg total) was given orally. Eighteen hours later,the patient complained of numbness and a tinglingsensation in the extremities; Trousseau's sign waspositive. A repeat of blood biochemistry revealedBUN 60 mg/dL, uric acid 8.7 mg/dL, creatinine2.3 mg/dL, calcium 5.9 mg/dL, phosphorus 8.5 mg/dL, potassium 3.9 mEq/L. Leukopheresis dimin-ished the WBC from 320,000/mm3 to 140,000/mm3;calcium gluconate infusion (75 mg/kg/d) was insti-tuted, followed by oral replacement. The patientcontinued to receive oral prednisolone in a reduceddose as well as vincristine (1.5 mg/m2) on the thirdday. On the sixth day of the treatment thelaboratory results were as follows: WBC 2800/mm3 (40% blasts), BUN 32 mg/dL, uric acid4.1 mg/dL, creatinine 0.9 mg/dL, calcium 7.7 mg/

dL, phosphorus 1.7 mg/dL, potassium 4.0 mEq/L.Treatment was continued with induction followedby consolidation and maintenance therapy. Thepatient is still in complete remission.

Case 2

A 13-yr-old boy complaining of malaise, fever andloss of appetite within the last week was admitted toour hospital. A physical examination revealedscarce petechiae, widespread microlymphadenopa-thy; liver and spleen were extended below coastalmargins 6 and 3 cm, respectively. Laboratoryexamination revealed haemoglobin 13.0 g/dL,WBC 33,700/mm3, platelet count 54,000/mm3,BUN 11 mg/dL, uric acid 12.0 mg/dL, creatinine1.0 mg/dL, albumin 4.7 g/dL, calcium 10.4 mg/dL,phosphorus 2.1 mg/dL, potassium 3.9 mEq/L,LDH 107 U/L, AST 57 IU/L, ALT 63 IU/L, andALP 616 IU/L. Urinalysis was normal, as was achest X-ray. Bone marrow morphology, showing90% blasts, was compatible with an acute lympho-blastic leukaemia (FAB-L2). Histochemical exam-ination revealed that the blasts were negative forperoxidase and PAS stain. Thirty-seven percent ofthe bone marrow blasts were CD7 positive, 29%CD5 positive, and they were CD10, CD19, CD20,CD22, CD14, CD33, CD34 and HLA-DR negative.Abdominal ultrasonography revealed hepatic andsplenic leukaemic in®ltration sparing the kidneys.

Following alkaline diuresis (3500 mL/m2/d;urine pH between 7.0 and 7.5) and allopurinol(10 mg/kg/d, t.i.d.); two doses of methylpredniso-lone (2 mg/kg, p.o., 90 mg twice) were given.Twenty-®ve hours after the dose of methylpredni-solone the patient complained of carpal spasm. A

Table 1. Acute tumour lysis cases following corticosteroids

Authors

Year of

publication Age Gender Diagnosis Corticosteroid Dose Interval Other drugs Treatment of ATLS Outcome

Dhingra et al. (9) 1988 30 M NHL DEXA 10 mg every 6 h 72 h ± Allopurinol, alkaline diuresis Recovery

Sparano et al. (11) 1990 19 M NHL DEXA 100 mg 12 h ± Allopurinol, alkaline diuresis Recovery

Smith RE et al. (12) 1990 70 M ALL DEXA 40 mg 24 h VCR, DOXO ? Recovery

Kataoka et al. (13) 1995 11 F ALL DEXA (?) (?) VCR+RT Allopurinol, alkaline diuresis Recovery

Tiley et al. (14) 1992 18 M ALL HYCOR 100 mg (?) ± Allopurinol, alkaline diuresis Recovery

Gomez et al. (17) 1987 75 M ALL Prednisone 1000 mg/m2 3 d VCR Allopurinol, alkaline diuresis Death

Loosveld et al. (15) 1991 18 M ALL Prednisone (?) 12 h ± Hemodialysis Recovery

Rajagopal et al. (16) 1992 35 F ALL Prednisone 35 mg 12 h ± Hemodialysis Recovery

Vachvanichsanong et al. (18) 1995 14 M ALL Prednisolone 60 mg/m2 72 h ± Hemodialysis Recovery

60 mg/m2 12 h VCR, DOXO Hemodialysis Recovery

Case 1 11 M ALL Prednisolone 12 mg 18 h ± Allopurinol, alkaline diuresis Recovery

Smith T et al. (10) 1988 36 M NHL MP 125 mg 24 h ± Allopurinol, alkaline diuresis Recovery

Coutinho et al. (19) 1997 44 F CLL MP 2000 mg 48 h ± ? Recovery

Yokoi et al. (20) 1997 33 M Thymoma MP 1000 mg 12 h CDDP, DOXO Allopurinol, alkaline diuresis Recovery

Case 2 13 M ALL MP 95 mg 24 h ± Allopurinol, alkaline diuresis Recovery

M, male; F, female; NHL, non-Hodgkin's lymphoma; ALL, acute lymphoblastic leukaemia; CLL, chronic lymphocytic leukaemia; DEXA, dexamethasone; HYCOR, hydrocortisone;MP, methylprednisolone; VCR, vincristine; DOXO, doxorubicin; RT, radiotherapy; CYC, cyclophosphamide; CDDP, cisplatin; ?, data not available.

ATLS following corticosteroid in ALL

405

repeat of blood biochemistry revealed BUN19 mg/dL, uric acid 6.0 mg/dL, creatinine 1.0 mg/dL, calcium 5.2 mg/dL, phosphorus 10.5 mg/dL,potassium 6.7 mEq/L. Peaked T-waves werenoticed on an ECG. Chemotherapy was discon-tinued. Diuresis and allopurinol were continuedand calcium infusion was instituted (75 mg/kg/d)followed by oral replacement. BUN and creatininelevels rose to 97 mg/dL and 1.6 mg/dL, respec-tively, within the next 24 h, blood biochemistrywas normal by the end of the fourth day, and noother complications were observed. Completeremission was achieved at the end of the sixthweek. The patient is still in remission receivingmaintenance chemotherapy.

Discussion

ATLS has been reported most commonly aftercombined cytotoxic chemotherapy in lymphoma,leukaemia and other malignancies. It is rarelyreported after treatment with steroid alone inhaematological malignancies. Single-agent therapywith amsacrine in T-cell leukaemia (7), interferon inT-cell lymphoma (8) and tamoxifen ¯are in breastcancer (3) have also reported to result in ATLS.

There are few reports concerning acute tumourlysis syndrome caused by corticosteroids (9±20).The characteristics of these patients are summarisedin Table 1. Reports concerning ATLS after the useof corticosteroids (dexamethasone, hydrocortisone,prednisone, prednisolone and methylprednisolone)in patients with ALL are very rare. Those secondaryto dexamethasone use were described by Smith et al.(12) and Kataoka et al. (13), but it was not possibleto ascertain the role of prednisolone alone, as otheragents were also used.

Vachvanichsanong et al. reported a 14-yr-oldwith hepatosplenomegaly, massive lymphadenopa-thy and mediastinal mass, whose WBC was 9900/mm3. The patient had two episodes of ATLS withoral prednisolone (60 mg/m2/d) alone and oralprednisolone, IV vincristine (1.5 mg/m2) and dox-orubicin (25 mg/m2), respectively (18). The ®rstepisode had occurred on the third day of pre-dnisolone; haemodialysis had been performed onthree consecutive days. The later episode hadstarted 12 h after prednisolone, vincristine anddoxorubicin, and the patient was treated with IVcalcium gluconate and haemodialysis four times. Inthe ®rst case reported in this paper (the 11-yr-old)ATLS had occurred after an oral dose of pre-dnisolone as small as 12 mg and within 18 h. Suchan early clinical presentation induced by a singledose of 12 mg of prednisolone may be attributed to

a higher tumour burden and leukaemic in®ltrationof both kidneys in the presented case.

The reported cases concerning ATLS andmethylprednisolone are as follows: a 36-yr-oldman with relapsed lymphoblastic lymphoma whoreceived 125 mg of methylprednisolone for treat-ment of an allergic reaction; a 44-yr-old womanwith CLL; and a case of thymoma. To the best ofour knowledge the second patient presented in thispaper is the ®rst case with ALL who developedATLS following a single dose of methylpredniso-lone (95 mg).

Our cases indicate that acute tumour lysissyndrome may occur after a single dose of cortico-steroid (as small as 12 mg of prednisolone). Oneshould be aware of this potentially life-threateningcomplication especially while prescribing cortico-steroids to patients with NHL and leukaemia.

References

1. COHEN LF, BALOW JE, MAGRATH IT, POPLACK DG, ZIEGLER

JL. Acute tumour lysis syndrome. A review of 37 patientswith Burkitt's lymphoma. Am J Med 1980;68:486±491.

2. ZUSMAN J, BROWN DM, NESBIT ME. Hyperphosphatemia,hyperphosphaturia and hypocalcemia in acute lymphoblas-tic leukaemia. N Engl J Med 1973;289:1335±1340.

3. CECH P, CONE L. Tumour lysis syndrome after tamoxifen¯are. N Engl J Med 1986;315:263±264.

4. BARTON JC. Tumour lysis syndrome in non-hematopoieticneoplasms. Cancer 1989;64:738±740.

5. VOGELZANG NJ, NELIMARK RA, NATH KA. Tumour lysissyndrome after induction chemotherapy of small-cellbronchogenic carcinoma. JAMA 1983;249:513±514.

6. HANDE KR, GARROW GC. Acute tumour lysis syndrome inpatients with high-grade non-Hodgkin's lymphomas. Am JMed 1993;94:133±139.

7. VOGLER WR, MORRIS JG, WINTON EF. Acute tumour lysis inT-cell leukaemia induced by amsacrine. Arch Int Med1983;143:165±166.

8. FER MR, BOTTINO GC, SHERVIN SA. Atypical tumour lysissyndrome in a patient with T-cell lymphoma treated withrecombinant leukocyte interferon. Am J Med 1984;77:953±956.

9. DHINGRA K, NEWCOM SR. Acute tumour lysis syndrome innon-Hodgkin lymphoma induced by dexamethasone. Am JHematol 1988;29:115±116.

10. SMITH T. Tumour lysis syndrome after steroid therapy foranaphylaxis. Southern Med J 1988;81:415±416.

11. SPARANO J, RAMIREZ M, WIERNIK PH. Increasing recognitionof corticosteroid-induced tumour lysis syndrome in non-Hodgkin lymphoma. Cancer 1990;65:1072±1073.

12. SMITH RE, STOIBER TR. Acute tumour lysis syndrome inprolymphocytic leukaemia. Am J Med 1980;88:547±548.

13. KATAOKA A, SHIMUZI K, MATSUMOTO T, et al. Epidural spinalcord compression as an initial symptom in childhood acutelymphoblastic leukaemia: rapid decompression by localirradiation and systemic chemotherapy. Pediatr HematolOncol 1995;12:179±184.

14. TILEY C, GRIMVADE D, FINDLAY M. Tumour lysis followinghydrocortisone prior to a blood product transfusion in T-celllymphoblastic leukaemia. Leukaemia Lymphoma 1992;8:143±146.

15. LOOSVELD OJ, SCHOUTEN HC, GAILLARD CA. Acute tumour

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lysis syndrome in a patient with acute lymphoblasticleukaemia after a single dose of prednisone. Br J Haematol1991;77:122±123.

16. RAJAGOPAL S, LIPTON JH, MESSNER HA. Corticosteroidinduced tumour lysis syndrome in acute lymphoblasticleukaemia. Am J Haematol 1992;41:66±67.

17. GOMEZ GA, HAN T. Acute tumour lysis syndrome inprolymphocytic leukaemia. Arch Intern Med 1987;147:375±376.

18. VACHVANICHSANONG P, MAIPANG M, DISSANEEWATE P,

WONGCHANCHAILERT M, LAISOMBAT V. Severe hyperpho-sphatemia following acute tumour lysis. Med Pediatr Oncol1995;24:63±66.

19. COUTINHO AK, SANTOS M DE O, PINCHZOWSKI H, FEHER O,DEL GIGLIO A. Tumour lysis syndrome in a case of chroniclymphocytic leukaemia induced by high-dose cortico-steroids. Am J Hematol 1997;54:85±86.

20. YOKOI K, MIYAZAWA N, KANO Y, et al. Tumour lysissyndrome in invasive thymoma and peripheral blood T-celllymphcytosis. Am J Clin Oncol 1997;20:86±89.

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