Medical and Pediatric Oncology 36:390±391 (2001)

BRIEF REPORTSecondary Acute Lymphoblastic Leukemia in a Child

Three Years After Treatment for Medulloblastoma

Kristina Casteels, MD, PhD,* Marleen Renard, MD, Stefaan Van Gool, MD, PhD, and Anne Uyttebroeck, MD

Patients with medulloblastomas require agressivemultimodality therapy including surgery, radiation ther-apy and chemotherapy. As the survival after this therapyis improving, it is likely that some of these patients willdevelop a secondary malignant condition, including leu-kemia. In general, secondary leukemias are of the myelo-blastic type [1].

One of our patients, however, developed acute lym-phoblastic leukemia (ALL) 3 years after the initialdiagnosis of medulloblastoma at age 5 years. The braintumor was resected and he then was treated according tothe GPOH-HIT 91 protocol that entails sandwich chemo-therapy consisting of ifosfamid, etoposide, methotrexate(MTX), cisplatin and cytarabine followed by radio-therapy (35.3 Gy craniospinal with a boost of 20 Gy to theposterior fossa). An MRI at the end of therapy showed noresidual tumor and no spinal metastases.

Three years after the initial diagnosis, the boy pre-sented with cervical adenopathy and general malaise. Achest X-ray ®lm revealed mediastinal lymph nodes.Hemoglobin and platelets were, respectively, 11.6 g/dland 135,000/ml, the WBC (white blood cell count) was22� 109/l with 26% blasts. Bone marrow examinationrevealed an acute lymphoblastic leukemia of T-celllineage with a translocation on 11q23 in more than 2%of the cells. Our patient was treated according to theEORTC-CLCG 58881 trial during the induction course.After remission, high doses of MTX (as central nervoussystem prophylaxis) were contra-indicated, because theyare known to cause encephalopathy when administeredafter irradiation [2]. For this reason he was further treatedaccording to the LSA2-L2 protocol [3,4].

DISCUSSION

After treatment for medulloblastoma, various types ofsecondary leukemia have been reported: acute myelo-blastic leukemia (AML), leukemia of mixed lineage andacute lymphoblastic leukemia (ALL) (Table I) [5±9]. In1997, a study of population-based data from the UnitedStates and Sweden was performed to estimate risks ofsecond neoplasms in patients with medulloblastoma [10].Overall, there was a 5.4-fold increase of second neo-

plasms. Twenty of the 1,262 patients with histologicallycon®rmed medulloblastoma developed a secondarycancer including three cases of ALL. All three hadreceived radiotherapy, but no chemotherapy as initialtherapy. Time to second malignancy was 8, 80 and102 months (Table I). Calaminus et al. [11] studied 39patients with medulloblastoma, one of whom developedALL 84 months after primary diagnosis and died duringinduction chemotherapy. He had received radiotherapy,vincristine and lomustine after resection of the tumor(G. Calaminus, personal communication).

Most secondary leukemias are said to be of the acutemyeloblastic type, but in our study of secondary leuke-mias after medulloblastoma there were four cases ofMDS/AML, one leukemia of mixed lineage and ®vecases of ALL, including our patient [5±11].

Secondary leukemias are reported after both radio-therapy and chemotherapy, but there is no clearcut expla-nantion for their etiology [12,13]. The majority ofsecondary leukemias resulting from the use of cytotoxicdrugs can be divided into two well-de®ned groups depen-ding on whether the patient has received (1) alkylatingagents, or (2) drugs binding to the enzyme DNA-topo-isomerase II. Alkylating agent-related leukemias are verysimilar to post-MDS leukemias being characterized by apreleukemic phase, tri-lineage dysplasia, frequent cyto-genetic abnormalities involving chromosome 5 and 7 anda poor prognosis. Topoisomerase II inhibitor-relatedleukemias are not preceded by a preleukemic phaseand show frequently balanced translocations involvingchromosome 11q23.

In our patient, such a translocation involving chromo-some 11q23 was found. Although this translocation hasbeen associated with leukemia occurring after chemo-therapy it is not clear whether it is really due to that

ÐÐÐÐÐÐDepartment of Pediatric Oncology, U.Z. Gasthuisberg, KatholiekeUniversiteit Leuven, Herestraat 49, 3000 Leuven, Belgium.

*Correspondence to: Dr. Kristina Casteels, Department of Pediatrics,U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

Received 7 September 2000; Accepted 26 October 2000

Key words: leukemia; medulloblastoma; secondary tumor

ß 2001 Wiley-Liss, Inc.

exposure since the same translocation is common inprimary ALL. Secondary leukemia is the preferentialdiagnosis in our patient, but genetic predisposition mustbe considered as well. Indeed, the occurrence of a braintumor in a child is a marker for an increased likelihood ofcentral nervous system tumors, leukemia and childhoodtumors in the family, and children with a central nervoussystem tumor and a second primary neoplasm are oftenpart of a familial cluster with increased risk of cancer[16,17]. In conclusion, it should be stressed that patientswith medulloblastoma should be followed up carefullyby regular physical examinations and complete bloodcounts. Therapy-related MDS, AML as well as ALL arepossible complications of irradiation with or withoutchemotherapy. We believe it is useful to report thesecases in order, ®rst, to expand the data base, and, second,to open new therapeutic perspectives for these patientswhose treatment options are restricted because of thetherapies already received, as was the case in our patient.

REFERENCES

1. Karp J, Smith M. The molecular pathogenesis of treatment-induced leukemias: foundations for treatment and prevention.Semin Oncol 1997;24:1±12.

2. Cruz-Sanchez FF, Artigas J, Cervos-Navarro J, et al. Brain lesionsfollowing combined treatment with methotrexate and craniospinalirradiation. J Neurooncol 1991;10:165±171.

3. Anderson JR, Wilson JR, Jenkin RDT, et al. Childhood non-Hodgkin's lymphoma. The results of a randomised therapeutic

trial comparing a 4 drug regimen (COMP) with a 10 drug regimen(LSA2-L2). N Engl J Med 1983;308:559±565.

4. Sullivan MP, Boyett J, Pullen J, et al. Pediatric Oncology Groupexperience with modi®ed LSA2-LA therapy in 107 children withnon-Hodgkin's lymphoma. Cancer 1985;55:323±336.

5. Haie C, Schlienger M, Constans J, Meder J, Reynaud A, GhenimC. Results of radiation treatment of medulloblastoma in adults. IntJ Radiat Oncol Biol Phys 1985;11:2051±2056.

6. Hayani A, Mahoney D, Taylor L. Therapy-related myelodysplas-tic syndrome in children with medulloblastoma following MOPPchemotherapy. J Neurooncol 1992;14:57±62.

7. Akyuz C, Emir S, Guler N, et al. Myelodysplastic syndrome in achild with a history of medulloblastoma. Turk J Pediatr 1998;40:131±134.

8. Blatt J, Penchansky L, Phebus C. Leukemia in a child with ahistory of medulloblastoma. Pediatr Hematol Oncol 1991;8:77±82.

9. Meadows A. Leukemia in a child with a history of medullo-blastoma. (Editorial) Pediatr Hematol Oncol 1991;8:vii.

10. Goldstein A, Yuen J, Tucker M. Second cancers after medullo-blastoma: population-based results from the United States andSweden. Cancer Causes Control 1997;8:865±871.

11. Calaminus G, Janben G, Lenard H, et al. Combined therapy ofmedulloblastoma: review of 46 patients treated in a singleinstitution. Neuropediatrics 1998;29:102±107.

12. Bloom H, Gees J, Bell J. The treatment and long-term prognosisof children with intracranial tumors: a study of 610 cases, 1950±1981. Int J Radiat Oncol Biol Phys 1990;18:723±745.

13. Leone G, Mele L, Pulsoni A, et al. The incidence of secondaryleukemias. Haematologica 1999;84:937±945.

14. Farwell J, Flannery J. Cancer in relatives of children with central-nervous-system neoplasms. N Engl J Med 1984;311:749±753.

15. Farwell J, Flannery J: Second primaries in children with centralnervous system tumors. J Neurooncol 1984;4: 371±375.

TABLE I. Patients With a History of Medulloblastoma and Secondary Leukemia

Age (years) at Time to second Treatment of medulloblastomadiagnosis of cancer (years after Leukemiamedulloblastoma initial diagnosis) subtype Surgery Radiotherapy Chemotherapy Reference

24 6 AML Y Y Y Haie et al. 1985 [5]6.5 3.2 Mixed lineage Y Y Y Blatt et al. 1991 [8]1 3.6 MDS, AML Y N Y Hayani et al. 1992 [6]7 1.4 MDS Y Y Y Hayani et al. 1992 [6]3 6.6 ALL Y Y N Goldstein et al. 1997 [10]8 8.5 ALL Y Y N Goldstein et al. 1997 [10]5 0.7 ALL Y Y N Goldstein et al. 1997 [10]4.7 7 ALL Y Y Y Calaminus et al. 1998 [11]15 1.2 y post-therapy MDS, AML Y Y Y Akyuz et al. 1998 [7]

Acute Leukemia After Medulloblastoma 391