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Down's Syndrome in Childhood Acute Lymphoblastic Leukemia

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Down's Syndrome in Childhood Acute Lymphoblastic Leukemia Leukemia (1998) 12, 645–651 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu Down’s syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials ¨ MDordelmann1, M Schrappe1, A Reiter1, M Zimmermann1, N Graf2, G Schott3, F Lampert4, J Harbott4, C Niemeyer5, ¨ ¨ J Ritter6,WDorffel7, G Neßler8,JKuhl9 and H Riehm1 for the BFM Group Departments Pediatric Hematology and Oncology, University-Children’s Hospitals, 1Hannover, 2Homburg, 3Berlin, 4Gie␤en, 5Freiburg, ¨ ¨ 6Munster, 7Berlin-Buch, 8Karlsruhe; 9Wurzburg Clinical characteristics, treatment response and outcome were treatment intensity. Authors from the Pediatric Oncology evaluated in children with Down’s syndrome (DS) and acute Group found the event-free survival (EFS) for children with DS lymphoblastic leukemia (ALL) as compared to other children with ALL (NDS). Sixty-one DS and 4049 NDS patients, receiving and ALL with 50% similar to other children with ALL, once intensive antileukemic treatment during four consecutive trials they received intensive chemotherapy. However, the ¨ (ALL-BFM 81, 83, 86 and 90) of the Berlin–Frankfurt–Munster improved EFS for the DS group was accompanied by severe Group (BFM), were retrospectively analyzed. DS and NDS chil- treatment toxicity that caused significant therapy reduction in dren did not differ with respect to sex, leukocyte count, CNS 44% of these patients.6 leukemia and cytogenetic translocations. The DS cohort was In this paper, we report the experience of the Berlin–Frank- slightly older (P = 0.04), presented predominantly with the com- ¨ mon while lacking the T immunophenotype (P = 0.005), had a furt–Munster Group (BFM) with DS and ALL. Analysis includes lower frequency of hyperdiploidy (P = 0.004) and tended to have clinical and biological characteristics, treatment response, a better initial steroid response (P = 0.057). Therapy-associated treatment-related toxicity and outcome in a large series of DS morbidity especially during high-dose methotrexate and a sub- patients in comparison with the general childhood ALL popu- sequent need for treatment modification occurred in 43% of all lation treated with the same therapy. DS patients. Event-free survival (EFS) was slightly worse in children with DS (58 ± 8% vs 70 ± 1%, P = 0.14), mainly due to rather late bone marrow recurrences. However, EFS in DS patients was comparable to the NDS group once they either Patients and methods received treatment with no major modifications (65 ± 9% vs 70 ± 1%, P = 0.66) or were Ͻ6 years of age, irrespectively of Patients therapy modifications (73 ± 9% vs 74 ± 1%, P = 0.7). Cox regression analysis revealed that DS was an adverse prognos- Down’s syndrome was identified in 61 of 4110 (1.5%) chil- tic factor for patients having completed therapy (P = 0.0107), but was not prognostic at diagnosis (P = 0.103). Age у6 years, dren with previously untreated ALL, who were enrolled onto suboptimal treatment and infectious problems contributed to four consecutive multicenter trials (ALL-BFM 81, 83, 86 and the slight inferior EFS in children with ALL and Down’s syn- 90) from 1 April 1981 to 1 January 1995. For all studies infor- drome. Therefore, most of these patients can be successfully med consent from the guardians was obtained for each treated if receiving intensive antileukemic treatment with no patient. Treatment protocols had been approved by the local major modifications, but they require more sophisticated man- ethical committee. All cases of DS had a diagnosis of trisomy agement of toxicity. Keywords: acute lymphoblastic leukemia; childhood; Down’s 21 established by typical physical abnormalities and cyto- syndrome genetic analysis. The diagnosis of ALL was based on standard morphologic studies and cytochemical staining of leukemic cells. Blast cell immunophenotype, karyotype and ploidy were 13–15 Introduction determined as described previously. Regular performance of selected studies as immunophenotyping, cytogenic analysis Children with Down’s syndrome (DS) have at least a 10- to and estimation of the initial treatment response after a 7-day 20-fold increased risk of developing acute lymphoblastic leu- exposure of prednisone were first instituted in trial ALL-BFM kemia (ALL) as compared to chromosomally normal chil- 83 and therefore not available for all patients. Because dren.1,2 Whereas one study reported a disproportionally low immunologic marker studies of trial ALL-BFM 83 were not suf- frequency of known adverse prognostic features such as cen- ficient to differentiate between common ALL immunopheno- tral nervous system leukemia, anterior mediastinal mass, T type (c-ALL) and pre-B-ALL, only data from trials ALL-BFM 86 immunophenotype and chromosomal translocations t(4,11) and 90 were considered for this analysis. and t(9;22) among ALL patients with DS,3 others found no In trials ALL-BFM 81 and 83, patients were stratified by leu- major differences.4–8 Most investigators found the rate of kemic cell burden (RF) only, based on peripheral blast count, liver and spleen size at the same time of diagnosis (RF = 0.2 achieving complete remission after induction therapy to be + + × + × similar between ALL patients with and without Down’s syn- log (blasts 1) 0.06 liver 0.04 spleen, with organ size in centimeters below costal margin) into one of the three treat- drome (NDS). In contrast, survival rates for DS patients were 16 4–12 ment arms. Children with a RF Ͻ1.2 were assigned to the inferior in most studies but ranged between 23 and 71%. у Ͻ The inferior outcome was mainly attributed to excessive ther- standard-risk group (SR); a RF between 1.2 and 1.7 quali- fied for the intermediate-risk group (IR). Patients were classi- apy-related toxicities caused either by altered drug metab- у у olism and/or poor tolerance of infection and therefore, less fied as being at high risk (HR) if they had a RF 1.7 or 5% marrow blasts on day 40.17 In trials ALL-BFM 86 and 90 the initial treatment response ¨ to prednisone (prednisone response = number of lymphoblasts Correspondence: M Dordelmann, Hannover Medical School, Chil- dren’s Hospital, Department of Pediatric Hematology/Oncology, in blood after a 7-day exposure to prednisone) was used as 30625 Hannover, Germany; Fax: 49 511 532 9029 an overriding stratification factor in combination with the leu- Received 9 June 1997; accepted 8 January 1998 kemic cell burden. A patient was considered to be at standard Down’s syndrome in childhood ALL ¨ MDordelmann et al 646 risk (SR) if he had Ͻ1000/␮l blood blasts on day 8 (prednisone EFS of 6 years (pEFS) was calculated. This process was good response), a RF Ͻ0.8, no CNS disease and no medias- repeated (n = 500) to get a ‘bootstrap’ estimate (median tinal mass. A patient was stratified into the intermediate-risk pEFS20). Multivarate risk analysis to estimate the prognostic group (IR) if he had a good prednisone response, a RF у0.8, significance of DS on EFS was performed using a Cox pro- or a RF Ͻ0.8 and CNS disease and/or presence of a medias- portional hazards model. Differences in clinical and biologi- tinal mass. Patients were classified as being at high risk (HR) cal characteristics at time of diagnosis were analyzed by the if they had у1000/␮l blood blasts on day 8 (poor prednisone Fisher’s exact test or Mann–Whitney U-test. Event-free survival response) or у5% marrow blasts on day 33 or an acute undif- was analyzed regarding age at a cut-off point of 6 years, since ferentiated leukemia. Additionally, in trial ALL-BFM 90 this cut-off point was found to be of prognostic significance patients with translocations t(9;22) and t(4;11) were con- by various authors.18,21 Survival rates were also compared for sidered as high-risk patients, regardless of their therapy DS children receiving treatment of different intensity due to response.18,19 therapy-associated toxicity. Therapy-related toxicity and modifications were evaluated in detail for 61 DS patients. Sig- nificant treatment reduction was defined as dose reduction of Treatment Ͼ20% in either one or more cytostatic agents or cranial irradiation in relation to the overall cumulative dose accord- Details of treatment regimens in trials ALL-BFM 81, 83, 86 ing to the applied protocol. Significant treatment delay was and 90 have been reported previously.17–19 Major treatment defined as a delay of Ͼ20% according to the expected treat- changes between all trials referred to the high-risk regimen ment duration per protocol element. The data represent except for the dosages of intravenous methotrexate (MTX) dur- patient follow-up to 1 January 1997. Only patients with an ing consolidation and prophylactic cranial irradiation (CRT), observation time of at least 24 months (diagnosis before 1 Jan- which are shown in Table 1. Since only one patient with DS uary 1995) were included in the analysis. The median obser- received high-risk treatment, the principal therapy compo- vation time for all patients is 5.1 years (range 2–14.5 years). nents were comparable for all DS children except for MTX Computations were performed using SAS (Statistical Analysis dosage and cranial irradiation. Cranial irradiation was perfor- System Version 6.10, SAS Institute Inc, Cary, NC, USA). med in different dosages according to risk category as outlined in Table 1 after induction in trial ALL-BFM 81 and after rein- duction in trials ALL-BFM 83, 86 and 90. Results Clinical and laboratory features Statistical analysis Sixty-one (1.5%) of 4110 children with ALL were reported to Event-free survival (EFS) was calculated from date of diagnosis have Down’s syndrome. Table 2 depicts the presenting clini- to last follow-up or to the first event (failure to achieve cal and biological findings in patients with DS as compared remission, early death, resistant leukemia, relapse or death of to other children with ALL.
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