Down's Syndrome in Childhood Acute Lymphoblastic Leukemia

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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 reinduction 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. any cause). Patients who failed to achieve a complete Sex ratio, leukocyte count and leukemic cell burden were response were assigned to a failure time of zero. The Kaplan– similar in both groups. Patients with DS tended to be older Meier method was used to estimate survival rates with com- than NDS patients (P = 0.04) with no infants in the DS group. parisons based on the two-sided log-rank test. Standard errors DS patients lacked CNS leukemia and were less likely to were calculated using Greenwoods formula. To get an esti- present with an anterior mediastinal mass. Comparison of mate for the outcome of NDS patients with a similar risk pro- major immunophenotypes revealed a predominance of com- file as DS patients a matched-pair analysis was done. Match- mon ALL and absence of T-ALL (P = 0.005) in DS, whereas ing variables included age at diagnosis (Ͻ2, 2–5 or Ͼ5 years), the incidence of pre-B-ALL was similar in both groups. Hyper- sex, initial leukocyte count (log 10 (WBC) within 15%), initial diploidy, indicated by a DNA index у1.16, was significantly peripheral blast count (within 15%), immunophenotype and less frequent in the DS cohort than that in the general ALL prednisone response. One control was randomly selected population (P = 0.004). For all DS patients, the cytogenetic from available matches and the Kaplan–Meier estimate for the form was trisomy 21 and one DS patient presented in addition with translocation t(4,11). In DS, the incidence of congenital heart disease was 26.2% as compared to 0.3% in NDS Table 1 Dosages of intravenous methotrexate (MTX) during con- patients (anomaly of coronary arteries (n = 1), atrial septal solidation and prophylactic cranial irradiation (CRT) in trials ALL-BFM defect II (n = 3), atrioventricular defect (n = 6), isolated ven- 81–90 tricular septal defect (n = 3), tetralogy of Fallot (n = 2), single mitral cleft (n = 1)). All but one defect had been surgically Trial ALL-BFM corrected before diagnosis of ALL.

81 83 86 90 Treatment response MTX (g/m2)a — 0.5 × 45× 45× 4 CRT (Gy) Initial treatment response to prednisone tended to be better in SR 18 — — — DS ALL as compared to patients with NDS ALL (good predni- IR 18 12/18 12/18 12 = HR 24 24 18 12 sone response in 98.1% vs 90.7%, P 0.057) but the difference did not reach statistical significance (Table 2). Only one aPatients in the standard risk group (RF Ͻ0.8) were randomised for DS patient showed a poor prednisone response, achieved receiving CRT (18 Gy) or four courses of intermediate dosage MTX complete remission following induction therapy, but suffered (0.5 g/m2 × 4). from bone marrow relapse after 1. years, and died 1 year later. Down’s syndrome in childhood ALL ¨ MDordelmann et al 647 Table 2 Frequency (%) of clinical features and initial treatment mucositis and profound bone marrow depression with HD- response in patients with ALL and Down’s syndrome (DS) and other MTX or recurrent severe pulmonary infections during mainte- children with ALL (NDS) nance therapy. Despite normal renal function tests prolonged renal MTX excretion was noted in six patients, which led to Feature DS patients NDS P value (n = 61) (n = 4049) MTX reduction in one and to significant treatment delay in four patients during consolidation therapy. Daunorubicin dos- Sex age was reduced in seven patients due to considerations Female 55.7 56.6 regarding cardiac function in two and caused by infectious Male 44.3 43.4 complications in five patients. In four patients, several proto- Age (years) col elements had to be reduced, in three cases because of Ͻ1 — 2.6 severe persistent infection, and in one because his guardians у Ͻ 1– 6 49.0 58.8 declined intensive chemotherapy. Diabetes mellitus у6 51.0 38.6 Median age (years) 6.03 4.7 0.04 developed in six patients during treatment with asparaginase Leukocyte count/␮l and steroids in induction and reinduction, but caused asparag- Ͻ10000 34.4 47.3 inase reduction in only one patient. In all patients the diabetic у10000–Ͻ20000 21.3 15.4 period stopped shortly after completing induction or reinduc- у20000–Ͻ50000 14.8 16.6 tion. Treatment had to be significantly postponed, equally dis- у 50000 29.5 20.7 tributed during induction, consolidation and reinduction, in Median/␮l 16800 11300 Leukemic cell 13 DS patients (21%), mainly caused by profound bone mar- mass (RF) row depression and concomitant infection. However, eight of Ͻ0.8 24.6 30.0 these 13 children received protocol treatment without signifi- у0.8–Ͻ1.2 37.7 33.3 cant reduction of cumulative dosages. у1.2–Ͻ1.7 32.8 29.7 We did not perform a detailed analysis, ie matched pair, у 1.7 3.3 7.0 regarding therapy morbidity and mortality compared to the Ploidy/DNA indexa Ͻ1.16 93.3 74.2 0.004 NDS controls. However, Table 3 shows the overall treatment у1.16 6.7 25.8 mortality being lower in the NDS cohort (1.8% vs 6.6%). Cytogenetics t(4;11) 1.8d 2.1d t(9;22) — 3.2d Treatment outcome CNS leukemia — 2.7 Mediastinal mass 1.6 8.9 0.05 Immunophenotypeb With a median observation time of 5.1 years (range 2–14.5 Pro-B-ALL — 5.2 years), there were no significant differences in outcome c-ALL 80 65.2 0.05 between DS patients and other children with ALL. However, Pre-B-ALL 20 16.4 in general, EFS tended to be slightly inferior for DS patients T-ALL — 13.0 0.005 as compared to NDS children (58 ± 8% vs 70 ± 1%, P = 0.14, Prednisone Figure 1). Comparative analysis with NDS non-hyperdiploid responsec ± Ͻ1000/␮l 98.1 90.7 0.058 patients (EFS 67 1%) (Figure 4) and matched pair analysis у1000/␮l 1.9 9.3 (NDS 66%) for EFS at 6 years revealed similar results, which Congenital heart 26.2 0.3 Ͻ0.0001 were included in the confidence interval for the correspond- disease ing Kaplan–Meier estimate for DS patients (58 ± 8%). More- over, comparison of DS patients with or without major therapy aNumber of patients examined: DS n = 30, NDS n = 2026. reduction and/or delay showed a slight disadvantage for the bOnly patients of trials ALL-BFM 86 and 90 (DS n = 45, NDS less intensively treated group (46 ± 13% vs 65 ± 9%, P = 0.28, = n 2695). Figure 2). However, DS children who received protocol treat- cOnly patients of trials ALL-BFM 83, 86 and 90 (DS n = 55, NDS = ment with no major modifications had a similar EFS as com- n 3355). ± ± = dPercent of patients examined. pared to NDS patients (65 9% vs 70 1%, P 0.66) as shown in Figures 1 and 2. Total duration of therapy with 18 months (n = 5, one relapse) vs 24 months (n = 9, three However, in both groups, a similar proportion of patients relapses) in trials ALL-BFM 81 and 83 had no influence on (96.7% vs 98.4%) achieved complete remission after 33 days outcome in the few DS patients analyzed. of induction therapy (Table 3). Comparison of children Ͻ6 years of age revealed no differences in EFS between DS and NDS patients (73 ± 9% vs 74 ± 1%, P = 0.7; Figure 3), regardless of therapy modifi- Therapy-related toxicity and treatment modifications cations. In contrast, DS patients у6 years of age fared slightly worse as compared to NDS children with similar age In 43% of the DS patients, therapy was either significantly (44 ± 11% vs 63 ± 1%, P = 0.22, Figure 3). Of the 26 DS reduced and/or postponed. Of 47 DS patients, who should patients, in whom therapy had to be reduced and/or delayed, have been irradiated according to the applied protocol, cran- 15 were less than 6 years of age, of whom only three (20%) ial irradiation was omitted in six (13%) and reduced in two suffered from relapse. In contrast, of the remaining 11 patients (4%) patients, due to considerations regarding intellectual у6 years of age, six (55%) relapsed. impairment. Cranial irradiation was generally well tolerated. Table 3 summarizes the causes of death and relapse pattern Chemotherapy had to be significantly reduced in a quarter of among the evaluated children. In DS, a substantial proportion the DS patients (n = 16). In the majority (n = 13), the metho- (n = 13) suffered from relapse after elective cessation of ther- trexate (MTX) dosage was affected either in consolidation apy (Figure 1). The leading cause of death in patients with DS (n = 8), in maintenance (n = 4) or in both (n = 1) due to severe was bone marrow (BM) recurrence (12 isolated BM, two com- Down’s syndrome in childhood ALL ¨ MDordelmann et al 648 Table 3 Outcome in patients with ALL and Down’s Syndrome (DS) and other ALL patients (NDS)

DS patients NDS

ALL Without therapy reduction With therapy reduction n = 61 n = 35 n = 26 n = 4049 n%n%n%n%

CR 59a 96.7 33a 94.3 26 100 3983 98.4 pEFS (6 years) 58 ± 865± 946± 13 70 ± 1 Events Non-response — — — 33 0.8 Therapy death 4a,b 6.6 2a 5.7 2b 7.7 71 1.8 Relapse 16 26.2 8 22.9 8 30.8 865 21.4 other — — — 35 0.9 Site of relapse Bone marrow 12 19.7 5 14.3 7 26.9 526 13.0 CNS 1 1.6 1 2.9 — 78 1.9 Testes 1 1.6 1 2.9 — 49 1.2 Bone marrow/CNS — — — 116 2.9 Bone marrow/Testes 2 3.3 1 2.9 1 3.8 44 1.1 Other — — — 52 1.3 Secondary maligancy — — — 12 0.3 Lost to follow-up 2 44

aTwo patients died during induction therapy due to septicemia. bOne patient with uncorrected VSD and severe pulmonary hypertension died of congestive heart failure; one patient died of pneumonia in CR.

Figure 2 Event-free survival in Down’s syndrome and ALL (DS- Figure 1 Event-free survival for children with Down’s syndrome ALL), treated without and with signiﬁcant therapy reduction. and ALL (DS-ALL) and other ALL children (NDS-ALL).

after elective cessation of therapy only were considered for bined BM/testicular), one patient suffered an isolated CNS and analysis (Table 4). one an isolated testicular relapse. Additional causes of failure included two induction deaths in the DS cohort from varicella sepsis and septicemia of unknown origin. Two DS patients Discussion died in remission from pneumonia and congestive heart failure, respectively. In this study, the incidence of DS among children with ALL Multivariate analysis for DS as an independent prognostic was 1.5% (n = 61), which is in accordance with the range of factor at diagnosis revealed no signiﬁcance after adjustment 1.6–2.1% reported by other groups.3,4,6 This study allows the for age, WBC and prednisone response. However, the pres- analysis of clinical characteristics and therapeutic outcome in ence of DS became signiﬁcant (P = 0.0107), when patients a comparatively large, homogeneous cohort of centrally diag- Down’s syndrome in childhood ALL ¨ MDordelmann et al 649 Table 4 Multivariate analysis of patient characteristics at diagnosis (n = 3410) and after cessation of therapy (n = 2602) for event-free survival in children with ALL (only patients of trials ALL-BFM 83, 86, 90)

Factor At After cession of diagnosis therapy

Worse Risk Probability Risk Probability category ratio χ2 ratio χ2

Prednisone poor 3.26 0.0001 1.28 0.067 response Age Ͻ1 year 3.22 0.0001 2.08 0.046 у6 years 1.74 0.0001 1.62 0.0001 Leukocyte у20.000 1.55 0.0001 0.96 0.72 count/␮l Down’s present 1.49 0.1031 2.48 0.0107 syndrome

(46 ± 13%). In contrast, there was no difference in EFS for DS children, who were either younger than 6 years of age, irrespective of treatment reduction (73 ± 9%) or protocol treatment received without major therapy modifications (65 ± 9%). Whereas two investigators reported a significantly worse EFS (23–28%) for DS ALL as compared to other ALL children Figure 3 Event-free survival for children with ALL according to age 5,8 Ͻ and у6 years with (DS-ALL) and without Down’s syndrome (59–64%), others disagreed. Reports from the Children’s (NDS-ALL). Cancer Group (CCG), the Pediatric Oncology Group (POG) and St Judes Children’s Research Hospital found a similar EFS in ALL children with and without DS once they achieved induction remission and were treated with intensive chemotherapy.3,4,6 Did the frequency of certain clinicobiologic features matter for outcome in DS? Our study confirmed previous published reports on DS-ALL, which found a lower frequency of tra- ditional adverse prognostic features such as mediastinal mass, central nervous system leukemia,3,4 T-immunophenotype3–6 or translocations t(9;22) and t(4;11).3,5,21,22 The significant lower frequency of hyperdiploidy among children with DS- ALL as compared to the control cohort is in accordance with other studies3,5 and might be an adverse prognostic feature for these patients. Hyperdiploidy is known to be associated with a favorable outcome for patients with B precursor ALL.15,23,24 Comparison of EFS for DS and NDS, non-hyperdiploid patients, showed that both groups did equally well when adequate therapy was administered (Figure 4). However, the significance of our ploidy data is limited because in almost 50% of the patients DNA index data were not available. In DS patients with ALL, being older than 6 years of age had an even more important influence on outcome than for other comparable children with ALL. However, an obvious expla- Figure 4 Event-free survival for children with DS-ALL and NDS- ALL with DNA index р1.16. nation for this observation is missing. Since DS can be considered as a model for accelerating aging, including premature aging of the immune system,25 one could speculate about nosed and similar intensively treated DS patients. However, even an enhanced aging due to cytotoxic therapy. This could our power to detect significant differences related to the pres- cause less tolerance of therapy and impaired immunologic ence of DS is still limited by the small number of such chil- surveillance for both infection and residual malignant cells. dren, particularly when numerous variables are analyzed. Several studies clearly identified DS patients at increased risk Because patients with DS presented with rather few known of treatment-related death due to infectious compli- adverse prognostic features, they could theoretically be cations.8,26,27 Various investigators reported abnormalities of expected to have a rather favorable EFS as compared to the circulating granulocytes in DS including morphology, enzyme general ALL population. However, we found EFS for DS ALL levels and ability to kill bacteria and abnormalities in the (58 ± 8%) slightly inferior as compared to NDS ALL (70 ± 1%). immune system including both cellular and humoral immun- The outcome was even worse for DS patients either being ity, which were in part more prominent in older DS chil- older than 6 years of age (44 ± 11%) and/or for patients need- dren.25,28,29 Moreover, although most DS patients are well ing treatment modifications due to treatment-related toxicity nourished and thrive well, they are known to have low levels Down’s syndrome in childhood ALL ¨ MDordelmann et al 650 of serum trace elements such as zinc and selenium, which precursor ALL, the predominance of rather late relapses are both known to be essential cofactors in T cell responses, among the DS cohort may simply represent the known tend- phagozyte function and antibody production.28,30–32 Finally, ency of B precursor ALL to relapse later or the known relapse parental refusal for aggressive therapy due to pre-existing dif- pattern of patients with a low tumor cell burden. ficulties managing daily life or parents’ and/or patients’ com- Although almost one-third of DS patients present with con- pliance may play a greater role in older DS patients.33–35 genital heart disease (CHD),36 the incidence of cardiac com- Did initial response to treatment matter? In the present plications aggravated by intensive antileukemic treatment is study, DS patients achieved a remission rate comparable to low. We noted one death associated with CHD in a patient the NDS group. This extends the findings of the United King- who had not undergone cardiac surgery and therefore dom Children’s Cancer Study Group and the POG who dem- presented with severe pulmonary hypertension and right ven- onstrated a similar failure rate for children with (3.3–7.7%) tricular failure at diagnosis. This extends the findings of pre- and without DS (1.6–7%) when using protocols based on vious reports, that found therapy-related death associated with intensive therapy and improved supportive care.6,8 In contrast, CHD in 3% (5/162) of their intensively treated DS patients.4,5,8 a retrospective survey from the CCG showed a higher rate of Life expectancy in DS is much better than generally induction failure, including death due to therapy compli- believed. For patients with DS without congenital heart cations, for children with DS ALL as compared to NDS ALL defects (73.8% of our patients) survival to age 30 is 79.2%.37 (19% vs 6%).4 Our results demonstrated, that patients with ALL and DS are Did treatment-related toxicity and treatment intensity mat- less likely to present with known adverse prognostic features ter? We found a similar outcome for children with DS and as compared to other children with ALL. Because of the NDS once it was possible to apply intensive treatment with importance of dose intensity for cure, it seems advisable to no major modifications. However, we noted the same result develop more tolerable treatment for children with DS and for patients younger than 6 years of age, irrespective of toxi- ALL without compromising treatment efficacy. Reduction of city and consecutive treatment modifications. Ragab and col- antifolate therapy during consolidation might be of advantage leagues6 reported almost half of their intensively treated DS in treating DS patients with ALL. Seven out of 11 DS patients patients were unable to tolerate therapy; especially due to (64%) from trials ALL-BFM 81 and 83, who were treated with methotrexate-associated toxicity, this drug had to be reduced intermediate-dose methotrexate (IDM = 0.5 g/m2) without sig- significantly. However, when compared to DS patients who nificant toxicity during consolidation, are in continuous com- were treated conventionally, the intensively treated patients plete remission. High-dose methotrexate during consolidation fared better, despite major treatment reduction. DS patients, (HDM = 5 g/m2) in trials ALL-BFM 86 and 90 caused signifi- treated at St Jude Children’s Research Hospital, showed no cant therapy toxicity and did not seem to improve EFS for DS significant difference in treatment outcome (65 ± 14.5%) as ALL. When considering both the predominance of favorable compared to children without DS (74 ± 1.6%), but suffered prognostic features and the low incidence of CNS leukemia disproportionally from methotrexate toxicity also. The authors and CNS relapse, IDM in consolidation might be sufficient to concluded, that although DS patients presented with tra- treat DS patients with ALL, at least with ‘BFM-type’ protocols. ditional favorable features and were expected to have a higher Furthermore, less therapy-associated toxicity with intermedi- relapse-free survival, regarding EFS ‘these patients fared no ate-dose methotrexate might enable the application of other better than other children with ALL, partly because of exces- more tolerable therapy components in time and at full dosage. sive therapy-related toxicities, which accounted for a third of However, regarding the predominance of late relapses, main- treatment failures’.3 As in the present study, the majority of tenance therapy including standard-dose oral methotrexate other investigators reported an unusual increased MTX toxicity (20 mg/m2/week) should neither be reduced nor shortened. in DS patients.3–5,6,8,9,11,12 One pharmacokinetic study in In summary, the combination of multiple rather than ther- patients with DS showed a slower than expected intracellular apy-related problems seemed to contribute to the inferior EFS clearance of methotexate (1 g/m2) and significant increased for children with DS and ALL. Sine most of the toxicity toxicity in comparison to other children with ALL.12 encountered is manageable with careful attention to the In the present study, total duration of therapy with 18 vs 24 known problems of therapy tolerance of such children, inten- months in trials ALL-BFM 81 and 83 had no significant influ- sive antileukemic therapy is recommended. However, sophis- ence for outcome in DS patients. However, since the BFM ticated supportive care including adequate nutrition, infection group has shown the total therapy duration of 24 months as prophylaxis, close monitoring of antimetabolite therapy and being significantly superior,17 this is probably due to the small extensive psycho-social support is urgently required. number of evaluable DS patients (n = 14). As has been shown in two other studies with intensive treatment-based regimens,3,6 Cox regression analysis revealed the Acknowledgements presence of DS at diagnosis not being significantly associated with a poorer EFS after adjustment for established prognostic This work was supported by a grant from the Madeleine factors such as prednisone response, age and leukocyte count. Schickedanz Stiftung. We thank E Odenwald, U Meyer, N ¨ However, when ALL patients after elective cessation of ther- Gotz and A Brandt for preparing the data of the ALL-BFM stud- apy were analyzed, DS became an important prognostic fac- ies. We gratefully acknowledge the following clinicians who tor. The reason for DS being a significant adverse prognostic submitted cases to this study: U Mittler, Magdeburg; J Treuner feature for children off therapy remains unclear. It might be a and E Maas, Stuttgart; J Wulff, Datteln; U Bode and G Fleisch- ¨ combination of different factors mentioned above such as age, hack, Bonn; D Niethammer and R Dopfer, Tubingen; M Lako- ¨ blast cell ploidy and applied treatment intensity. mek and A Pekrun, Gottingen; KM Debatin, Heidelberg; W In DS, the leading cause of treatment failure was bone mar- Rauh, Trier; B Kornhuber and K Siegler, Frankfurt; P Imbach, row recurrence later than 2. years. Since 98% of the DS Aarau; G Weinmann, Erfurt; A Gnekow, Augsburg; R Dicker- ¨ patients presented with standard- or intermediate-risk features hoff, Sankt Augustin; G Henze, Berlin; C Bender Gotze, ¨ ¨ ¨ (according to the BFM risk stratification) and 100% with B Munchen; S Muller-Weihrich, Munchen; H Wehinger, Kassel; Down’s syndrome in childhood ALL ¨ MDordelmann et al ¨ 651 P Bucsky, Lubeck; W Eberl, Braunschweig; A Jobke, lymphoblastic leukemia patients. Results and conclusions of the ¨ Nurnberg; A Hofmann, Chemnitz. multicenter trial ALL-BFM 86. Blood 1994; 84: 3122–3133. 19 Schrappe M, Reiter A, Sauter S, Ludwig WD, Wormann B, Harbott J, Bender-Gotze C, Dorffel W, Dopfer R, Frey E, Riehm H. Concept and interim result of the ALL-BFM 90 therapy study in treatment References of acute lymphoblastic leukemia in children and adolescents: the significance of initial therapy response in blood and bone marrow. ¨ 1 Avet Loiseau H, Mechinaud F, Harousseau JL. Clonal hematologic Klin Padiatr 1994; 206: 208–221. disorders in Down syndrome. J Pediatr Hematol Oncol 1995; 17: 20 Efron B. Bootstrap methods: another jackknife. Ann Stat 1979; 7: 19–24. 1–26. 2 Zipursky A, Poon A, Doyle J. Leukemia in Down syndrome. Pedi- 21 Smith M, Artur D, Camitta B, Carroll AJ, Crist W, Gaynon P, atr Hematol Oncol 1992; 9: 139–149. Gelber R, Heerema N, Korn EL, Link M, Murphy S, Pui CH, Pullen 3 Pui CH, Raimondi SC, Borowitz MJ, Land VJ, Behm FG, Pullen J, Reaman G, Sallan SE, Sather H, Shuster J, Simon R, Trigg M, DJ, Hancock ML, Shuster JJ, Steuber CP, Crist WM. Immunopheno- Tubergen D, Uckun F, Ungerleider R. Uniform approach to risk types and karyotypes of leukemic cells in children with Down syn- classification and treatment assignment for children with acute drome and acute lymphoblastic leukemia. J Clin Oncol 1993; 11: lymphoblastic leukemia. J Clin Oncol 1996; 14: 18–24. 1361–1367. 22 Mitelman F, Heim S, Mandahl N. Trisomy 21 in neoplastic cells. 4 Robison LL, Nesbit ME Jr, Sather HN, Level C, Shahidi N, Kennedy Am J Med Genet Suppl 1990; 7: 262–266. A, Hammond D. Down syndrome and acute leukemia in children: 23 Shen JJ, Williams BJ, Zipursky A, Doyle J, Sherman SL, Jacobs PA, a 10-year retrospective survey from Childrens Cancer Study Shugar AL, Soukup SW, Hassold TJ. Cytogenetic and molecular Group. J Pediatr 1984; 105: 235–242. studies of Down syndrome individuals with leukemia. Am J Hum 5 Kalwinsky DK, Raimondi SC, Bunin NJ, Fairclough D, Pui CH, Genet 1995; 56: 915–925. Relling MV, Ribeiro R, Rivera GK. Clinical and biological charac- 24 Pui CH, Crist WM, Look AT. Biology and clinical significance of teristics of acute lymphocytic leukemia in children with Down cytogenetic abnormalities in childhood acute lymphoblastic leu- syndrome. Am J Med Genet Suppl 1990; 7: 267–271. kemia. Blood 1990; 76: 1449–1463. 6 Ragab AH, Abdel Mageed A, Shuster JJ, Frankel LS, Pullen J, van 25 Trueworthy R, Shuster J, Look T, Crist W, Borowitz M, Carroll Eys J, Sullivan MP, Boyett J, Borowitz M, Crist WM. Clinical A, Frankel L, Harris M, Wagner H, Haggard M et al. Ploidy of characteristics and treatment outcome of children with acute lym- lymphoblasts is the strongest predictor of treatment outcome in B- phocytic leukemia and Down’s syndrome. Cancer 1991; 67: progenitor cell acute lymphoblastic leukemia of childhood. J Clin 1057–1063. Oncol 1992; 10: 606–613. 7 Watson MS, Carroll AJ, Shuster JJ, Steuber CP, Borowitz MJ, Behm 26 Cossarizza A, Monti D, Montagnani G, Ortolani C, Masi M, Zan- FG, Pullen DJ, Land VJ. Trisomy 21 in childhood acute lympho- notti M, Franceschi C. Precocious aging of the immune system blastic leukemia. Blood 1993; 82: 3098–3102. in Down syndrome: alteration of B lymphocytes, T-lymphocyte 8 Levitt GA, Stiller CA, Chessells JM. Prognosis of Down’s syndrome subsets, and cells with natural killer markers. Am J Med Genet with acute leukaemia. Arch Dis Child 1990; 65: 212–216. Suppl 1990; 7: 213–218. 9 Peeters MA, Poon A. Down syndrome and leukemia: unusual 27 Atra A, Richards SM, Chessells JM. Remission death in acute lym- clinical aspects and unexpected methotrexate sensitivity. Eur J phoblastic leukaemia: a changing pattern. Arch Dis Child 1993; Pediatr 1987; 146: 416–422. 69: 550–554. 10 Peeters MA, Poon A, Zipursky A, Lejeune J. Toxicity of leukaemia 28 Wheeler K, Chessels JM, Bailey CC et al. Treatment related deaths therapy in children with Down syndrome. Lancet 1986; 2: 1279 during induction and in first remission ina cute lymphoblastic leu- (letter). kaemia: MRC UKALL X. Arch Dis Child 1996; 74: 101–107. 11 Blatt J, Albo V, Prin W, Orlando S, Wollman M. Excessive chemo- 29 Ugazio AG, Maccario R, Notarangelo LD, Burgio GR. Immu- therapy-related myelotoxicity in children with Down syndrome nology of Down syndrome. Am J Med Genet Suppl 1990; 7: and acute lymphoblastic leukaemia. Lancet 1986; 2: 914 (letter). 204–212. ´ 12 Garre ML, Relling MV, Kalwinsky D, Dodge R, Crom WR, Abro- 30 Anneren G, Magnusson CG, Lilja G, Nordvall SL. Abnormal serum mowitch M, Pui CH, Evans WE. Pharmacokinetics and toxicity of IgG subclass pattern in children with Down’s syndrome. Arch Dis methotrexate in children with Down syndrome and acute lympho- Child 1992; 67: 628–631. cytic leukemia. J Pediatr 1987; 111: 606–612. 31 Bjorksten B, Back O, Gustavson KH, Hallmans G, Hagglof B, 13 Ludwig WD, Bartram CR, Ritter J et al. Ambigous phenotypes and Tarnvik A. Zinc and immune function in Down’s syndrome. Acta genotypes in 16 children as characterized by multiparameter Paediatr Scand 1980; 69: 183–187. ´ analysis. Blood 1988, 71: 1518–1528. 32 Anneren G, Magnusson CGM, Nordvall SL. Increase in serum con- 14 Harbott J, Ritterbach J, Ludwig WD et al. Clinical significance of centration of IgG2 and IgG4 by selenium supplementation in chil- cytogenetic studies in childhood acute leukemia: experience of dren with Down’s syndrome. Arch Dis Child 1990; 65: 1353– the BFM trials. Rec Res Cancer Res 1993; 131: 123–128. 1355. ¨ 15 Hiddemann W, Wormann B, Ritter J et al. Frequency and clinical 33 Smith SD, Rosen D, Trueworthy RC, Lowman JT. A reliable significance of DNA aneuploidy in acute leukemia. Ann NJ Acad method for evaluating drug compliance in children with cancer. Sci 1986; 468: 227–233. Cancer 1979; 43: 169–173. ¨ 16 Langermann HJ, Henze G, Wulf M et al. Abschatzung der Tumor- 34 Richardson JL, Shelton DR, Krailo M, Levine AM. The effect of ¨ zellmasse bei der akuten lymphoblastischen Leukamie im Kindes- compliance with treatment on survival among patients with hema- alter: Prognostische Bedeutung und praktische Anwendung. Klin tologic malignancies. J Clin Oncol 1990; 8: 356–364. ¨ Padiatr 1982; 194: 209–213. 35 Tamaroff MH, Festa RS, Adesman AR, Walco GA. Therapeutic 17 Riehm H, Gadner H, Henze G, Kornhuber B, Lampert F, Nie- adherence to oral medication regimens by adolescents with can- thammer D, Reiter A, Schellong G. Results and significance of six cer. II. Clinical and psychologic correlates. J Pediatr 1992; 120: randomized trials in four consecutive ALL-BFM studies. Haematol 812–817. Bluttransfus 1990; 33: 439–450. 36 Pueschel SM. Clinical aspects of Down syndrome from infancy to 18 Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, adulthood. Am J Med Genet Suppl 1990; 7: 52–56. Henze G, Zimmermann M, Lampert F, Havers W, Niethammer 37 Baird PA, Sadovnick AD. Life expectancy in Down syndrome. J D, Riehm H. Chemotherapy in 998 unselected childhood acute Pediatr 1987; 110: 849–854.