Down's syndrome in childhood acute lymphoblastic leukemia - Nature

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 ¨ M Dordelmann1, M Schrappe1, A Reiter1, M Zimmermann1, N Graf2, G Schott3, F Lampert4, J Harbott4, C Niemeyer5, ¨ ¨ J Ritter6, W Dorffel7, G Neßler8, J Kuhl9 and H Riehm1 for the BFM Group Departments Pediatric Hematology and Oncology, University-Children’s Hospitals, 1Hannover, 2Homburg, 3Berlin, 4Gie␤en, 5Freiburg, ¨ ¨ 6 Munster, 7Berlin-Buch, 8Karlsruhe; 9Wurzburg

Clinical characteristics, treatment response and outcome were evaluated in children with Down’s syndrome (DS) and acute lymphoblastic leukemia (ALL) as compared to other children with ALL (NDS). Sixty-one DS and 4049 NDS patients, receiving intensive antileukemic treatment during four consecutive trials ¨ (ALL-BFM 81, 83, 86 and 90) of the Berlin–Frankfurt–Munster Group (BFM), were retrospectively analyzed. DS and NDS children did not differ with respect to sex, leukocyte count, CNS leukemia and cytogenetic translocations. The DS cohort was slightly older (P = 0.04), presented predominantly with the common while lacking the T immunophenotype (P = 0.005), had a lower frequency of hyperdiploidy (P = 0.004) and tended to have a better initial steroid response (P = 0.057). Therapy-associated morbidity especially during high-dose methotrexate and a subsequent need for treatment modification occurred in 43% of all 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 received treatment with no major modifications (65 ± 9% vs 70 ± 1%, P = 0.66) or were ⬍6 years of age, irrespectively of therapy modifications (73 ± 9% vs 74 ± 1%, P = 0.7). Cox regression analysis revealed that DS was an adverse prognostic factor for patients having completed therapy (P = 0.0107), but was not prognostic at diagnosis (P = 0.103). Age ⭓6 years, suboptimal treatment and infectious problems contributed to the slight inferior EFS in children with ALL and Down’s syndrome. Therefore, most of these patients can be successfully treated if receiving intensive antileukemic treatment with no major modifications, but they require more sophisticated management of toxicity. Keywords: acute lymphoblastic leukemia; childhood; Down’s syndrome

Introduction Children with Down’s syndrome (DS) have at least a 10- to 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) as compared to chromosomally normal children.1,2 Whereas one study reported a disproportionally low frequency of known adverse prognostic features such as central nervous system leukemia, anterior mediastinal mass, T immunophenotype and chromosomal translocations t(4,11) and t(9;22) among ALL patients with DS,3 others found no major differences.4–8 Most investigators found the rate of achieving complete remission after induction therapy to be similar between ALL patients with and without Down’s syndrome (NDS). In contrast, survival rates for DS patients were inferior in most studies but ranged between 23 and 71%.4–12 The inferior outcome was mainly attributed to excessive therapy-related toxicities caused either by altered drug metabolism and/or poor tolerance of infection and therefore, less ¨ Correspondence: M Dordelmann, Hannover Medical School, Children’s Hospital, Department of Pediatric Hematology/Oncology, 30625 Hannover, Germany; Fax: 49 511 532 9029 Received 9 June 1997; accepted 8 January 1998

treatment intensity. Authors from the Pediatric Oncology Group found the event-free survival (EFS) for children with DS and ALL with 50% similar to other children with ALL, once they received intensive chemotherapy. However, the improved EFS for the DS group was accompanied by severe treatment toxicity that caused significant therapy reduction in 44% of these patients.6 In this paper, we report the experience of the Berlin–Frank¨ furt–Munster Group (BFM) with DS and ALL. Analysis includes clinical and biological characteristics, treatment response, treatment-related toxicity and outcome in a large series of DS patients in comparison with the general childhood ALL population treated with the same therapy. Patients and methods

Patients Down’s syndrome was identified in 61 of 4110 (1.5%) children with previously untreated ALL, who were enrolled onto four consecutive multicenter trials (ALL-BFM 81, 83, 86 and 90) from 1 April 1981 to 1 January 1995. For all studies informed consent from the guardians was obtained for each patient. Treatment protocols had been approved by the local ethical committee. All cases of DS had a diagnosis of trisomy 21 established by typical physical abnormalities and cytogenetic analysis. The diagnosis of ALL was based on standard morphologic studies and cytochemical staining of leukemic cells. Blast cell immunophenotype, karyotype and ploidy were determined as described previously.13–15 Regular performance of selected studies as immunophenotyping, cytogenic analysis and estimation of the initial treatment response after a 7-day exposure of prednisone were first instituted in trial ALL-BFM 83 and therefore not available for all patients. Because immunologic marker studies of trial ALL-BFM 83 were not sufficient to differentiate between common ALL immunophenotype (c-ALL) and pre-B-ALL, only data from trials ALL-BFM 86 and 90 were considered for this analysis. In trials ALL-BFM 81 and 83, patients were stratified by leukemic cell burden (RF) only, based on peripheral blast count, liver and spleen size at the same time of diagnosis (RF = 0.2 log (blasts +1) +0.06× liver+ 0.04 × spleen, with organ size in centimeters below costal margin) into one of the three treatment arms.16 Children with a RF ⬍1.2 were assigned to the standard-risk group (SR); a RF between ⭓1.2 and ⬍1.7 qualified for the intermediate-risk group (IR). Patients were classified 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 in blood after a 7-day exposure to prednisone) was used as an overriding stratification factor in combination with the leukemic cell burden. A patient was considered to be at standard

Down’s syndrome in childhood ALL ¨ M Dordelmann et al

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risk (SR) if he had ⬍1000/␮l blood blasts on day 8 (prednisone good response), a RF ⬍0.8, no CNS disease and no mediastinal mass. A patient was stratified into the intermediate-risk group (IR) if he had a good prednisone response, a RF ⭓0.8, or a RF ⬍0.8 and CNS disease and/or presence of a mediastinal mass. Patients were classified as being at high risk (HR) if they had ⭓1000/␮l blood blasts on day 8 (poor prednisone response) or ⭓5% marrow blasts on day 33 or an acute undifferentiated leukemia. Additionally, in trial ALL-BFM 90 patients with translocations t(9;22) and t(4;11) were considered as high-risk patients, regardless of their therapy response.18,19

Treatment Details of treatment regimens in trials ALL-BFM 81, 83, 86 and 90 have been reported previously.17–19 Major treatment changes between all trials referred to the high-risk regimen except for the dosages of intravenous methotrexate (MTX) during consolidation and prophylactic cranial irradiation (CRT), which are shown in Table 1. Since only one patient with DS received high-risk treatment, the principal therapy components were comparable for all DS children except for MTX dosage and cranial irradiation. Cranial irradiation was performed 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.

EFS of 6 years (pEFS) was calculated. This process was repeated (n = 500) to get a ‘bootstrap’ estimate (median pEFS20). Multivarate risk analysis to estimate the prognostic significance of DS on EFS was performed using a Cox proportional hazards model. Differences in clinical and biological characteristics at time of diagnosis were analyzed by the Fisher’s exact test or Mann–Whitney U-test. Event-free survival was analyzed regarding age at a cut-off point of 6 years, since this cut-off point was found to be of prognostic significance by various authors.18,21 Survival rates were also compared for DS children receiving treatment of different intensity due to therapy-associated toxicity. Therapy-related toxicity and modifications were evaluated in detail for 61 DS patients. Significant treatment reduction was defined as dose reduction of ⬎20% in either one or more cytostatic agents or cranial irradiation in relation to the overall cumulative dose according to the applied protocol. Significant treatment delay was defined as a delay of ⬎20% according to the expected treatment duration per protocol element. The data represent patient follow-up to 1 January 1997. Only patients with an observation time of at least 24 months (diagnosis before 1 January 1995) were included in the analysis. The median observation time for all patients is 5.1 years (range 2–14.5 years). Computations were performed using SAS (Statistical Analysis System Version 6.10, SAS Institute Inc, Cary, NC, USA). Results

Clinical and laboratory features Statistical analysis Event-free survival (EFS) was calculated from date of diagnosis to last follow-up or to the first event (failure to achieve remission, early death, resistant leukemia, relapse or death of any cause). Patients who failed to achieve a complete response were assigned to a failure time of zero. The Kaplan– Meier method was used to estimate survival rates with comparisons based on the two-sided log-rank test. Standard errors were calculated using Greenwoods formula. To get an estimate for the outcome of NDS patients with a similar risk profile as DS patients a matched-pair analysis was done. Matching variables included age at diagnosis (⬍2, 2–5 or ⬎5 years), sex, initial leukocyte count (log 10 (WBC) within 15%), initial peripheral blast count (within 15%), immunophenotype and prednisone response. One control was randomly selected from available matches and the Kaplan–Meier estimate for the

Table 1 Dosages of intravenous methotrexate (MTX) during consolidation and prophylactic cranial irradiation (CRT) in trials ALL-BFM 81–90

Trial ALL-BFM

MTX (g/m2)a CRT (Gy) SR IR HR

81

83

86

90

—

0.5 × 4

5×4

5×4

18 18 24

— 12/18 24

— 12/18 18

— 12 12

a Patients in the standard risk group (RF ⬍0.8) were randomised for receiving CRT (18 Gy) or four courses of intermediate dosage MTX (0.5 g/m2 × 4).

Sixty-one (1.5%) of 4110 children with ALL were reported to have Down’s syndrome. Table 2 depicts the presenting clinical and biological findings in patients with DS as compared to other children with ALL. Sex ratio, leukocyte count and leukemic cell burden were similar in both groups. Patients with DS tended to be older than NDS patients (P = 0.04) with no infants in the DS group. DS patients lacked CNS leukemia and were less likely to present with an anterior mediastinal mass. Comparison of major immunophenotypes revealed a predominance of common ALL and absence of T-ALL (P = 0.005) in DS, whereas the incidence of pre-B-ALL was similar in both groups. Hyperdiploidy, indicated by a DNA index ⭓1.16, was significantly less frequent in the DS cohort than that in the general ALL population (P = 0.004). For all DS patients, the cytogenetic 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 patients (anomaly of coronary arteries (n = 1), atrial septal defect II (n = 3), atrioventricular defect (n = 6), isolated ventricular septal defect (n = 3), tetralogy of Fallot (n = 2), single mitral cleft (n = 1)). All but one defect had been surgically corrected before diagnosis of ALL.

Treatment response Initial treatment response to prednisone tended to be better in DS ALL as compared to patients with NDS ALL (good prednisone response in 98.1% vs 90.7%, P = 0.057) but the difference did not reach statistical significance (Table 2). Only one DS patient showed a poor prednisone response, achieved complete remission following induction therapy, but suffered from bone marrow relapse after 1. years, and died 1 year later.


Table 2 Frequency (%) of clinical features and initial treatment response in patients with ALL and Down’s syndrome (DS) and other children with ALL (NDS)

Feature

Sex Female Male Age (years) ⬍1 ⭓1–⬍6 ⭓6 Median age (years) Leukocyte count/␮l ⬍10000 ⭓10000–⬍20000 ⭓20000–⬍50000 ⭓50000 Median/␮l Leukemic cell mass (RF) ⬍0.8 ⭓0.8–⬍1.2 ⭓1.2–⬍1.7 ⭓1.7 Ploidy/DNA indexa ⬍1.16 ⭓1.16 Cytogenetics t(4;11) t(9;22) CNS leukemia Mediastinal mass Immunophenotypeb Pro-B-ALL c-ALL Pre-B-ALL T-ALL Prednisone responsec ⬍1000/␮l ⭓1000/␮l Congenital heart disease

DS patients (n = 61)

NDS (n = 4049)

55.7 44.3

56.6 43.4

— 49.0 51.0 6.03

2.6 58.8 38.6 4.7

34.4 21.3 14.8 29.5 16800

47.3 15.4 16.6 20.7 11300

24.6 37.7 32.8 3.3

30.0 33.3 29.7 7.0

93.3 6.7

74.2 25.8

1.8d — — 1.6

2.1d 3.2d 2.7 8.9

— 80 20 —

5.2 65.2 16.4 13.0

98.1 1.9 26.2

90.7 9.3 0.3

P value

0.04

0.004

mucositis and profound bone marrow depression with HDMTX or recurrent severe pulmonary infections during maintenance therapy. Despite normal renal function tests prolonged renal MTX excretion was noted in six patients, which led to MTX reduction in one and to significant treatment delay in four patients during consolidation therapy. Daunorubicin dosage was reduced in seven patients due to considerations regarding cardiac function in two and caused by infectious complications in five patients. In four patients, several protocol elements had to be reduced, in three cases because of severe persistent infection, and in one because his guardians declined intensive chemotherapy. Diabetes mellitus developed in six patients during treatment with asparaginase and steroids in induction and reinduction, but caused asparaginase reduction in only one patient. In all patients the diabetic period stopped shortly after completing induction or reinduction. Treatment had to be significantly postponed, equally distributed during induction, consolidation and reinduction, in 13 DS patients (21%), mainly caused by profound bone marrow depression and concomitant infection. However, eight of these 13 children received protocol treatment without significant reduction of cumulative dosages. We did not perform a detailed analysis, ie matched pair, regarding therapy morbidity and mortality compared to the NDS controls. However, Table 3 shows the overall treatment mortality being lower in the NDS cohort (1.8% vs 6.6%).

Treatment outcome 0.05 0.05 0.005 0.058 ⬍0.0001

Number of patients examined: DS n = 30, NDS n = 2026. Only patients of trials ALL-BFM 86 and 90 (DS n = 45, NDS n = 2695). c Only patients of trials ALL-BFM 83, 86 and 90 (DS n = 55, NDS n = 3355). d Percent of patients examined. a

b

However, in both groups, a similar proportion of patients (96.7% vs 98.4%) achieved complete remission after 33 days of induction therapy (Table 3).

Therapy-related toxicity and treatment modifications In 43% of the DS patients, therapy was either significantly reduced and/or postponed. Of 47 DS patients, who should have been irradiated according to the applied protocol, cranial irradiation was omitted in six (13%) and reduced in two (4%) patients, due to considerations regarding intellectual impairment. Cranial irradiation was generally well tolerated. Chemotherapy had to be significantly reduced in a quarter of the DS patients (n = 16). In the majority (n = 13), the methotrexate (MTX) dosage was affected either in consolidation (n = 8), in maintenance (n = 4) or in both (n = 1) due to severe

With a median observation time of 5.1 years (range 2–14.5 years), there were no significant differences in outcome between DS patients and other children with ALL. However, in general, EFS tended to be slightly inferior for DS patients as compared to NDS children (58 ± 8% vs 70 ± 1%, P = 0.14, Figure 1). Comparative analysis with NDS non-hyperdiploid patients (EFS 67 ± 1%) (Figure 4) and matched pair analysis (NDS 66%) for EFS at 6 years revealed similar results, which were included in the confidence interval for the corresponding Kaplan–Meier estimate for DS patients (58 ± 8%). Moreover, comparison of DS patients with or without major therapy reduction and/or delay showed a slight disadvantage for the less intensively treated group (46 ± 13% vs 65 ± 9%, P = 0.28, Figure 2). However, DS children who received protocol treatment with no major modifications had a similar EFS as compared 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 relapses) in trials ALL-BFM 81 and 83 had no influence on outcome in the few DS patients analyzed. Comparison of children ⬍6 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 modifications. In contrast, DS patients ⭓6 years of age fared slightly worse as compared to NDS children with similar age (44 ± 11% vs 63 ± 1%, P = 0.22, Figure 3). Of the 26 DS patients, in whom therapy had to be reduced and/or delayed, 15 were less than 6 years of age, of whom only three (20%) suffered from relapse. In contrast, of the remaining 11 patients ⭓6 years of age, six (55%) relapsed. Table 3 summarizes the causes of death and relapse pattern among the evaluated children. In DS, a substantial proportion (n = 13) suffered from relapse after elective cessation of therapy (Figure 1). The leading cause of death in patients with DS was bone marrow (BM) recurrence (12 isolated BM, two com-

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Table 3

Outcome in patients with ALL and Down’s Syndrome (DS) and other ALL patients (NDS)

DS patients ALL n = 61

CR pEFS (6 years)

n

%

59a

96.7 58 ± 8

Events Non-response Therapy death Relapse other

— 4a,b 16 —

Site of relapse Bone marrow CNS Testes Bone marrow/CNS Bone marrow/Testes Other

12 1 1 — 2 —

Secondary maligancy Lost to follow-up

— 2

6.6 26.2

19.7 1.6 1.6 3.3

Without therapy reduction n = 35 n % 33a

— 2a 8 — 5 1 1 — 1 —

94.3 65 ± 9

5.7 22.9

14.3 2.9 2.9 2.9

—

NDS With therapy reduction n = 26 n % 26

— 2b 8 — 7 — — — 1 — —

100 46 ± 13

7.7 30.8

26.9

3.8

n = 4049 n

%

3983

98.4 70 ± 1

33 71 865 35

0.8 1.8 21.4 0.9

526 78 49 116 44 52

13.0 1.9 1.2 2.9 1.1 1.3

12 44

0.3

a

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

b

Figure 1 Event-free survival for children with Down’s syndrome and ALL (DS-ALL) and other ALL children (NDS-ALL).

bined BM/testicular), one patient suffered an isolated CNS and 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 died in remission from pneumonia and congestive heart failure, respectively. Multivariate analysis for DS as an independent prognostic factor at diagnosis revealed no significance after adjustment for age, WBC and prednisone response. However, the presence of DS became significant (P = 0.0107), when patients

Figure 2 Event-free survival in Down’s syndrome and ALL (DSALL), treated without and with significant therapy reduction.

after elective cessation of therapy only were considered for analysis (Table 4). Discussion In this study, the incidence of DS among children with ALL was 1.5% (n = 61), which is in accordance with the range of 1.6–2.1% reported by other groups.3,4,6 This study allows the analysis of clinical characteristics and therapeutic outcome in a comparatively large, homogeneous cohort of centrally diag-


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

Prednisone response Age Leukocyte count/␮l Down’s syndrome

Figure 3 Event-free survival for children with ALL according to age ⬍ and ⭓6 years with (DS-ALL) and without Down’s syndrome (NDS-ALL).

Figure 4 Event-free survival for children with DS-ALL and NDSALL with DNA index ⭐1.16.

nosed and similar intensively treated DS patients. However, our power to detect significant differences related to the presence of DS is still limited by the small number of such children, particularly when numerous variables are analyzed. Because patients with DS presented with rather few known adverse prognostic features, they could theoretically be expected to have a rather favorable EFS as compared to the general ALL population. However, we found EFS for DS ALL (58 ± 8%) slightly inferior as compared to NDS ALL (70 ± 1%). The outcome was even worse for DS patients either being older than 6 years of age (44 ± 11%) and/or for patients needing treatment modifications due to treatment-related toxicity

At diagnosis

After cession of therapy

Worse category

Risk ratio

Probability χ2

Risk ratio

Probability χ2

poor

3.26

0.0001

1.28

0.067

⬍1 year ⭓6 years ⭓20.000

3.22 1.74 1.55

0.0001 0.0001 0.0001

2.08 1.62 0.96

0.046 0.0001 0.72

present

1.49

0.1031

2.48

0.0107

(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 (59–64%),5,8 others disagreed. Reports from the Children’s 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 traditional 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 DSALL 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 explanation 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 even an enhanced aging due to cytotoxic therapy. This could cause less tolerance of therapy and impaired immunologic surveillance for both infection and residual malignant cells. Several studies clearly identified DS patients at increased risk of treatment-related death due to infectious complications.8,26,27 Various investigators reported abnormalities of circulating granulocytes in DS including morphology, enzyme levels and ability to kill bacteria and abnormalities in the immune system including both cellular and humoral immunity, which were in part more prominent in older DS children.25,28,29 Moreover, although most DS patients are well nourished and thrive well, they are known to have low levels

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of serum trace elements such as zinc and selenium, which are both known to be essential cofactors in T cell responses, phagozyte function and antibody production.28,30–32 Finally, parental refusal for aggressive therapy due to pre-existing difficulties managing daily life or parents’ and/or patients’ compliance may play a greater role in older DS patients.33–35 Did initial response to treatment matter? In the present study, DS patients achieved a remission rate comparable to the NDS group. This extends the findings of the United Kingdom Children’s Cancer Study Group and the POG who demonstrated a similar failure rate for children with (3.3–7.7%) and without DS (1.6–7%) when using protocols based on intensive therapy and improved supportive care.6,8 In contrast, a retrospective survey from the CCG showed a higher rate of induction failure, including death due to therapy complications, for children with DS ALL as compared to NDS ALL (19% vs 6%).4 Did treatment-related toxicity and treatment intensity matter? We found a similar outcome for children with DS and NDS once it was possible to apply intensive treatment with no major modifications. However, we noted the same result for patients younger than 6 years of age, irrespective of toxicity and consecutive treatment modifications. Ragab and colleagues6 reported almost half of their intensively treated DS patients were unable to tolerate therapy; especially due to methotrexate-associated toxicity, this drug had to be reduced significantly. However, when compared to DS patients who were treated conventionally, the intensively treated patients fared better, despite major treatment reduction. DS patients, treated at St Jude Children’s Research Hospital, showed no significant difference in treatment outcome (65 ± 14.5%) as compared to children without DS (74 ± 1.6%), but suffered disproportionally from methotrexate toxicity also. The authors concluded, that although DS patients presented with traditional favorable features and were expected to have a higher relapse-free survival, regarding EFS ‘these patients fared no better than other children with ALL, partly because of excessive therapy-related toxicities, which accounted for a third of treatment failures’.3 As in the present study, the majority of other investigators reported an unusual increased MTX toxicity in DS patients.3–5,6,8,9,11,12 One pharmacokinetic study in patients with DS showed a slower than expected intracellular clearance of methotexate (1 g/m2) and significant increased toxicity in comparison to other children with ALL.12 In the present study, total duration of therapy with 18 vs 24 months in trials ALL-BFM 81 and 83 had no significant influence for outcome in DS patients. However, since the BFM group has shown the total therapy duration of 24 months as being significantly superior,17 this is probably due to the small 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 presence of DS at diagnosis not being significantly associated with a poorer EFS after adjustment for established prognostic factors such as prednisone response, age and leukocyte count. However, when ALL patients after elective cessation of therapy were analyzed, DS became an important prognostic factor. The reason for DS being a significant adverse prognostic feature for children off therapy remains unclear. It might be a combination of different factors mentioned above such as age, blast cell ploidy and applied treatment intensity. In DS, the leading cause of treatment failure was bone marrow recurrence later than 2. years. Since 98% of the DS patients presented with standard- or intermediate-risk features (according to the BFM risk stratification) and 100% with B

precursor ALL, the predominance of rather late relapses among the DS cohort may simply represent the known tendency of B precursor ALL to relapse later or the known relapse pattern of patients with a low tumor cell burden. Although almost one-third of DS patients present with congenital heart disease (CHD),36 the incidence of cardiac complications aggravated by intensive antileukemic treatment is low. We noted one death associated with CHD in a patient who had not undergone cardiac surgery and therefore presented with severe pulmonary hypertension and right ventricular failure at diagnosis. This extends the findings of previous reports, that found therapy-related death associated with CHD in 3% (5/162) of their intensively treated DS patients.4,5,8 Life expectancy in DS is much better than generally believed. For patients with DS without congenital heart defects (73.8% of our patients) survival to age 30 is 79.2%.37 Our results demonstrated, that patients with ALL and DS are less likely to present with known adverse prognostic features as compared to other children with ALL. Because of the importance of dose intensity for cure, it seems advisable to develop more tolerable treatment for children with DS and ALL without compromising treatment efficacy. Reduction of antifolate therapy during consolidation might be of advantage in treating DS patients with ALL. Seven out of 11 DS patients (64%) from trials ALL-BFM 81 and 83, who were treated with intermediate-dose methotrexate (IDM = 0.5 g/m2) without significant toxicity during consolidation, are in continuous complete remission. High-dose methotrexate during consolidation (HDM = 5 g/m2) in trials ALL-BFM 86 and 90 caused significant therapy toxicity and did not seem to improve EFS for DS ALL. When considering both the predominance of favorable prognostic features and the low incidence of CNS leukemia and CNS relapse, IDM in consolidation might be sufficient to treat DS patients with ALL, at least with ‘BFM-type’ protocols. Furthermore, less therapy-associated toxicity with intermediate-dose methotrexate might enable the application of other more tolerable therapy components in time and at full dosage. However, regarding the predominance of late relapses, maintenance therapy including standard-dose oral methotrexate (20 mg/m2/week) should neither be reduced nor shortened. In summary, the combination of multiple rather than therapy-related problems seemed to contribute to the inferior EFS for children with DS and ALL. Sine most of the toxicity encountered is manageable with careful attention to the known problems of therapy tolerance of such children, intensive antileukemic therapy is recommended. However, sophisticated supportive care including adequate nutrition, infection prophylaxis, close monitoring of antimetabolite therapy and extensive psycho-social support is urgently required. Acknowledgements This work was supported by a grant from the Madeleine Schickedanz Stiftung. We thank E Odenwald, U Meyer, N ¨ Gotz and A Brandt for preparing the data of the ALL-BFM studies. We gratefully acknowledge the following clinicians who submitted cases to this study: U Mittler, Magdeburg; J Treuner and E Maas, Stuttgart; J Wulff, Datteln; U Bode and G Fleisch¨ hack, Bonn; D Niethammer and R Dopfer, Tubingen; M Lako¨ mek and A Pekrun, Gottingen; KM Debatin, Heidelberg; W Rauh, Trier; B Kornhuber and K Siegler, Frankfurt; P Imbach, Aarau; G Weinmann, Erfurt; A Gnekow, Augsburg; R Dicker¨ hoff, Sankt Augustin; G Henze, Berlin; C Bender Gotze, ¨ ¨ ¨ Munchen; S Muller-Weihrich, Munchen; H Wehinger, Kassel;


¨ P Bucsky, Lubeck; W Eberl, Braunschweig; A Jobke, ¨ Nurnberg; A Hofmann, Chemnitz.

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