The Dutch Childhood Oncology Group (DCOG) has used two treatment strategies for children with acute lymphoblastic leukemia (ALL) based on Pinkel's St Jude Total Therapy or the Berlin–Frankfurt–Münster (BFM) backbone. In four successive protocols, 1734 children were treated. Studies ALL-6 and ALL-9 followed the Total Therapy approach; cranial irradiation was replaced by medium-dose methotrexate infusions and prolonged triple intrathecal therapy; dexamethasone was used instead of prednisone. Studies ALL-7 and ALL-8 had a BFM backbone, including more intensive remission induction, early reinduction and maintenance therapy without vincristine and prednisone pulses. The 5-year event-free survival and overall survival increased from 65.4 to 80.6% (P<0.001) and from 78.7 to 86.4% (P=0.07) in ALL-7 and ALL-9, respectively. In ALL-7 and ALL-8 National Cancer Institute (NCI) high-risk criteria, male gender, T-lineage ALL and high white blood cells (WBCs) predict poor outcome. In ALL-9 NCI criteria, gender, WBC >100 × 109/l, and T-lineage ALL have prognostic impact. We conclude that the chemotherapy-only approach in children with ALL in Total Therapy-based strategies and BFM-backbone treatment does not jeopardize survival and preserves cognitive functioning. This experience is implemented in the current DCOG-ALL-10 study using a BFM backbone and minimal residual disease-based stratification.
The Dutch Childhood Leukemia Study Group (DCLSG) was founded in 1972 and renamed Dutch Childhood Oncology Group (DCOG) in 2001 when the scope of malignant diseases covered was extended from leukemia and non-Hodgkin's lymphoma to all types of pediatric cancer. From 1972 to 1984, the DCLSG conducted five studies in acute lymphoblastic leukemia (ALL), overall based on the Pinkel's St Jude Total Therapy approach and involving combination chemotherapy and central nervous system (CNS) irradiation as presymptomatic CNS treatment.1 Five-year event-free survival (EFS) data for ALL-II (215 patients), ALL-III (217 non-high-risk (NHR) patients ≈70% of patients) and ALL-V (246 NHR patients) were 35, 42 and 57%, respectively.2, 3
In the early 1980s of the last century, the cognitive and endocrine devastating late effects of cranial irradiation, especially in young children, became clear. The DCOG was among the first to abandon this method of CNS prophylaxis unless overt meningeal involvement was present at initial presentation. In the DCLSG-ALL-6 study (1984–1988), elective cranial irradiation was omitted and replaced by medium high-dose (2000 mg/m2 in 24 h infusion) methotrexate infusions with citrovorum factor rescue and prolonged triple intrathecal therapy; dexamethasone was used instead of prednisone during induction and maintenance. This ALL-6 study was eligible only to NHR patients, whereas high-risk (HR) patients were treated by the institutional pilot protocols.4, 5
In 1986, the DCLSG founded together with the German–Austrian Berlin–Frankfurt–Münster (BFM) cooperative group and the Italian AIEOP cooperative group the international BFM study group (I-BFM-SG) and adopted the BFM backbone strategy in protocols DCSLG-ALL-7 and ALL-8, which ran from 1988 to 1991 and from 1991 to 1997, respectively. Also the BFM risk stratification criteria, based on initial day 8 prednisone response, tumor load (BFM risk factor) and cell biological characteristics, were adopted at that time. Both studies were almost identical to the German BFM counterparts (ALL-BFM-86 and ALL-BFM-90, respectively),6, 7 except for the alternative CNS prophylaxis. Briefly, this risk-adaptive strategy included a more intensive remission induction protocol including daunorubicin, cyclophosphamide and cytosine-arabinoside in addition to the Total Therapy approach. Another major difference was the reinduction protocol II and maintenance therapy with methotrexate and 6-mercaptopurine (MP) but without vincristine and prednisone pulses.8, 9
When in the early 1990 s of the last century, the favorable EFS and overall survival (OS) data of the DCLSG-ALL-6 study emerged, the DCLSG felt that the ‘Total Therapy’ concept and stratification criteria of DCLSG-ALL-6 should be reintroduced for all patients with ALL in the Netherlands. This DCLSG-ALL-9 study started in 1997, using the DCLSG-ALL-6 treatment strategy for NHR patients. For HR patients an intensified treatment piloted at the Groningen University Medical Center was adopted. On top of the ALL-6 NHR-backbone, the HR patients received a more intensive CNS prophylaxis and two intensification courses as described below.10
This paper reviews the long-term outcome of the Dutch studies based on the Total Therapy approach (ALL-6 and ALL-9) and those based on BFM approach (ALL-7 and ALL-8).
Materials and methods
Patients and treatment
From 1984 to 2004, 1734 consecutive patients in the Netherlands with newly diagnosed ALL were enrolled on four successive treatment protocols (DCLSG-ALL-6, -7, -8 and -9). ALL-7, -8 and -9 protocols were population-based, whereas ALL-6 only recruited NHR patients (see below). The diagnosis of ALL was based on centralized cytomorphologic examination of bone marrow smears and immunophenotype of leukemic cells. Cytogenetic analysis of leukemic cells was performed by the treating institutions' laboratory and centrally reviewed by a panel of Dutch cytogeneticists. In all four protocols, patients were excluded if they were treated with systemic corticosteroids and/or cytostatic drugs less than 4 weeks before diagnosis or when they were diagnosed with a mature B-ALL, either morphologic (FAB type L3) or immunophenotypic (surface immunoglobulin M positive). Complete remission (CR) was defined as <5% blasts in the bone marrow and recovery of normal hematopoiesis, absence of peripheral blood leukemic cells and no evidence of disease at any other site. In all studies, but ALL-8, relapse was defined as ⩾20% (ALL-8 ⩾25%) blast cells in the bone marrow and/or blast cells in the peripheral blood, CNS involvement or leukemic infiltrations elsewhere. CNS involvement at diagnosis or relapse was defined as the cytomorphological presence of blasts in two successive cerebrospinal fluid specimens, collected at least 24 h apart without major blood contamination, confirmed by the central DCOG laboratory; from study ALL-7 this was further specified as a cerebrospinal fluid cell count ⩾5/μl with blasts in an atraumatic (<15 erythrocytes per μl) sample. If neurological symptoms were present, a computed tomography or magnetic resonance imaging of the brain was required to make a diagnosis of CNS involvement. All treatment protocols were approved by the appropriate Medical ethics Committees of the participating institutions. Informed consent was obtained according to the institutional guidelines before treatment and before randomization, if applicable.
Details of the studies have been described in earlier publications.5, 8, 9, 10 These are briefly described below and summarized in Figures 1a and b. Protocol ALL-6 opened to children with newly diagnosed ALL in the Netherlands diagnosed from December 1984 to July 1988. This study was limited to NHR patients, defined as age 0–15 years, initial white blood cell (WBC) count less than 50 × 109/l, no mediastinal mass and no CNS leukemia at diagnosis. This included 70% of newly diagnosed ALL patients in this age group. Patients received a 6-week remission induction with vincristine, dexamethasone and Escherichia coli l-asparaginase, followed by 3 weekly medium high-dose (2 g/m2) (MD-MTX) courses with citrovorum factor rescue and maintenance treatment with 5 weeks of daily oral 6-MP and weekly oral MTX alternated with 2 weeks of weekly vincristine intravenous push and daily oral dexamethasone. Triple intrathecal therapy was given during the induction and CNS-prophylaxis as well as every 7th week during the first year of maintenance therapy for a total of 12 triple intrathecal therapy injections. Total duration of therapy was 116 weeks.5
Protocol ALL-7 was open from July 1988 through September 1991 for all newly diagnosed de novo ALL patients who were 0 through 15 years of age. Chemotherapy and risk group stratification, based on tumor mass and early response to treatment into standard risk (SRG), risk (RG) and experimental group (EG), were similar to that of ALL-BFM-86, but cranial irradiation (18 Gy) after protocol II was restricted to patient's age ⩾1 year with initial CNS involvement (±2% of all patients). A randomized study on late intensification (protocol S) was performed in RG patients, who were in continuous CR after 1 year. EG patients in first CR with a matched sibling donor were offered allogeneic bone marrow transplantation after protocol E. During the study, in October 1990, the early reinduction course (protocol II) was introduced for SRG patients due to apparently worse results in the patients not receiving this protocol II. Total treatment duration was 18 months for all patients.8
Patients with newly diagnosed ALL who were 0–18 years of age were eligible for the ALL-8 study when diagnosed between October 1991 and December 1996. The ALL-8 study was comparable with the ALL-BFM-90 protocol with a few modifications: (a) prophylactic cranial irradiation (12 Gy) after protocol II was restricted to patients aged ⩾1 year with initial CNS involvement. (b) SRG patients did not receive protocol IB and (c) reduced doses of HD-MTX (2 instead of 5 g/m2) were given during protocol M.9 Patients were stratified into three risk groups, standard- (SRG), medium- (MRG) or high-risk group (HRG), identical to those in the ALL-BFM-90 study. Patients with a risk factor >0.8 or with a mediastinal mass, CNS involvement or T-ALL immunophenotype were stratified into MRG. HRG characteristics were acute undifferentiated leukemia (AUL), t(4;11), t(9;22) or BCR-ABL rearrangements, no CR on day 33 and a poor prednisone response on day 8 (>1000 per μl peripheral blood blasts). Other patients were stratified into SRG. In collaboration with other members of the International BFM Study Group (I-BFM-SG), Italian (AIEOP), Dutch and Hungarian SRG patients were randomized to receive or not to receive 20 weekly high doses (25 000 U/m2) of intramuscular Erwinia l-asparaginase (HD-L-ASP) during early maintenance treatment (IDH protocol).11 Also Dutch MRG patients were randomized to receive either conventional doses (25 mg/m2/day for 56 days) of 6-MP orally or 4 high doses (1300 mg/m2) of 24 h intravenous 6-MP during protocol M. Bone marrow transplantation after one series of three HR blocks was optional for HRG patients with a matched sibling donor. The total duration of chemotherapy for all patients was 24 months. Also, in the ALL-8 study an extensive research project was performed in cooperation with the I-BFM-SG to determine the prognostic relevance of minimal residual disease detected by immunoglobulin gene rearrangement and T-cell receptor rearrangement targets.12, 13
Protocol ALL-9 was open from January 1997 through October 2004 and eligible for all patients with an initial diagnosis of ALL aged 0–18 years. They were stratified into an NHR and HR group. NHR patients had an initial WBC count <50 × 109/l, no mediastinal mass, no initial CNS involvement, no testicular disease, no T-cell immunophenotype (from March 1998), absence of t(9;22) or BCR-ABL rearrangement and absence of 11q23 abnormalities with mixed lineage leukemia rearrangement. Part of the patients were included in research projects that studied pharmacokinetics and—dynamics of one additional dose of vincristine14 or PEG-asparaginase before start of therapy.15, 16 The treatment protocol for NHR patients was identical to the ALL-6. HR patients received several intensification elements on top of the NHR schedule: (a) Daunorubicin was added to the 3 drug induction. (b) For consolidation, 4 times 2-weekly HD-MTX (3 g/m2) infusions were given together with 8 weeks of oral 6-MP and (c) two intensification courses were given, the first one consisting of l-asparaginase, daunorubicin, 6-MP, vincristine and dexamethasone. The second intensification consisted of six 4-day courses of cyclophosphamide and cytosine-arabinoside. Maintenance treatment was identical to that given to the NHR group, but MTX was given intravenously instead of orally. HR patients received 15 doses of triple intrathecal therapy over the total treatment duration of 109 weeks; if they had initial CNS involvement, two additional doses during induction were given.
The duration of EFS was defined as the time from diagnosis until the date of failure (induction failure, relapse, death or the development of a second malignancy) or until the date of last contact for all event-free survivors. Patients who did not achieve CR were considered as treatment failures on day 0. The Kaplan–Meier method was used to calculate EFS and OS curves; these were compared with the log-rank test. All analyses were based on intention to treat. For those who achieved CR cumulative incidences of isolated CNS or any CNS relapse, as well as testicular relapse, second malignancies and toxic deaths were constructed by the method of Kalbfleisch and Prentice17, 18 and the functions were compared with Gray's test.19 All analyses concerning cumulative incidence were made with mstate library. Prognostic factors for the four DCLSG studies were analyzed including the prognostic significance of the NCI/Rome criteria (SR is WBC <50 × 109/l and age 1–9 years) either B- (70% of SR) or T lineage (30% of SR).20, 21
Overall treatment outcome
The treatment outcome according to the DCOG-ALL studies from 1984 to 2004 is shown in Table 1. A steady improvement of both EFS and OS of childhood ALL patients treated according to the ALL-7, -8 and -9 studies is seen (Figure 2). The numbers at risk and the cumulative incidence (%±s.e.) of isolated CNS, any CNS and testicular relapses as well as the cumulative incidence of second malignant disease and toxic deaths other than infectious deaths for the studies is shown in Table 2. It is difficult to compare the results of ALL-6 that only enrolled NHR patients with the results of the later studies. When comparing ALL-7 patients with ALL-8 and ALL-9 patients at 5 years of follow-up, no statistically significant difference could be found for CNS-only relapses (P=0.123); for any CNS relapses, the outcome was barely significant (P=0.056). For testicular relapses, no difference could be found. For second malignancies, ALL-9 shows a favorable result but few patients are at-risk at 10 years compared with ALL-7 and ALL-8. At 5 years of follow-up, the number of toxic deaths in remission from ALL-9 is higher than those in ALL-8 (P=0.048). Especially, the number of infectious deaths (15 out of 23 toxic deaths) is worrying and may be due to the prolonged exposure to dexamethasone in these patients.22
Protocol-specific treatment outcome
Presenting patient characteristics and biological features as well as treatment results are shown in Figure 3 and Tables 1, 2 and 3. One hundred and ninety NHR children and no HR children were enrolled into this study. Remission induction failed in seven patients (3.7%). After a median follow-up time of 218 (range 59–282) months, the EFS estimate at 10 years is 82.0±2.8% and the OS 85.0±2.6%. Relapses occurred in 26 out of 188 (13.8%) patients. At 10 years of follow-up, the cumulative risk estimates for both isolated CNS and any CNS relapses were 1.1±0.7%. For testicular relapse, this risk was estimated to be 0.5±0.5% at 10 years. Secondary malignancies were low (2 out of 162; one acute myeloid leukemia (AML) and one thyroid carcinoma) with a cumulative risk estimate of 0.5±0.5% at 10 years. The toxic death in remission rate estimate at 10 years was 2.2±1.1%.5
Presenting patient characteristics and biological features as well as treatment results are shown in Figures 2 and 4 and Tables 1, 2 and 4. In this study, 218 children (SRG 74, RG 127 and EG 17) were enrolled. Remission induction failed in five patients (2.3%). After a median follow-up time of 186 (range 3–242) months, the EFS estimate at 5 years is 65.4±3.2% and the OS is 78.7±2.8% (EFS at 10 years is 63.9±3.3% and the OS is 76.8±2.9%). Relapses occurred in 68 out of 215 (31.6%) patients; CNS-only relapses were 12 out of 215 (5.6%) and these occurred exclusively in patients before the introduction of early reinduction protocol II. At 10 years of follow-up, the cumulative risk estimates for isolated CNS and any CNS relapses were 5.6±1.6 and 7.0±1.8%, respectively. For testicular relapse, this risk was estimated to be 2.3±0.1% at 10 years. Secondary malignancies were 7 out 147 (one AML, two thyroid carcinoma, one B-cell ALL, one muco-epidermoid carcinoma, one osteosarcoma and one soft tissue sarcoma) with a cumulative risk estimate of 2.4±1.0%. The toxic death in remission rate estimate was 2.9±1.2%. Late intensification with protocol S was limited to the first 51 patients and could not show a difference in EFS.8
Presenting patient characteristics and biological features as well as treatment results are shown in Figures 2 and 5 and Tables 1, 2 and 5. Four hundred and sixty-seven children (170 SRG, 241 MRG and 56 HRG patients) were enrolled into this study; three of them were older than 15 years of age, none of them relapsed or died. Remission induction failed in six patients (1.3%). After a median follow-up time of 144 (range 13–198) months, the EFS estimate at 5 years is 72.9±2.1% and the OS is 83.0±1.7% (EFS at 10 years is 70.0±2.1% and the OS is 79.6±1.9%). Relapses occurred in 117 out of 465 (25.2%); CNS-only relapses were 17 out of 465 (3.7%). At 10 years of follow-up, the cumulative risk estimates for isolated CNS and any CNS relapses were 3.5±0.9 and 4.6±1.0%, respectively. For testicular relapse, this risk was estimated to be 2.0±0.6% at 10 years. Secondary malignancies were 6 out of 348 (one AML, two secondary ALL, one MDS and two planocellular carcinoma of skin) with a cumulative risk estimate of 1.4±0.6%. The toxic death in remission rate estimate was 1.6±0.6%.9
The results of the Italian–Dutch–Hungarian (IDH) randomized study of high-dose Erwinia l-asparaginase during early maintenance was reported previously.11 In the Netherlands, 165 SRG patients were eligible for randomization, but only 85 (52%) were randomized. For the IDH study as a whole it was concluded that the application of extended high-dose l-asparaginase may improve outcome.11
Two hundred and thirty-five MRG patients were eligible for randomization to oral or high-dose intravenous 6-MP, but only 187 (76%) patients were randomized. No benefit was observed from HD-6MP.
The results of the I-BFM-SG for semiquantitative measurement of minimal residual disease were reported elsewhere. Minimal residual disease levels in the first 3 months of therapy had strong independent prognostic impact and is used in the current DCOG ALL-10 protocol for risk group stratification.12
Presenting patient characteristics and biological features as well as treatment results are shown in Figures 2 and 6 and Tables 1, 2 and 6. In this study, 859 children (601 NHR and 258 HR) were enrolled; 11 of these 859 patients were older than 15 years of age. Data from one patient are missing, another patient died before treatment and remission induction failed in 12 patients (1.4%). Nine patients died in induction (five bacterial infection, one fungal disease, one tumor lysis, one veno-occlusive disease and one accidental intrathecal vincristine injection). After a median follow-up time of 72 (range 5–133) months, the EFS estimate at 5 years is 80.6±1.4 and the OS is 86.4±1.2%. Patients >15 years of age had lower EFS than 10- to15-year-old patients, but their OS did not differ. Relapses occurred in 133 out of 857 (15.4%); CNS only relapses were 22 out of 857 (2.6%) At 5 and 10 years of follow-up, the cumulative risk estimates for isolated CNS and any CNS relapses were 2.6±0.6 and 3.3±0.6%, respectively. For testicular relapse, this risk was estimated to be 1.1±0.4 and 1.7±0.6% at 5 and 10 years, respectively. Secondary malignancies were 2 out of 699 (one AML and one melanoma) with a cumulative risk estimate of 0.1±0.1%. The toxic death in remission rate estimate was 2.8±0.6% and included 23 patients (15 infections mainly Gram-negative sepsis, 3 post-bone marrow transplantation, 2 accidental intrathecal vincristine injection and 3 unknown causes). Concurrent with the ALL-9 study, a nationwide prospective longitudinal study of neurocognitive functioning in these chemotherapy-only treated ALL patients was carried out and reported elsewhere. Despite intensive and potentially neurotoxic treatment, no evident negative neuropsychological late effects were found 4.5 years after diagnosis, except for effects on complex fine-motor functioning.23 Results of the pharmacokinetic and dynamic studies of vincristine and PEG-asparaginase given upfront before start of the combination chemotherapy are published elsewhere.14, 15, 16
Treatment results according to presenting features
Tables 3, 4, 5, 6 show the outcomes per study according to the NCI criteria.20 In the BFM-based protocols ALL-7 and ALL-8, a poor outcome is related to NCI HR criteria, male gender (only ALL-8 study), T-lineage ALL and a high WBC. Patients with t(9;22) and t(4;11) have a poorer outcome and the outcome of infants is extremely poor on these protocols.
In the ALL-9 protocol, also NCI criteria, gender, T-lineage and t(9;22) and t(4;11) have prognostic impact. A high WBC is associated with a poor outcome only for cases with WBC >100 × 109/l. Patients older than 10 years have a less favourable outcome. Hyperdiploidy and especially TEL/AML1 are associated with a favourable outcome. Infants were not eligible for this study but were enrolled in the Interfant-99 study.23
Multivariate analysis using gender, NCI criteria, B- or T-cell lineage, CNS positivity status and DNA ploidy as prognostic variables showed NCI criteria and CNS positivity of prognostic importance for EFS and OS in the study ALL-8. In the study ALL-9, NCI criteria and DNA ploidy had prognostic impact for EFS and OS; in the ALL-7 study, NCI criteria were also of prognostic importance but only for OS.
From the 1970s, the DCLSG, now DCOG, studies in children with ALL in the Netherlands have been population based. In the last decades, the overall 5-year EFS in children with ALL in the Netherlands improved from 65.4% in ALL-7 (1988–1991) to 72.9% in ALL-8 (1991–1997) and to 80.6% in ALL-9 (1997–2004). The corresponding improved overall 5-year survival rates were 78.7, 83.0 and 86.4%, respectively. These results confirm that the omission of cranial irradiation in both Total Therapy-based strategies and BFM backbone treatment does not jeopardize the overall good treatment results. Omission of cranial irradiation as CNS prophylaxis in patients without initial CNS disease (CNS3 patients) has also resulted in preserved cognitive functioning in survivors.23 BFM-based protocols have not proved suitable for the treatment of infants with ALL in the Netherlands. Infants have benefited from the introduction of the Interfant Study.24
From the BFM-backbone study ALL-7, it became evident that early reinduction with protocol II is required to avoid a worse outcome mainly because of the high incidence of CNS relapses. Another contributing factor to the worse outcome in ALL-7 patients may be the relatively short duration of treatment (18 months) in this study.8 In the BFM-backbone study ALL-8, early reduction of chemotherapy in SRG patients (using only protocol Ia) was applied and appeared to have no negative impact on prognosis. Patients may benefit from longer exposure to l-asparaginase;11 the results may have been even better if l-asparaginase with a longer half-life than Erwinia l-asparaginase had been used. In both the ALL-7 and ALL-8 study patients, the adverse effect of a traumatic lumbar puncture with the presence of blasts at diagnosis is suggested and those patients may benefit from additional CNS-directed chemotherapy.25, 26, 27
The DCOG Total Therapy-based treatment strategies ALL-6 and ALL-9 study made clear that many children with ALL can be cured without using anthracyclines, cyclofosphamide and epipodophyllotoxins, such as etoposide. This may especially hold true for the majority of patients with TEL/AML1 rearranged ALL. However, this dexamethasone- and antimetabolite-based therapy leads to a worse outcome in children >10 years of age at diagnosis as is described in more detail elsewhere.28 Moreover, the extensive and prolonged use of dexamethasone led to a high infectious death rate during maintenance.22 Enhanced supportive care measures might decrease or prevent these deaths. In addition, the use of pulses of shorter duration (5 days of dexamethasone every 3 weeks instead of 14 days every 7 weeks) with the same cumulative dose may overcome this high toxic death rate.
We conclude that the DCOG has used two types of treatment protocols, that is, Total Therapy-based protocols and BFM-based protocols in the past two decades. This experience is now implemented in the current ALL10 protocol that uses minimal residual disease to stratify therapy for patients who get BFM therapy for the first 3 months, identical as in the BFM-2000 study. Thereafter, patients at low risk of relapse receive a reduced reintensification course and maintenance without steroid/vincristine pulses. The small group of patients at very HR of relapse gets intensive blocks of chemotherapy followed by stem cell transplantation. The largest intermediate group of patients receives intensified therapy mainly by prolonged exposure to PEG-asparaginase and by using short pulses of dexamethasone/vincristine during maintenance.
Conflict of interest
The authors declare no conflict of interest.
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We thank all patients, the physicians participating in the DCOG studies and members of the involved DCLSG Protocol Committees (Bökkerink JPM, Bruin MCA, de Vaan GAM, Hählen K, Hakvoort-Cammel FGAJ, Korthof ET, Schouten TJ, Taminiau JAJM, van den Berg H, van den Heuvel-Eibrink MM, van der Does-van den Berg A, van Leeuwen EF, van Weel-Sipman MH, van Wering ER, Weening RS).
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Kamps, W., van der Pal-de Bruin, K., Veerman, A. et al. Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia 24, 309–319 (2010). https://doi.org/10.1038/leu.2009.258
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