Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies

Authors


  • Supported by the Israel Cancer Association.

  • There is no financial conflict of interest.

Batia Stark, MD, The Centre of Paediatric Haematology/Oncology and the Cancer Cytogenetic Laboratory, Schneider Children’s Medical Centre of Israel, Petah Tiqwa 49202, Israel. E-mail: bstark@clalit.org.il

Summary

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders – medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1–18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin–Frankfurt–Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 ± 5·9% and the INS 98 (n = 43), 83·7 ± 5·6% (P = 0·12); the cumulative incidence (CI) of any CNS relapse was 5·0 ± 2·8% and 2·3 ± 2·3% (P = 0·50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) ≥100 × 109/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61·9 ± 5·3% in INS 89 and 72·9 ± 5·8% in INS 98, (P = 0·21); the CI of any CNS relapse was 7·1 ± 2·8% and 1·7 ± 1·7% (P = 0·142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

A marked improvement in the outcome of childhood acute lymphoblastic leukaemia (ALL) was achieved with the introduction of preventive central nervous system (CNS) therapy in the early 1970s, mostly cranial irradiation (CRT) and short-term intrathecal (IT) methotrexate (MTX) (Pinkel & Woo, 1994; Pui, 2006; Pui & Howard, 2008; Pui et al, 2008). However, concerns about late adverse effects of CRT, including lifelong secondary brain tumours, endocrinopathies, increased mortality and morbidity, and neurocognitive deficits (Jankovic et al, 1994; Löning et al, 2000; Reddick et al, 2006; Spiegler et al, 2006; Goshen et al, 2007; Hijiya et al, 2007; Waber et al, 2007; Mody et al, 2008) led to the development of alternative CNS-directed strategies (Clarke et al, 2003), including reduced-dose radiotherapy (Reiter et al, 1994; Schrappe et al, 2000a,b; Möricke et al, 2008) or its replacement with additional IT injections and effective systemic chemotherapy. By the 1990s, most of the large cooperative groups no used preventive CRT (pCRT) for the majority of non-very-high-risk patients with B-cell-lineage ALL (Tubergen et al, 1993; Reiter et al, 1994; Nachman et al, 1998; Gaynon et al, 2000; Maloney et al, 2000; Manera et al, 2000; Schrappe et al, 2000a,b; Stark et al, 2000; Vilmer et al, 2000; Kamps et al, 2002; Clarke et al, 2003; Hill et al, 2004; Pui et al, 2004; Saarinen-Pihkala et al, 2004; Matloub et al, 2006; Nathan et al, 2006; Moghrabi et al, 2007; Möricke et al, 2008; Seibel et al, 2008). Triple intrathecal therapy (TIT), consisting of cytarabine and steroids in addition to MTX, was administered by some groups (Pullen et al, 1993; Maloney et al, 2000; Manera et al, 2000; Stark et al, 2000; Pui et al, 2004; Moghrabi et al, 2007) and found to be more effective for isolated CNS control than IT MTX; however, no advantage in EFS was ultimately proven (Matloub et al, 2006).

In patients with T-cell leukaemia, who are at higher risk of CNS recurrence, most investigators were more cautious and limited the elimination of pCRT to a much lower proportion of patients. In a collaborative group overview of randomized trials of CNS-directed therapy, uncertainty remained regarding T-ALL because of the small number of patients (Clarke et al, 2003).

The present study evaluated the outcome of patients with T-ALL treated with the Berlin–Frankfurt–Munster (BFM)-based protocols modified by the substitution of pCRT with extended TIT in the group of good early prednisone responders (medium risk group, MR), which accounted for the majority of T-ALL patients.

Patients and methods

Patients

Two consecutive, non-randomized, T-ALL Israel National Studies (INS) were reviewed. The studies had recruited 143 patients with T-ALL, comprising 22·7% of the total 630 newly diagnosed ALL patients aged 1–18 years, between May 1989 and 2003. Of these, 84 were enrolled in the ALL-INS 89 (May 1989–January 1998) and 59 in the ALL-INS 98 (February 1998–May 2003).

Informed consent was obtained from the guardians of all patients, and the protocols were approved by the hospital ethics committees.

Diagnosis

The diagnosis of T-ALL was based on morphological French–American–British criteria, negative staining for myeloperoxidase or Sudan black and immunophenotypical expression of T-cell surface antigens CD7 or CD2, often with CD5, CD3, CD4, or CD8 in more than 20% of blasts and nuclear deoxynucleotide transferase (TdT) or intracytoplasmic CD3 in more than 10%. Unequivocal cases were reviewed centrally. CNS involvement at diagnosis and relapse was defined as more than five mononuclear cells/mm3 on chamber count and presence of blasts in a cytospin preparation.

Patient stratification and treatment

The T-ALL patients were assigned to MR and high-risk (HR) groups by early response to treatment (as in the ALL-BFM 90; Schrappe et al, 2000a,b). HR criteria were prednisone-poor response (PPR) after 7 d of monotherapy with prednisone and one dose of TIT, with the presence of ≥1 × 109 blasts/l in peripheral blood (PB) on day 8 and/or no bone marrow (BM) remission (M2/M3) after induction phase 1A (day 33 or day 40). The remaining patients were considered MR.

The ALL-INS 89 and ALL-INS 98 protocols for T-cell ALL were based on the ALL-BFM 86/90 (Reiter et al, 1994; Schrappe et al, 2000a,b) and ALL-BFM 95 (Möricke et al, 2008), respectively. Some modifications in systemic therapy and, mostly, in CNS preventive therapy were made in the MR group only (Table I): In the INS 89, pCRT was replaced by extended TIT (×18) in all MR patients, and in the INS 98, prompted by the results reported by the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) (Conter et al, 1997), pCRT (12 Gy) was reindicated for patients with white blood cell count (WBC) ≥100 × 109/l. CNS involvement was treated with cranial radiation at a dose of 18 or 24 Gy. Within the MR group, 14 patients actually received more intensified protocols because of a very high WBC (n = 8) and/or high leukemic cell mass (n = 5) and/or CNS involvement (n = 4). As their outcome did not differ from the other MR patients, and because of the relatively limited total number of patients, they were included in the study.

Table I.   Treatment schedule for medium risk (MR) group T-ALL INS 89 and INS 98*.
TreatmentALL-INS 89†
mg/m2Days
  1. *In T-ALL INS 98 MR modification from previous INS 89 included: systemically, the omission of etoposide (VP-16) i.v., and during maintenance, the addition of six cycles every 10 weeks with vincristine 1·5 mg/m2 IV days 1, 8 and dexamethasone 6 mg/m2 PO days 1–8.

  2. †Based on ALL-Berlin–Frankfurt–Munster (BFM) 86 RG and ALL- BFM 90 MR (Schrappe et al, 2000a, b; Reiter et al, 1994).

  3. ‡Daunorubicin dose by ALL BFM 86: 40 mg/m2 decreased in later trial to 30 mg/m2.

  4. §Escherichia-colil-asparaginase by ALL BFM 86 was administered starting on day 19.

  5. ¶Triple intrathecal therapy (IT) doses were age-adjusted as follows: methotrexate IT: <1 year, 6 mg; 1 < 2 years, 8 mg; 2 < 3 years, 10 mg; 3 years, 12 mg. Cytarabine IT: <1 year, 16 mg; 1 < 2 years, 20 mg; 2 < 3 years, 26 mg; 3 years, 30 mg. Hydrocortisone: <1 year, 16 mg; 1 < 2 years, 20 mg; 2 < 3 years, 26 mg; 3 years, 30 mg.

  6. **Methotrexate i.v. was given for 24 h with leucovorin rescue of 15 mg/m2 IV at 36 h after starting MTX infusion and then 6-hourly for six doses.

  7. ††In T-ALL INS 98 MR, preventive cranial radiotherapy 12 Gy to patients with WBC ≥100 × 109/l was added.

  8. ‡‡Maintenance duration until 24 months in continuous complete remission.

Induction protocol I
 Prednisone (p.o.)601–28
 Vincristine (i.v.)1·58, 15, 22, 29
 Daunorubicin (i.v.)30‡8, 15, 22, 29
 l-asparaginase (i.m.)10 000 i/u12§, 15, 18, 21, 24, 27, 30, 33
 Cyclophosphamide (i.v.)100036, 64
 Cytarabine (i.v.)7538–41, 45–48, 52–55, 59–62
 6-Mercaptopurine (p.o)6036–62
 TIT¶By age¶1, 15, 29, 45, 59
Consolidation
 Methotrexate (i.v.)5000**8, 22, 36, 50
 VP-16 (i.v.)*1501, 15, 29, 43
 Mercaptopurine (p.o)251–56
 TIT¶By age¶8, 22, 36, 50
Reinduction protocol II
 Dexamethasone (p.o)101–21
 Vincristine (i.v.)1·58, 15, 22, 29
 Doxorubicin (i.v.)308, 15, 22, 29
 l-asparaginase (i.m.)10 000 U8, 11, 15, 18
 Thioguanine (p.o)6036–49
 Cyclophosphamide (i.v.)100036
 Cytarabine (i.v.)7538–41, 45–48
 TIT¶By age¶38, 45
 Cranial radiotherapy††0
Maintenance‡‡
 Mercaptopurine (p.o)50Daily
 Methotrexate (p.o)20Weekly
 Vincristine (i.v.)*0
 Dexamethasone (p.o)*0
 TIT¶By age¶q 8 weeks × 7

The HR group received the ALL-BFM 90 and BFM 95 HR protocols without modification, and pCRT (12 or 18 Gy) was indicated in all (Schrappe et al, 2000a,b; Arico et al, 2002; Schrauder et al, 2006; Möricke et al, 2008).

Statistical analysis

The duration of event-free survival (EFS) was defined as the time from diagnosis to the date of failure: induction failure, death, relapse, or the development of a second malignancy or until the date of last contact in complete remission. Patients who did not attain complete remission were considered failures at time zero. Overall survival (OS) was calculated from diagnosis to death (from any cause). Disease-free survival (DFS) was calculated from complete remission to the first event or the last follow-up date. For all analyses, patients lost to follow-up were censored at the time of their withdrawal. Follow-up data were updated as of December 2008. All analyses were performed on the basis of ‘intention to treat’. The Kaplan–Meier method was used to estimate survival rates; differences were compared with the log-rank test. Cumulative incidence (CI) functions were constructed by the method of Kalbfleisch and Prentice. DFS and CI rates were compared using Gray’s test (Gray, 1988) with the appropriate competing risks. Cox proportional hazards model was used for multivariate analysis. Differences in the distribution of individual parameters among patient subgroups were analysed with Fisher’s exact test. P values < 0·05 were considered significant. The R-2.6.2 package (The R Foundation for Statistical Computing) was used for analysis of the data.

Results

Patient characteristics

The features of the 143 patients with T-ALL in the ALL-INS 89 and ALL-INS 98 trials are presented in Table II. Median age was 8·28 years. The initial median WBC was 68 × 109/l, and CNS involvement was present in 7·7%. Thirty-two of the 135 (23·7%) stratifiable patients were assigned to the HR group because of a PPR on day 8 (n = 31) or lack of BM remission on day 33 (n = 1); 103 were from the MR group. Eight patients were not stratifiable because the PB blast count on day 8 was missing (all in the ALL-INS 89 trial). Their characteristics and outcome did not differ from the patients who were stratified (results not shown).

Table II.   T-ALL INS 89/98 (combined): patient characteristics, prognostic factors and, EFS for all and within risk groups.
Prognostic factorsAllMRHR
5-year EFS5-year EFS5-year EFS
N% (SE)PN% (SE)PN% (SE)P
  1. *National Cancer Institute (NCI) risk group criteria: standard risk (SR) group: age 1 < 10 years and WBC <50 × 109/l. High risk (HR) group: all other PBd8 blasts: peripheral blood blast count on day 8.

Overall14366·4 (3·9)10375·7 (4·2)3237·5 (8·6)
Gender
 Male10262·7 (4·8)0·227174·6 (5·2)0·992634·6 (9·3)0·39
 Female4175·6 (6·7)3278·1 (7·3)650·0 (20·4)
Age (years)
 1 < 108658·1 (5·3)0·016168·9 (5·9)0·032128·6 (9·9)0·42
 ≥105778·9 (5·3)4285·7 (5·3)1154·5 (15·0)
WBC (×109/l)
 <1008966·3 (5·0)0·997173·2 (5·2)0·341330·7 (12·8)0·47
 ≥1005466·6 (6·4)3281·2 (6·9)1942·1 (11·3)
Initial CNS leukaemia
 Yes1145·5 (15·0)0·03955·6 (16·6)0·0320·00·01
 No13268·2 (4·1)9477·7 (4·3)3040·0 (8·9)
NCI-risk group*
 SR3666·7 (7·9)0·923076·7 (7·7)0·9440·00·02
 HR10766·4 (4·6)7375·3 (5·0)2842·9 (9·4)
PBd8 blasts
 <1 × 109/l10475·0 (4·2)0·00      
 ≥1 × 109/l3138·7 (8·7)      

Patient characteristics and outcome in the ALL-INS 89 compared to the ALL-INS 98

Comparison of the patient characteristics between the two trials showed that the ALL-INS 89 had a higher incidence of CNS involvement (11·9% vs. 1·7%, P = 0·03) and of a high (≥1·7) BFM risk factor (BFM-RF), an estimate of leukemic cell mass calculated by the WBC and liver and spleen size (25% vs. 11·9%, P = 0·06) (Schrappe et al, 2000a,b; see Table SI for equation).

The treatment results of the ALL-INS 89 (median follow-up 15·2 years, range 11–19·7) and ALL-INS 98 (median follow-up 8·1 years, range 5·7–11) were similar (Table III): 5-year EFS was 61·9 ± 5·3% and 72·8 ± 5·8% respectively (P = 0·217), and OS, 69·0 ± 5·0% and 74·6 ± 5·7%, respectively (P =0·358). ALL-INS 98 was associated with a significant decrease in the CI of all relapses (10·2 ± 5% vs. 29·8 ± 5% in the ALL-INS 89, P = 0·005) (Table III), but a higher cumulative death rate in induction (3·4 ± 2·4% vs. 0%, P = 0·091) and complete remission (8·5 ± 3·7% vs. 3·6 ± 2·0%, P = 0·214) (Table III).

Table III.   Comparison of treatment results between ALL INS 98 to INS 89 protocols.
 INS 89INS 98P
5-year Cl5-year CI
[N]% (SE)[N]% (SE)
  1. CI, cumulative incidence; SE, standard error; CR, complete remission; EFS, event-free survival; OS, overall survival; CNS, central nervous system.

Overall [patients][84] [59]  
 Death in Induction 0·0 3·4 (2·4)0·091
 No CR 2·4 (1·7) 3·4 (2·4)0·720
 Death in first CR 3·6 (2·0) 8·5 (3·7)0·214
 Relapses (any) 29·8 (5·0) 10·2 (4·0)0·005
  CNS isolated 2·4 (1·7) 1·7 (1·7)0·785
  CNS combined 4·8 (2·3) 0·00·091
 5-year EFS 61·9 (5·3) 72·9 (5·8)0·217
 5-year OS 69·0 (5·0) 74·6 (5·7)0·358
MR group [patients][60] [43]  
 Death in induction 0·0 4·7 (3·2)0·093
 No CR 0·0 0·0
 Death in first CR 1·7 (1·7) 2·3 (2·3)0·807
 Relapses (any) 26·7 (5·8) 9·3 (4·5)0·029
  CNS isolated 1·7 (1·7) 2·3 (2·3)0·807
  CNS combined 3·3 (2·3) 0·00·229
 5-year EFS [n events] 70·0 (5·9) 83·7 (5·6)0·120
 5-year OS [n events] 80·0 (5·2) 86·0 (5·3)0·231
HR group [patients][16] [16]  
 Death in induction 0·0 0·0 
 No CR 12·5 (8·3) 12·5 (8·3)1·0
 Death in first CR 12·5 (8·5) 25·0 (11·2)0·421
 Relapses (any) 43·8 (13·5) 12·5 (8·8)0·037
  CNS isolated 0·0 0·0
  CNS combined 12·5 (8·7) 0·00·155
 5-year EFS 31·3 (11·6) 43·8 (12·4)0·416
 5-year OS 31·3 (11·6) 43·8 (12·4)0·474

Within the MR group, the incidence of CNS involvement in the ALL-INS 89 was higher than in the ALL-INS 98: 13·3% vs. 2·3% (P = 0·08). Compared with the ALL-INS 89, the ALL-INS 98 MR was associated with a trend of improved 5-year EFS, of 83·7 ± 5·6% vs. 70 ± 5·9%, (P = 0·12) (Table III, Fig 1) and a lower cumulative relapse incidence (9·3 ± 4·5% vs. 26·7 ± 5·8%, P = 0·029) but an increased cumulative death rate in induction (4·7 ± 3·2% vs. 0%, P = 0·093). CNS relapse rate did not differ [2·3 ± 2·3% vs. 5·0 ± 2·8% (P = 0·5)].

Figure 1.

 Probability of 5-year event-free survival (EFS) in ALL-INS 89 compared to INS 98 by risk group (MR versus HR: INS 98 P = 0·001, INS 89 P < 0·001).

In the HR group, no significant differences in outcome were noted between the protocols (Table III, Fig 1).

Treatment results of INS 89/98 combined

The 5-year EFS of all T-ALL patients in both studies (n = 143) was 66·4 ± 3·9%, and the OS, 71·3 ± 3·8% (Table II, Table SI). Relapses occurred in 31 patients (5-year CI 21·7 ± 3·5%), all within 5 years, including three isolated CNS relapses (CI 2·1 ± 1·2%) and four combined CNS relapses (CI 2·8 ± 1·4%) (Table SI).

On univariate analysis, the adverse prognostic factors for EFS (Table II) were younger age (1 to <10 years) (P = 0·01), initial CNS involvement (P = 0·029), and most prominently, PB early response to prednisone (< 0·001) (Table II).

On multivariate Cox regression analysis, the significant predictors of poor EFS were BFM HR group [hazard ratio 5·97, 95% confidence interval (3·05, 11·67), P < 0·01], CNS involvement [hazard ratio 5·25, 95% confidence interval (2·18, 12·63), P < 0·001] and age younger than 10 years [hazard ratio 2·59, 95% confidence interval (1·28, 5·25), P = 0·008]. Findings were not significant for WBC ≥100 × 109/l or ≥200 × 109/l.

For CNS relapses, CNS involvement at diagnosis was a significant univariate predictor (CI 27·3 ± 14·5% vs. 3 ± 1·5%, P < 0·001), whereas age, BFM-RF, BFM-risk group, and WBC ≥100 × 109/l were not.

MR group INS 89/98: impact of extended TIT replacing pCRT

Treatment modification of the ALL-BFM protocol and omission of pCRT were applied in the MR group, which accounted for 76% of the T-ALL population. The characteristics of the 103 MR patients are shown in Table II. The 5-year EFS was 75·7 ± 4·2% and the OS, 82·5 ± 3·7% (Table SI). The CI of all relapses was 19·4 ± 3·9%, and of any CNS relapses (isolated + combined), 3·8 ± 1·9%. In patients without CNS involvement at diagnosis, the CI of CNS relapses was 2·1 ± 1·5% (Table SI).

To study the impact of extended TIT or pCRT in the MR group, we analysed the outcome results for the 91 patients without initial CNS involvement who were in first remission for at least 6 months at the time pCRT was scheduled in the original ALL-BFM 86/90/95 protocols (Table IV). Twelve of them were actually irradiated, and their 5-year DFS and CI of any CNS relapse were similar to the 79 non-irradiated patients (Table IV). Most of the patients with WBC <100 × 109/l (n = 62/64) were not irradiated, and their 5-year DFS was 79·0 ± 5·2%, and CI of all relapses, 16·1 ± 4·7%, without any CNS relapse. Twenty-seven patients had WBC ≥100 × 109/l, of whom 10 were actually irradiated (12 Gy in eight, 18 Gy in two) and 17 received extended TIT. Their characteristics were similar (Table SII). Outcome was the same in the irradiated (pCRT) and non-irradiated patients (Table IV): DFS, 80·0 ± 12·6% and 82·4 ± 9·2% respectively (P = 0·79); OS (10-year), 80 ± 12·6% and 85·6 ± 9·5% (P = 0·554); cumulative any-relapse incidence, 20 ± 13·4% and 17·6 ± 9·6% (P = 0·79); any CNS relapse, 10 ± 9·5% and 5·9 ± 5·7% (one patient in each group) (P = 0·64).

Table IV.   Comparison of outcome between pCRT versus extended TIT of T-ALL MR group INS 89/98 without initial CNS leukaemia and in CCR >6 months.
 pCRTExtended TITP
5-year outcome5-year outcome
[N]% (SE)[N]% (SE)
  1. CCR, continuous complete remission; DFS, disease-free survival; CNS, central nervous system; CI, cumulative incidence.

  2. *One patient relapsed in each group.

Overall [patients][12] [79]  
 DFS 83·3 (10·8) 79·7 (4·5)0·855
 CI relapses (any) 16·7 (11·3) 16·5 (4·2)0·913
 CI CNS relapses (any) 8·3 (8·3)* 1·3 (1·3)*0·119
WBC <100 × 109/l[2] [62]  
 DFS 100 79·0 (5·2)0·494
 CI relapses (any) 0·0 16·1 (4·7)0·542
 CI CNS relapses (any) 0·0 0·0 
WBC ≥100 × 109/l[10] [17]  
 DFS 80·0 (12·6) 82·4 (9·2)0·79
 CI relapses (any) 20·0 (13·4) 17·6 (9·6)0·79
 CI CNS relapses (any) 10·0 (9·5)* 5·9 (5·7)*0·64

HR group INS 89/98

In the HR group, pCRT was indicated in all patients. The 5-year EFS and OS was 37·5 ± 8·6%, and the 5-year CI of all relapses and CNS relapses was 28·1 ± 8·2% and 6·3 ± 4·4%, respectively (Table SI). Seven patients in the HR group who were alive at 6 months in first remission did not actually receive pCRT, although it was indicated in all. Their 5-year DFS was lower than that of the irradiated patients (n = 14): 28·6 ± 17·1% vs. 71·4 ± 12·1% (P = 0·049).

Discussion

T-cell leukaemia accounts for 10–15% (in our study, 23%) of childhood ALL. It is associated with distinct biological characteristics (Winter et al, 2007; Aifantis et al, 2008), clinical high risk features, and a historically worse prognosis and higher risk of CNS relapse than B-lineage leukaemia (Uckun et al, 1998; Pui, 2006; Pui et al, 2008). The allocation of patients with T-ALL to distinct or HR protocols, including intensive presymptomatic CNS treatment, has led to an improvement in their outcome comparable to B-lineage ALL. Although the indications for cranial irradiation have become more restricted, it is still used in a relatively high proportion of T-ALL patients. In the present studies, pCRT was omitted from large proportion (76%) of T-ALL patients, namely, the good early responders to steroids, relying on our previous favourable results for non-T ALL (Stark et al, 2000) and the introduction of intensified systemic treatment (modified ALL-BFM protocols), including high dose MTX (HD-MTX). Compared to other trials, it seems that replacing pCRT with extended TIT did not jeopardize systemic and CNS control: 5-year EFS was 61·9 ± 5·3% in the INS 89 and 72·9 ± 5·8% in the INS 98 (= 0·21), and CI of any CNS relapse was 7·1 ± 2·8% and 1·7 ± 1·7% (= 0·142) respectively; specifically for the non-irradiated MR group, 5-year EFS was 70 ± 5·9% in the INS 89 and 83·7 ± 5·6% in the INS 98 and CNS relapse rate was 5·0 ± 2·8% and 2·3 ± 2·3% (P = 0·5), respectively. These results (for the whole cohort of T-ALL patients and the MR group) are similar to those in the original ALL-BFM 90 (Schrappe et al, 2000a,b) and ALL-BFM 95 (Möricke et al, 2008; M. Schrappe, Department of Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany, personal communication), in which all T-ALL patients were irradiated (Table V).

Table V.   CNS-preventive therapy and treatment outcome from clinical trials in the 1990s in childhood T-ALL.
StudyYear Patients (n)Risk group WBC (×109/l)CNS Invl. (%)Indicated pCRT (%) [Gy]IT therapy HD-MTX/m25-year EFS, % (SE)CI of any CNS Rel. % (SE)RemarksReference
  1. Pts, patients; WBC, white blood count; CNS, central nervous system; Invl, involved at diagnosis; pCRT, preventive cranial radiotherapy; IT, intrathecal; HD, high dose; MTX, methotrexate; EFS, event-free survival; CI, cumulative incidence; Rel, relapse; INS, Israel National Study group; BFM, Berlin–Frankfurt–Münster; AIEOP, Associazione Italiana di Ematologia ed Oncologia Pediatrica; EORTC, European Organization for Research and Treatment of Cancer; DCLSG, Dutch Childhood Leukemia Study Group; CCG, Children’s Cancer Group; NOPHO, Nordic Society of Pediatric Hematology and Oncology; SJCRH, St Jude Children’s Research Hospital; POG, Pediatric Oncology Group; UKALL, United Kingdom Medical Research Council Working Party on Childhood Leukaemia; DFCI, Dana-Farber Cancer Institute consortium; NCI, National Cancer Institute; SR, standard risk; MR, medium risk; IR, intermediate risk; HR, high-risk; VHR, very high risk; TIT, triple intrathecal therapy; Dexa, dexamethasone; Rnd, randomization; Asparg, asparaginase; ARA, cytarabine; V, Vincristine; PGR, prednisone-good response/responder; RF, Risk Factor; vs., versus; i.v., intravenous; VANDA, Dexamethasone, Cytarabine, Mitoxantrone, Etoposide, Asparaginase and Methotrexate (IT); 6MP, 6-mercaptopurine; (i), isolated CNS relapse in patient without CNS involvement; Pred Res, prednisone response; Cont, continuation.

INS 891989–9884AllAll1221 [12]TIT5 g × 461·9 (5·3)7·1 (2·8)Based on ALL-BFM 86/90Present
60BFM-MRAll13[0]TIT × 185 g × 470·0 (5·9)5·0 (2·8) 
42BFM-MR<10010[0]TIT × 185 g × 469·0 (7·1)4·8 (3·3) 
18BFM-MR≥10022[0]TIT × 185 g × 472·2 (10·6)5·6 (5·6) 
16BFM-HRAll12100 [12]TIT × 125 g × 431·3 (11·6)12·5 (8·7) 
22NCI-SR<5010   63·6 (10·3)4·5 (4·6) 
62NCI-HR><5013   61·3 (6·2)8·1 (3·5) 
INS 981998–200359AllAll 1·727 [12]TIT5 g × 472·9 (5·8)1·7 (1·7)Based on ALL-BFM 95Present
43BFM-MRAll 2·3[0]TIT × 185 g × 483·7 (5·6)2·3 (2·3) 
29BFM-MR<100 0·0[0]TIT × 185 g × 479·3 (7·5)0·0 (0·0) 
14BFM-MR≥100 7·1[0]TIT × 185 g × 492·9 (6·9)7·1 (7·1) 
16BFM-HRAll 0·0100 [12]TIT × 125 g × 443·8 (12·4)0·0 (0·0) 
14NCI-SR<50 0·0   71·4 (12·1)0·0 (0·0) 
45NCI-HR><50 2·2   73·3 (6·6)2·2 (2·2) 
         (6 years)   
BFM 901990–95284AllAll 100 [12]MX5 g × 4/661·1 (3·0) Dexa. in re-inductionSchrappe et al (2000a,b)
180BFM-MRAll 100 [12]MX × 115 g × 480·0 (3·0) MR: Rnd ± Asparg in re-induction
100BFM-HRAll 100 [12]MX × 3, TIT × 95 g × 632·0 (3·0) HR: HR-pulses × 9, HD-ARA
         (6 years)   
BFM 951995–2000277AllAll 100 [12]MX5 g × 474·8 (2·6) Dexa. in re-inductionMöricke et al (2008)
197BFM-MRAll 100 [12]MX × 115 g × 486·0 (2·5) MR: Rnd ± HD-ARA, Maint: V + Dexa.
87BFM-HRAll 100 [12]MX × 5, TIT × 65 g × 4  HR: re-induction × 1, HD-ARA
72NCI-SR<50 100 [12]  90·1 (3·5)  
203NCI-HR><50 100 [12]  69·2 (3·3)  
         (3 years)   
AIEOP 911991–9569AIEOP-IRAll 0– [0]MX × 1 TIT × 195 g × 467·4 (5·9) Part of ALL-BFM 90, AIEOP IR:PGR, age <15 years, RF ≤ 1·7 CNS-negativeConter et al (1997)
123BFM-IRAll 100 [12]MX × 115 g × 488·3 (3·2) 
55AIEOP-IR<100 [0]  80·6 (5·6) 
99BFM-IR<100 100 [12]  85·1 (5·7)  
14AIEOP-IR>100 [0]  17·9 (11·0)  
  24BFM-IR>100 100 [12] 81·9 (8·2) 
EORTC 5888011989–98299AllAll [0]  64·4 (2·9)13·3 (2·3)IR: Based on BFM-90. Rnd: E-coli vs. Erwinia, ±HD-ARA, ±i.v. 6MP.Vilmer et al (2000)
 BFM-IRALL  MX × 105 g × 4  
 BFM-HRALL  MX × 10 TIT × 65 g × 10  VHR: Intensification with VANDA
80NCI-SR<50 [0]  68·4 (5·4) Similar outcome for WBC
219NCI-HR><50 [0]  62·9 (3·5) ≥or <100 × 109/l
DCLSG ALL 81991–9656AllAll9[0]MX5 g × 4/671. (6)(i) 7 (4)Based on ALL-BFM 90Kamps et al (2002)
40BFM-MRAll [0]MX × 115 g × 483 (6) MR: Rnd ±i.v. 6MP
16BFM-HRAll [0]MX × 3, TIT × 95 g × 644 (12)  
14NCI-SR<50 [0]  86 (9) CNS relapse rate similar between WBC> or <100 × 109/l regardless of Pred Res
42NCI-HR><50 [0]  67 (6) 
CCG 19611996–2002235NCI-HR RER><50 [0]ARA × 1 MX × 13 7119/235RER: rapid early response: BM blasts <25% on day 7. Rnd between: Augmented‘BFM’ with PEG-Asparg.Seibel et al (2008)
 NCI-HR RER><50 [0] Capizzi82·9 
 NCI-HR RER><50 [0] 72·9 Standard CCG Modified BFM
NOPHO HR 921992–2000133AllAll 66 [18]MX × 18/228 g × 462 (4)12 (3)Modified ALL-BFM + HD-ARASaarinen-Pihkala et al (2004)
33NCI-SR<50 [0]  69 (8)  
100NCI-HR><50 100 [18]  60 (5) VHR: Maint. LSA2L2
SJCRH XIIIB1994–9843AllAll 70 [18]TIT × 13-262 g × 1071·9 (6·8) Up-front Rnd: ±i.v. 6MPPui et al (2004, 2008)
13 <100 [0]TIT × 26   Post remission: weekly rotation of drug pairs, including etoposide
30 ≥100 100 [18]    
         (3 years)   
POG 8704 90861987–92144POG-HR>5016100 [24/18]TIT × 763 (4)7 (3)Induction six drugs. Cont: rotating drug combination including teniposidePullen et al (1999), Maloney et al (2000), Amylon et al (1999)
POG 9296/7/81992–9578POG-HR>5023[0]TIT × 161 g × 1065 (6)18 (5)Added to above: HD-RA, ID-6MP, PEG-Asparg. Without teniposideLaver et al (2000)Winter et al (2007)
         (10 years)   
UKALL XI1990–9754 <50 [0]MX × 14/166–8 g × 351 >50: Rnd: ITMX vs. IT MX + HD-MX.Hill et al (2004)
51 ≥50 100 [24]MX × 755∼16≥50 Rnd: ITMX + HD-MX vs. pCRT
60 ≥50 [0]MX × 168 g × 352∼27 
DFCI 95-011996–200052AllAll 100 [18]MX/ARA × 124 g × 185 (5) Doxorubicin 300 mg/m2 Intensification with E. coli Asparg. Pulses: V + HD-PredMoghrabi et al (2007)
12NCI-SR<50    83 (11) 
40NCI-HR><50    85 (6) 

Using the ALL-BFM 90 protocol, three different studies omitted pCRT in T-ALL patients (Table V). In the Italian ALL-AIEOP 91 trial (Conter et al, 1997), substituting extended TIT (17 doses) for pCRT in good prednisone responders (i.e. intermediate risk group) yielded a similar EFS to the irradiated BFM 90 patients, but only in those with WBC count <100 × 109/l. Among patients with WBC ≥100 × 109/l, those who were not irradiated (n = 14) fared much worse than the irradiated patients (n = 24). By contrast, our 17 nonirradiated good prednisone responders with WBC ≥100 × 109/l had the same outcome as the 10 irradiated patients (and, indeed, as the rest of the good responders with a WBC <100 × 109/l) in terms of systemic and CNS leukaemia control. This discrepancy was hard to explain, and the number of patients was too small to reach definitive conclusions. Nevertheless, it is noteworthy that the AIEOP trial used the Erwinia product, which has proven to be less effective for ALL than E-coli asparaginase (Vilmer et al, 2000; Moghrabi et al, 2007). In the other two studies using the ALL-BFM 90, the Children’s Leukemia Cooperative Group-European Organization for Research and Treatment of Cancer (CLCG-EORTEC) 58881 (Vilmer et al, 2000) and the Dutch Childhood Leukemia Study Group (DLCSG)ALL-8 (Kamps et al, 2002), pCRT was eliminated in all T-ALL patients. The cure rate was similar to the BFM 90 (Table V), although the incidence of CNS relapse was relatively high in the EORTEC study. The results of both trials were not influenced by the WBC (</>100 × 100/l). Applying an increased-intensity augmented ‘BFM’ regimen, the Children’s Cancer Group (CCG) 1961 (Seibel et al, 2008) eliminated pCRT in the T-ALL National Cancer Institute (NCI)-HR group rapid early (BM day 7) responders (RER), and achieved better results than for their standard modified BFM (Table V). Comparable results (5-year EFS, 81·3 ± 6·9%) were noted in the INS 98 when analysed by the criteria of NCI-HR (Smith et al, 1996) in prednisone RER (comprising 73% of our MR group). The Nordic Society for Pediatric Hematology and Oncology (NOPHO) 92 (Saarinen-Pihkala et al, 2004) and Saint Jude Children’s Research Hospital (SJCRH) XIIIB (Pui et al, 2004; Pui & Howard, 2008) trials omitted pCRT from smaller proportions (around 30%) of T-ALL patients, who had a low WBC of <50 × 109/l (NOPHO 92) or <100 × 109/l (SJCRH XIIIB). Their results were in line with those of the present study and the BFM 90 and 95, respectively (Table V). In the Pediatric Oncology Group (POG) studies (9296/7/8), when extended TIT was intensified by incorporating intermediate-dose MTX, high-dose cytarabine and intensive PEG-asparaginase (Amylon et al, 1999; Laver et al, 2000; Winter et al, 2006), the EFS achieved in patients with T-ALL and WBC >50 × 109/l was similar to that of irradiated patients from historical POG studies (Pullen et al, 1999; Laver et al, 2000; Maloney et al, 2000) (Table V). In the only recent prospective randomized study, the Medical Research Council (MRC) UKALL XI (Hill et al, 2004), in which the efficacy of pCRT was compared to IT MTX with HD-MTX in T-ALL patients with WBC ≥50 × 109/l, the cure rate was the same in both arms, and did not differ from the nonirradiated patients with lower WBC (Table V). The best results (5-year EFS, 85 ± 5%) were achieved in the small group of the Dana Farber Cancer Institute (DFCI) 95-01 study (Moghrabi et al, 2007), wherein all T-ALL patients received pCRT. However, given that the findings were also better than for other protocols using pCRT in all patients (Pui et al, 2004; Möricke et al, 2008) and that the study was not randomized, we cannot differentiate the relative contribution of systemic therapy from that of pCRT (Table V).

The most prominent and consistent poor prognostic factor of T-ALL in our and other studies was the poor early response to prednisone and induction treatment (Reiter et al, 1994; Nachman et al, 1997; Griffin et al, 2000; Schrappe et al, 2000a; Arico et al, 2002; Kamps et al, 2002). The other conventional, widely applied, clinical and laboratory prognostic factors, such as gender, age, WBC, CNS involvement and NCI-risk group classification, failed to discriminate clear risk groups (Pullen et al, 1999; Goldberg et al, 2003; Moghrabi et al, 2007; Pui et al, 2008).

A large proportion of patients with T-ALL in our study were spared the severe late effects of CRT. However, there are still concerns regarding the morbidity and, to some degree, the neurocognitive impairments related to HD-MTX, dosages of leucovorin rescue, dexamethasone and intrathecal chemotherapy (Reddick et al, 2006; Spiegler et al, 2006; Waber et al, 2007; Jansen et al, 2008; Peterson et al, 2008). In the future, the determination of the specific germline gene polymorphism of the patient, which influences both the efficacy (Cheok & Evans, 2006) and toxicity (neurotoxicity) of MTX (Cheok & Evans, 2006; Kishi et al, 2007; Huang et al, 2008), may improve the individualization of drug dosages, thereby minimizing side effects and optimizing treatment.

Our trials demonstrated that, for the 75% of children with T-ALL – good early prednisone responders – regardless of the WBC, extended TIT in the context of the intensive BFM-based protocols did not compromise outcome. Given that these results were comparable to studies in which preventive irradiation was administered to a wider proportion of patients, it seems reasonable to exclude pCRT in non-HR T-ALL patients.

Acknowledgements

This manuscript is dedicated to the memory of Prof Rina Zaizov Marx, who laid the foundation for Pediatric Oncology in Israel. We thank Prof D. Steinberg for helping with the statistical analysis, and Ms Vardit Shai, Dina Kugel and Bella Lagun for processing the data.

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