Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia

Stark, Batia; Sharon, Rivka; Rechavi, Gideon; Attias, Dina; Ballin, Ami; Cividalli, Gabriel; Burstein, Yoav; Sthoeger, Dalia; Abramov, Ayala; Zaizov, Rina

doi:10.1002/(sici)1097-0142(20000101)88:1<205::aid-cncr28>3.0.co;2-7

Cited by 11 publications

(12 citation statements)

References 55 publications

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“…To clarify the role of diff erent CNS-directed therapies, a meta-analysis which was published in 2003, revealed that a long-term intrathecal therapy leads to EFS rates comparable with those of radiotherapy [21]. It was concluded from that meta-analysis that radiotherapy can be replaced by multiple intrathecal doses of chemotherapy and that intravenous MTX reduces systemic relapses.…”

Section: Discussioncontrasting

confidence: 42%

“…Previous studies indicated that leukaemic relapse was the most common cause of off -therapy events, accounting for approximately 90% of failures [16]. Th e incidence of relapse in analysed patients was only 11.1% (65 children) and it was lower compared with the results obtained by other authors [17,18]. Our data revealed that this systemic high dose of methotrexate was associated with a low rate of CNS relapse, and a testicular one as well.…”

Section: Discussionmentioning

confidence: 99%

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Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m2 versus 3.0 g/m2 methotrexate i.v. according to the modified ALL-BFM 90 protocol. The report of Polish paediatric Leukemia/lymphoma study group

Derwich

Wachowiak

Zając‐Spychała

et al. 2011

memo

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Purpose: A non objective randomised, retrospective study was performed to assess and compare the effi cacy of two different high doses of methotrexate (HD-MTX) in combination with intrathecal therapy in children with standard risk (SR) ALL as central nervous system (CNS) preventive therapy in a place of cranial radiation.Patients and methods: Between July 1993 and April 2002, in 650 children standard risk (SR) ALL were diagnosed and treated in Poland according to the modifi ed ALL-BFM 90 protocol. Methotrexate was used in the dose of either 3.0 g/m 2 (group A) or 5.0 g/m 2 (group B) four times in two week intervals during consolidation (protocol M).Results: Probability for 10-year event-free survival (pEFS) and relapse-free survival (pRFS) for all evaluated patients (n = 611) was 0.77 ± 0.02 and 0.82 ± 0.02, respectively. EFS probability for group A (n = 411) was 0.73 ± 0.03 and for group B (n = 200) -0.85 ± 0.04, whilst RFS probability for group A was 0.79 ± 0.04 and for group B -0.89 ± 0.03, and these differences proved statistically signifi cant (P = 0.0050 and P = 0.0012). In multivariate analysis, T-cell immunophenotype (P = 0.0046) and age older than 10 years (P = 0.0250) had a signifi cantly adverse impact on the outcome.Conclusions: HD-MTX used in dose 5.0 g/m 2 has been found to be more eff ective in the treatment of SR ALL in children than HD-MTX in dose 3.0 g/m 2 .Keywords: Standard risk acute lymphoblastic leukaemia, children, prophylaxis of central nervous system, high dose methotrexate.Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m 2 versus 3.0 g/m 2 methotrexate i.v. according to the modifi ed ALL-BFM 90 protocol.

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Section: Discussioncontrasting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m2 versus 3.0 g/m2 methotrexate i.v. according to the modified ALL-BFM 90 protocol. The report of Polish paediatric Leukemia/lymphoma study group

Derwich

Wachowiak

Zając‐Spychała

et al. 2011

memo

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“…The National Israeli Study, using a modified ALL‐BFM 86 protocol (INS 89) showed the efficacy of extended triple IT chemotherapy in non‐high risk patients (Stark et al , 2000).…”

Section: Discussionmentioning

confidence: 99%

Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk‐stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172)

Hill

Richards²,

Gibson

et al. 2003

Br J Haematol

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SummaryConcern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow-up is 7 years 9 months; event-free survival (EFS) and overall survival were 63AE1% and 84AE6%, respectively, at 5 years and 59AE8% and 79AE4% at 10 years. The isolated CNS relapse rate was 7AE0% at 10 years. Patients were randomized for CNS-directed therapy within white blood cell (WBC) groups. For WBC <50 · 10 9 /l, high-dose intravenous methotrexate (HDMTX) (6-8 g/m 2 ) with intrathecal methotrexate (ITMTX) was compared with ITMTX alone, and was significantly better at preventing isolated and combined CNS relapse, but non-CNS relapses were similar. There was no significant difference in EFS at 10 years, 64AE1% [95% confidence interval (CI) 60AE4-67AE8] with HDMTX plus ITMTX, and 63AE0% (95% CI 59AE5-66AE5) with ITMTX alone. For WBC ‡50 · 10 9 /l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non-significant increase in non-CNS relapses. EFS was not significantly different, being 55AE2% (95% CI 47AE8-62AE6) at 10 years with XRT and 52AE1% (95% CI 44AE8-59AE4) with HDMTX plus ITMTX.

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“…17 The results of the DCLSG ALL-8 study confirm the conclusion of the previous DCLSG ALL-7 study, the AIEOP-ALL91 study and the INS 89 trial, that BFM-oriented treatment without cranial irradiation leads to comparable overall treatment results as the original BFM treatment with cranial irradiation. 2,17,18 The CCG-105 study, involving intermediate risk ALL patients (including 44% of all newly diagnosed patients) has already demonstrated no significant differences in CNS relapse rate, EFS or survival between patients who in BFMoriented treatment received intrathecal methotrexate only as CNS prophylaxis as compared with cranial irradiation. 19 The DCLSG ALL8 study shows that the majority (94%) of newly diagnosed patients can be spared cranial irradiation without jeopardizing the favorable BFM treatment results.…”

Section: Leukemiamentioning

confidence: 99%

BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996)

et al. 2002

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Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can succesfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixtyseven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients Ͼ1 year of age at diagnosis unfavorable prognostic factors were male sex, Ͼ25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) Ͼ50 × 10 9 /l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.

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Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia

Cited by 11 publications

References 55 publications

Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m2 versus 3.0 g/m2 methotrexate i.v. according to the modified ALL-BFM 90 protocol. The report of Polish paediatric Leukemia/lymphoma study group

Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m2 versus 3.0 g/m2 methotrexate i.v. according to the modified ALL-BFM 90 protocol. The report of Polish paediatric Leukemia/lymphoma study group

Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk‐stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172)

BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996)

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