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ALL-REZ BFM Study for Treatment of Children with ALL - Relapse

ALL-REZ BFM Study for Treatment of Children with ALL - Relapse. 25% of children with ALL suffer relapses Multi-centre study to optimise risk adapted treatment About 100 participating centres Since 1983 more than 2000 relapses registered

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ALL-REZ BFM Study for Treatment of Children with ALL - Relapse

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  1. ALL-REZ BFM Study for Treatment of Children with ALL - Relapse • 25% of children with ALL suffer relapses • Multi-centre study to optimise risk adapted treatment • About 100 participating centres • Since 1983 more than 2000 relapses registered • About 100 study patients per year with 1st ALL relapse • Treatment elements: Chemotherapy / Irradiation / BMT

  2. Results of Consecutive Trials 1983-1996 Trial n Objective Results 83 91 - Risk groups A,B,C - feasibility R1/2 - Multi-drug courses R1/2 - relevance time/site - Prot. E for HR patients - high toxicity of Prot.E 85 130 - MTX 1g vs. 12g/m² - no difference of EFS - Protocol F - acceptable toxicity 87 148 - Sequence MTX vs. ARA-C - no difference of CR/EFS - Cran. irrad. for BM-relapse - improvement of EFS 90 373 - Introduction of block R3 - no improvement of EFS - MTX 1g vs. 5g/m² - no difference of EFS - Treatment of PPG in several pilot studies

  3. Results of Pilot Studies, 1st and 2nd Relapse Trial n Objective Results P87/88 62 - Cis-Platin ind./cons. - CR/EFS unsatisfactory P89 86 - MTX 5g/m², new rescue - acceptable toxicity P91/92 87 - Tailored therapy for PPG - high toxicity IDA-Ind 59 - Th. window for Idarubicin - antileukaemic efficacy P94 31 - I and S blocks for S4 - feasible

  4. EFS by Immunophenotype 1.0 .8 .6 .4 .2 log rank test: p < 0.0001 0.0 0 2 4 6 8 10 years non-T (n = 1022; 284 in CCR; EFS = 0.29 ± 0.02) pre-T / T (n = 176; 12 in CCR; EFS = 0.08 ± 0.03)

  5. 1.0 .8 .6 log rank test: DF = 2; p < 0.0001 .4 log rank test: p = 0.027 log rank test: p = 0.0002 .2 0.0 0 2 4 6 8 10 years Isol. EM (n = 209; 94 in CCR; EFS = 0.45 ± 0.04) Comb. BM (n = 301; 102 in CCR; EFS = 0.37 ± 0.04) Isol. BM (n = 805; 175 in CCR; EFS = 0.18 ± 0.02) EFS by Site

  6. 1.0 .8 .6 log rank test: DF = 2; p < 0.0001 .4 log rank test: p < 0.0001 .2 log rank test: p < 0.0001 0.0 0 2 4 6 8 10 years late (n = 581; 264 in CCR; EFS = 0.41 ± 0.03) early (n = 379; 70 in CCR; EFS = 0.19 ± 0.03) very early (n = 355; 37 in CCR; EFS = 0.09 ± 0.02) EFS by Time of Relapse

  7. Parameters p Risk ratio < 0.0001 Time of relapse late 1 early 3.74 very early 6.27 < 0.0001 Immunophenotype non-T 1032 1 T / pre-T 2.24 Site < 0.0001 Isol.EM 1 Comb.BM 2.06 Isol.BM 3.51 Multivariate Cox-Regression for EFS after Chemotherapy

  8. EFS by Time Interval between Courses R1 and R2 1.0 / 0.51 (SD = 0.06) 0.5 / 0.39 (SD = 0.05) 0.27 (SD = 0.06) / p < .001 0 0 1 2 3 4 5 6 7 8 9 10 years May 2, 2000 R1 to R2: < 21 days N = 94 38 in CCR 21-25 days N = 129 40 in CCR > 25 days N = 78 14 in CCR

  9. ALL-REZ BMF 95/96: Strategic Groups S1 - S4 non-T (pre-) T site / extra- BM BM extra- BM BM timepoint med. comb. isol. med. comb. isol. very early S2 S4 S4 S2 S4 S4 early S2 S2 S3 S2 S4 S4 late S1 S2 S2 S1 S4 S4

  10. 1.0 log rank test: DF = 3; p < 0.0001 .8 .6 log rank test: p < 0.0001 .4 log rank test: p < 0.0001 .2 log rank test: p < 0.0001 0.0 0 2 4 6 8 10 years S1 (n = 65; 46 in CCR; EFS = 0.72 ± 0.07) S2 (n = 731; 294 in CCR; EFS = 0.36 ± 0.02) S3 (n = 187; 11 in CCR; EFS = 0.03 ± 0.02) S4 (n = 332; 20 in CCR; EFS = 0.03 ± 0.02) EFS by Strategic Groups S1 - S4

  11. Treatment Schedule of Trial ALL-REZ BFM 96 group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 S1  C F1 F2 R1 R2 R1 R2 R1 R2 D 12 S2  G? G? G? R C F1 F2 R1 R2 R1 R2 R1 R2 R1 R2 D 24 S3 G? G? G? R C F1 F2 R1 R2 bone marrow transplantation S4 G G G G I S S S bone marrow transplantation

  12. DEXA 20 mg/m²/d PO VCR 1.5 mg/m²/d IV MTX 1 g/m²/36h IV ASP 10 000 U/m²/6h IV MTX / ARA-C / PRED IT day 1 2 3 4 5 6 Design of Chemotherapy: Course F1

  13. DEXA 20 mg/m²/d PO VCR 1.5 mg/m²/d IV ARA-C 3 g/m²/3h IV ASP 10 000 U/m²/6h IV MTX / ARA-C / PRED IT day 1 2 3 4 5 6 Design of Chemotherapy: Course F2

  14. DEXA 20 mg/m²/d PO 6-MP 100 mg/m²/d PO VCR 1.5 mg/m²/d IV MTX 1 g/m²/36h IV ARA-C 2 g/m²/3h IV ASP 10 000 U/m²/6h IV MTX / ARA-C / PRED IT day 1 2 3 4 5 6 Design of Chemotherapy: Course R1

  15. DEXA 20 mg/m²/d PO 6-TG 100 mg/m²/d PO VDS 3 mg/m²/d IV MTX 1 g/m²/36h IV IFO 400 mg/m²/1h IV DNR 35 mg/m²/24h IV ASP 10 000 U/m²/6h IV MTX / ARA-C/ PRED IT day 1 2 3 4 5 6 Design of Chemotherapy: Course R2

  16. DEXA 6 mg/m²/d PO 6-TG 100 mg/m²/d PO VCR 1.5 mg/m²/d IV IDA 10 mg/m²/24h IV MTX / ARA-C / PRED IT week 1 2 3 Design of Chemotherapy: Course I

  17. DEXA 6 mg/m²/d PO VCR 1.5 mg/m²/d IV IDA 16 mg/m²/48h IV VP16 100 mg/m²/2h IV Thiotepa 30 mg/m²/0.5h IV ASP 10 000 U/m²/6h IV MTX / ARA-C / PRED IT day 1 2 3 4 5 6 Design of Chemotherapy: Course S

  18. Strategy of Study ALL-REZ BFM 96 S1: Reproduction of good results S2: Improvement of CR and EFS by increased intensity of initial therapy (G-CSF?) and by etoposide - reinductions during maintenance therapy S3: G-CSF randomization, obligatory BMT S4: Reduction of toxicity (I-/S-blocks), obligatory BMT

  19. Transplantation Modalities ALL-REZ BFM 96 MRD - BMT: S3/4, subgroups of S2 MUD - BMT : S3/4, if no MRD available, optional for subgroups of S2 Autologous (+ immunomodulation) or haploidentical BMT: S3/4, if no MRD/MUD available within 3 - 4 months

  20. 1.0 .8 .6 .4 .2 0.0 0 2 4 6 8 10 years EFS of Patients with Late Isolated (non-T) BM Relapse by Initial PBC log rank test: DF = 2; p = 0.003 log rank test: p = 0.025 log rank test: p = 0.0045 1/µl (n = 51; 28 in CCR; EFS = 0.46 ± 0.10) 1 u. 10000/µl (n = 249;104 in CCR; EFS = 0.32 ± 0.04) 10000/µl (n = 63; 16 in CCR; EFS = 0.17 ± 0.07)

  21. Conclusions • More than 2/3 of children with ALL-relapse die from the disease • Adequate post-remission therapy for patients with good prognosis (S1) is chemotherapy, for patients with bad prognosis (S3/4) BMT • Adequate post-remission therapy for patients with intermediate prognosis (S2) remains unclear • Prospective controlled trials are needed to determine the best post-remission therapy for patients with intermediate prognosis

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