Risk stratification in childhood Acute Lymphoblastic leukaemia

1. Risk stratification in childhood Acute Lymphoblastic leukaemia Dr Mary Taj Royal Marsden Hospital

3. Chemotherapy is the mainstay of treatment Radiotherapy only given for CNS positive disease CNS Prophylaxis Induction Intensification Continuing Treatment

4. Determination of risk groups…. Risk stratification is based on clinical and biological features and has helped tailor intensity of treatment according to risk of relapse.

5. Prognostic factors - ALL Factor Favourable Unfavourable Age >1<9 yrs <1&>10yrs WBC <20 x 109/l >100 x 109/l steroid response <1 x 109/l 1 x 109/l BM D7/14 M1/M2 M3 Chromsome No >50 <45 DNA index 1.16 <1.16 Translocations t(12;21) t(9;22); t(4;11); AML1 gene amplification 5 y EFS >80% 10-60%

6. Hyperdiploidy (37%) t(12;21) (21-24%) t(1;19) (5-8%) t(4;11) (4-8%) t(9;22) (3-4%) t(8;14) (2%) Hypodiploidy (1%) AML1 gene ampli 80-90% 85-90% 70-80% 20-30% 25-35% 70-80% 20-30% 50% ALL Genetic subgroups and survival

7. ALL - EFS vs cytoreduction

8. CCG 1882 trialAugmented Rx for high risk ALL & SER

10. ALL 97/99 -risk groups Standard Risk>1<10 yrs 60-65% WBC  50 x 109/lREG A Intermediate Risk 10 yrs 20-30% WBC  50 x109/l REG B High RiskSlow Early response 10-12% BCR ABL +veREG C Hypodiploidy MLL gene (12-24m)

11. Reg A - Induction PEG asp vs E.coli 5 vs 4 wks

12. Why do we need further risk stratification • 25 % children still relapse and require salvage therapy • 50 % of patients survived on previous less intensive protocols so are probably over-treated • 60 % relapses occur in RER group

13. Minimal residual disease Detects submicroscopic disease amplification of Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangements by polymerase chain reaction (PCR) sensitivity: 1 leukaemic cell in 10,000 normal cells

14. Prognostic factors MRD & relapseVan Dongen et al, Lancet 1998

15. Value of MRD status at EOI • <5% relapse risk if MRD –ve at EOI • 30-40% relapse risk if MRD +ve at EOI

16. ALL 2003- study design wk11 D15 D8 D28 MRD Reg A/B Regimen A (Age 1-9 + WCC<50) >10-4 BM M1/2 Reg C BM M3 2 intensification Neg Neg BM M1/2 Regimen B (Age >10 or WCC>50) 1 intensification Pos<10-4 BM M3 2 intensification Indeterminate Regimen C Hypo <45 t(4;11) M1 <5% blasts M2 5-25% blasts M3 >25% blasts

17. Role of Bone Marrow transplant • Indications for BMT in 1st CR: • BCR/ABL +ve • MLL +ve or hypodiploidy • M2/M3 BM at D28 • AML 1 gene amplification

18. To summarise • Risk stratification determines intensity • With current stratification EFS for Reg A > 85% • It remains to be seen whether MRD can be used for further modifying treatment after Day 28 • Now that we can determine which groups need BMT in first CR there should be fewer replapses.

19. R3: ALL relapse - risk groups H H Key: S = standard risk; I = intermediate risk; H = high risk BM = isolated BM; Extramed = CNS, testicular or other, Combined = BM + extramed

20. MRD pre BMT vs outcome

21. Risk stratification at relapse • Depends on timing and site of relapse. • MRD status at week 5 determines need for transplant. • MRD status prior to transplant determines risk of relapse.