First relapsed childhood ALL Role of chemotherapy

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1 First relapsed childhood ALL Role of chemotherapy Thirachit Chotsampancharoen, M.D. Division of Pediatric Hematology/Oncology Department of Pediatrics Prince of Songkla University Hat-Yai, Songkhla 25 Oct 2018

2 Case scenario I 7 year-old girl with history of easy bruising and intermittent fever for 1 month WBC 18,000, Hb7, Plt 29,000 with 30% circulating blasts Bone marrow revealed acute lymphoblastic leukemia Immunophenotype: B-lineage Normal cytogenetics (46;XX), no blasts in the CNS (CNS-1) Enrolled on TPOG standard risk protocol and remission after induction, ongoing to maintenance phase Clinical and BM remission after complete of treatment (off therapy 1 year)

3 Case scenario I After complete of treatment (off therapy 1 year) She had easy bruising WBC 20,000, Hb 6, Plt 39,000 with 40% circulating blasts Bone marrow confirmed relapse B-lineage ALL with normal cytogenetics (46;XX), no blasts in the CNS (CNS-1) Others: WNL What should we do for this condition? Transplantation or Chemotherapy?

4 Treatment of childhood relapsed ALL Is HSCT only answer for childhood relapsed? Yes / No Is there any role of chemotherapy for relapsed? Yes / No

5 Outcome of treatment of newly diagnosed childhood ALL Outcome of non-treatment of newly diagnosed childhood ALL Pui C. Engl J Med 2006;354: Chotsampancharoen T. Acta Haematol 2018;140:203-8

6 Outcome of relapsed ALL Oskarsson T. Haematologica 2016;101:68-76 Rivera GK. Cancer 2005;103:368-76

7 Outcome of relapsed childhood ALL Oskarsson T. Haematologica 2016;101:68-76

8 HSCT versus Chemotherapy For children with ALL in second remission, BMT from HLA siblings results in fewer relapses and longer EFS than does chemotherapy Barrett AJ, N Engl J Med 1994;331:1253-8

9 HSCT versus Chemotherapy For children with relapsed ALL, BMT from HLA siblings results in longer EFS than Chemotherapy Boulad F, J Clin Oncol 1999;17:

10 HSCT versus Chemotherapy P> relapsed ALL in UK ALL R1 trail No significant difference in survival outcome between the donor and no donor groups (chemotherapy) There was the possibility of EFS benefit with HSCT, especially in patients with early relapsed Harrison G. Ann Oncol 2000;11:

11 Treatment of relapsed precursor-b ALL with chemotherapy: POG Study relapsed childhood ALL EFS for the whole group was 40 % at 8 years and not related to age at relapse, initial WBC, sex, or induction regimen EFS was significantly better in patients with a longer duration of CR1 regardless of whether the cut was made at 24 mo or 36 mo (p<.005) This study demonstrate no significant difference in EFS in chemotherapy alone (45%) or HSCT (50%) p= HSCT may improve the outcome of children with early marrow relapse but is of less value to patients with later marrow relapse or isolated CNS relapse Kelly ME, J Pediatr Hematol Oncol 2013;35:509-13

12 HSCT is superior than CT in all relapsed ALL? Homogeneous population in all childhood relapsed ALL?

13 Outcome for relapsed ALL BMT 38% v CT 30.7 % (p 0.423) River GK. Cancer 2005;103:368-76

14 Outcome for BM relapsed ALL The 5-year EFS with an late relapsed (> 36 months) was 42.6% v 12.5 % among children with early relapsed (< 36 months) The 5-year EFS were 28% for B blast V 5% for T blast cell lineages, respectively. Rivera GK. Cancer 2005;103:368-76

15 Site of relapsed isolated CNS isolated BM isolated testes Gaynon PS. Cancer 1998;82:

16 Site of relapsed Chessels JM, Br J Hematol1998;102:

17 Risk classifications of relapsed ALL Homogeneous population in relapsed ALL? Timing of relapsed- strong evidence for clonal resistant Immunophenotype of leukemic cell- B lineage Site of relapsed Locatelli F, Blood 2012 Locatelli F, Curr Opin Oncol 2013

18 Berlin Frankfurt Munster (BFM) classification Very early relapse: < 18 months from diagnosis (during treatment) Early relapse:>18 months from diagnosis, but < 6 months from treatment discontinuation Late relapse: >6 months from stop treatment COG classification Early relapse <36 months from initial diagnosis Late marrow relapse >36 months from initial diagnosis Locatelli F, Curr Opin Oncol 2013

19 Berlin Frankfurt Munster (BFM) classification Locatelli F, Curr Opin Oncol 2013

20 Berlin Frankfurt Munster (BFM) classification Early and T Locatelli F, Curr Opin Oncol 2013

21 Risk classification of relapsed ALL Locatelli F, Blood 2012

22 Risk classifications of relapsed ALL Timing of relapsed Immunophenotype of leukemic cell Site of relapsed More??? Locatelli F, Blood 2012 Locatelli F, Curr Opin Oncol 2013

23 Outcome of children with first marrow relapse of acute lymphoblastic leukemia: COG study Timing MRD EFS by timing and MRD Raetz EA. J Clin Oncol 2008;26:3971-8

24 Outcome of children with first marrow relapse of acute lymphoblastic leukemia: COG study Early marrow relapse Late marrow relapse B: Early marrow relapse: 12-month EFS 67% versus 42% for MRD-negative versus - positive patients. C: Late marrow relapse: 12-month EFS 86% versus 77% in MRD-negative versus - positive patients Raetz EA. J Clin Oncol 2008;26:3971-8

25 Outcome of children with first marrow relapse of acute lymphoblastic leukemia: COG study MRD was measured by flow cytometry MRD 0.01% v MRD >0.01% Raetz EA. J Clin Oncol 2008;26:3971-8

26 Risk classifications of relapsed ALL Timing of relapsed Immunophenotype of leukemic cell Site of relapsed Isolated bone marrow Combined Isolated extramedullary (CNS, testicular) Minimal residual disease (MRD) Locatelli F, Blood 2012 Locatelli F, Curr Opin Oncol 2013

27 Outcome of relapsed ALL: results of trial ALL-REZ BFM 90 A : early isolated bone marrow or combined relapses B : late isolated or combined BM relapses C : isolated extramedullary relapses Tallen G, J Clin Oncol 2010;28:

28 Tallen G, J Clin Oncol 2010;28:

29 Outcome of relapsed ALL: results of trial ALL-REZ BFM 90 HSCT was individually considered for HR patients EFS were significantly higher after HSCT than after chemotherapy alone in HR No benefit in intermediate-risk patients Tallen G, J Clin Oncol 2010;28:

30 Long-term results of trial ALL-REZ BFM 95/96 in relapsed childhood ALL Eckert C, European J Cancer 2013;49:

31 Long-term results of trial ALL-REZ BFM 95/96 in relapsed childhood ALL MRD after RE-induction is the strongest predictor of prognosis in intermediate risk relapsed ALL Eckert C, European J Cancer 2013;49:

32 Long-term results of trial ALL-REZ BFM 95/96 in relapsed childhood ALL Transplant Non transplant Influence of HSCT v CT on prognosis of intermediate risk relapses with molecular good and poor response to induction Eckert C, European J Cancer 2013;49:

33 HSCT versus Chemotherapy IR HR Borgmann A, Blood 2003;101;3835-9

34 HSCT versus Chemotherapy IR HSCT CT P = Borgmann A, Blood 2003;101;3835-9

35 Pathway Parker C, Lancet 2010;376:

36 Key points 1. HSCT is not complete answer for all relapsed childhood ALL 2. Risk stratified Standard, Intermediate and High-risk groups Timing of relapsed Site of relapse Leukemic cell immunophenotype MRD 3. Even HSCT is the good choice for high-risk relapsed ALL but the outcome of HSCT in high risk is not adequate answer 4. New modality strategies 5. HSCT had a price to pay

37 New modalities treatment relapsed childhood ALL Bhojwani D, Pui CH, Lancet Oncol 2013;14:205-17

38 Case scenario Late relapse B-lineage ALL- intermediate risk- BFM BFM-REZ protocol re-induction- CR, MRD after 3 course < 0.01% and continue for maintenance phase No HSCT Continue remission for 8 years after complete treatment of relapsed

39 Treatment of Relapsed ALL Is HSCT only answer for childhood relapsed? No Is there any role of chemotherapy for relapsed? Yes

40 Next Samart prospective trial: HSCT in relapsed ALL

41 Questions

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