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Ph positive ALL; Is transplant still necessary? Adele K. Fielding MB BS, PhD

Ph positive ALL; Is transplant still necessary? Adele K. Fielding MB BS, PhD. Chair UK National Cancer Research Institute Adult ALL Subgroup. Outline of talk. Why we use alloHSCT in Ph+ ALL – what is the evidence it is of value?

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Ph positive ALL; Is transplant still necessary? Adele K. Fielding MB BS, PhD

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  1. Ph positive ALL;Is transplant still necessary?Adele K. Fielding MB BS, PhD Chair UK National Cancer Research Institute Adult ALL Subgroup

  2. Outline of talk Why we use alloHSCT in Ph+ ALL – what is the evidence it is of value? Why is it so difficult to draw firm conclusions about the role of alloHSCT? Where does non-myeloablative alloHSCT fit in? Now we have TKIs, do we still need transplant Illustrate various points above with some data from UKALL12/ECOG2993 Conclusions about current role of TKI and alloHSCT

  3. Ph+ ALL - the scope of the problem Long been concluded that patients witht(9;22) have a poor outcome with conventional therapy Considered“Very high risk” by all clinical studies Typically ‘assigned’ to alloHSCT

  4. Ph+ ALL - the scope of the problem Poor risk Good risk *Moorman et al Blood 2007 **Hann et al BJH 2002

  5. Age in ALL; tolerance of therapy ? Group Induction Resistance to Death % induction Rx “Children” AIEOP-91 1.4 2.1 COALL-92 0.4 0.9 DFCI-01 0.5 1.3 EORTCCCLG 0.9 1.3 SJ CRH 13B 1.2 0.8 “Adults” GMALL05/93 6 11 GOELAM-02 3 18 HyperCVAD 5 3 JALSG-93 6 16 LALA-94 5 11 After Pui and Evans, NEJM 2006

  6. Myeloablative allogeneic HSCT The most active anti-ALL therapy currently available, but also the most toxic For whom? • Age • Status of disease • At what level of relapse-risk Convincing data Useful data Conflicting data What is the best method ? • Conditioning regimen • Stem cell source • Unrelated vs. sibling donor • Role of T cell depletion • GVHD prophylaxis/ KGF e.g. palifermin • Post-BMT interventions e.g. DLI, TKI Scant data

  7. GVL effect The most active anti-ALL therapy currently available, but also the most toxic Fielding et al Blood 2009 UKALL12/ECOG2993

  8. OS > 600 patients after relapse At what level of relapse-risk? 100 75 Fielding et al 2007 UKALL12/ECOG2993 50 Percent surviving 7% 25 0 0 1 2 3 4 5 Time (years) Other large relapse studies: Tavernier et al 2007 LALA94 DFS 5 yr 12% Oriol et al 2010 PETHEMA OS 5yr 10%

  9. Myeloablative alloHSCT A ‘transplanters’ perspective? “That which doesn’t kill us makes us stronger” Nietzsche “If it doesn’t feel bad, it can’t be doing you any good” Alice Fielding (my mum)

  10. Sibling Myeloablativeallo HSCT Pre-TKI era *prospective studies

  11. UD donor Myeloablativeallo HSCT; preTKI era • Retrospective studies, not all patients Ph+ • Mixed ages • Some patients beyond CR1 Equivalent outcome between unrelated and sibling donor: Cornillissen, 2001 Blood Dahlke, 2006 BMT Kiehl, 2004 J ClinOncol

  12. UD donor Myeloablativeallo HSCTOS UKALL12/ECOG2993 Pre-TKI 100 75 PERCENT 50 44 Sib 36 MUD 25 19 chemo 0 1 2 3 4 5 0 At risk: TIME IN YEARS Sib 45 35 29 18 25 19 MUD 31 23 12 11 12 11 Chemo 82 43 23 12 19 15 Fielding et al Blood 2009

  13. Difficulties in studying the alloHSCT question 1. Trial Design Equipoise problems in designing RCTs with myeloablative alloHSCT as an arm Impossibility of “donor vs. no donor”analysis in modern transplant studies where UD are commonly available

  14. Difficulties in studying the alloHSCT question 2. Selection bias “Transplant only” retrospective studies do not include a denominator. Hence, benefit can only apply to those selected for reporting Those might be only a tiny fraction of the at-risk population & are unlikely to be representative

  15. Difficulties in studying the alloHSCT question 3. Immortal time bias A patient receiving a transplant within a prospective study is guaranteed to have entered CR and survived, disease free to the time of transplant A simple analysis by therapy received during trial doesn’t represent the reality for a future new patient accurately

  16. Immortal time bias: an example * P=0.001 Fielding et al, Blood 2009 UKALL12/ECOG2993 – pre TKI era

  17. Immortal time bias: an example Fielding et al Blood 2009 UKALL12/ECOG2993

  18. Myeloablative Allo in Ph ALL • Weight of evidence has been interpreted In favour of myeloablative allo HSCT Those patients who • Achieve CR • Have a donor • Are fit enough to have a transplant • …Receive the transplant Will have a better outcome than those who don’t

  19. Non-myeloablativealloHSCT

  20. Non-myeloablativealloHSCT • Likely to be • much more regimen-dependent, • more dependent on disease burden at allo • require more focused post-transplant monitoring (+ intervention ?) than myeloablative

  21. TKI in Ph ALL 1. Is there a higher CR rate with no excess cost ? 2. Do TKI facilitate alloBMT? 3. Is there a survival advantage for TKI-containing regimens? 4. Does this advantage occur in the absence of alloHSCT For purpose of this talk TKI = largely Imatinib Data on dasatinib during induction are much fewer/shorter follow up

  22. TKI in Ph+ ALLCautionary note Hu et al. Nat Genet. 2004 Requirement of Src kinases for BCR-ABL-induced B-ALL but not CML. Pfeifer et al Blood 2007 BCR-ABL KD mutation in 40% at presentation Soverini et al Hematolgica 2011 2-4 clones of 200 for each patient harboured pre-exisiting KD mutations

  23. Induction therapy Ph pos ALL:Imatinib Imatinib added to induction/consol’n. • N CR(%) CR1 SCT (%) • Thomas 2004 20 93 50 • Yanda 2006 80 96 49 • Wassmann 2006 92 95 77 • De Labarthe 2007 45 96 51 • Ribera 2009 30 90 78 • Bassan 2010 59 92 63 • Fielding 2014 175 92 46 • Chalandon ongoing 188 95/100 • Older • Ottman 2007 55 96 N/A • Vignetti 2007 30 96 N/A • Children only sibs • Schultz 92

  24. Induction therapy Ph pos ALL:Imatinib Imatinib added to induction/consol’n. • N OS time • Thomas 2004 20 75 20m • Yanda 2006 80 75 12m • Wassmann 2006 92 36/43 24m • De Labarthe 2007 45 65 18m • Ribera 2009 30 30 4yr • Bassan 2010 59 38 5yr • Fielding 2011 175 43 3yr • Chalandon ongoing 188 62 2yr • Older • Ottman 2007 55 74 12m • Vignetti 2007 30 42 24m • Children • Schultz 92 80(EFS) 3yr

  25. Induction therapy PhposALL:Dasatinib Dasatinib added to induction/consol’n. • N CR(%) CR1 SCT (%) combo • Ravandi 35 94 50 hyperCVAD • Foa 48 100 N/A Steroid • Rousselot 71 90 N/A EWALL elderly backbone

  26. Induction therapy PhposALL:Dasatinib Dasatinib added to induction/consol’n. • N OS time • Ravandi 35 64 24m • Foa 48 80.7 10m • Rousselot 71 median 21.7m

  27. TKI without transplant in Ph+ ALL • Older patients • Patients unfit for alloHSCT • Those fit, but without any donor • Children, in whom there is reluctance to use UDs

  28. TKI without transplant in Ph ALL NoBMT BMT JALSG: Yanada et al, JCO 2006

  29. Children with Ph+ ALL Risk:benefit ratio of Rx is unfavourable for UD Arico et al, NEJM 2009

  30. Children with Ph+ ALL;COG study 93 Ph+ N=25 chemo+ im 87.7% N=11 UD HSCT 71.6% N=25sibHSCT 56.6% Schultz et al, 2009 J Clin Onc

  31. UKALLXII/ECOG2993 Ph+: up to 65y response determination All patients IMATINIB 600mg od Early Imatinib N=89 Late Imatinib (as a consolidation) N=86 INDUCTION Phase 1 Phase 2 Allogeneic HSCT (Etoposide/TBI) up to 55y. no donor/unfit for allo Autologous HSCT (Etoposide/TBI) recommend

  32. Patient characteristics * Pre-imatinib results: Fielding et al, Blood 2009, “imatinib” paper Fielding et al Blood 2014

  33. Response to Induction

  34. Flow Chart of Post-InductionTherapy N = 175 Induction death/No CR 14 (8%) Protocol deviation induction 24 (14%) Chemo/imatinib 39/137 eligible (28%) 39/175 total (22%) Total alive/CR 137 (77%) Myeloablativeallo HSCT 82/137 eligible (60%) 82/175 total (46%) 43 sibling donor 33 Matched unrelated donor 3 cord blood 2 Mismatched unrelated donor 1 Haploidentical donor “Non-protocol” RIC alloHSCT 11/137 eligible (8%) 11/175 total (6%) 6 sibling donor 5 Matched unrelated donor

  35. Protocol BMT rate Pre-imatinib 28% Imatinib 46% Transplant details Reach 84 day in CR 78% 66% .009 Median days diag to BMT 135d 160d <.0001 % elig pt receiving BMT 71% 55% <.0001 Both imatinib, overall better BMT practice contributed to the improved alloHSCT rate after imatinib

  36. Overall outcomes Imatinib vs.Pre-Imatinib Median FU Pre-imatinib 10 years Median FU Imatinib 3 years

  37. OS Imatinib vs. pre-Imatinib 100 Pre-imatinib versus imatinib, p=0.0003 75 Percent surviving 50 imatinib 32% 25 19% Pre-imatinib 0 0 1 2 3 4 5 6 7 8 9 10 Time (years) At risk: 266 144 81 67 57 54 49 46 41 40 35 175 115 9 4 0 0 Imatinib 81 69 53 31 17 Pre-imatinib

  38. Relapse risk Imatinib vs. Pre-Imatinib 100 64% Imatinib 75 % relapsing 50 47% Pre-imatinib 25 0 1 2 3 Time in years 2P = 0·0001

  39. OS within imatinib cohort from diagnosis, by treatment in CR1 100 Protocol alloHSCT 75 50% Percent surviving 50 39% Non-protocol RIC alloHSCT 25 19% No alloHSCT 0 0 1 2 3 4 At risk: Time (years) 76 57 45 42 31 Protocol alloHSCT 11 8 6 5 3 Non-protocol RIC alloHSCT No alloHSCT 38 20 9 7 6

  40. Relapse risk within imatinib cohort by treatment in CR1 100 73% No BMT 75 % relapsing 49% Non Protocol BMT 50 25 25% Prot BMT 0 1 2 0 3 Time (years)

  41. Outcome by timing of imatinib start

  42. Multivariate Cox Regression OS

  43. OS for patients not receiving alloHSCT 100 ALL CRs but NO BMT 75 50 24% Imatinib 25 18%Pre-imatinib 0 1 2 3 Univariate: unadjusted p=0.08 Cox, allowing for age and WBC p=0.02 % still alive 100 Excl. Rel/died within median time to BMT 75 50 24% Imatinib 25 22% Pre-imatinib 0 1 2 3 Time in years Univariate unadjusted: p>0.1 Cox, allowing for age and WBC p=0.05

  44. TKI post alloHSCT Yes/No? PETHEMA: post myeloablative alloHSCT poorly tolerated only 62% started, many discontinued U of Minn trend towards better outcome on those given imatinib (v. small study) Seattle RIC allo – trend towards better outcome when imatinib was given but no effect on relapse For everyone or selected patients ? GMALL up-front at 3 months vs. only upon BCR-ABL re-appearance Poorly tolerated when started early No difference so far between the groups For how long? No idea….! Most studies select 1-2 years - empirically

  45. Conclusions • Higher CR rate by 10% with no increase in TRM when imatinib is added to therapy • Imatinib almost doubled the rate of alloHSCT in UKALL12/ECOG2993 • Overall, significantly improved outcomes in all endpoints measured are typical in imatinib containing regimens Overall Outcomes for Ph+ ALL Rx are now encouraging: UKALL 62% GMALL 72%OS @3y imatinib/allo JALSG 65%

  46. Conclusions • improved outcome in TKI era relates mostly to a higher rate of alloHSCT --- modest (?no) long term benefit to imatinib where HSCT not achieved • UKALL12/E2993 and GMALL studies – still poor outcome where no myeloablative alloHSCT No role for omitting alloHSCT in adults with Ph+ ALL • Not yet clear how best to use TKI post allo

  47. Strong argument for future, large international co-operative studies I think I’d rather manage a large international collaboration of transplant physicians

  48. Funded: UKALL12/ECOG2993Ph positive arm: imatinib Adele K. FieldingGeorgina BuckLetizia ForoniHillard LazarusMark LitzowSelina M. LugerDavid I. MarksAndrew K. McMillanAnthony MoormanElisabeth PaiettaSusan M. RichardsJacob M. RoweMarty S. TallmanAnthony H.Goldstone UK National Cancer Research Institute Adult ALL Subgroup USA Eastern Co-operative Oncology Group

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