Ph positive ALL;Is transplant still

necessary?

Adele K. Fielding MB BS, PhD

Chair UK National Cancer Research InstituteAdult ALL Subgroup

Outline of talkWhy 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

Ph+ ALL - the scope of the problem

Long been concluded that patients with t(9;22) have a poor outcome with conventional therapy

Considered “Very high risk” by all clinical studies

Typically ‘assigned’ to alloHSCT

Karyotype*% Adults **% Children

t(4;11) 5 1

t(9;22) 21 2

t(12;21) <1 19

High hyperdiploidy 9 32

*Moorman et al Blood 2007

Poor risk

Good risk

**Hann et al BJH 2002

Ph+ ALL - the scope of the problem

Age in ALL; tolerance of therapy ?

Group Induction Resistance to Death % induction Rx

“Children”AIEOP-91 1.4 2.1COALL-92 0.4 0.9DFCI-01 0.5 1.3EORTCCCLG 0.9 1.3SJ CRH 13B 1.2 0.8

“Adults”GMALL05/93 6 11GOELAM-02 3 18HyperCVAD 5 3JALSG-93 6 16LALA-94 5 11

After Pui and Evans, NEJM 2006

Myeloablative allogeneic HSCTThe most active anti-ALL therapy currently available, but

also the most toxic

Useful data Convincing data

Conflicting dataScant 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

For whom?•Age•Status of disease•At what level of relapse-risk

GVL effect

Fielding et al Blood 2009 UKALL12/ECOG2993

The most active anti-ALL therapy currently available, but also the most toxic

0

25

50

75

100

Perc

ent s

urvi

ving

0 1 2 3 4 5Time (years)

7%

OS > 600 patients after relapse

Fielding et al 2007 UKALL12/ECOG2993

At what level of relapse-risk?

Other large relapse studies:Tavernier et al 2007 LALA94 DFS 5 yr 12%Oriol et al 2010 PETHEMA OS 5yr 10%

“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)

Myeloablative alloHSCTA ‘transplanters’ perspective?

Sibling Myeloablative allo HSCTPre-TKI era

*prospective studies

UD donor Myeloablative allo HSCT; preTKI era

Equivalent outcome between unrelated and sibling donor:

Cornillissen, 2001 Blood

Dahlke, 2006 BMT

Kiehl, 2004 J Clin Oncol

•Retrospective studies, not all patients Ph+ •Mixed ages•Some patients beyond CR1

UD donor Myeloablative allo HSCTOS UKALL12/ECOG2993

Pre-TKI

0 1 2 3 4 50

25

50

75

100

PER

CEN

T

TIME IN YEARSAt risk:

Sib 45 35 29 25 19 18MUD 31 23 12 12 11 11Chemo 82 43 23 19 15 12

Fielding et al Blood 2009

44 Sib 36 MUD

19 chemo

Difficulties in studying the alloHSCT question

1. Trial DesignEquipoise 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

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

Difficulties in studying the alloHSCT question

3. Immortal time biasA 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

Fielding et al, Blood 2009 UKALL12/ECOG2993 – pre TKI era

Immortal time bias: an example

* P=0.001

Immortal time bias: an example

Fielding et al Blood 2009UKALL12/ECOG2993

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

Non-myeloablative alloHSCT

Non-myeloablative alloHSCT

Likely to be much more regimen-dependent, more dependent on disease burden at allorequire more focused post-transplant monitoring (+ intervention ?) than myeloablative

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

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 20112-4 clones of 200 for each patient harboured pre-exisiting KD mutations

Induction therapy Ph pos ALL:Imatinib

N CR(%) CR1 SCT (%)Thomas 2004 20 93 50Yanda 2006 80 96 49Wassmann 2006 92 95 77De Labarthe 2007 45 96 51Ribera 2009 30 90 78Bassan 2010 59 92 63Fielding 2014 175 92 46Chalandon ongoing 188 95/100OlderOttman 2007 55 96 N/A Vignetti 2007 30 96 N/A Children only sibsSchultz 92

Imatinib added to induction/consol’n.

Induction therapy Ph pos ALL:Imatinib

N OS timeThomas 2004 20 75 20mYanda 2006 80 75 12mWassmann 2006 92 36/43 24mDe Labarthe 2007 45 65 18mRibera 2009 30 30 4yrBassan 2010 59 38 5yrFielding 2011 175 43 3yrChalandon ongoing 188 62 2yrOlderOttman 2007 55 74 12mVignetti 2007 30 42 24mChildrenSchultz 92 80(EFS) 3yr

Imatinib added to induction/consol’n.

Induction therapy Ph pos ALL:Dasatinib

N CR(%) CR1 SCT (%) combo

Ravandi 35 94 50 hyperCVADFoa 48 100 N/A SteroidRousselot 71 90 N/A EWALL elderly backbone

Dasatinib added to induction/consol’n.

Induction therapy Ph pos ALL:Dasatinib

N OS time

Ravandi 35 64 24mFoa 48 80.7 10mRousselot 71 median 21.7m

Dasatinib added to induction/consol’n.

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

JALSG: Yanada et al, JCO 2006

TKI without transplant in Ph ALL

NoBMT

BMT

Children with Ph+ ALL

Arico et al, NEJM 2009

Risk:benefit ratio of Rx is unfavourable for UD

Children with Ph+ ALL;COG study93 Ph+

Schultz et al, 2009 J Clin Onc

N=25 chemo+ im 87.7%

N=25 sibHSCT 56.6%N=11 UD HSCT 71.6%

UKALLXII/ECOG2993 Ph+: up to 65yINDUCTION

Phase 1

Phase 2

Autologous HSCTAutologous HSCT(Etoposide/TBI) (Etoposide/TBI)

recommendrecommend

Allogeneic Allogeneic HSCTHSCT

(Etoposide/TBI)(Etoposide/TBI)up to 55y.up to 55y.

no donor/unfit for allo

All patients IMATINIB 600mg od

Early Imatinib N=89Early Imatinib N=89responsedetermination

Late Imatinib (as a consolidation) N=86Late Imatinib (as a consolidation) N=86

Patient characteristics

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

Response to Induction

Flow Chart of Post-Induction Therapy

N = 175

Total alive/CR 137 (77%)

Induction death/No CR 14 (8%)Protocol deviation induction 24 (14%)

Myeloablative allo HSCT 82/137 eligible (60%) 82/175 total (46%)

43 sibling donor33 Matched unrelated donor3 cord blood2 Mismatched unrelated donor1 Haploidentical donor

“Non-protocol” RIC alloHSCT

11/137 eligible (8%)11/175 total (6%)

6 sibling donor5 Matched unrelated donor

Chemo/imatinib

39/137 eligible (28%)39/175 total (22%)

Transplant detailsProtocol BMT rate

Pre-imatinib 28%Imatinib 46%

Both imatinib, overall better BMT practice contributed to the improved alloHSCT rate after imatinib

Reach 84 day in CR 78% 66% .009Median days diag to BMT 135d 160d <.0001% elig pt receiving BMT 71% 55% <.0001

Overall outcomes Imatinib vs.Pre-Imatinib

Median FU Pre-imatinib 10 yearsMedian FU Imatinib 3 years

OSImatinib vs. pre-Imatinib

Pre-imatinib

0 1 2 3 4 5 6 7 8 9 100

25

50

75

100

19%

32%

At risk:

266 144 81 67 57 54 49 46 41 40 35

Imatinib 175 115 81 69 53 31 17 9 4 0 0

Pre-imatinib

imatinib

Pre-imatinib versus imatinib, p=0.0003

Perc

ent s

urvi

ving

Time (years)

1 2 30

25

50

75

100

% re

laps

ing

Time in years

64% Imatinib

47% Pre-imatinib

2P = 0·0001

Relapse risk Imatinib vs. Pre-Imatinib

OS within imatinib cohortfrom diagnosis, by treatment in CR1

0 1 2 3 40

25

50

75

100

Perc

ent s

urvi

ving

Time (years)

50%

39%

19%

At risk:Protocol alloHSCT 76 57 45 42 31

Non-protocol RIC alloHSCT 11 8 6 5 3

No alloHSCT 38 20 9 7 6

Protocol alloHSCT

Non-protocol RIC alloHSCT

No alloHSCT

Relapse risk within imatinib cohortby treatment in CR1

0 1 2 30

25

50

75

100

% re

laps

ing

Time (years)

25% Prot BMT

49% Non Protocol BMT

73% No BMT

Outcome by timing of imatinib start

Multivariate Cox Regression OS

Co-Variate HR 95%CI P

Imatinib 0.56 0.44 - 0.71 <0.0001

Age 1.02 1.02 - 1.03 <0.0001

Pres.WCC 1.32 1.21 - 1.43 <0.0001

OS for patients not receiving alloHSCT

0 1 2 3

25

50

75

100

% s

till a

live

Time in years

22% Pre-imatinib 24% Imatinib

Univariate unadjusted: p>0.1Cox, allowing for age and WBC p=0.05

0 1 2 3

255075100

18%Pre-imatinib 24% Imatinib

Univariate: unadjusted p=0.08Cox, allowing for age and WBC p=0.02

ALL CRs but NO BMT

Excl. Rel/died within median time to BMT

TKI post alloHSCTYes/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-appearancePoorly tolerated when started earlyNo difference so far between the groups

For how long?No idea….! Most studies select 1-2 years - empirically

•Higher CR rate by 10% with no increase in TRMwhen 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/alloJALSG 65%

Conclusions

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

I think I’d rather manage a large international collaboration

of transplant physicians

Strong argument for future, large international co-operative studies

UKALL12/ECOG2993Ph positive arm: imatinib

Adele K. FieldingGeorgina BuckLetizia Foroni

Hillard LazarusMark Litzow

Selina M. LugerDavid I. Marks

Andrew K. McMillanAnthony MoormanElisabeth Paietta

Susan M. RichardsJacob M. Rowe

Marty S. TallmanAnthony H.Goldstone

Funded:

UK National Cancer Research Institute

Adult ALL Subgroup

USAEastern Co-operativeOncology Group