Who, when and how to transplant - PowerPoint Presentation

Slide1

Who, when and how to transplant adults with AML

Prof C Craddock CBE

Queen Elizabeth Hospital, Birmingham

Slide2

Summary of talkRight transplant:Defining the benefit of a myeloablative

sibling allograft in CR1

The role of reduced intensity allografts in

2017

Right patient (and donor):

Defining risk of transplant toxicity more accurately

Expanding donor options

Dynamic assessment of patient benefit in CR1 allografts

Right time:

Improving outcome of RIC allografts in AML

Should transplant be postponed to CR2

Slide3

Introduction

Conventional chemotherapy is ineffective in many adults with AML the majority of whom are destined to die of resistant disease

Allogeneic transplantation delivers maximal anti-

leukaemic

activity through a combination of dose intensification and a potent graft-versus-leukaemia effect

The curative potential of

allografting

has been limited by both transplant toxicity and the absence of a suitable donor for the majority of patients

The advent of reduced intensity conditioning regimens and an

increased availability of alternative donors means that

allografting

now plays a central role in the management of adults with AML in

2017

Slide4

“

Kill me tomorrow let me live tonight” Othello

Slide5

Improved outcome in young adults with AML undergoing an allogeneic bone marrow transplant

Bacigalupo et al 1997

Slide6

Cumulative incidence of transplant related mortality in patients grafted before or after 1990

Bacigalupo et al 1997

Slide7

Evidence base supporting allogeneic transplantation in AML 1st CRRetrospective studies reporting outcome after SCT can be misleading because of selection bias

Randomised

trials of transplantation versus chemotherapy can be misleading because of lead time bias

Donor-v-no donor analyses identify improved DFS but meta-analyses required to confirm survival benefit

Challenge of ascertaining benefit of transplantation in era of alternative donors and molecular markers

Slide8

Disease free survival of patients with AML in 1st CR according to age and donor availability

Cornelissen et al 2007

Slide9

Increased availability of allogeneic transplants: the status of reduced intensity conditioning (RIC) regimens in 2017Accumulating data confirm RIC regimen deliver:Marked reduction in transplant toxicity in sibling and alternative donor

allografts

A potent GVL effect can be exerted in patients up to the age of 75

T replete RIC

allografts, particularly from alternative donors, are associated with high rates of GVHDDisease relapse remains the dominant cause of treatment failure

Slide10

Analysis of Survival Benefit of RIC Allografts in UK NCRN AML 15 TrialAML 15 trial examined whether an alemtuzumab based RIC allograft as consolidation improved outcome compared with chemotherapy

In AML 15 patients over 40 were eligible to have a sibling or unrelated allograft in CR1

Since the anti-leukaemic activity of a RIC allograft was uncertain the possibility existed that a RIC allograft as course 3 might represent under-treatment so transplants were performed as course 4

Patients without a donor were allocated to receive two or three courses of consolidation chemotherapy

Outcome was assessed by Mantal-Byar analysis

Slide11

Survival from CR in Patients Age 40-60: intermediate risk cytogeneticsRussell et al 2015

Slide12

Survival from CR in Patients Age 40-60: adverse risk cytogeneticsRussell et al 2012

Slide13

Increased Availability of Allogeneic SCT in High Risk AML: Equivalence of Outcome Between Matched S

ibling

and 10/10

Unrelated Donors

Schlenk et al. NEJM 2012

Slide14

Outcome after Myeloablative Allograft for Leukaemia According to Stem Cell Source Brunstein et al Blood 2010

Slide15

Prediction of transplant toxicity: refining the HCT-CI

Sorror

et al 2007: Studied outcome of 244 consecutive patients with AML transplanted at two US institutions: FHCRC and MDACC

Included patients transplanted using a myeloablative or reduced intensity conditioning regimen

Adapted Charlson

co-morbidity index to transplant setting (HCT-CI) and demonstrated correlation with TRM, DFS and OS

Extension to specific patients now required: age, disease stage, conditioning regimen, stem cell source

Slide16

“When sorrows come, they come not

single spies but in battalions” Hamlet

Slide17

Modified HCT-CI Sorror et al 2007

Slide18

Kaplan-Meier curves for overall survival stratified by HCT-CI scores in patients transplanted at (A) FHCRC and (B) MDACC

Sorror

et al 2007

Slide19

Outcome After FMC Allograft In Patients with AML

Greater than 60 years

Nikolousis et al

2014

Slide20

Identification of patients in CR1 who will benefit from transplantAll decisions concerning allogeneic transplantation are patient specific and survival benefit is dependent on the reduction in relapse risk outweighing transplant related mortalityThere has been considerable progress in assessing both of these parameters in the last decade

Allografting

exerts a potent anti-

tumour

effect across all cytogenetic groupsIncreased donor availabilty

Other important factors include:

- salvage options if patient is not transplanted

- donor characteristics

- patient preference after careful discussion of both short and long term toxicity of transplantation

Slide21

Recommendations for Allogeneic SCT in 1st

CR based on Integrated Risk Profile

AML Risk

Group

AML Risk Assessment

ChemoRx

SCT

NRM Score Justifying

Allo

SCT As Preferred Rx

Risk of Relapse

A/C to Consolidation

HCT-CI

NRM

Good

NPM1+

CEPA -/-

Inv 16

t(8;21) WBC<20

30-35%

15-20%

<1

10-15%

I’mediate

t(8:21) WBC>20

Normal

cyto

: WBC <100

CR after 1

st

Course

50-55%

20-25%

<

2

<20-25%

Poor

Normal

cyto

: WBC>100

No CR after 1

st

cycle

induction

Adverse risk

cyto

70-80%

30-40%

<

3-4

<35%

Very poor

Monosomal

karyotype

Abn

3q26

>90%

50%

<5

<40%

After

Cornellissen

et

al Nature Rev Med

2012

Slide22

What is the role of allogeneic transplantation in primary refractory AML?Myeloablative sibling allografts have been reported to produce survival rates in the region of 20-30% for patients with primary refractory AML (PREF)

Forman et al (1991): 42% 5 yr DFS in refractory AML

Fung

et al (2003) 31% 3 yr DFS:

8% DFS in 12 patients transplanted using an unrelated donorAdvances in tissue typing and the increased size of donor registries have led to improvements in outcome after unrelated donor transplantationThere is very little data relating to outcome in patients with PREF AML transplanted using an unrelated donor

Slide23

Overall survival (OS) according to number of prior induction courses, bone marrow blasts and patient CMV serostatus

Craddock et al 2010

Slide24

“If it were done when ‘tis done then

‘twere well it were done quickly” Macbeth

Slide25

Disease relapse occurs in 20-75% of patients post-allograft and now represents the major cause of treatment failureOptimize cytotoxic properties of the conditioning regimenTarget leukemia-specific antigens post-transplant: - Optimizing a GVL effect pharmacologically or by cellular therapy- Adjunctive biological therapies with direct anti-tumor effect

Salvage therapies

Conditioning

Salvage

Stem cell

infusion

Maintenance

3

2

1

Strategies with the potential to reduce the risk of disease recurrence in patients allografted for AML

Slide26

FLAMSA-Bu Trial Design: Adverse Risk Cyto and Advanced Phase Disease

1:1 Randomisation

Stratified by the following:

Underlying disease (AML

s

MDS)

Disease status at transplant (CR1 or CR2

vs

primary refractory disease)

Age ( >60

vs

<60)

Donor type (sibling

vs

unrelated)

Control arm

Fludarabine/Busulphan/Alemtuzumab (FBA)

Fludarabine/Melphalan/Alemtuzumab (FMA

)

Experimental arm

Flamsa-Bu

Day 0

PBSCT

2 year follow-up for survival

Slide27

Craddock C, et al. Haematologica. 2010;95:989–95

A potent and manipulable GVL effect is exerted after a RIC allograft for AML

Slide28

Relapse post-transplant is determined by a dynamic competition between GVL and residual disease Although a potent GVL effect is exerted after allo-SCT for AML and MDS many patients relapse early-plausibly before the genesis of a clinically significant GVL effectThe expansion kinetics of residual clones post-transplant may be a key determinant of relapse risk

Strategies which manipulate either the timing of disease recurrence or accelerate a GVL effect may reduce relapse

Slide29

Buying time for the GVL effectTransplant

Late

Relapse

Early

Relapse

GVL

Therapeutic intervention

Slide30

Buying time for the GVL effectGVL

Transplant

Slide31

Buying time for the GVL effectRelapse

GVL

Transplant

Slide32

Buying time for the GVL effectTransplant

Therapeutic intervention

Relapse

GVL

Slide33

Buying time for the GVL effectRelapse

GVL

Transplant

Therapeutic intervention

Slide34

How can a GVL effect be optimised? Early DLI is associated with a high rate of GVHD which compromises its safe administrationThe risk of DLI induced GVHD decreases when it is administered more than one year post-transplant

Post-transplant maintenance has the potential to decrease relapse through distinct mechanisms:

Targeting leukemic stem/progenitor population

Manipulating the kinetics of relapse and “buying time” for genesis of an effective GVL response

Postponing the requirement for DLI until toxicity is reducedDirectly manipulating the alloreactive response

Slide35

Can adjunctive post-transplant therapies improve the outcome of allografts in AML/MDS?Chen, et al (2014): maintenance sorafenib well tolerated in patients allografted for FLT3/ITD+ AML

DNMT inhibitors

Decitabine

(DEC) has significant activity in AML

Azacitidine (AZA) has significant activity against leukaemic hematopoiesis in vitro and

in vivo

DEC and AZA up-regulates expression of aberrantly methylated

tumour

antigens

Slide36

Sorafenib maintenance for patients with FLT3-ITD AML in first CRA retrospective analysis of 81 consecutive patients with FLT3-ITD AML who received HCT in first CR:26 patients received sorafenib (an oral FLT3 / multikinase inhibitor) as post-transplant maintenance; 55 control patients did not

Median time to initiating sorafenib was 68 days post-HCT

Brunner et al. Br J

Haematol

2016;175:496-504.Overall survival

HCT,

hematopoietic cell transplantation;

ITD,

internal tandem duplication.

Relapse rate

2-year cumulative incidence of relapse:

sorafenib 8.2%; controls 37.7%; p<0.01

These findings suggest a potential benefit of post-transplant FLT3 inhibition in

FLT3

-ITD AML

Slide37

Can adjunctive post-transplant therapies improve the outcome of allografts in AML/MDS?Chen, et al

(2014): maintenance

sorafenib

well tolerated in patients allografted for FLT3/ITD+ AML

DNMT inhibitorsDecitabine (DEC) and Azacitidine (AZA) have significant activity against leukaemic hematopoiesis in vitro and in vivo DEC and AZA up-regulate expression of aberrantly methylated tumour antigens

Slide38

Day 0

FMC RIC

ALLOGRAFT

Day 30

AZA

36 mg/m

2

5 days

Day 60

Day 120

Day 90

Day 150

Day 365

AZA

AZA

AZA

AZA

AZA

DLI administration

(if relapse/mixed chimerism)

Commence AZA 36 mg/m

2

on Day +42 if ANC >0.5, Plt >50

AZA discontinued at 12/12 post-SCT

UK NCRN RICAZA trial of adjunctive AZA after RIC allogeneic SCT in AML/MDS

Slide39

RICAZA: Clinical outcomes37 patients commenced AZA at a median of 54 days after a FLU/MEL/alemtuzumab allograftPost-transplant AZA was well tolerated and 31 patients completed at least 3 cycles of AZA;16 patients completing 10 cycles

4 patients developed chronic limited GVHD, but none developed chronic extensive GVHD

16 patients relapsed at a median of 8 months post-transplant

Slide40

Survival according to post-transplant CD8+ T-cell response to tumor antigens

Craddock et al BBMT 2016

Slide41

Management of overt disease relapse after allogeneic SCT for AMLIn patients relapsing post-allograft, acquisition of CR is a pre-requisite of long-term survivalApproximately 20–30% of patients treated with salvage chemotherapy achieve a second CR but toxicity is significantAlternative salvage strategies include:Immunosuppression taperA

hypomethylating

agent

Slide42

Overall survival after salvage azacitidine in 272 patients relapsing after an allograft for AML/MDSCraddock et al 2016 Haematologica in press

Risk

Score

OS 2 years after AZA (%)

Response (PR/CR after AZA) (%)

Response (CR after AZA) (%)

0 (n=49)

40.2 (25.4–54.0)

52.7 (37–66.2)

40.7 (26.1–54.8)

1 (n=74)

15.1 (6.6–23.6)

23.3 (14.3–33.5)

12.7 (6.2–21.6)

2–3 (n=149)

2.2 (0–4.6)

<10–12

15.7 (10.2–22.1)

10–5

7.4 (3.9–12.4)

4 10–7

Slide43

Combined lenalidomide and azacitidine as an alternative salvage strategy in patients relapsing post-allograftLenalidomide (LEN) demonstrates anti-tumor activity in high-risk AML/MDSLEN exhibits multiple immunomodulatory activities including T- and NK-cell activationSockel, et al (2012) LENAMAINT study10 mg/day LEN x 21 days per month commencing 2 months post-allograft

Trial discontinued because of severe acute GVHD within 2 weeks of commencing LEN in 6/10 patients

UK NCRN VIOLA study: combined LEN/AZA in patients with AML/MDS who relapse post-allograft

Slide44

Treatment Schedule

Slide45

Allogeneic SCT in AML: what has been achieved?

Near universal donor availability coupled with the advent of RIC regimens permit consideration of

allografting

in the management of all newly diagnosed patients with AML who are under 70 years

Improved prediction of both TRM and relapse risk in patients underpin rational risk adapted decision making in individual patientsA donor search is indicated in

the great

majority of fit adults with AML in CR1 over 50 years old

Optimal RIC regimens in AML are yet to be defined and prospective

randomised

trials are urgently required

Disease relapse is now the major cause of failure and strategies which augment ant-

tumour

activity without increasing transplant toxicity are required