pre-transplant hypomethylation vs induction chemotherapy for … · 2013-11-13 · pre-transplant...

Pre-Transplant

Hypomethylation vs Induction

Chemotherapy

for MDS

H.Joachim Deeg MD

Fred Hutchinson Cancer Research Center ,

University of Washington,

SCCA, Seattle WA

Berlin, October 10-13, 2013

I have no disclosures to make

Why Pre-transplant Therapy?

• “Buy time” prior to transplant (“bridging”)

• Cytoreduction

– Lower risk of post-HCT relapse in responders

– Lower MDS burden – time for donor cells to exert GvL

effect

• Modification of gene expression

– Enhanced GvL effect?

• Retrospective studies are inconclusive

– Induction chemotherapy vs. no cytoreduction1

– Hypomethylating agents vs. induction chemotherapy2,3

1. Scott BL, et al. Biol Blood Marrow Transplant. 2005 Jan;11(1):65-73.

2. Gerds AT, et al. Biol Blood Marrow Transplant. 2012 Aug;18(8):1211-8.

3. Damaj G, et al. J Clin Oncol. 2012 Dec 20;30(36):4533-40.

Pre-HCT Disease Burden and Post-

HCT Relapse

Warlick E, et al. Biol Blood Marrow Transplant. 2009 Jan;15(1):30-8.

R

elap

se (

CI%

)

IPSS low (N=16)

IPSS int-1 (N=54)

IPSS int-2(N=24)

IPSS high (N=8)

IPSS and Post-HCT Relapse

Deeg et al., Blood 2002

Oral tBUCY

Smith GC, Pell JP. BMJ. 2003 Dec 20;327(7429):1459-61.

0

10

20

30

40

50

60

Inci

de

nce

pe

r 1

00

,00

0 p

er

Year

Age at Diagnosis

Age-Specific (Crude) SEER Incidence Rates of MDS (M &F) 2000-2009

72% 28%

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2009),

National Cancer Institute, DCCPS,

So,

-most patients with MDS are “older”

-older patients are more likely to

get hypomethylating therapy

-and are more likely to undergo RIC

-relapse incidence increases…..…..

Outcome after Low Intensity Conditioning

Laport et al, BBMT, 2008 Seattle Consortium

Relapse

OS

120 patients, 42-73 (median 59) years old

All MDS categories

Conditioning with Flu + 2Gy

RFS RFS: HR for >60 years 0.73, p= 0.1

Pre-HCT Factors impacting

Rejection with RIC

• Prior Chemotherapy

(p=0.003)

• Marrow (p=0.003)

Factors Considered: Dx, HSC source, risk group, CD3 dose, CD34 dose,

pt and donor sex, sex mm, class I mm, age>55, ds duration, prior transfusions, prior chemo, prior HSCT, dx type, blasts at HSCT

Disease Burden,

Pre-HCT Therapy,

And Conditioning

Intensity

Deeg et al, Leukemia, 2006

IC vs Hypo.

Relapse by 5-Group Karyotype

Very good (n=13)

Very poor (n=109)

Poor (n=159)

Good (n=461)

Intermediate (n=184)

HJ Deeg et al, Blood, 2012

In general, poor responses to

hypomethylation in patients with

high risk cytogenetics

So, what are the data?

Azacitidine Pre-HCT

• 54 consecutive patients with MDS

• 30 azacitidine vs 24 no aza

– 16 received IC

• 1-year estimates for aza vs no aza

– Cumulative incidence of relapse 20% vs 32%

– OS 47% vs 60%

– Relapse-free survival 41% vs 51%

Field T, et al. Bone Marrow Transplant 2010;45:255-60.

Azacitidine Pre-HCT F

ield

T, e

t a

l. B

MT

2010;4

5:2

55-6

0.

Pre-HCT Azacitidine vs. IC

Gerds AT, et al. BBMT, 2012 , 18:1211

Pre-HCT Azacitidine vs. IC

AZA

IC

Gerds AT, et al. BBMT, 2012 , 18:1211

HCT after azacitidine failure

• 37 patients received HCT 1- 26 (median 5)

ms after failure

– 28 direct

– 9 after other salvage attempts

• Median survival 19 months

– 17 months in pts with progressive disease

– Not reached in pts with stable disease

T.Prebet et al, JCO.29:3322, 2011

Survival by

disease status

following

pre-HCT

therapy

(MDS + AML)

de Lima, M. et al. Blood 2004

Pre-HCT Hypomethylation vs. Induction for MDS

Ziegler J, New Yorker; November 24, 2008.

Toast !

or

Toasted?

Study Schema (FHCRC # 2661)

Induction Chemotherapy

A.Gerds et al

Although hypomethylation is

being used with increasing

frequency,

we have no controlled data to

support that approach

And what are the concerns?

• Results from non-randomized studies are difficult to interpret – selection bias

• Responses to HMA are delayed

– acquisition of new comorbidities

– inferior HCT outcome after HMA failure

• Less profound “debulking”

– higher relapse incidence

• Hypomethylation-associated reduction in GVHD may further increase risk of relapse

Thank you

But…

• Results reported from non-randomized

studies are difficult to interpret because

of obvious bias in patient selection

• Time delay to response with

hypomethylation – new co-morbidities

• Can we separate pre-HCT therapy from

the effect of the conditioning regimen?

• Why is minimal residual disease

detrimental in AML but not in MDS?

Azacitidine “failure”: Survival by salvage treatment

in azacitidine treated patients

Th. Prébet et al. JCO 2011;29:3322-3327

HCT

Myeloblast Phenotype and Relapse in MDS

B.Scott et al, Blood, 2008

Risk model for non-transplanted patients:

K. Naqvi et al. JCO 2011

↑ IPSS

Age ≥ 65

↑ Comorbidity

Feasibility Studies

De Padua Silva L, et al. Bone Marrow Transplant. 2009 Jun;43(11):839-43.

Lübbert M, et al. Bone Marrow Transplant. 2009 Nov;44(9):585-8.

Cogle CR, et al. Clin Adv Hematol Oncol. 2010 Jan;8(1):40-6.

Kim DY, et. Bone Marrow Transplant. 2012 Mar;47(3):374-9.

Impact of MRD in AML

%

Relapse Survival

No MRD (n=39) 77%

No MRD (n=39) 30%

MRD (n=13) 88%

MRD (n=13) 24%

Gyurkocza et al (unpub.)

Pre-HCT Hypomethylation vs. Induction for MDS

Ziegler J, New Yorker; November 24, 2008.

Study Design

• Phase II randomized study

– Detecting a signal of difference

– Establishing the testing protocol (feasibility of

a research plan)

Challenges Developing this Protocol

• Internal validity–external validity paradox

• Specificity – generalizability paradox

Rigorous

control

Reality-

based

Valid in a

specific context

Widely

generalizable

Green, LW,. Fam Pract. 2008 Dec;25 Suppl 1:i20-4.

Primary Aim and Hypothesis

• Primary aim

– Examine the effect of HMA versus IC as initial therapy on

survival in HCT–eligible patients

• Hypothesis

– HMA will lead to an improved survival

Study population

• Key inclusion criteria:

– de novo or secondary MDS and CMML (2008

WHO)

– Bone marrow myeloblast count ≥ 5% and <

20%.

– Considered HCT candidates and appropriate

for IC

• Key exclusion criteria: – Previous treatment for MDS with IC or HMA

Primary Endpoint

• Failure-free survival at 18 months

– Lack of adequate response to initial therapy

• Progressive disease*

• Need to change cytoreductive therapy

– Relapse at any time after response*

– Death

*Adapted from: Cheson BD, et al. Blood. 2006 Jul 15;108(2):419-25.

Secondary Endpoints

• Secondary endpoints

– Incidence of initial treatment failure

– Number of patients who are transplanted

– Quality of life

– Impact on comorbidities

– Cost analysis during initial treatment

– Post-transplant OS, relapse, and NRM

– Incidence of GVHD

Methods

• Arm A – HMA-Containing regimen that is not considered IC

• Clinical trial

• Standard of care (azacitidine 75 mg/m2)

• Arm B – IC that does not include HMA as part of regimen

• Clinical trial

• Standard of care: “7+3”

• Additional cycles are allowed to maintain response prior to HCT

• Intention-to-treat analysis – Off study treatment, but will continue to follow for outcome

Methods

• Conditioning

– Most appropriate conditioning regimen based

on patient characteristics at the time of HCT

• Donor Source

– Most appropriate based on conditioning

regimen and available donor

Statistical Considerations

• It is not practical to enroll sufficient patients to this trial to

show a statistically significant difference in FFS

• Different benchmark for a positive study result

• HMA must perform just as well as IC to proceed to a phase III

study (n= 60)

Assumed-true 18 month FFS probability

Prob of obs HMA ≥ IC Hypomethylating Intensive Chemo

50% 30% 0.96

45% 30% 0.91

50% 60% 0.26

Limitations and Future Directions

• Lack of consistent conditioning and donor

source

• Fewer than anticipated patients may undergo

HCT

• Future directions

– Randomized, multi-center, phase III study

– Explore information to causes of study failure to aid in

design of alternative cytoreductive strategy

Conclusions

• There is currently no consensus on the appropriate pre-

HCT therapy

• Results from this study will provide controlled,

prospective data on the impact of HMA and IC on

transplantability and transplant outcome, thereby guiding

clinical practice

Pre-HCT IC vs. No Induction

Relapse-Free Survival Non-Relapse Mortality

Scott BL, et al. Biol Blood Marrow Transplant. 2005 Jan;11(1):65-73.

No Induction (N = 92)

Induction (N = 33)

Hypomethylating Agents

• Azacitidine and decitabine

– Favorable toxicity profile

– Outpatient administration

– Delay progression of MDS to AML

Pre-HCT Azacitidine vs. IC

Gerds AT, et al. Biol Blood Marrow Transplant. 2012 Aug;18(8):1211-8.

P = 0.98 P = 0.24

Azacitidine (N = 35)

Induction (N = 33)

Conclusions: 1. Azacitidine prior to transplantation is

feasible

2. Outcomes appear to be similar between

induction chemotherapy and azacitidine

Pre-HCT Azacitidine vs. IC

Damaj G, et al. J Clin Oncol. 2012 Dec 20;30(36):4533-40.

Conclusions:

1. With the goal of down-staging underlying disease before HCT, azacitidine alone led to outcomes similar to those for standard IC.

Response Criteria

Adapted from: Cheson BD, et al. Blood. 2006 Jul 15;108(2):419-25.

The Transplant “Package” Pre-transplant

Transplant

Post-transplant

Response

No Response

Non-Myeloablative ? Myeloablative ?

Reduced Intensitity?

Induction Y/N What kind?

MMF x2/x3/day? Extent of chimerism, time ? DLI?

Co-morbidity

high low

PBPC vs BM

3.66 3.77

4.27

4.49 4.31

4.69 4.81

3

3.5

4

4.5

5

5.5

6

Inci

de

nce

pe

r 1

00

,00

pe

r Ye

ar

Year

Age-Adjusted SEER Incidence Rates All Ages, All Races, Both Sexes

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2009),

National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2012,

based on the November 2011 submission.

R² = 0.88907

- Increased awareness

- Better diagnostics

- Increasing survivorship for other

cancers (secondary MDS)

- Aging population

Pro

ba

bilit

y o

f R

ela

ps

e

Y ears S ince T ransp lan t

0 1 2 3 4 5 6

0 .0 0

0 .2 5

0 .5 0

0 .7 5

1 .0 0

| | | | | | | | | | | | | | | | | | | | | | | | |

| | | | | | | | | | | | |

| | | | | | |

| | | | | | | | | | |

F lo w sco re 4 (N = 4 5 )

F lo w sco re 2 -3 (N = 3 2 )

F lo w sco re 0 -1 (N = 3 4 )

0 .3 3

0 .1 5

0 .0 3

P < 0 .01

Flow Score and Post-Transplant Relapse

B.Scott, D. Wells et al

D.Wells, M.Benesch et al, BLOOD, 2003

Flow Score Discrimination within IPSS Risk Groups

Event free survival according to CR

status prior to alloHSCT

AML/MDS

OS for patients in CR

63% at 1 year and 55% at 2 years

Cumulative incidence of relapse for patients in CR at 2 years is 26%

EFS for patients in CR

59% at 1 year and 54% at 2 years

AML/MDS

CR

Not in CR

Not in CR with PB

Event-free survival of patients with AML/MDS according to pre-transplant

characteristic (n=72)

Survival by

disease

status

de Lima, M. et al. Blood 2004

RA(RS) - No Induction Chemotherapy -

B.Scott et al, Leukemia, in press

Flu+2Gy TBI

tBUCY Flu+2Gy TBI (n=9)

tBUCU (n=49)

Relapse-free Survival Relapse

p=NS p=NS

RAEB/tAML Responsive to Induction

Chemotherapy

B.Scott et al, Leukemia, in press

Flu+2Gy TBI (n=20)

tBUCY (n=29)

tBUCY

Flu+2Gy TBI

Relapse-free Survival Relapse

Myeloblast

Phenotype

and Relapse

in MDS

B.Scott et al, Blood, 2008

MDS/sAML Treatment Package

Gerds AT, Scott BL, Curr Hematol Malig Rep. 2012 Dec;7(4):292-9.

Patient and Disease

Characteristics

Pre-transplant Management

Transplantation Program Post-transplant

Management

Time of

Pre-transplant

Transplant

Post-transplant

Remission or Detectable

Disease

Patient Characteristics Age

Comorbidities

Disease Characteristics Cytogenetic risk

Prognostic scores Response to treatment

Response or No-response

Pre-transplant Management • Disease reduction: yes/no • Induction chemotherapy • Hypomethylating agent

• Timing of transplant

Transplantation Program • Conditioning intensity

• Related or unrelated donor • Graft source

• Immune suppression

Post-transplant Management • Surveillance techniques

• Timing: prophylactic, pre-emptive, after relapse

• Optimal agent • Duration of treatment

Azacitidine Pretransplant

• 54 consecutive patients transplanted for

MDS

• 30 azacitidine vs 24 did not

– 16 patients received induction chemotherapy

• 1-year estimates for Aza vs not

– OS 47% vs 60%

– Relapse-free survival 41% vs 51%

– Cumulative incidence of relapse 20% vs 32%

Field T, et al. Bone Marrow Transplant 2010;45:255-60.

Azacitidine Pretransplant

Field T, et al. Bone Marrow Transplant 2010;45:255-60.

Pre-HCT Azacitidine vs. IC

Gerds AT, et al. Biol Blood Marrow Transplant. 2012 Aug;18(8):1211-8.

Pre-HCT Azacitidine vs. IC

.

Gerds AT, et al. Biol Blood Marrow Transplant. 2012 Aug;18(8):1211-8.

Pre-HCT Azacitidine vs. IC

Damaj G, et al. J Clin Oncol. 2012 Dec 20;30(36):4533-40.

Pre-HCT Azacitidine vs. IC

Damaj G, et al. J Clin Oncol. 2012 Dec 20;30(36):4533-40.

*Model included recipient age, cytogenetic risk, responder/non-responder, donor age, donor type, donor CMV status

*

Is Induction Chemotherapy Necessary?

Design

“Advanced MDS”

“Advanced MDS” ?

Relapse

Response

Induction Chemo Transplant

No Induction Chemo

Transplant

Transplant

Patient Characteristics Characteristic

Yes No

No. of patients 33 92

Age, range (median), y 2-64 (45) 3-66 (50)

Gender, M/F, no of patients 17/16 59/33

Etiology, no. of patients

De novo 28 60

Secondary 5 32

Disease duration, range (median), mo 1-43 (6) 1-62 (6)

FAB stage, no. of patients

RAEB 3 62

RAEB-T 6 22

tAML 24 8

IPSS risk group, no. of patients

Low 0 1

Intermediate-1 10 20

Intermediate-2 8 37

High 15 33

Not scored‡ 0 1‡

Donor, no. of patients

HLA-identical sibling 16 46

Alternative related donor§ 0 3

HLA-identical unrelated 17 43

Source of Stem Cells, no of patients

Peripheral Blood 18 27

Bone Marrow 15 65

Conditioning Regimen

tBuCy 21 55BuTBI 12 37

Induction Chemotherapy

Scott et al. Biol Blood Marrow Transplant 2005;11:65-73

Induction Chemo vs. No Induction

Chemo RFS

Scott et al. Biol Blood Marrow Transplant 2005;11:65-73

Impact of Flow Score on Survival

No Pre-HCT Induction Chemo Pre-HCT Induction Chemo

Scott et al. Biol Blood Marrow Transplant 2005;11:65-73

MDS/sAML Treatment Package

Patient and Disease

Characteristics

Pre-transplant Management

Transplantation Program Post-transplant

Management

Time of

FHCRC 2661

HMA vs. IC

BMT-CTN 0901

(FHCRC 2497)

RIC vs. FIC

FHCRC 2240

Post-HCT

Azacitidine

A. Gerds

Pre-HCT Azacitidine vs. IC

.

Gerds AT, et al. Biol Blood Marrow Transplant. 2012 Aug;18(8):1211-8.