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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.
