hematopoietic stem cell transplantation (hct) for mds

Jdr10_1.ppt

Hematopoietic Stem Cell Transplantation (HCT)

for MDS

Mary M. Horowitz, MD, MS

Indications for Hematopoietic Stem Cell Transplants in the United States

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

Multiple

Myeloma

NHL AML HD ALL MDS Aplastic

Anemia

CML Other

Leuk

Non-

Malig

Disease

Other

Cancer

Allogeneic (Total N=7,012)

Autologous (Total N=9,778)

Num

ber

of

Tra

nspla

nts

MDS is 3rd most common indication for allogeneic HCT

Years

0 2 6 1 3 4 5

HCT is a Curative Therapy for MDS: Probability of Survival after Allogeneic

Transplants for MDS, 2000-2009

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

bability o

f Surv

ival, %

P < 0.0001

Early, sibling donor (N=667)

Early, unrelated donor (N=752)

Advanced, sibling donor (N=1,188)

Advanced, unrelated donor (N=1,400)

Indications for Hematopoietic Stem Cell Transplants in the United States

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

Multiple

Myeloma

NHL AML HD ALL MDS Aplastic

Anemia

CML Other

Leuk

Non-

Malig

Disease

Other

Cancer

Allogeneic (Total N=7,012)

Autologous (Total N=9,778)

Num

ber

of

Tra

nspla

nts

MDS is 3rd most common indication for allogeneic HCT – but <10% of MDS patients undergo HCT

Patients Receiving HCT for MDS in the U.S. 2010-2011

Related Donor

Unrelated Donor

Total

Number 515 806 1321

Median age (range)

57y (1-74y)

57y (1-75y)

57y (1-75y)

<60y 66% 62% 62%

60-64y 21% 20% 21%

65+y 13% 18% 17%

AGE DISTRIBUTION OF PATIENTS WITH MDS

0%

5%

10%

15%

20%

25% Patients with MDS

Patients transplanted for MDS

PROPORTION OF PATIENTS WITH MDS TRANSPLANTED – BY AGE

0%

10%

20%

30%

40%

50%

60%

70%

80%

Does Age Matter?

Life Expectancy

Average life expectancy for:

Newborn ~ 76 years

50 year old ~ 30 years (80)






Life Expectancy, years

AGE Normal IPSS-R Very Low

IPSS-R Low

IPSS-R Inter-mediate

IPSS-R High

IPSS-R Very High

50y 30 >13 9 5 2 1

55y 25 >13 9 5 2 1

60y 22 10 6 3 2 1

65y 18 10 6 3 2 1

70y 14 7 5 3 2 1

75y 10 7 5 3 2 1

TRANSPLANT-RELATED MORTALITY BY AGE

0

5

10

15

20

25

30

35

40

45

30-39y 40-49y 50-59y 60-69y

TRANSPLANT-RELATED MORTALITY BY AGE Standard vs Reduced Intensity Conditioning

0

5

10

15

20

25

30

35

40

45

30-39y 40-49y 50-59y 60-69y

Standard NST

EBMT Study of HCT for Patients 50+ years with MDS or sAML

1,333 patients, transplanted 1998 - 2006

Median age: 56y (range 50-74y)

884 50-60 (median 54)

449 >60 (median 63)

Donor type

811 HLA-matched sibs

409 matched unrelated donors

113 mismatched unrelated donors

Conditioning

500 Myeloablative/ 833 Reduced Intensity

Lim et al, J Clin Oncol 2010

Relative Risk of Outcomes by Age (>60 versus 50-60)

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

TRM Relapse Mortality

50-60 >60

TRM

36% 39%

Relapse

32% 41%

Survival 34% 24%

CIBMTR Study of Transplants for Patients with AML or MDS

1,080 patients, transplanted 1995 – 2005

545 AML CR1

535 MDS

4 age groups considered:

40–54 years

55–59 years

60–64 years

65+ years

All received reduced intensity conditioning

McClune et al, J Clin Oncol 2010

40–54 55–59 60–64 65-78

No. of Patients

208 146 126 55

Advanced MDS *

57% 64% 64% 57%

Int/High Risk Cytogenetics

52% 55% 54% 48%

tMDS 21% 23% 21% 22%

Patient Characteristics—MDS

* RAEB, RAEB-T, CMML or ≥ 5% blasts

40–54 55–59 60–64 65-78

No. of Patients

208 146 126 55

Median Age 50y 57y 62y 67y

KPS <80% 13% 13% 13% 19%

Unrelated donor

57% 62% 58% 73%

Patient Characteristics—MDS

Transplant Outcomes

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Non-engraftment Acute GVHD Chronic GVHD

40-54y

55-59y

60-64y

65+y

Transplant-related Mortality and Relapse after HCT in patients 40+ years receiving reduced

intensity conditioning, 1995-2005, by age

Tp08_10.ppt

0 1 3 4

100

0

20

40

60

80

90

10

30

50

70

2

Years

Transplant-related Mortality

65+ yrs

60-64 yrs

55-59 yrs

40-54 yrs

p=0.66

Years

0 1 3 4

0

100

20

40

60

80

90

10

30

50

70

2

Relapse

40-54 yrs

60-64 yrs

55-59 yrs

p=0.87

65+ yrs

MDS-free survival of patients 40+ years receiving allogeneic HCT for MDS with reduced

intensity conditioning, 1995-2005

Prob

ab

ilit

y,

%

Months

0 12 24 60 48 36

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Tp08_5.ppt

40-54 yrs

55-59 yrs

60-64 yrs

65+ yrs

p=0.84

Overall survival of patients 40+ years receiving allogeneic HCT for MDS with reduced intensity

conditioning, 1995-2005

Prob

ab

ilit

y,

%

Months

0 12 24 60 48 36

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Tp08_3.ppt

40-54 yrs

55-59 yrs

60-64 yrs

65+ yrs

p=0.37

Years

0 1 3 4

0

100

20

40

60

80

90

10

30

50

70

2 0 1 3 4

100

0

20

40

60

80

90

10

30

50

70

2

Years

MDS-free survival of patients 40+ years receiving nonmyeloablative allogeneic HSCT

for MDS, 1995-2005, by age and status

Tp08_12.ppt

Late MDS Early MDS

60-64 yrs

40-54 yrs

55-59 yrs

60-64 yrs

65+ yrs

40-54 yrs

55-59 yrs

65+ yrs

Log-rank p=0.378 Log-rank p=0.307

What Factors Do Influence Transplant Outcomes?

Lim, et al:

Advanced disease stage: 1.55, p<0.01 Poor risk cytogenetics: 1.73, p<0.01 McClune, et al:

KPS <80: 1.63, p=0.001 Poor risk cytogenetics: 1.22, p=.1* Mismatched donor: 1.85, p=0.005

* Significant for DFS

MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH

SURVIVAL

IPSS at diagnosis

Low-risk 1.00 Int-1 1.02 (0.69-1.51) 0.89 Int-2 1.44 (0.97-2.14) 0.06 High-risk 1.78 (1.08-2.95) 0.02 Also, KPS, Donor type

MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH SURVIVAL IN MORE

RECENT COHORT: Saber, et al. Abstract #355

Monday morning, B312-B313a

Sorror HCT-CI Hematopoietic Cell Transplantation-specific

Comorbidity Index (Blood 2005) Comorbidities HCT-CI Score

Lung 2-3

Liver 1-3

Heart valve 3

Prior solid tumor (not skin) 3

Kidney 2

Peptic ulcer 2

Rheumatologic 2

Infection 1

Heart 1

Cerebrovascular 1

Inflammatory Bowel Disease 1

Obesity 1

Diabetes 1

Psychiatric 1

Survival by Sorror HCT-CI

N=177 N=67

Sorror et al, Blood 2007;110:4606

HCT-CI is independent of Age and KPS (Multivariate Analysis of Survival)

Risk Factor HR p

HCT-CI

>3 vs 0-2 1.97 0.002

Age

> 50 vs < 50 yrs 1.99 0.006

KPS

<80% vs >80% 1.42 0.045

Sorror et al, Cancer 2008; 112: 1992

*other factors not shown

Iron Overload – A Problem for Transfusion-Dependent MDS Patients

Alessandrio, et al. Haematologica 2010: Study of 357 patients transplanted for MDS in 1997-2007: Significant effect of transfusion-dependence and ferritin levels in patients receiving myeloablative conditioning

Conditioning Regimens

Should all older patients receive reduced intensity conditioning?

CIBMTR Study of Conditioning Regimen Intensity in HCT for

Leukemia and MDS Luger, et al. BMT 2012

HLA-identical sibling or URD HCT for AML or MDS, reported to the CIBMTR, 1997-2004

5,179 patients

Age 18-70 years; 503 60-70

Conditioning Regimen Intensity: CIBMTR Categories*

Myeloablative: Cy/TBI (n=1635), Bu/Cy (n=1575)

TBI 500 cGy, or 800 cGy fx (n=144)

Mel 150 mg/m2 (n=57)

Bu 9 mg/kg (n=320)

Reduced-intensity (RIC): TBI 500 cGy, or 800 cGy fx (n=149)

Mel 150 mg/m2 (n=378)

Bu 9 mg/kg (n=514)

Non-myeloablative (NST): TBI 200 cGy (n=34), Flu/TBI 200 cGy (n=245)

Flu/Cy (n=128)

*Consensus criteria CIBMTR Regimen Related Toxicity Working Committee

Adjusted Probability of Overall Survival

Wsp08_18.ppt

Ad

just

ed P

rob

ab

ilit

y, %

Years

0 1 2 5 4 3

100

0

20

40

60

80

90

10

30

50

70

Myeloablative (N = 3,731)

RIC BM (N = 273)

RIC PB (N = 768)

NST (N = 407)

NST vs Myeloablative, p 0.01

NST vs RIC PB, p=0.02

CIBMTR Study of Conditioning Regimen Intensity in HCT for

Leukemia and MDS Luger, et al. BMT 2012

HLA-identical sibling or URD HCT for AML or MDS, reported to the CIBMTR, 1997-2004

5,179 patients

Age 18-70 years; 503 60-70 years

Myeloablative: 3721 patients – only 3% were 60-70 years

Age and Prevalence of Comorbidities

Sorror et al, Blood 2007;110:4606

> 3

1-2

0

BMT CTN 0901: A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia

BMT CTN 0901

Advanced MDS/ AML< 5% blasts

18 Month Overall Survival

Patients randomized

RIC regimens1

Bu/Flu2

Flu/Mel

MAC Regimens Bu/Flu Bu/Cy Cy/TBI

GVHD

Prophylaxis

per

Institutional

practice

1Bu <9mg/kg PO or IV

equivalent, Mel

<150mg/m2 2 IV or PO Bu

3T-replete bone

marrow or peripheral

blood.

Centers choose one

myeloablative and one

reduced intensity

regimen for each

patient before

randomization

Eligibility: Inclusion Criteria

Age ≤ 65 yrs

AML or MDS <5% bone marrow blasts

Available HLA-matched related or matched unrelated donor (8/8 or 7/8)

Peripheral blood or bone marrow stem cells

Statistical Considerations

Superiority trial to test a difference of 15% in 18 mo OS.

Plan accrual of 356 patients

178 per arm

Actual vs Projected Accrual

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100

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400 Ju

n-1

1

Sep-1

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Dec-1

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Mar-

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Jun-1

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Sep-1

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Dec-1

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Mar-

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Jun-1

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Sep-1

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Jun-1

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Dec-1

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Jun-1

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Sep-1

5

Projected

Actual

THE DECISION – Whether and When

SU

RV

IV

AL,

%

TIME

Factors to Consider: Effect on Life Expectancy


IPSS-R Low


IPSS-R High

IPSS-R Very High

50y 30 >13 9 5 2 1

55y 25 >13 9 5 2 1

60y 22 10 6 3 2 1

65y 18 10 6 3 2 1

70y 14 7 5 3 2 1

75y 10 7 5 3 2 1

Factors to Consider: Effect on Life Expectancy


IPSS-R Low


IPSS-R High

IPSS-R Very High

50y 30 ? -21 -25 -28 -29

55y 25 ? -16 -20 -23 -24

60y 22 -12 -16 -19 -20 -59

65y 18 -8 -12 -15 -16 -17

70y 14 -7 -9 -11 -12 -13

75y 10 -3 -5 -7 -8 -9


SU

RV

IV

AL,

%

TIME

THE DECISION S

UR

VIV

AL,

%

TIME

Factors to Consider

Effect on non-HCT outcome

Effect on HCT outcome

Older age (after 40) (up to 70)

High HCT-CI

Low KPS ?

High IPSS

Mismatched donor

Treatment-related MDS

Hypomethyl failure ?

Decision Analysis: Life Expectancy Estimate (Years) After Allogeneic HCT for MDS in Patients <60y

Immediate

Transplant

Transplant

in 2 Years

Transplant at

Progression

Low 6.51 6.86 7.21

Int-1 4.61 4.74 5.16

Int-2 4.93 3.21 2.84

High 3.20 2.75 2.75

Cutler C, et al. Blood 2004;104:579.

Decision Analysis: Life Expectancy Estimate (Years) After Allogeneic HCT for MDS in Patients 60-70

IPSS Outcome Non-HCT Early HCT

Low/Int-1 LE 77 mo 48 mo

QALE 46 mo 44 mo

Int-2/High LE 28 mo 38 mo

QALE 15 mo 35 mo

J. Koreth, et al. ASH 2011


SU

RV

IV

AL,

%

TIME

THE DECISION

MDS04_3.ppt

SU

RV

IV

AL,

%

TIME

Factors to Consider

Effect on non-HCT outcome

Effect on HCT outcome

Older age (after 40) (up to 70)

High HCT-CI

Low KPS ?

High IPSS

Mismatched donor

Treatment related

Hypomethyl failure ?

Cohort Comparison: HCT vs Azacitidine for MDS in Patients 60-70

HCT: 103 Patients receiving HCT in German MDS and Transplant Study Groups, Fred Hutchinson

AZA: 75 Patients in a French cohort who did not have a donor or were not considered for HCT because of guidelines that preclude offering HCT to patients older than 60 years

Platzbecker, et al. BBMT 2012

Cohort Comparison: HCT vs Azacitidine for MDS in Pts 60-70

AZA – At Dx

HCT – At Dx

AZA – At Rx

HCT – At Rx

Age 65 63 66 64

FAB RAEB RAEB-T AML CMML

80% 15% 0% 5%

73% 16% 0% 12%

60% 28% 9% 3%

40% 10% 42% 9%

IPSS Int-1 Int-2 High AML Unk

19% 40% 31% 0 11%

19% 35% 30% 0 16%

5% 39% 49% 0 7%

9% 22% 18% 42% 9%

Poor risk cytog. 31% 24% 43% 27%


Cohort Comparison: HCT vs Azacitidine for MDS in Pts 60-70

AZA HCT

NRM @ 2 years 34% 33%

Relapse/Prog @ 2 years

52% 30%

Survival @ 2 years 23% 39%

Survival @ 5 years NA 35%


BMT CTN 1102:

Multi-Center Phase III Trial Comparing Reduced

Intensity Allogeneic Hematopoietic Cell Transplant

to Hypomethylating Therapy or Best Supportive Care

in Patients Age 50 or Older with Intermediate-2 and

High Risk Myelodysplastic Syndrome

Co-chairs

Corey Cutler, Dana Farber Cancer Institute

Ryotaro Nakamura, City of Hope Cancer Center

Primary Objective

- Compare the three-year overall survival probabilities

between the two study arms using an intent-to-treat

analysis

Arm 1: RIC alloHCT

Arm 2: Non-Transplant Therapy / Best Supportive Care

Secondary Objectives

- Compare leukemia-free survival (LFS) at 3 years from

enrollment

- Compare QOL measures between treatment arms

Study Objectives

Basic Design

Eligibility:

De novo MDS with CURRENT or PRIOR

Intermediate-2 / High-risk IPSS Score

Aged 50-75 years

Any therapy prior to registration

KPS > 70 / ECOG ≤ 1

Donor vs. No Donor Comparison of Patients

Referred for Transplantation

Intention to Treat

No mandate of transplant or non-transplant regimen

No-Donor Determination

Follow-up for Survival, AML progression, and QOL – 3 yrs*

Screening/Study Enrollment

Donor Search (3 months)

No-Donor Arm

Donor Arm

Donor

Donor

Donor

Alternative Donor

HCT

HCT

HCT

QOL baseline

QOL 6 mos

QOL 12 mos

QOL 18 mos

QOL 24 mos

QOL 36 mos

Standard CIBMTR follow-up

Standard CIBMTR Follow-up

Standard CIBMTR Follow-up

Every 3rd month heme follow-up (contact with treating MD’s office)



Not HCT candidate

* From the time of enrollment

Study Schema

Paying for HCT for MDS in Older Patients in the US

Most people with MDS are >65 years old

Most people over 65 have health insurance through Medicare/CMS

Before 2010, CMS did not explicitly cover BMT coverage for MDS

Local decisions

Few covered

The Request - 2009

ASBMT, NMDP, ASH, ASCO and others organized a formal request for CMS to consider covering HCT for MDS

Supporting data (McClune et al, 2010; Cutler et al, 2004; others)

CMS formally accepted request

CMS held public comment periods, performs National Coverage Analysis.

Review focused on those 65 and older

Coverage with Evidence Development

CMS issued decision Aug 2010 allowing “coverage with evidence development (CED)”

Suggests insufficient evidence

“..evidence does not demonstrate that the use of HCT improves health outcomes in Medicare beneficiaries with MDS.”

“paucity of evidence regarding the use of HCT in patients with MDS who are 65 years or older”

Will cover costs of HCT if patients enrolled in a study that will provide CMS with data (“evidence”) to determine the value of the procedure in the Medicare population

To qualify for CED, a trial must address at least one of the following 3 questions

1. Prospectively, compared to Medicare beneficiaries with MDS who do not receive HCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes?

2. Prospectively, in Medicare beneficiaries with MDS who receive HCT, how do IPSS score, patient age, cytopenias and comorbidities predict outcomes?

3. Prospectively, in Medicare beneficiaries with MDS who receive HCT, what treatment facility characteristics predict meaningful clinical improvement in outcomes?

CIBMTR Cohort Study

CIBMTR leveraged existing infrastructure to launch a study using EXISTING data collection mechanisms and CIBMTR observational protocol (already IRB approved at US centers) – opened December 2010

Will address Questions 2 and 3

Compares outcomes in patients 55-64 and 65+

Evaluate prognostic factors, including IPSS and center characteristics

Data on first 120 patients

Similar early mortality (~20%) in the 2 age groups

Atallah, et al. Poster 1983, Saturday evening

0

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2005 2006 2007 2008 2009 2010 2011 2012

Num

ber

of tr

ansp

lant

s

Related ≥ 65y

Unrelated ≥ 65y

US Allogeneic Transplants for MDS in patients older than 65, 1990-2012

Preventing Relapse

Relapse is the single most common cause of death after HCT for MDS

Strategies to prevent relapse:

Posttransplant azacytidine

Donor lymphocyte infusion

Monitoring for MRD/pre-emptive therapy

SUMMARY

HCT is a curative therapy for MDS that is under-utilized

Decisions about when and whether to apply this therapy depend on patient and disease factors predicting natural history of the MDS and the risk for transplant-related mortality

Future studies are needed to identify the patients most likely to benefit and to improve posttransplant disease control

hematopoietic stem cell transplantation (hct) for mds

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