Hematopoietic Cell Transplant (HCT) in Older Individuals Keith M. Sullivan, MD Duke University Medical Center ASBMT Corporate Retreat September 2012.

Hematopoietic Cell Transplant (HCT)

in Older Individuals

Keith M. Sullivan, MD

Duke University Medical Center ASBMT Corporate Retreat

September 2012

Oeppen & Vaupel. Science 296: 1029, 2002.

Record female life expectancy from 1840 to the present

Edwards, BK, et al. Cancer 94: 2786, 2002.

Projected number of cancer cases for 2000 through 2050

Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances.

Nabel EG, Braunwald E. N Engl J Med 2012;366:54-63.

Transp

lants

, %

80

100

60

40

20

0

SUM10_9.ppt

Slide 7

Trends in transplantation,by transplant type and recipient age*

1999-2008

Allogeneic Transplants Autologous Transplants

1999-2003 2004-2008 1999-2003 2004-2008

£ 20 yrs21-40 yrs41-50 yrs51-60 yrs> 60 yrs

* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma

Trends in transplantation,by transplant type and recipient age*

1999-2008

Transp

lants

, %

80

100

60

40

20

0

Allogeneic Transplants Autologous Transplants

1995-2001 2002-20081988-19941995-2001 2002-20081988-1994

* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple MyelomaSUM10_29.ppt

Slide 8

< 60 years³ 60 years

< 50 years³ 50 years

Num

ber

of

Transp

lants

9,000

11,000

7,000

6,000

3,000

0

5,000

8,000

10,000

4,000

2,000

1,000

1999 2000 2001 2002 2003 2004 2005 2007 20082006 * *

* Data incomplete

Reduced Intensity Conditioning, Age ³ 50 years

Reduced Intensity Conditioning, Age < 50 years

Standard Myeloablative Conditioning

SUM10_23.ppt

Allogeneic transplantations by conditioning regimen intensity and patient age, registered with CIBMTR 1999-2008

Slide 21

Older Patients Eligible

Transplants for patients over age 50 now account for 35% of all NMDP-facilitated transplants

National Marrow Donor Program® © 2008

CIBMTR: Survival Analysis of Patientws with Multiple Myeloma treated with HCT

(1990-2004)

Age group N= 100-day TRM(probability)

5 yr OS(probability)

40-49 3291 4% 50%

50-59 6410 4% 47%

60-69 4370 4% 42%

>70 514 5% 37%

CIBMTR: Center for International Blood and Bone Marrow Transplant Research

Patients with MM receiving Autologous HCTDuke Experience

Age group 2009 2010 2011<65 50 62 67>65 12 (20%) 18 (22%) 29 (30%)Total 62 80 96

No difference in toxicity and TRM in comparison to younger population of patients

Conclusions: Is age per se a negative prognostic factor? Age has a negative impact on prognosis mainly because

Referral biasUnder-treatment

And should age impact on treatment decision? We need a better risk stratification in older patients

based on:Comorbidity Performance statusSocial support Not on age

Factors Determining Outcome after HCT

• Stage of Malignant Disease• Functional Performance Status• Other CoMorbid Conditions

Relapse Risk in Nonmyeloablative Allogeneic HCT

(834 pts prepared with 2 Gy TBI +/- Flu, 1997-2006)

Low Risk High Risk_________

CLL in CR MDS: RAEB, RAEBT

Low Grade NHL (CR or Not) MDS after chemotherapy

MM in CR AML after MDS

Mantle cell NHL (CR or not) AML not in CR

MPD High Grade NHL not in CR

High grade NHL in CR Hodgkins

ALL in CR-1 CML in CR2 or AP/BC

CMML

ALL in CR-2+

3 year Survival: 60% 3 year Survival: 26%

2 year Relapse: 0-0.24 per pt yr 2 year Relapse: 0.52 per pt yrKahl, et al

Blood 110: 2744, 2007

Karnofsky Functional Performance Normal activity and hard work; no special care100 Normal

101 Normal activity; minor symptoms/signs of disease

102 Normal activity with effort

Unable to work; lives at home with varying assistance103 Cares for self, unable to carry on normal activity

104 Needs occasional assistance

105 Needs considerable assistance and frequent medical care

Unable to care for self; institutional care106 Disabled, requires special care

107 Hospital admission

108 Hospital admission, supportive care

109 Moribund

0 Dead

CoMorbid Conditions at HCT

Figure 3. Kaplan-Meier probabilities of survival among patients with

hematologic malignancies treated with allo-NMA-HCT as stratified into

four risk groups based on a consolidated HCT-CI and KPS scale. Group

I (solid black line) includes patients with HCT-CI scores of 0 to 2 and a

KPS of 80%; group II (dotted black line) includes patients with

HCT-CI scores of 0 to 2 and a KPS of 80%; group III (solid blue line)

includes patients with HCT-CI scores of 3 and a KPS of 80%; group

IV (dotted blue line) includes patients with HCT-CI scores of 3 and a

KPS of 80%. Survival rates at 2 years were 68%, 58%, 41%, 32%

for risk groups I, II, III, and IV, respectively. (From Sorror et al., 2008.45

Reprinted with permission. ©2008, Wiley InterScience.)

Nonmyeloablative (NMA) Allogeneic HCT for

Older Patients

(JAMA 2011)

NMA Allografts for Older Patients(Study Design)

Patients and Centers• 372 patients age 60-75 years• Enrolled in 18 centers between 1998-2008

Regimen and Transplant• 2 Gy TBI +/- Fludarabine (30 mg/m2 x 3)• Allogeneic donors (related and unrelated, HLA-matched and

mismatched), unmodified PBMCT• Post-transplant MMF and CNI

Protocol Exclusion• DLCO < 50% to < 70%• Cardiac EF < 35% to < 40%• KPS < 50% to < 70%• Cirrhosis with portal hypertension Sorror et al

JAMA 306:1874,2011

Patient Characteristics by Age60-64 years 65-69 years 70-75 years

Number pts 218 121 33

Relapse Risk (%)

Low 19 16 15

Standard 49 48 36

High 31 34 48

Donor (%)

HLA-match sibling 48 46 63

HLA-match URD 40 46 30

HLA-mismatch 10 7 6

HCT-CI (%)

0 22 20 21

1-2 30 35 24

3-4 33 26 42

> 5 13 17 12

5-year Outcomes by Age(Percent)

60-64 years 65-69 years 70-75 years

Outcomes (%) (N = 218) (N = 121)________ N = 33)

Non relapse Mortality 27 26 31

Relapse 38 45 42

Overall Survival 38 33 25

PFS 34 29 27

Hospitalized 54 36 55

Acute GVHD (II-IV) 54 50 52

Chronic GVHD 42 41 49

Graft rejections 4 4 3

Survival by Relapse Risk and HCT-CoMorbidity Index (CI)

(Patients 60-75 years)

HCT – CI Scores

Relapse Risk 0 1-2 > 3

Low 69% 56% 56%

Standard 45% 44% 23%

High 41% 15% 23%

Conclusions

1. Older age (60-75 yrs), per se, is not a risk factor for adverse outcome following NMA allogeneic HCT

2. Among older allograft recipients, overall survival is decreased with:

High-Risk Malignancy (HR2.22) HCT-CI 3 (HR 1.97)

Blommestein et al, Ann Hematol 2012; E-

pub

Life But At What Cost?QALY* Cost$50,000 US Medicare Renal Dialysis Coverage (1982)

($121,000, 2008 inflation adjusted)$30,000-50,000 UK NICE2

$109,000 Lower bound ($109K-297K) plausible range QALY saved on base case analysis of expenditures

$113,000 WHO: 3x per capita GDP4

??? Public discourse needed to decide on worthwhile services5

*QALY, Quality-Adjusted Life-Year1. Health Affairs 2000; 19: 92-1092. www.nice.org.uk/media/B52/A7/Methods Guide Updated June2008.pdf3. Medical Care 2008; 46: 349-3564. Health Econ 2000; 9: 235-2515. Medical Care 2008; 46: 343-345

What Services Are Worthwhile?

Cost Net Benefit Value Example

High High Depends on Cost & Benefits ICD, HAART for HIV

_______________________________________________________________

Low High High HIV screening_______________________________________________________________

High Low Low MRI for low back pain

Owens DK et al, Ann Intern Med 2011; 154: 178-80

Cost of Chronic Transfusionfor Stroke Prevention in SCD

• Data were collected on 21 patients for 296 patient months

• Charges ranged from $9828 to $50,852 per patient per year

• Charges for patients who required chelation therapy ranged from $31,143 to $50,852 per patient per year (median, $38 607)

• Charges are approx. $400 000 per patient decade for patients who require deferoxamine chelation

Wayne, Schoenike, and Pegelow; Blood 96:2369, 2000

Cost of BMT – Stroke Indication

• Matched related donor

• $260,000 hosp. charges

• supportive care after BMT is 9-fold lower than for SCA patients

• avg. lifespan of male survivors is 72 years

• age at BMT: 10 years

• Mean medical costs in SCA patients receiving 12 transfusions/year and regular DFO (2008) - $59,233

• DFO $10,899 and DFO admin $8,722

• average lifespan for HbSS males is 42 years

BMT Supportive care

Bilenker JH, et al J Ped Hem/Onc 1998; 20:528 Delea TE et al Am J Hematol 2008; 83:263

Cost of BMT

ICE =

Incremental cost-effectiveness (cost of treatment per year of life gained)

ICE =Cost (BMT-supportive care)

# years survival (BMT-supportive care)

Cost of BMT – stroke patient

ICE =

ICE =

Incremental cost-effectiveness

[59,000x10]+[260,000]+[6550x62]-[59,000x32]

72-42

- $21,063 per YOL gained

ICE of moderate HTN in middle aged men: $13,500 per YOL gained

• National Policy to Eliminate:– Procedures without evidence of benefit

• Local Innovations to Discover:– Care that is Faster, Cheaper, Better