Keith M. Sullivan, MD
Duke University Medical Center
ASBMT Corporate Retreat
September 2012

Record female life expectancy from 1840 to the present
Oeppen & Vaupel. Science 296: 1029, 2002.

Projected number of cancer cases for 2000 through 2050
Edwards, BK, et al. Cancer 94: 2786, 2002.

Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances.
Nabel EG, Braunwald E. N Engl J Med 2012;366:54-63.

100
Trends in transplantation, by transplant type and recipient age *
1999-2008
80
 20 yrs
21-40 yrs
41-50 yrs
51-60 yrs
> 60 yrs
60
40
20
0
1999-2003 2004-2008 1999-2003 2004-2008
Allogeneic Transplants Autologous Transplants
* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Slide 7
SUM10_9.ppt

60
40
20
100
Trends in transplantation, by transplant type and recipient age *
1999-2008
< 50 years
 50 years
< 60 years
 60 years
80
0
1988-1994 1995-2001 2002-2008 1988-1994 1995-2001 2002-2008
Allogeneic Transplants Autologous Transplants
* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Slide 8
SUM10_29.ppt

Allogeneic transplantations by conditioning regimen intensity and patient age, registered with CIBMTR 1999-2008
11,000
10,000
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
Reduced Intensity Conditioning, Age  50 years
Reduced Intensity Conditioning, Age < 50 years
Standard Myeloablative Conditioning
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
* Data incomplete
Slide 21
SUM10_23.ppt

Older Patients Eligible
 Transplants for patients over age 50 now account for 35% of all NMDP-facilitated transplants
National Marrow Donor Program
® © 2008

40-49
50-59
60-69
>70
CIBMTR: Survival Analysis of Patientws with
Multiple Myeloma treated with HCT
(1990-2004)
Age group N=
3291
6410
4370
514
100-day TRM
(probability)
4%
4%
4%
5%
5 yr OS
(probability)
50%
47%
42%
37%
CIBMTR: Center for International Blood and Bone Marrow Transplant Research

Patients with MM receiving Autologous HCT
Duke Experience
Age group 2009
<65 50
>65
Total
12 (20%)
62
2010
62
18 (22%)
80
2011
67
29 (30%)
96
No difference in toxicity and TRM in comparison to younger population of patients

 Is age per se a negative prognostic factor?
 Age has a negative impact on prognosis mainly because
 Referral bias
 Under-treatment
 And should age impact on treatment decision?
 We need a better risk stratification in older patients based on:
 Comorbidity
 Performance status
 Social support
 Not on age

• 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)
MM in CR
MDS after chemotherapy
AML after MDS
Mantle cell NHL (CR or not)
MPD
High grade NHL in CR
ALL in CR-1
AML not in CR
High Grade NHL not in CR
Hodgkins
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 yr
Kahl, et al
Blood 110: 2744, 2007

Normal activity and hard work; no special care
100 Normal
90 Normal activity; minor symptoms/signs of disease
80 Normal activity with effort
Unable to work; lives at home with varying assistance
70 Cares for self, unable to carry on normal activity
60 Needs occasional assistance
50 Needs considerable assistance and frequent medical care
Unable to care for self; institutional care
40 Disabled, requires special care
30 Hospital admission
20 Hospital admission, supportive care
10 Moribund
0 Dead

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.)

( 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 Age
60-64 years 65-69 years 70-75 years
Number pts
Relapse Risk (%)
Low
Standard
High
218
19
49
31
Donor (%)
HLA-match sibling 48
HLA-match URD 40
HLA-mismatch 10
HCT-CI (%)
0
1-2
3-4
> 5
22
30
33
13
121
16
48
34
20
35
26
17
46
46
7
33
15
36
48
63
30
6
21
24
42
12

5-year Outcomes by Age
(Percent)
Outcomes (%)
60-64 years 65-69 years 70-75 years
(N = 218) (N = 121)________ N = 33)
Non relapse Mortality 27
Relapse 38
Overall Survival
PFS
Hospitalized
Acute GVHD (II-IV)
38
34
54
54
Chronic GVHD 42
Graft rejections 4
26
45
33
29
36
50
41
4
31
42
25
27
55
52
49
3

Survival by Relapse Risk and HCT-
CoMorbidity Index (CI)
(Patients 60-75 years)
Relapse Risk 0
HCT – CI Scores
1-2 > 3
Low 69% 56% 56%
Standard
High
45% 44% 23%
41% 15% 23%

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

QALY* Cost
$50,000 US Medicare Renal Dialysis Coverage (1982)
($121,000, 2008 inflation adjusted)
$30,000-50,000 UK NICE 2
$109,000
$113,000
???
Lower bound ($109K-297K) plausible range QALY saved on base case analysis of expenditures
WHO: 3x per capita GDP 4
Public discourse needed to decide on worthwhile services 5
*QALY, Quality-Adjusted Life-Year
1. Health Affairs 2000; 19: 92-109
2. www.nice.org.uk/media/B52/A7/Methods Guide Updated June2008.pdf
3. Medical Care 2008; 46: 349-356
4. Health Econ 2000; 9: 235-251
5. Medical Care 2008; 46: 343-345

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

•
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

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

Incremental cost-effectiveness
(cost of treatment per year of life gained)
ICE =Cost (BMT-supportive care)
ICE =
# years survival (BMT-supportive care)

Incremental cost-effectiveness
[59,000x10]+[260,000]+[6550x62]-[59,000x32]
ICE =
72-42
ICE =
- $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