Hematopoietic Cell Transplant (HCT) in Older Individuals

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 1999 Reduced Intensity Conditioning, Age  50 years Reduced Intensity Conditioning, Age < 50 years Standard Myeloablative Conditioning 2000 2001 2002 2003 2004 2005 2006 2007 * 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

CIBMTR: Survival Analysis of Patientws with Multiple Myeloma treated with HCT (1990-2004) Age group N=

40-49 50-59 60-69 >70 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

<65 >65 Total

2009

50 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

Conclusions:

 

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

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) 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% 2 year Relapse: 0-0.24 per pt yr 3 year Survival: 26% 2 year Relapse: 0.52 per pt yr Kahl, et al Blood 110: 2744, 2007

Karnofsky Functional Performance

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 60 50 Cares for self, unable to carry on normal activity Needs occasional assistance Needs considerable assistance and frequent medical care

Unable to care for self; institutional care

40 Disabled, requires special care 30 20 Hospital admission Hospital admission, supportive care 10 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 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 46 46 7 20 35 26 17 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%

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

QALY* Cost

Life But At What Cost?

$50,000 $109,000 US Medicare Renal Dialysis Coverage (1982) ($121,000, 2008 inflation adjusted) $30,000-50,000 UK NICE 2 $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

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 Transfusion for 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

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

Cost of BMT

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

ICE =

# years survival (BMT-supportive care)

Cost of BMT – stroke patient

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