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, Record female life expectancy from 1840 to the present

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

Transplants, % SUM10_9.ppt Slide 7 Trends in transplantation, by transplant type and recipient age* Allogeneic TransplantsAutologous Transplants  20 yrs yrs yrs yrs 60 yrs * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma

Trends in transplantation, by transplant type and recipient age* Transplants, % Allogeneic TransplantsAutologous Transplants * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma SUM10_29.ppt Slide 8  60 years  60 years  50 years  50 years

Number of Transplants 9,000 11,000 7,000 6,000 3, ,000 8,000 10,000 4,000 2,000 1, * * Data incomplete Reduced Intensity Conditioning, Age 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 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 ( ) Age group N= 100-day TRM (probability) 5 yr OS (probability) %50% %47% %42% >705145%37% CIBMTR: Center for International Blood and Bone Marrow Transplant Research

Patients with MM receiving Autologous HCT Duke Experience Age group < >6512 (20%)18 (22%)29 (30%) Total 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, ) Low Risk High Risk_________ CLL in CR MDS: RAEB, RAEBT Low Grade NHL (CR or Not)MDS after chemotherapy MM in CRAML after MDS Mantle cell NHL (CR or not)AML not in CR MPDHigh Grade NHL not in CR High grade NHL in CRHodgkins ALL in CR-1CML in CR2 or AP/BC CMML ALL in CR-2+ 3 year Survival: 60%3 year Survival: 26% 2 year Relapse: per pt yr2 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 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

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., 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 years Enrolled in 18 centers between 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 years65-69 years70-75 years Number pts Relapse Risk (%) Low Standard High Donor (%) HLA-match sibling HLA-match URD HLA-mismatch HCT-CI (%) >

5-year Outcomes by Age (Percent) years years years Outcomes (%) (N = 218) (N = 121)________ N = 33) Non relapse Mortality Relapse Overall Survival PFS Hospitalized Acute GVHD (II-IV) Chronic GVHD Graft rejections 4 4 3

Survival by Relapse Risk and HCT- CoMorbidity Index (CI) (Patients years) HCT – CI Scores Relapse Risk 0 1-2> 3 Low 69%56%56% Standard45%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) $30,000-50,000UK NICE 2 $109,000Lower bound ($109K-297K) plausible range QALY saved on base case analysis of expenditures $113,000WHO: 3x per capita GDP 4 ???Public discourse needed to decide on worthwhile services 5 *QALY, Quality-Adjusted Life-Year 1.Health Affairs 2000; 19: Guide Updated June2008.pdf 3.Medical Care 2008; 46: Health Econ 2000; 9: Medical Care 2008; 46:

What Services Are Worthwhile? Cost Net BenefitValue Example High HighDepends on Cost & BenefitsICD, HAART for HIV _______________________________________________________________ Low HighHighHIV screening _______________________________________________________________ High Low LowMRI for low back pain Owens DK et al, Ann Intern Med 2011; 154:

Cost of Chronic Transfusion for Stroke Prevention in SCD Data were collected on 21 patients for 296 patient months Data were collected on 21 patients for 296 patient months Charges ranged from $9828 to $50,852 per patient per year 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 for patients who required chelation therapy ranged from $31,143 to $50,852 per patient per year (median, $38 607) Charges are approx. $ per patient decade for patients who require deferoxamine chelation Charges are approx. $ 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 Matched related donor $260,000 hosp. charges $260,000 hosp. charges supportive care after BMT is 9-fold lower than for SCA patients supportive care after BMT is 9-fold lower than for SCA patients avg. lifespan of male survivors is 72 years avg. lifespan of male survivors is 72 years age at BMT: 10 years age at BMT: 10 years Mean medical costs in SCA patients receiving 12 transfusions/year and regular DFO (2008) - $59,233 Mean medical costs in SCA patients receiving 12 transfusions/year and regular DFO (2008) - $59,233 DFO $10,899 and DFO admin $8,722 DFO $10,899 and DFO admin $8,722 average lifespan for HbSS males is 42 years 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 Incremental cost-effectiveness (cost of treatment per year of life gained) (cost of treatment per year of life gained) ICE =Cost (BMT-supportive care) # years survival (BMT-supportive care)

Cost of BMT – stroke patient ICE = Incremental cost-effectiveness Incremental cost-effectiveness[59,000x10]+[260,000]+[6550x62]-[59,000x32] $21,063 per YOL gained - $21,063 per YOL gained ICE of moderate HTN in middle aged men: $13,500 per YOL gained $13,500 per YOL gained

National Policy to Eliminate: – Procedures without evidence of benefit Local Innovations to Discover : – Care that is Faster, Cheaper, Better