Who is fit for transplant? Comorbidities prior to Hematopoietic Cell Transplantation Marcelo C. Pasquini, MD, MS CIBMTR Medical College of Wisconsin Outline Clinical relevance of studying risk factors of toxicity. Changes in transplant-related mortality over time. Determinants t of toxicity it Individual vs. collective impact on outcome. Comorbidities Collection of Comorbidity Data Patient-related: Age Weight Performance score Comorbidities Genetics Determinants of transplant related toxicity Transplant-related: Cond. intensity GVHD proph Donor type HLA matching Graft source Year of transplant Disease-related: Prior treatment Disease status Transplant activity worldwide 198-29 Transplant activity in the U.S. 198-29 nts Transplan 35, 3, 25, 2, 15, 1, Autologous Allogeneic Transpla ants 18, 15, 12, 9, 6, Autologous Related Donor Unrelated Donor 5, 3, '8 '81 '82 '83 '84 '85 '86 '87 '88 '89 '9 '91 '92 '93 '94 '95 '96 '97 '98 '99 ' '1 '2 '3 '4 '5 '6 '7 '8 '9 '8 '81 '82 '83 '84 '85 '86 '87 '88 '89 '9 '91 '92 '93 '94 '95 '96 '97 '98 '99 ' '1 '2 '3 '4' '5 '6 '7 '8 '9 Slide 3 SUM1_3.ppt Slide 4 SUM1_4.ppt 1
1 8 Trends in transplantation by type and recipient age* 1988-28 <5 years >=5 years <6 years >=6 years 5, 4,5 4, Allogeneic transplants in patients 2years, by donor type and graft source, registered with CIBMTR 1991-28 Related-BM or PB Unrelated BM or PB Unrelated CB s, % Transplants 6 4 2 nsplants Number of Tran 3,5 3, 2,5 2, 1,5 1, 5 1988-1994 1995-21 22-28 1988-1994 1995-21 22-28 Allogeneic Transplants Autologous Transplants * 1991-92 1993-94 1995-96 1997-98 1999-21-2 23-4 25-6 27-8 * Data incomplete * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Slide 8 SUM1_29.ppt Slide 12 SUM1_14.ppt nsplants Number of Tran 11, 1, 9, 8, 7, 6, 5, 4, 3, 2, 1, Allogeneic transplantations by conditioning regimen intensity and patient age, registered with CIBMTR 1999-28 Reduced Intensity Conditioning, Age >=5 yrs Reduced Intensity Conditioning, Age < 5 yrs Standard Myeloablative Conditioning 1999 2 21 22 23 24 25 26 27* 28* * Data incomplete Slide 21 SUM1_23.ppt nts Transplan 3, 2,5 2, 1,5 1, 5 Number of allogeneic transplants, by disease, registered with CIBMTR 1998-28 AML ALL CML AA LYM/MM/CLL 1998 1999 2 21 22 23 24 25 26 27* 28* * Data incomplete Slide 23 SUM1_25.ppt Transplant Related Mortality Trends in Transplant Outcome: Transplant Related Mortality Any death that occurs in the absence of disease. Disease relapse is a competing risk. Causes Regimen toxicity Immunesuppression Graft-versus-host disease (GVHD) 2
Transplant Related Mortality Trends in 2 Decades: Eligibility Patients who Had transplants performed between 1985 and 24 Had AML in 1 st or 2 nd CR Were less than 5 years Received a graft from an HLA-matched sibling or an unrelated adult donor Received a bone marrow or peripheral blood graft Received myeloablative conditioning: TBICy (+/- other) or BU/Cy (+/- other). Baseline Characteristics Related Donors 1985-1989 199-1994 1995-1999 2-24 CR1 N= 3,74 1124 1283 91 46 Median age 27 3 31 31 Unknown Cytogenetics* 56% 4% 25% 12% Marrow graft 1% 99% 73% 43% CR2 N= 75 22 232 22 124 Median age 28 3 34 29 Unknown Cytogenetics 69% 51% 22% 14% Marrow graft 1% 99% 65% 29% * Cytogenetics at diagnosis Transplant Related Mortality: Sibling Donor HCT for AML in CR1 Treatment-related Mortality: Sibling Donor HCT for AML in CR2 Cumulative Inciden nce of TRM, % 1 8 6 4 2 Months P*=<.1 at 3 years 1995-1999, N=91 1985-1989, N=1124 199-1994, N=1283 2-24, N=46 12 24 36 *pointwise estimate, % Incidence, 1 8 6 4 2 Months 1985-1989 199-1994 1995-1999 2-24 12 24 36 Maa9_58.ppt Transplant Related Mortality*: HLAmatch sibling donor HCT for AML 1.6 1985-1989 199-1994 1995-1999 2-24 Adjusted Probability of Overall Survival*: Sibling HCT for AML in CR2 1 8 2-24, 53% @3y 1995-1999, 48% @ 3y 1 8 RELATIVE E RISK 1.. P<.1 9.9.8.7 P<.1.8.7.6 P<.1.7.5.4 P=.14 CR1 CR2 *Adjusted for significant changes in patient and disease characteristics 1.1.8.6 P<.1.8.6.4.5.3.2 P<.1 ty, % Probabili 6 4 2 p=.2, Cox model 1985-1989, 39% @ 3y 199-1994, 47% @ 3y 12 24 36 Months *Adjusted for patient and disease characteristics (age, cytogenetics and interval from relapse to HCT). 6 4 2 Maa9_52.ppt 3
Comparison of TRM between 2-24 and 1985-1989: Subgroup analysis CR1 All patients, adjusted Age<2 Age>=2 Bone Marrow only CSA+MTX only All patients, adjusted CR2 Determinants of Toxicity: individual vs. collective impact on outcome. Age<2 Age>=2 Bone Marrow only CSA+MTX only..5 1. Relative Risk 1.5 2. Determinants of transplant related toxicity Transplant-related: Cond. intensity GVHD proph Donor type HLA matching Graft source Year of transplant Disease-related: Prior treatment Disease status Obesity Trends* Among U.S. Adults BRFSS, 199, 1998, 27 (*BMI 3, or about 3 lbs. overweight for 5 4 person) 199 27 1998 Patient-related: Age Weight Performance score Comorbidities Genetics No Data <1% 1% 14% 15% 19% 2% 24% 25% 29% 3% Obesity prior to Transplant Increase number of patients morbidly obese. Implications: Chemotherapy dosing Cell dosing TBI administration Does weight matter? Are the effects of obesity the same regardless of transplant type? Outcomes in Lymphoma by BMI How does BMI influence outcomes in autologous HCT for lymphoma? Navarro et al., BBMT 26 12:541-51 4
1 Outcomes in Lymphoma by BMI How does BMI influence outcomes in autologous HCT for lymphoma? Obesity in Patients with Multiple Myeloma undergoing Autologous HCT 1 9 OS ability, % Adjusted Prob Entire Cohort n=187 8 7 6 5 4 3 2 1 Overweight (n=465) Severely obese (n=122) Obese (n=196) Normal (n=287) 2 4 6 8 1 Years ability, % Adjusted Prob Navarro et al., BBMT 26 12:541-51 DT Vogl, et al. CIBMTR MM3-1 unpublished data 21 Results-Multivariate Analysis Related Allogeneic HCT in AML by Weight BMI Group Normal Underweight Overweight Obese n=1161 n=31 n=543 n=268 Death 1. 1.86 (1.24-2.78) 2 1.7 1.23 (1.4-1.47) 1 47) Treatment failure 1. 2.8 (1.37-3.15) Relapse 1. 2.2 (1.18-3.47) TRM 1. 2.22 (1.17-4.22) 1.1 1.19 (1.-1.42).92 1.7 1.14 1.32 (1.2-1.7) Results-Multivariate Analysis Unrelated Allogeneic HCT in AML by Weight BMI Group Normal Underweight Overweight Obese n=846 n=31 n=523 n=368 Death 1..86.96 1.4 Treatment failure 1..91.93.99 Relapse 1. 1.4.82 (.68-.99).76 (.6-.96) TRM 1..85 1.3 1.16 Navarro et al., BBMT 21 Navarro et al., BBMT 21 Obesity and Transplant Outcomes The individual impact of obesity on survival and TRM is not as distinct. Link of obesity with other comorbidities Weight is linked with disease Underweight and malignancies/prior treatment Is BMI the most appropriate measurement to define obesity? Better Definition of Obesity: Waist to Hip Ratio + BMI WHR is associated with mortality in patients with diabetes and hypertension 5
Collective Impact of Different Factors Performance Score Karnofsky, Lansky, Zubrod/ECOG/WHO Apply to malignancies Design to assess both patient and disease-specific specific risk factors Co-morbidities: Collective impact of other diseases or condition present that may influence outcome. Karnofsky Performance Score Index Specific Criteria General 1 9 Normal, no complaints, no evidence of disease. Able to carry on normal activity, minor signs or symptoms of disease. Able to carry on normal activity; no special care needed. 8 Normal activity with effort, some signs or symptoms of disease. 7 Care for self, unable to carry on normal activity or to do work. Unable to work, able to live at home and care for 6 Requires occasional assistance from others but able to care for most needs. 5 Requires considerable assistance from others and frequent medical care 4 Disabled, requires special care and assistance. 3 Severely disabled, hospitalization indicated, but death not imminent. 2 Very sick, hospitalization necessary, active supportive treatment necessary. 1 Moribund Dead most personal needs, varying amount of assistance needed. Unable to care for self, requires institutional or hospital care or equivalent, disease may be rapidly progressing. Charlson Comorbidity Index HCT CI (n=78) Sorror M. Blood, 25 HCT-CI The validation set Percent survival Percent NRM Score 3 (28%) Score 2 (3%) Score 1-2 (34%) Score 1 (1%) Score (38%) Score (87%) Months after HCT CCI Why Collect comorbidities in the CIBMTR Forms? Important clinical question If validated may assist patient selection for transplant, or selection of transplant procedure. Use in center specific analysis to adjust on how sick patients are being transplant at a given center. 6
HCT-CI Scoring comorbidities Cardiovascular Arrhythmia (1): Atrial fibrillation (AF) Atrial flutter Ventricular arrhythmias (Tachycardia or fibrillation) Sick sinus syndrome Cardiac problems (1): Coronary artery disease Myocardial infarction Congestive heart failure Ejection fraction (EF) 5% Valvular disease (3): Any proven valve stenosis or malfunction with the exception of asymptomatic mitral valve prolapse Prosthetic aortic or mitral valves Gastrointestinal Inflammatory bowel disease (1) Ulcerative colitis Crohn s disease Peptic ulcer (2) Previously required treatment Previously bled from ulcer Diabetes (1) Type I Type II Endocrine requiring treatment with oral hypoglycemic drugs or insulin Neurology Cerebro-vascular disease (1) History of transient ischemic attacks History of a cerebro-vascular accident Obesity (1) Patients with body mass index of >35 (weight in kg/ height x height in m) Infection (1) Documented or suspected and requiring treatment before, during, and after start of conditioning regimen 7
Psychiatric disturbances (1) Depression Anxiety Previously diagnosed and receiving specific treatment Diagnosed and started treatment at the time of HCT Renal (2) Serum creatinine >2 mg/dl On dialysis Had prior renal transplantation Preceding solid malignancy (3) Requiring treatment Excluding non-melanoma skin cancer Rheumatologic (2) Systemic lupus erythmatosis (SLE) Rheumatoid arthritis (RA) Polymyositis Mixed connective tissue disease Polymyalgia rheumatica Hepatic Mild (1) Chronic hepatitis Bilirubin 1.5 x >upper limit of normal (ULN) AST or ALT > 2.5 x ULN Moderate-severe (3) Cirrhosis or fibrosis proved by liver biopsy Bilirubin >1.5 x ULN AST or ALT >2.5 x ULN Pulmonary Moderate (2) Diffusion capacity of CO (DLco) 8%- 66% FEV1 8%-66% Shortness of breath on exertion Severe (3) DLco 65% FEV1 65% Shortness of breath at rest Requiring supplemental oxygen Validation of HCT-CI with CIBMTR data HCT CI incorporated in data collection forms in 27 Objectives: To validate the instrument Assess the impact of age Reliability: who determines the score? To date Accrual Allogeneic: RIC (n=2,64) and Myeloablative (n=6,81) Autologous (n=13,424) Nonmalignant diseases (n=868) Analysis will start this year (minimun follow up of 1 year in all patients) 8
Distribution of Comorbidity Index according to conditioning regimen Distribution of Comorbidity Index for Autologous HCT and Allogeneic HCT for Nonmalignant Diseases 6 5 4 HCT CI HCT CI 1 2 HCT CI>3 8 7 6 5 HCT CI HCT CI 1 2 HCT CI>3 % 3 % 4 2 1 3 2 1 Myeloablative N=681 RIC N=264 Autologous N=13,424 Nonmalignant diseases N=868 Most common reported commorbidity Comorbidity NST/RIC Myeloablative Autologous Other Specify 33% 25% 27% Moderate 14% 14% 13% Pulmonary Psychiatric 13% 12% 11% Cardiac 12% 6% 8% Moderate/seve 1% 7% 6% re Hepatic Diabetes 1% 7% 9% Obesity 6% 6% 7% Other Comorbidities, Examples Abdominal Diffuse Large B-cell lymphoma, AML, breast cancer, CLL, CML, colon cancer Aortic stenosis Insomnia Heavy smoker Tubal ligation High lipids or high cholesterol Indigestion Gall bladder Helpful hints on what to report Sufficient detail on the comorbidity Comorbidity past medical history Use judgement regarding relevant conditions. Is the comorbidity associate with the primary disease being treated? Is the patient receiving any medical intervention for the condition If uncertain, discuss with staff. 9
HCT-CI Score Assignment Physician assignment along with KPS Post hoc assignment with chart review Are there any differences? Compare assigned scores blindly: Comorbities reported by centers Randomly Selected Cases Blinded review Center assigned HCT-CI Refinement of HCT-CI Sorror et al: Ferritin and Albumin predicted survival Pavlu et al (Hammersmith Hospital) C-Reactive protein Compute HCT-CI Comparison Pavlu et al Blood, 21 Patient-related: Age Weight Performance score Comorbidities Genetics Determinants of transplant related toxicity Transplant-related: Cond. intensity GVHD proph Donor type HLA matching Graft source Year of transplant Disease-related: Prior treatment Disease status Conclusion Presently transplants are safer than in the past. Better patient and donor selection, supportive care and experience of transplanters contributed to this improvement. Conclusion Further improve will require: 1. Refinement in patient assessments: Better commorbidity assessments Incorporation of laboratory markers 2. Match best transplant approach for an individual patient according to these assessments. Acknowledgements RRT Working Committee: Vincent Ho, MD Philip McCarthy, MD Kenneth Cooke, MD Brent Logan, PhD Xiaochun Zhu, MS Comorbidities Mohamed Sorror, MD Trends in Transplant outcomes John Horan, MD Obesity Studies Willis Navarro, MD Collin Barker, MD Dan Vogl, MD Erica Campagnaro, MD Hillard Lazarus, MD CIBMTR J. Douglas Rizzo Mary M. Horowitz 1