Late effects after HSCT Yves Chalandon Hematology Division, University Hospital of Geneva (HUG) Switzerland Hôpitaux Universitaires de Genève
Company name Disclosures of: Yves Chalandon Research support Employee Consultant Stockholder Speakers bureau Novartis X X Bristol Myers Squibb X X Pfizer X Advisory board
Transplants Transplant activity worldwide 1980-2010 14,000 12,000 Autologous Related Donor Unrelated Donor 10,000 8,000 6,000 4,000 2,000 0 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03'04' '05 '06 '07 '08 '09 '10 CIBMTR
Transplants, % Trends in Transplants by Type and Recipient Age* 2000-2009 100 80 <=20 yrs 21-40 yrs 41-50 yrs 51-60 yrs >60 yrs 60 40 20 0 2000-2004 2005-2009 2000-2004 2005-2009 Allogeneic Transplants Autologous Transplants * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma
Aim of HSCT Cure from the primary disease Recovery of the health status go back to the normal Normal physical and psychological functioning Normal family, professional and social integration Good subjective well being
Outcomes of HSCT in selected diseases EA Copelan N Engl J Med, 2006
One-Year Survival, % One-year survival after myeloablative conditioning for acute leukemias in any remission phase, CML or MDS, age <50 years, by year of transplant and graft source, 1988-2009 100 80 HLA-matched sibling Unrelated Donor 60 40 20 0 1988-90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09
Reduced mortality after allo-hsct over the past decade Gooley et al. N Engl J Med, 2010
Causes of Death after Transplants performed in 2008-2009 HLA-identical Sibling Primary Disease (47%) New Malignancy (1%) GVHD (14%) Primary Disease (33%) Unrelated Donor New Malignancy (1%) GVHD (15%) Infection (12%) Organ Failure (4%) Other (21%) Primary Disease (73%) Autologous New Malignancy (1%) Other (29%) Organ Failure (6%) Infection (16%) Infection (8%) Organ Failure (2%) Other (16%)
Late morbidity and mortality in long term survivors Bhatia et al. Blood 2007
The mortality post-hsct = tip of iceberg The morbidity and late effects
Decrease health status after HSCT Chronic health condition after HSCT Grade 1= mild conditions Grade 5= death from chronic conditions C-L Sun et al. Blood 2010;116:3129
Decrease health status after HSCT 60-70% pts report at least 1 chronic condition 15-20% pts report severe/life-threatening cond At 10 yrs post-allohsct ~60% chronic health condition 10 yrs severe/death related chronic cond 35% HSCT pts twice as likely as sibling chronic cond HSCT 3.5 x severe/life-threatening cond If cgvhd 4.7 x severe/life-threatening cond C-L Sun et al. Blood 2010;116:3129
Decrease health status after HSCT Number of new late effect after auto or allo HSCT N Khera et al. JCO 2012;30:71
Decrease health status after HSCT also as compared to conventionally treated cancer survivors Prevalence of chronic health conditions among HSCT survivors (BMTSS) compared with conventionally treated cancer survivors (CCSS) and sibling controls (CCSS) in childhood Prevalence of adverse health status among HSCT survivors (BMTSS) compared with conventionally treated cancer survivors (CCSS) and sibling controls (CCSS) in childhood SH Armenian et al. Blood 2011;118:1413
Life after allohsct (long-term survivors) G. Socié et al. Blood 2003;101:3129 A.Tichelli et al. Expert Rev Hematol 2009;2:583
Causes of long-term effects after allohsct 1 Patient (age, gender, CMV, comorbidities ) 3 Conditioning 5 Graft Source Disease features 2 6 Supportive Care -6-5 -4-3 -2-1 0 +14 +21 +100 >180 4 GVHD prophylaxis and therapy
Late effects after HSCT Malignant late effects Non-malignant late effects Late relapses Endocrine dysfunction Secondary leukemia after Thyroid autohsct Gonadal, fertility Donor type leukemia of Growth and development secondary leukemia postallohsct Skeletal disorders Ocular, skin and mucosa troubles Secondary solid tumors Respiratory tract problems Liver complications Chronic kidney disorders Any organ or tissue can be Neurological complications the target of a late effects Cardio-vascular complications G. Socié et al. Blood 2003;101:3129 A.Tichelli et al. Expert Rev Hematol 2009;2:583
Time appearance of late effects Late effect= complications occurring 3 mths or later post-hsct compromising longterm survivorship A.Tichelli et al. Expert Rev Hematol 2009;2:583
Changes of pattern regarding the late effect over time
Relevant changes over time in HSCT procedures Conditioning regimen - MAC/RIC - TBI (doses and replaced by BU) Donor type 100 80 60 40 20 0 Bone Marrow (BM) Peripheral Blood (PB) Cord Blood (CB) 2000-2004 2005-2009 2000-2004 2005-2009 Age 20 yrs Age 20 yrs - Unrelated vs related donor Age of patients ( over years up to 75) Stem cell source - of PBSC and CB Indications for HSCT
Decrease of TBI in autohsct and over time use of TBI - Auto HSCT - Since year 2000 TBI related late effects in allohsct treated over the last 10-15 yrs Organ function affected by TBI: - Fertility - Cataracts - Endocrine dysfunctions - Secondary solid tumors
Decrease use of TBI induces change of pattern of late effects Main risk factors for cataract: - TBI - Dose, fraction or not, dose rate - Steroids G. Socié et al. Blood 2003;101:3129 A.Tichelli et al. Expert Rev Hematol 2009;2:583
Transplants, % 100 80 <=20 yrs 21-40 yrs 41-50 yrs 51-60 yrs >60 yrs 60 40 20 0 2000-2004 2005-2009 2000-2004 2005-2009 Allogeneic Transplants Autologous Transplants * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma
Increase of GvHD over time induces increase in late effects and mortality
Late effect as a direct consequence of transplant procedure Intervention: Change in conditioning PreBMT intervention Early treatment G. Socié et al. Blood 2003;101:3129
Late effects can affect every organ
Evidence of premature cardiovascular event after allohsct A. Tichelli et al. Blood 2007;110:3463
Diabetes and hypertension are more frequent after allohsct than after autohsct or in sibling as well as after TBI
De novo cardiovascular risk factors are more frequent after allohsct than autohsct A. Tichelli et al. Blood 2007;110:3463
Early intervention on CV risk factor in long term survivors may prevent late CV complications Counseling and screening Dietary counseling Patients at risk should be encouraged to promptly report symptoms in HSCT clinic Heart healthy lifestyle - Stop smoking - Maintain BMI between 20-25 - Aerobic exercise - Psychological issues Screening? ECHO? ECG? BNP? Treatment Diabetes Dyslipidemia Hypertension Treat end organ damage Endocrine replacement? Treat sub-clinical cardiac dysfunction? Armenian et Bhatia Haematologica 2008;93:1132 Shankar et al. Pediatrics 2008;121:e387
Liver complications after HSCT cgvhd Chronic viral hepatitis and cirrhosis Hepatocellular carcinoma Iron overload Nodular regenerative hyperplasia
hypogonadism Iron overload after HSCT In up to 88% of long term survivors Due to prolonged dyserythropoiesis, iron absorption, transfusions Iron accumulation in liver, heart, gonads Effects: - Contribute to fibrosis, cirrhosis and hepatoca, cardiac dysfunction and higher incidence of fungal infections (mucor etc..) Other possible effects - Diabetes, impotence, growth retardation,
Late genito-urinary complication after HSCT Renal complications Gonadal failure and sexuality Gynecological cgvhd Fertility
Renal complications after HSCT Calcineurin inhibitors glomerular thrombosis, tubular injury and arteriopathy with interstitial fibrosis Antibiotics and antifungal tubular damages CMV infection glomerular lesions. CMV ttt with foscarnet tubulointerstitial nephritis and irreversible damage related to crystalization in renal tubules Radiation destruction of glomeruli and tubules + interstitial fibrosis TTP or microangiopathy renal failure
Gonadal failure and fertility Depends: - The age of the patient at time of transplant The younger the better chance of recovery - TBI: dose and fraction - Chemotherapy: type and dosage Conditioning regimen - TBI 12-14 Gy - CY 120 mg/kg - Etoposide 60 mg/kg - BU (16 (12.8) mg/kg) CY (120 mg/kg)
Fertility after HSCT in childhood and adolescence N= 344 pts from 7 centers, 60% Male Median age at study:19(12-35) yrs Median fup: 6 (3-12) yrs Overall infertility rate: 75% - 69% in male - 83% in female Fertility rate: - Malignancy: 21% - Non-malignancy: 42% Risk factors for infertility: Female: - Start of conditioning 13 yrs - BU conditioning Male: - TBI conditioning - Pre-pubertal HSCT A Borgmann-Staudt et al. BMT 2012;47:271
Pregnancies and complications compared to normal populations N Salooja et al. Lancet 2001;358:271
Spermatogenesis after HSCT A Rovo et al. ASH 2010
Paternity after HSCT A Rovo et al. ASH 2011
Secondary malignancies
Late malignancies Secondary cancers in long term cancer survivors A. Tichelli and G. Socié ASH 2010
MDS/ Leukemia after auto HSCT Secondary cancers in long term cancer survivors Lenz et al. JCO 2004
Solid tumors after allohsct JD. Rizzo et al. Blood 2009 ;113:1175
Solid tumors after allohsct JD. Rizzo et al. Blood 2009;113:1175
Breast cancers after allohsct DL. Friedman et al. Blood 2008;111:939
RIC may partially reduces late effects RIC acute toxicity Cumulative incidence and severity of chronic GvHD are not affected A.Tichelli EBMT course 2011
Knowing about late effects allows intervention at different levels A.Tichelli EBMT course 2011
Quality of life (QOL)
Decrease Quality of Life (QOL) in long term survivors HRQL HRQL HRQL HRQL 100 100 80 80 60 60 40 40 20 20 0 0 HR: 0.35 (95% CI 0.28-058) for workers Single Married Divorced/ separated With partner School/ training Disability insurance Working full time Working part time and disability insurance Working part time 100 100 80 80 60 60 40 40 20 20 0 Without cgvhd With cgvhd N=124, between 1984-2004, med time from HSCT 7.3 (1-21) yrs QOL assessed with EORTC QLQ-C30 0 HR: 0.27 (95% CI 0.12-059) for younger < 25 years 25-30 years 35-45 years >45 years S Bieri et al. BMT 2008;42:819
Social issues after HSCT (n=124) Prior to HSCT After HSCT Working full time 80 36 36 Working part time 18 26 60% School/training 21 12 Retired 1 2 Disability insurance 4 48 48 (13 partial) S Bieri et al. BMT 2008;42:819
Familial issues (n=124) Prior to HSCT After HSCT Married 65 61 Significant other 16 13 Single 38 29 Divorced/separated 3 18 Widowed 2 3 29 S Bieri et al. BMT 2008;42:819
Significant changes of QLQ-C30 compared to an age adjusted healthy population EORTC QLQ-C30 Mean scores Mean scores P patients controls Physical function 83.9 (32.6) 89.9 0.01 Role function 74.6 (32.6) 92.8 0.004 Emotional function 72.2 (28.8) 82.8 < 0.0001 Cognitive function 74.7 (28.5) 86.5 < 0.0001 Social function 73.4 (31.9) 85.8 < 0.0001 Global quality of life 71.2 (21.6) 73.7 < 0.03 Dyspnea 27.4 (33.7) 14.3 < 0.0001 Sleep disturbance 32 (35.2) 20.4 < 0.0001 Financial impact 24.2 (33.8) 9 < 0.0001 S Bieri et al. BMT 2008;42:819
Conclusions Due to increased number of patients that live longer, late effects will be more and more important in the care of HSCT patients There is a change in the pattern of late effects due to increased use of RIC and use of TBI + age of pts Physicians and health care providers should take into account this important problem and try to impact on it with prevention measures, counseling and treatment that are needed Secondary malignancies should be looked after early enough to be able to treat them with a curative potential
Thank you for your attention 55