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Recognition and Treatment of HCT Late Effects

Recognition and Treatment of HCT Late Effects. Shernan Holtan, MD, Assistant Professor Center for Hematologic Malignancies September 13, 2013. NED. Current HCT Procedures. Expanding in indication and eligible patients ~60,000 HCT procedures worldwide per year.

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Recognition and Treatment of HCT Late Effects

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  1. Recognition and Treatment of HCT Late Effects Shernan Holtan, MD, Assistant Professor Center for Hematologic Malignancies September 13, 2013

  2. NED

  3. Current HCT Procedures • Expanding in indication and eligible patients • ~60,000 HCT procedures worldwide per year

  4. HCT trends and survival data • http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/Pages/index.aspx

  5. Outcomes are Improving… Wingard et al, J ClinOncol, (16): 2230-9 (2011) Among >10,000 allogeneic HCT survivors, 85% were alive at 10 years post-transplant!

  6. Improvements are despite increasing age and unrelated donors • Hahn al, J ClinOncol, (31): 2437-2449 (2013) • 38,060 HCT procedures in US/Canada, 1994-2005 • Transplants increased by ~45%, with 165% increase in unrelated donors (URD) • PBSC 6  63% • UCB 2  10% • Median age 33  40 yo • Day +100 survival >85% • 1 year survival improved in URD allo (63%)

  7. …but we still have work to do • Mortality rates in long-term HCT survivors is 4-9 times that of general population

  8. Non-Malignant Late Effects Khera et al, Journal of Clinical Oncology 30: 71-77(2012) • Incidence of 14 non-malignant late effects in 1,087 survivors, 1/04 – 6/09 • Self-reported outcomes from patient questionnaires • MSK, endocrine, CV, organ-specific, psychiatric domains • cGVHD excluded in this report • CI of any late effect at 5 years: • Autologous 44.8% (2.5% with 3+ late effects) • Allogeneic 79% (25.5% with 3+ late effects)

  9. Incidence of Post-HCT late Effects LEAutoAlloP Osteoporosis 9.7% 23.0% <0.001 DM 3.0% 22.9% <0.001 Adrenal Insuff 1.3% 13.4% <0.001 Iron overload 0.7% 25.4% <0.001 Lung disease 8.2% 36.9% <0.001 DVT (non-catheter) 5.6% 10.9% 0.01 No significance difference in incidence of AVN, joint replacement, thyroid disease, stroke, CAD, suicide/suicide attempt, dialysis in auto vs. allo HCT.

  10. QOL burden of Late Effects • No strong association between age and QOL • Those with 3+ late effects reported: • Worse physical functioning • Higher likelihood of mod/severe limitation of usual activities • Lower likelihood of full-time work or study • Mental functioning not associated with number of late effects

  11. Guidelines for Late Effects Monitoring Recommended screening and preventive practices: 2012 update Majhail et al, Biol Blood Marrow Transplant 18: 348-371 (2012)

  12. NMDP Smart Phone App:

  13. Recommended Screening and Preventive Practices, 2012 • Immunity and infections • Ocular complications • Oral complications • Respiratory complications • Cardiac/vascular complications • Liver complications • Renal and genitourinary complications • Complications of muscle and connective tissue • Skeletal complications • CNS and peripheral nervous complications • Endocrine complications • Mucocutaneous complications • Secondary cancers • Psychosocial adjustment and sexual complications • Fertility • General screening and preventive health

  14. Immunity and Infections • Immunizations and antimicrobial prophylaxis • Postponing immunizations in patients with cGVHD not recommended, except for live vaccines • HSV/VZV, encapsulated bacteria, fungi/mold, PcP • CD4 counts and IgG levels are decent surrogate

  15. Ocular Complications • Keratoconjunctivitissicca in 40-60% cGVHD; infectious keratitis must be ruled out • Cataracts in 40-70% of TBI recipients at 10 years • Expert evaluation recommended for those experiencing eye symptoms • Autologous serum drops can reduce inflammation

  16. Oral Complications • Decreased saliva production common in TBI recipients, cGVHD • Artificial saliva, sugar-free candies, sialogogues (pilocarpine, cevimeline), frequent water sipping • Squamous cell CA risk heightened in tobacco users, Fanconi anemia, cGVHD • At least annual oral/dental evaluations recommended

  17. Respiratory complications • Treatment-related lung toxicity (TBI, BCNU, bleomycin, busulfan, methotrexate) • Bronchiolotis Obliterans Syndrome (BOS) • 2-14% allogeneic HCT recipients (“pulmonary GVHD”) • New-onset airflow obstruction • <20% 5 year survival if poor response to immunosuppression • Cryptogenic Organizing Pneumonia (COP) • Previously “BOOP,” less common than BOS • Typically restrictive pattern, presenting with cough, low-grade fevers, shortness of breath • 80% of patients expected to improve with steroids

  18. Cardiac/Vascular Complications • CV risk ~3-5 x increased over general population • Anthracyclines and cardiomyopathy • <400 mg/m2: negligible incidence of CHF • 550 mg/m2: 7% • 700 mg/m2: 18% • Mediastinal radiation = risk of restrictive cardiomyopathy, conduction defects, CAD, valvular abnormalities • Appropriate management of risk factors (DM, HTN, dyslipidemia) important to mitigate against CAD risk

  19. Liver Complications • Viral hepatitis • Cirrhosis in HCV infection is accelerated in transplant recipients (18 vs 40 years) • Iron overload • Serum ferritin monitoring in those with elevated levels, LFT abnormalities, or ongoing RBC transfusions • Hepatic iron content estimation • Biopsy vs non-invasive imaging • Chelation vs. phlebotomy • Associated with infection risk (impaired neutrophil, monocyte function) • cGVHD

  20. Renal and Genitourinary Complications • Incidence of chronic kidney disease 5-65% • Transplant-associated thrombotic microangiopathy, glomerulonephritis, nephrotic syndrome, radiation nephritis • Risks: age, myeloma, medications (cyclosporine, tacrolimus, sirolimus, acyclovir, amphotericin B) • Hemorrhagic cystitis • Viral (BK and adenovirus) • Cyclophosphamide • Management of HTN and DM critical

  21. Muscle and Connective Tissue • Steroid myopathy • Myositis (rare but distinctive cGVHD manifestation) • Sclerosis of skin and subcutanous tissue diagnostic of cGVHD • Early intervention important to prevent contractures • Physical therapy and massage can help

  22. How can we better educate/screen our patients for GVHD? GVHD assessment video http://www.fhcrc.org/content/public/en/labs/clinical/projects/gvhd.html • NMDP App

  23. Skeletal Complications • High incidence of bone density loss • 25% osteoporosis • 50% osteopenia • Physical inactivity, hypogonadism, steroid exposure, calcium/vitamin D deficiency contribute • Screening DEXA should be performed at 1 year post-HCT in women, allo recipients, prolonged steroid exposure

  24. Nervous System Complications • Peripheral neuropathy from chemotherapy • Calcineurin inhibitor-associated neurotoxicity • TBI and intrathecal chemotherapy-associated leukoencephalopathy • Infections • Cognitive deficits – 10% incidence • Neuropsychologic deficits – 20% incidence

  25. Endocrine complications • 10-50% hypothyroidism after myeloablative conditioning • Annual thyroid function tests recommended • Hypogonadism is common, and supplementation can be considered • Adrenal failure risk after prolonged corticosteroid exposure

  26. Mucocutaneous complications • 70% of cGVHD will have skin involvement • Risk of skin cancer increased in HCT recipients • Skin protection from excessive sun exposure is important • Annual dermatology evaluation • Vaginal cGVHD can lead to strictures, and early intervention recommended

  27. Secondary Cancers • Treatment-related MDS/AML post-autologous HCT = ~4%. • Associated with age, alkylating agents, topo II inhibitors, radiation, difficult stem cell harvests • Post-transplant lymphoproliferative disorder • Related to severe immune compromise (esp. T-cell depleted grafts) and EBV, early treatment with rituximab in patients without mass lesions • Solid tumors account for 5-10% of late deaths and are strongly associated with radiation. • ~10% with skin cancer 20 years post-HCT • 17% females with breast cancer after TBI

  28. Psychosocial and Sexual complications • Psychological distress is a significant number of survivors • Self-regulatory capacity can be “fatigued” • Emotional and physical side effects can impact sexual function • Infertility is common but not universal • Spontaneous or assisted pregnancies should be delayed for at least 2 years after HCT • Women exposed to TBI have higher rate of preterm delivery and low birth weight infants

  29. General Screening • http://www.uspreventiveservicestaskforce.org/

  30. Supportive Care Jim et al, Biol Blood Marrow Transplant 18: S12 – S16 (2012) • Energy and stamina • Chemo-brain and emotional distress • Screening and preventive practices

  31. Energy and Stamina • Inflammation and HPA-axis changes • Aerobic exercise and strength training encouraged • Can be home-based exercise • No well-controlled studies of pharmacologic agents in HCT pts • Agents used off-label in cancer fatigue • Modafinil (Provigil): FDA-approved for narcolepsy, showed benefit in 2 uncontrolled studies of cancer fatigue, possibly fewer side effects than other stimulants • Methylphenidate (Ritalin): Most commonly prescribed psychostimulant, FDA-approved for ADHD, possible higher potential for abuse

  32. Chemo-brain and Emotional Distress • HCT recipients are highly resiliant, but majority experience at least transient changes in emotional stability and cognitive function • Cognitive rehabilitation studies are ongoing, compensatory mechanisms can be helpful • Depression, anxiety, and post-traumatic stress are reported in nearly half of HCT-recipients • May actually be more profound in caregivers

  33. Compliance

  34. Who is at risk for non-adherence to guidelines? Khera et al, Biol Blood Marrow Transplant 17: 995-1003 (2011) • Questionnaire mailed to 3,066 adult survivors > 2 years post-HCT • Survivor health • Adherence to guidelines • Financial concerns • 51% response rate • Respondents tended to be: • Older at present (54 .5 vs 47.4 yrs), p<0.001 • Older at HCT (42.2 vs. 32.6 yrs), p<0.001 • More men, Hispanic/Latino subjects, marrow recipients of MA conditioning in non-respondent group

  35. Preventive Care Practices, con’t • 85% said health was good to excellent • 44% worked or went to school full-time • 56% could do usual activities without limitation • 76% saw their doctor in past 3 months • Median adherence to guidelines = 75% • Skin examination = 61% • Mammography = 90% • Thyroid screening = 50% • Cholesterol testing = 91% • 87% interested in assistance with health maintenance from transplant center • 27% felt knowledgeable about recommended tests for transplant survivors

  36. Preventive Care Practices, Con’t • 98% of respondents had medical insurance • 3% of respondents filed for bankruptcy • Lower guideline adherence rates associated with: • Autologous HCT, concerns about medical costs, >15 years post-HCT, non-white race, male sex, lower physical functioning, absence of cGVHD, <40 y.o., self-reported lack of knowledge about tests • Lower self-reported lack of knowledge about recommended survivor tests was associated with: • Autologous HCT, males, absent cGVHD, non-whites, >65 y.o., and >15 years post-HCT

  37. Questions? Thank you! holtan@ohsu.edu

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