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R ECOGNITION AND T REATMENT OF HCT L ATE E FFECTS Shernan Holtan, MD, Assistant Professor Center for Hematologic Malignancies September 13, 2013.

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Presentation on theme: "R ECOGNITION AND T REATMENT OF HCT L ATE E FFECTS Shernan Holtan, MD, Assistant Professor Center for Hematologic Malignancies September 13, 2013."— Presentation transcript:

1 R ECOGNITION AND T REATMENT OF HCT L ATE E FFECTS Shernan Holtan, MD, Assistant Professor Center for Hematologic Malignancies September 13, 2013


3 C URRENT HCT P ROCEDURES Expanding in indication and eligible patients ~60,000 HCT procedures worldwide per year

4 HCT TRENDS AND SURVIVAL DATA ports/SummarySlides/Pages/index.aspx

5 O UTCOMES ARE I MPROVING … Wingard et al, J Clin Oncol, (16): 2230-9 (2011) Among >10,000 allogeneic HCT survivors, 85% were alive at 10 years post-transplant!

6 I MPROVEMENTS ARE DESPITE INCREASING AGE AND UNRELATED DONORS Hahn al, J Clin Oncol, (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 N ON -M ALIGNANT L ATE E FFECTS 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 I NCIDENCE OF P OST -HCT LATE E FFECTS LEAutoAllo P Osteoporosis9.7%23.0%<0.001 DM3.0%22.9%<0.001 Adrenal Insuff1.3%13.4%<0.001 Iron overload0.7%25.4%<0.001 Lung disease8.2%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 L ATE E FFECTS 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 G UIDELINES FOR L ATE E FFECTS M ONITORING Recommended screening and preventive practices: 2012 update Majhail et al, Biol Blood Marrow Transplant 18: 348-371 (2012)


13 R ECOMMENDED S CREENING AND P REVENTIVE P RACTICES, 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 I MMUNITY AND I NFECTIONS 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 O CULAR C OMPLICATIONS Keratoconjunctivitis sicca 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 O RAL C OMPLICATIONS 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 R ESPIRATORY 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 C ARDIAC /V ASCULAR C OMPLICATIONS 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 L IVER C OMPLICATIONS 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 R ENAL AND G ENITOURINARY C OMPLICATIONS 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 M USCLE AND C ONNECTIVE T ISSUE 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 H OW CAN WE BETTER EDUCATE / SCREEN OUR PATIENTS FOR GVHD? GVHD assessment video projects/gvhd.html NMDP App

23 S KELETAL C OMPLICATIONS 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 N ERVOUS S YSTEM C OMPLICATIONS Peripheral neuropathy from chemotherapy Calcineurin inhibitor-associated neurotoxicity TBI and intrathecal chemotherapy-associated leukoencephalopathy Infections Cognitive deficits – 10% incidence Neuropsychologic deficits – 20% incidence

25 E NDOCRINE 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 M UCOCUTANEOUS 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 S ECONDARY C ANCERS 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 P SYCHOSOCIAL AND S EXUAL 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


30 S UPPORTIVE C ARE Jim et al, Biol Blood Marrow Transplant 18: S12 – S16 (2012) Energy and stamina Chemo-brain and emotional distress Screening and preventive practices

31 E NERGY AND S TAMINA 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


33 C HEMO - BRAIN AND E MOTIONAL D ISTRESS 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



36 W HO 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

37 P REVENTIVE C ARE P RACTICES, 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

38 P REVENTIVE C ARE P RACTICES, C ON ’ 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

39 Q UESTIONS ? Thank you!

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