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

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

HCT TRENDS AND SURVIVAL DATA

http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/Pages/index.aspx

OUTCOMES ARE IMPROVING…

Wingard et al, J Clin Oncol, (16): 2230-9 (2011)

Among >10,000 allogeneic HCT survivors,

85%

were alive at 10 years post-transplant!

IMPROVEMENTS 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%)

…BUT WE STILL HAVE WORK TO DO

Mortality rates in long-term HCT survivors is 4-9 times that of general population

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)

INCIDENCE OF POST-HCT LATE EFFECTS

LE Auto Allo P

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.

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

GUIDELINES FOR LATE EFFECTS MONITORING

Recommended screening and preventive practices: 2012 update

Majhail et al, Biol Blood Marrow Transplant 18: 348-371 (2012)

NMDP SMART PHONE APP:

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

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

OCULAR COMPLICATIONS

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

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

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

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

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

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

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

HOW CAN WE BETTER EDUCATE/SCREEN OUR PATIENTS FOR GVHD?

GVHD assessment videohttp://www.fhcrc.org/content/public/en/labs/clinical/projects/gvhd.html

NMDP App

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

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

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

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

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

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

GENERAL SCREENING

http://www.uspreventiveservicestaskforce.org/

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

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

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

COMPLIANCE

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

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

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

QUESTIONS? Thank you!

[email protected]