Transcript Coping with Long Term Side Effects of Autologous and

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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HCT TRENDS AND SURVIVAL DATA
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http://www.cibmtr.org/ReferenceCenter/SlidesRe
ports/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
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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
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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
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MSK, endocrine, CV, organ-specific, psychiatric domains
 cGVHD excluded in this report
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CI of any late effect at 5 years:
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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
DM
Adrenal Insuff
Iron overload
Lung disease
DVT (non-catheter)
9.7%
3.0%
1.3%
0.7%
8.2%
5.6%
23.0%
22.9%
13.4%
25.4%
36.9%
10.9%
<0.001
<0.001
<0.001
<0.001
<0.001
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:
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Worse physical functioning
 Higher likelihood of mod/severe limitation of usual
activities
 Lower likelihood of full-time work or study
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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
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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
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Immunizations and antimicrobial prophylaxis
Postponing immunizations in patients with cGVHD
not recommended, except for live vaccines
 HSV/VZV, encapsulated bacteria, fungi/mold, PcP
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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
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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
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RESPIRATORY COMPLICATIONS
Treatment-related lung toxicity (TBI, BCNU,
bleomycin, busulfan, methotrexate)
 Bronchiolotis Obliterans Syndrome (BOS)
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2-14% allogeneic HCT recipients (“pulmonary GVHD”)
 New-onset airflow obstruction
 <20% 5 year survival if poor response to
immunosuppression
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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
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CARDIAC/VASCULAR COMPLICATIONS
CV risk ~3-5 x increased over general population
 Anthracyclines and cardiomyopathy
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<400 mg/m2: negligible incidence of CHF
 550 mg/m2: 7%
 700 mg/m2: 18%
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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
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LIVER COMPLICATIONS
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Viral hepatitis
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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
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Biopsy vs non-invasive imaging
 Chelation vs. phlebotomy
 Associated with infection risk (impaired neutrophil,
monocyte function)
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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
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Viral (BK and adenovirus)
 Cyclophosphamide
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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
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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
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NMDP App
SKELETAL COMPLICATIONS
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High incidence of bone density loss
25% osteoporosis
 50% osteopenia
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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
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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
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ENDOCRINE COMPLICATIONS
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10-50% hypothyroidism after myeloablative
conditioning
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Annual thyroid function tests recommended
Hypogonadism is common, and supplementation
can be considered
 Adrenal failure risk after prolonged corticosteroid
exposure
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MUCOCUTANEOUS COMPLICATIONS
70% of cGVHD will have
skin involvement
 Risk of skin cancer
increased in HCT
recipients
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Skin protection from
excessive sun exposure is
important
Annual dermatology
evaluation
Vaginal cGVHD can lead
to strictures, and early
intervention
recommended
SECONDARY CANCERS
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Treatment-related MDS/AML post-autologous
HCT = ~4%.
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Post-transplant lymphoproliferative disorder
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Associated with age, alkylating agents, topo II
inhibitors, radiation, difficult stem cell harvests
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
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PSYCHOSOCIAL AND SEXUAL
COMPLICATIONS
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Psychological distress is a significant number of
survivors
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Self-regulatory capacity can be “fatigued”
Emotional and physical side effects can impact
sexual function
 Infertility is common but not universal
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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
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GENERAL SCREENING
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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
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ENERGY AND STAMINA
Inflammation and HPA-axis changes
 Aerobic exercise and strength training
encouraged
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Can be home-based exercise
No well-controlled studies of pharmacologic
agents in HCT pts
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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
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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
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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)
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Questionnaire mailed to 3,066 adult survivors > 2
years post-HCT
Survivor health
 Adherence to guidelines
 Financial concerns
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51% response rate
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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
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More men, Hispanic/Latino subjects, marrow
recipients of MA conditioning in non-respondent
group
PREVENTIVE CARE PRACTICES, CON’T
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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%
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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:
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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:
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Autologous HCT, males, absent cGVHD, non-whites,
>65 y.o., and >15 years post-HCT
QUESTIONS?
Thank you!
[email protected]