Its not over after day 100:
Studying Late Effects of
Hematopoietic Cell Transplantation
Thriving in the long run
Daniel Weisdorf, MD
October, 2011
thanks to Linda Burns,
Stephanie Lee, Navneet Majhail
Allo
sib
HCT
97
HTN
One Survivor’s History:
Nearly the whole story
Chronic GVHD mouth, GI tract, skin ---
98
99
00
Hypogonadism
Herpes zoster
01
02
03
Hip
arthroplasty
Osteoporosis
Renal insufficiency
Secondary
hyperparathyroidism
Cataracts
04
05
06
Tongue
dysplasia
LRD renal tx
AVN hip
Vertebral
compression
fractures
Esophageal
strictures
Lipid panel
Overview
• What is the problem
• Recommended screening and preventive
practices – Organ problems & Second Cancers
– Joint Recommendations of the EBMT, CIBMTR,
ASBMT (Rizzo et al BBMT 2006; 12:136)
– Update being submitted for publication
• Prospective trial challenges
– Specific organ problems
– Guides for Health Screening
– BMT Survivors’ Study
Leaving the Transplant Center
Challenges in studying
Late effects
• The problem….
Too many issues
Incidence & risk factors not well defined
Patients are remote from HCT center
Chronic morbidity; not acute
Less pressing than cancer or GVHD
So it gets less attention
HCT oncologists may not be eager 1o care docs
How big is the Problem?
• 30,000-40,000 transplants each year
• Increasing number of patients cured
• Sequelae cause substantial morbidity
• Optimizing outcomes requires:
– Prevention
– Early detection of complications
– Mitigation of disability
It’s a big puzzle
Non-HCT related co-morbidities
Transplant long-term effects
Getting older concerns
Transplant late effects
Relapse
What are the Problems?
Several categories
•Later onset medical problems
eyes, bones, fertility, thyroid, dental etc
•Risk factors for later or progressive injury to
heart,
kidneys,
liver
metabolic, vascular, viral
•2nd cancers
What are other Problems?
•Later manifestations of peri-HCT illness
Neurocognitive
Psychiatric
Lungs
Good care can limit morbidity
• Screen for the signs/symptoms
– H&P, Labs, Imaging
– Educate patients for self-screening
• Screen for the risk factors
– Metabolic syndrome -- cardiovascular
– Subclinical -- early intervention
Identifying the problems
• Early detection
– 2nd cancers
– Who should get screening
Late mortality: in 2 year
disease free survivors
Bhatia, Blood, 2007
Late causes of death (2 yr)
Chronic GVHD 25%
Relapse 50%
Infection 7%
Secondary ca 7%
Other 4%
Organ failure 7%
Median age at HCT: 26 years
Most received marrow from HLA-id siblings
Socie et al, NEJM 1999
Bhatia et al, Blood 2007
Late causes of death (5 yr)
Relapse 14%
Chronic GVHD 11%
Unknown 4%
Infection 17%
Other 9%
Respiratory 7%
Cardiovasc 10%
Secondary ca 28%
75% of really late deaths
Median age at HCT: ~ 32 years
Most received marrow from HLA-id siblings
N=2160, 286 deaths
Martin P, JCO 2010
Chronic health conditions in
2 year disease-free survivors
Gr 3-5 illnesses 35% at 10 y
N=1022 HLA-ID sib
Median FU 7.3 yrs
Sun CL et al, Blood 2010
Any Chronic health conditions:
10 year survivors
N=366 survivors + 306 sibs
Median FU 15 yrs (10-28)
70% @15 yrs; 40% severe/life threatening
Kersey, Sun CL et al, ASH 2011
Healthy Behaviors: Survivors vs. Sibs
Survivors not better at screening--mammograms
Armenian, BMT, 2011
Survivors slightly better at trying to stay healthy
Armenian, BMT, 2011
It’s no longer a question of staying healthy.
It’s a question of finding a sickness you like.
-Jackie Mason
Major Risk Factors
Chemotherapy
Immunosuppressants,
Chronic GVHD and Steroids
TBI
Immune deficiency
Chronic GVHD
Late infections
LATE EFFECTS
Fertility, hypogonadism
Growth and development
Thyroid dysfunction
Dental disease
Cataracts
Second malignancies
Neurocognitive dysfunction
Sicca syndrome
Osteoporosis
Osteonecrosis
Lung dysfunction
Iron overload
Psychosocial Adjustment
• 65% report fatigue and sleeping
disorders
• 25% problems with intimacy
• Occupational disability
• Depression in patient and caregivers
Recommendation: High vigilance,
minimal screening every 6 months
Adverse Psychological Outcomes:
Survivors vs. their Sibs
CL Sun et al, 2011
Adverse Psychological Outcomes:
Survivors: Improvements over tme
CL Sun et al, 2011
Nervous System
• 20% impaired memory, attention/verbal
fluency
• Calcineurin-induced CNS toxicity
• Leukoencephalopathy
• Peripheral neuropathy
– Chemotherapy
– cGVHD
Cataracts and TBI
Benyunes et al. Int J Radiat Oncol Biol Phys 1995;32:661.
Oral Complications
Secondary to TBI and cGHVD
– Decreased saliva production
– Intra-oral malignancies (cGHVD)
– Increased risk of dental caries
Recommendations: Dental evaluation at 6-12 months post
transplant: caries, adequacy of saliva production, dental
hygiene,
? fluoride treatments
Endocrine Abnormalities
• Thyroid dysfunction
– Subclinical-compensated hypothyroidism
– Overt hypothyroidism
– Autoimmune thyroid disease
• Hypoadrenalism
• Growth retardation/delayed puberty
• Fertility/hypogonadism
Recommendations: Yearly screening of thyroid function;
annual gynecologic/endocrine assessment for women and in
men per symptoms; consider hormone replacement
Pulmonary Late Effects
• 15-40% of patients
• Factors:
–
–
–
–
cytoxic agents
irradiation
infections
immune-mediated lung injury
• Restrictive lung disease
• Chronic obstructive lung disease
Recommendations: Controversial – screen at
one year (allo HCT) or by symptoms
Hepatitis
Prospective EBMT study in “post screening” era
Locasciulli A et al. Transplantation 1994:14:833
HBsAg (%)
HCV-RNA (%)
SCT recipients
3.1
6.0
“de novo” infections
2.0
7.4
Positive donors
2.6
3.6
Recommendation: LFTs yearly, monitor viral load, liver bx in HCV
Renal
• True incidence of end-stage disease
unknown
• Glomerulonephritis, nephrotic syndrome
• Dysfunction related to chemotherapy,
TBI, age, antimicrobials,
immunosuppressants
Metabolic Syndrome
Metabolic Syndrome
•
•
•
•
•
Transplant at City of Hope or U of MN 1974-1998
HCT = 1276; siblings 383
Survived ≥2 yrs post transplant
Median age at transplant = 32.9 yrs
Median f/u = 7.1 yrs
Baker KS et al, 2005
Compared with their siblings, allo HCT
survivors were:
•
4.1 x more likely to report diabetes
•
2.3 x more likely to report hypertension
•
7.9 x more likely to report stroke
There were no differences in auto HCT
survivors and their siblings
Osteonecrosis
• Total dose/duration of steroids and TBI are
risk factors
• Mean time from transplant 18 months
• MRI required for diagnosis
• Sites
- Hip 80%
- Knee 10%
Recommendation: Screening is not recommended; perform MRI if
symptomatic
Osteoporosis
Characterized by reduced bone mass and
increased susceptibility to fracture
Normal
Osteoporosis
Bone Loss in HCT
• Varying degrees in up to 50% of adult
pts after allo HCT
• Conflicting data in auto HCT (females at
greater risk)
• Greatest bone loss in first 6 months
Factors Predisposing to Bone Loss
• Glucocorticoid
– decreases in bone formation and vit D3 concentration
•
•
•
•
•
•
•
•
Cyclosporine/tacrolimus
Hypogonadism
TBI
Hypomagnesemia
Reduced physical activity
Direct effect of GVHD on bone cells
Abnormal cytokine-mediated bone turnover
G-CSF
Second Malignancies
•
•
•
•
•
•
3372 consecutive patients
1974 - 2001
Malignant (78%) and non-malignant diseases
Median age 24 years (range 0.1-67)
Auto (35%), MRD (42%), URD (23%)
78% received TBI containing prep
• Median f/u = 5 yrs (range 0.5-25)
• Person years of f/u = 10,494 years
Baker et al. J Clin Onc 2003;21:1352
Second Malignancies
• 147 post-transplant malignancies/137 pts
• 8.1 fold increased risk
• Increased risk for MDS/AML, NHL/PTLPD,
HL, and solid tumors
• Solid tumors – melanoma, brain, oral
Second Malignancies
Baker et al. J Clin Onc 2003;21:1352
MDS after autografting Pre HCT factors are important
Higher risks with: extended alkylator, More TBI, PBSC
CUMULATIVE INCIDENCE (%)
10
9
8
NHL+HD: 2,733 pts
7
56 cases
8.1%± 2.9%
at 7 yrs
6
5
4
NHL
n=37
HD
3
n=19
2
1
0
0
1
2
3
4
5
6
7
191
84
YEARS SINCE TRANSPLANT
N at risk:
2,733 1,832
1,275
883
567
331
Metayer, Blood, 2003
Challenges to Care & Study of
Late Effects
• Impending shortage of physicians
• Oncologists are not interested in PCP role
• Shared care model common &
communication often difficult
• Randomized studies suggest nononcologists can provide quality
survivorship care for solid tumor survivors
Family Physicians vs. Specialists
• Multi-center study (N=968) of early stage
breast cancer 9-15 months after adjuvant
treatment
• Randomized to follow-up care with their
own family physician vs. oncologist
• No differences
– recurrent disease (11.2% vs. 13.2%)
– deaths (6% vs. 6.2%)
– serious clinical events (3.5% vs. 3.7%)
Grunfeld E et al, JCO 2006
Survivorship Care Plan – Part 1
• Comprehensive treatment summary
– Cancer type, extent
– Treatment(s)
– Potential complications
IOM 2005;
“From Cancer Patient to Cancer Survivor:
Lost in Transition”
Survivorship Care Plan – Part 2
• Risk-based follow-up care plan
– Planned schedule for screening: cancer
recurrence & treatment complications
– Teachable moment: General and
cancer-specific preventive practices
– Employment, insurance issues
– Psychosocial screening and support
– Provider assignments
Continuing Obstacles to Study
Still limited literature—Registry
observational studies
Late complications—low incidence
Limited by recall, bias and followup
Continuing Obstacles to Study
Prospective studies need to be:
Large and thus expensive
Study lots of detail in a few
Few details in many
or
If f/u interventions are important, then
center practices may matter
Continuing Obstacles to Study
Are late effects from HCT or
from pre-HCT therapy
Do comorbidities which preclude HCT
select out those at lesser risk for late
effects?
Will liberalizing the age & comorbidity
eligibility for HCT alter the incidence
and severity of late effects?
Continuing Obstacles to Study
Aging
of survivors
of investigators
of methods for study
Should we use electronic f/u
Social media for symptom recording
Design the longterm followapp
BMT CLINIC