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
Dec 25, 2015
Its not over after day 100:Studying Late Effects of
Hematopoietic Cell TransplantationThriving in the long run
Daniel Weisdorf, MD
October, 2011
thanks to Linda Burns,Stephanie Lee, Navneet Majhail
One Survivor’s History: Nearly the whole storyAllo
sib HCT
97 98 99 00 01 02 03 04 05 06
Tongue dysplasia
LRD renal tx
Esophageal strictures
AVN hip
Vertebral compression fractures
Hip arthroplasty
Hypogonadism
Herpes zoster
Osteoporosis
Renal insufficiency
Secondary hyperparathyroidism
Chronic GVHD mouth, GI tract, skin ---
HTN
Cataracts 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
Non-HCT related co-morbidities
Relapse
Getting older concernsTransplant long-term effects
Transplant late effects
It’s a big puzzle
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)
Socie et al, NEJM 1999Bhatia et al, Blood 2007
Median age at HCT: 26 yearsMost received marrow from HLA-id siblings
Chronic GVHD 25%
Infection 7%
Secondary ca 7%
Organ failure 7%Other 4%
Relapse 50%
25% of late deaths
Late causes of death (5 yr)
Martin P, JCO 2010
Median age at HCT: ~ 32 yearsMost received marrow from HLA-id siblingsN=2160, 286 deaths
Chronic GVHD 11%
Infection 17%
Secondary ca 28%Cardiovasc 10%
Respiratory 7%
Other 9%
Unknown 4%
Relapse 14%
75% of really late deaths
Chronic health conditions in 2 year disease-free survivors
Sun CL et al, Blood 2010
N=1022 HLA-ID sibMedian FU 7.3 yrs
Gr 3-5 illnesses 35% at 10 y
Any Chronic health conditions: 10 year survivors
Kersey, Sun CL et al, ASH 2011
N=366 survivors + 306 sibsMedian FU 15 yrs (10-28) 70% @15 yrs; 40% severe/life threatening
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
TBI Immunosuppressants,Chronic GVHD and Steroids
Immune deficiencyChronic GVHD
Late infections
Chemotherapy
Major Risk Factors
Fertility, hypogonadismGrowth and developmentThyroid dysfunctionDental diseaseCataractsSecond malignancies
Neurocognitive dysfunctionSicca syndromeOsteoporosisOsteonecrosisLung dysfunctionIron overload
LATE EFFECTS
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
HepatitisProspective EBMT study in “post screening” era
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
Locasciulli A et al. Transplantation 1994:14:833
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
0
1
2
3
4
5
6
7
8
9
10
0 1 2 3 4 5 6 7YEARS SINCE TRANSPLANT
CU
MU
LAT
IVE
IN
CID
EN
CE
(%
)
NHLn=37 HD
n=19
8.1%± 2.9%at 7 yrs
NHL+HD: 2,733 pts 56 cases
N at risk:
2,733 1,832 1,275 883 567 331 191 84
MDS after autografting Pre HCT factors are important Higher risks with: extended alkylator, More TBI, PBSC
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 non-oncologists 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”
• 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
Survivorship Care Plan – Part 2
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 orFew details in many
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