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