P di t i L t Eff tPediatric Late Effects

Navneet Majhail, MD, MS

Assistant Scientific Director

DisclosuresDisclosures

No relevant financial conflicts of interest to d ldisclose

ObjectivesObjectives

Review late effects of HCT in childrenReview CIBMTR data forms for collecting such data

Causes of Late Deaths After HCT

AUTOLOGOUS ALLOGENEIC

Causes of Late Deaths After HCT

Organ Organ toxicity

Infection gtoxicity

InfectionOther

GVHD

Relapse Relapse

Second cancers

Other Second cancers

cancers

cancers

Relative Mortality in HCT SurvivorsRelative Mortality in HCT Survivors

AML ALL

Mortality in general population

Mortality in gene al pop lationgeneral population general population

What Are Late Complications?What Are Late Complications?

Side effects that occur months to years after ltransplant

Can be:New medical problemsNew medical problemsPersistent or worsening pre-transplant medical problems

All t l t i t i k f All transplant survivors are at risk for developing late complications!

Late Effects in Pediatric HCT SurvivorsLate Effects in Pediatric HCT Survivors

Second CancersPTLD

Vital Organ Function

PTLDMDS/AML

Solid cancers

QOL

Vital Organ FunctionCardiac

PulmonaryRenal

Growth and developmentLinear growth

Skeletal maturationQOL Renal

EndocrineGastrointestinalVision/Hearing

Intellectual functionEmotional/social maturation

Sexual development

Fertility and ReproductionFertility

Vision/Hearing

Health of offspring

Risk Factors for Late ComplicationsRisk Factors for Late Complications

Cognitive DysfunctionCognitive DysfunctionCognitive deficits

Information processing deficits Information-processing deficits Receptive and expressive languageAttention span

Visual and perceptual motor skills

Academic difficulties - reading, language, maths; significant drops in IQ scoressignificant drops in IQ scoresRisk factors

Primary Diagnosis: ALL, NHL, brain tumorsgRadiation: whole brain, TBIChemotherapy: IT or high dose IV MTX, IT Ara-CYoung age:

Ocular Late EffectsOcular Late Effects

CataractsIncidence 20-45%Risk factors: Age, TBI, corticosteroids

Ocular sicca syndromeOcular sicca syndromeIncidence 20-60%Risk factors: chronic GVHD, TBI

Ischemic microvascular retinopathyRisk factors: chronic GVHD

Cardiac ComplicationsCardiac Complications

ManifestationsCoronary artery diseaseCerebrovascular diseaseMetabolic syndrome, hypertensiony , ypCongestive heart failure

Risk factorsR di i hRadiation to chestCumulative anthracycline doseGeneral population risk factors (e.g., diabetes)

Bronchiolitis ObliteransBronchiolitis Obliterans

Incidence 2-14% (allogeneic HCT)Risk factors: chronic GVHDCharacteristic bronchiolar obstruction & air trapping

Liver Late EffectsLiver Late Effects

Iron overloadPredisposes to cirrhosis and heart failureRisk factor: Red cell transfusions

Viral hepatitisPrevalence: 3-6% Ri k f t I f t d d Risk factors: Infected donor, blood products

Kidney Late EffectsKidney Late Effects

Chronic kidney diseaseIncidence: 20-60%Common manifestations

Progression of early onset ARFg yThrombotic microangiopathyNephrotic syndromeIdiopathicIdiopathic

Risk factors: Age, TBI, GVHD, drugs, hypertension

Growth AbnormalitiesGrowth Abnormalities

Growth primarily mediated by growth and hsex hormones

Children receiving HCT have impaired growth velocity and total height

Risk FactorsAge

HypothyroidismHypothyroidism

Normal thyroid function required for normal h h h h ldheight growth in childrenIncidence 15-50%Risk factorsRisk factors

Increasing dose of radiation/TBISingle dose TBIOlder age at radiationFemale gender

OsteoporosisOsteoporosis

Incidence: 10-50%Risk factors: steroids, cyclosporine, TBI, age

Avascular NecrosisAvascular Necrosis

Prevalence: 5 - 15%Risk factors: steroids, TBI

InfertilityInfertility

Poorly studied area of late effectsMajority of children who receive HCT will become infertilePregnancies have been reported after HCTPregnancies have been reported after HCT

Women who get pregnant have higher risk of maternal complicationsNo increase in risk of fetal abnormalities or adverse pregnancy outcomes

Risk factors: TBI, especially single dose, p y g

Form 2300: Yearly Followup For >2 years post-HCT

Secondary CancersSecondary Cancers

Secondary CancersSecondary Cancers

Cancers that occur after transplantDifferent from the cancer for which transplant was performedCancer treatments may cause them or Cancer treatments may cause them or increase their risk

Types of Secondary CancersTypes of Secondary Cancers

Post-transplant lymphoproliferative d d ( )disorders (PTLD)Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)myeloid leukemia (AML)Solid cancers

PTLDPTLD

Origin in donor B-lymphocytesIncidence 1-2% after allogeneic HCT, rare after autologous HCT80% of cases occur within 1 year of HCT80% of cases occur within 1-year of HCTRisk factor: Degree of immunosuppression

T-cell depletionpUnrelated donor HCTAcute or chronic GVHD

Epstein-Barr Virus and PTLDEpstein Barr Virus and PTLDPrimary EBV infection

Memory B-cellT-cellNatural killer cell

HCT

Clinical Presentation of PTLDClinical Presentation of PTLD

Clinically present as lymphomaLymph node enlargementEnlargement of liver and spleenFevers, weight loss, night sweats, g , g

Diagnostic workupLymph node & bone marrow biopsyI i (CT PET )Imaging (CT scan or PET scan)Confirm presence of EBV (PCR)

EBV reactivation vs. PTLDea a o s

Treatment of PTLDTreatment of PTLD

~90% mortalityAntiviral drugs

Acyclovir, ganciclovir - not effective

Destroy B cellsDestroy B-cellsRituximab

Replete T-cellspDonor lymphocyte infusionsEBV cytotoxic T-cells

ChemotherapyChemotherapy

MDS/AML

Malignant disorders of bone marrow

MDS/AML

Specifically involves myeloid lineageOccurs after autologous HCT, very rare after allogeneic HCTallogeneic HCT

Incidence 5-15%Latency period of 2-5 yearsCharacteristic cytogenetic abnormalities (11q23 translocation, monosomy 5 or 7)

Risk Factors for MDS/AMLRisk Factors for MDS/AMLHost factors

AgeGenetic diseases

DNA repair polymorphisms

MDS/AMLLifestyle factors

SmokingTransplant factors

Chemotherapy exposuregEnvironmental exposures

py pTBI

Pre-HCT treatment factorsChemotherapy exposure

(alkylators etopside)(alkylators, etopside)Radiation therapy

Clinical PresentationClinical Presentation

Related to dysfunctional hematopoiesisAnemiaThrombocytopeniaLeukopenia or leukocytosisp y

DiagnosisComplete blood count and peripheral smearB bi ( i h i di )Bone marrow biopsy (with cytogenetic studies)

Long term survival

Secondary Solid CancersSecondary Solid Cancers

Latency period of 3-5 yrs, incidence increases hwith time~1-2% at 5 yrs, ~1-6% at 10 yrs, ~2-15% at 15 yrs after HCT

Risk 2-3 fold higher compared to general population Ri k f t d t i tRisk factors determine cancer type

Chronic GVHD: squamous cell (epithelial) cancers (skin, oral cavity, tongue and oro-pharynx)Total body irradiation: non-squamous cancers (breast cancer, soft tissue sarcoma, CNS tumors)

Secondary Cancers After HCTSecondary Cancers After HCT

Form 2300: Yearly Followup For >2 years post-HCTy p y p

Take Home PointsTake Home Points

Patients Have Different Risks for Late EffectsPatients Have Different Risks for Late Effects

RISKS ARE NOT SAME

16 year old with Hodgkin’s lymphoma treated with

1 year old with ALL treated with allogeneic HCT andlymphoma treated with

autologous HCTwith allogeneic HCT and

has GVHD

Getting Late Effects Data is HardGetting Late Effects Data is Hard

We recognize challenges to capturing late ff deffects data

Patients not followed by centersSignificant variation in screening and Significant variation in screening and treatment practicesChildren may move as they grow upy y g p

Surviving the Cure!

More research is needed on late effects of h ld

Surviving the Cure!

HCT in children

Overall long-term mortality is higher than their healthy peerstheir healthy peers

Deaths driven by late complications, not relapserelapse

CIBMTR is an optimal mechanism to study late complications of HCT

But we need good data!!

www.cibmtr.org

QUESTIONS?QUESTIONS?