1

Where in the TED Where in the TED Does HCT Stuff Go?Does HCT Stuff Go?

Diane J. Knutson

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Key ConceptsKey Concepts

What is an HSCT?

Why perform one?

Who can benefit?

Mechanics of transplant

Early and Late complications

Where on “new” TED?

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Introducing PreIntroducing Pre--TED & PostTED & Post--TEDTED

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2

Blood is MadeBlood is Madein the Bone Marrowin the Bone Marrow

Axial skeleton

Inner spongy bone

Bone marrow is in the holes

Bone marrow is a highly organized/ regulated organ

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Bone Marrow: The Source of Bone Marrow: The Source of Blood and Our Immune SystemBlood and Our Immune System

Blood stem cells

Pluripotent

Self renewing

Highly regulated production

Cytokines (SCF, IL3)

Growth factors (G-CSF)Normal bone marrow

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Hematopoiesis Scheme

Stem CellCompartment

LymphoidCompartment

MyeloidCompartment

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3

Goals of HSCTGoals of HSCT

Provide stem cell replacement

Autologous and allogeneic

Destroy malignancy

Potentially lethal chemotherapy/radiation

Immunotherapy

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Indications for AllogeneicHematopoietic Stem Cell Transplants,

2003 – Worldwide

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

AML ALL CML Lymphoma MDS/MPS OtherLeukemia

OtherCancer

AplasticAnemia

Other Non-malignantDisease

Tra

nsp

lants

Related donor (Total N=8,800)Unrelated donor (Total N=4,900)

Slide 7

PrePre--TED AMLTED AML

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4

0

20

40

60

80

100

Mort

ality

, %

0

20

40

60

80

100

Mort

ality

, %

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100-day Mortality after HLA-identical Sibling Myeloablative Transplants,

2002-2003

1st Complete Remission2nd Complete RemissionNot in RemissionChronic PhaseAccelerated PhaseBlast Phase

AML ALL CML MDS Aplastic ImmuneAnemia Deficiency

Slide 12

Acute Leukemia sectionAcute Leukemia section

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Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

Allogeneic

HLA-identical Other Unrelatedsibling relative

Bone Peripheral Umbilicalmarrow Blood cord blood

Negative Positive Ex vivoselection selection expansion

Bone Peripheralmarrow blood

Negative Positive Ex vivoselection selection expansion

Donor

Collection

Manipulation

Autologous

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5

Basics of HLABasics of HLA

HLA = human leukocyte antigens

Proteins on cell surfaces that are key players in immune response

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HLAHLA

Class 1 = HLA- A, B, C

Class 2 = HLA- DR, DP, DQ

Differ in types of organisms they recognize and cells on which they are found

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HLA Compatible DonorHLA Compatible Donor

Varies among HSCT centers

Varies among protocols

Current acceptable donor

A, B – serologic match?

DRB1 – allele match

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Antigen Antigen vsvs AlleleAllele

Antigen = protein on surface of cells (serology)

Allele = gene (DNA)

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What is a “Match” ?

A1, A2, DR1B7, B8, DR3

A1, A3, DR1B7, B8, DR3

A*0101, A*0201, DRB1*0101B*0702, B*0801, DRB1*0301

A*0101, A*0301, DRB1*0101B*0702, B*0803, DRB1*0304

DNA-BasedSerology

P:

D:

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PrePre--TED Donor TypeTED Donor Type

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Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

Allogeneic

HLA-identical Other Unrelatedsibling relative

Bone Peripheral Umbilicalmarrow Blood cord blood

Negative Positive Ex vivoselection selection expansion

Bone Peripheralmarrow blood

Negative Positive Ex vivoselection selection expansion

Donor

Collection

Manipulation

Autologous

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Timeline of HSCT

Complications:

Blood & Marrow Changes:

BMT Process:

Supportive Therapy:

TIME LINE -12 -4 -2 0 1 2 6 60months

Marrowfailure

Diseaseremission

Diseaserecurrence

Continuous complete

remission (cure)

High-dose myeloablative

therapy

Primary diagnosis and

treatment

Relapse and salvage

therapyDisease State:

AntibioticsNutrition

AntiemeticsGrowth factors

Red cell transfusionsPlatelet transfusions

Donor search or obtain autologous stem cells Chemo XRT

PBSC/BM harvests in ABMT

Secondary tumors, cataracts, endocrine changes, QoL

Acute and/or chronic GvHDViral infections

CMV, VZV, PCP, IPBacterial infectionsHSV mucositis VOD

BM/SCre-infusion

Marrow function

Immune functioneg: DHAP and GF and PBSC

Collect & freezegcsf

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Allogeneic Stem Cell Sourcesby Recipient Age

1997-2004

Age ≤20 yrs Age >20 yrs

0

20

40

60

80

100

1997-2000 2001-2004 1997-2000 2001-2004

Tra

nsp

lants

, %

Bone Marrow (BM)Peripheral Blood (PB)Cord Blood (CB)

Slide 2

8

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Cord Blood Transplants,Registered with the CIBMTR,

1997-2004

0

100

200

300

400

500

1997 1998 1999 2000 2001 2002 2003 2004

Tra

nsp

lants

* *

* Data incomplete

RelatedUnrelated

Slide 11

Cell Source sectionCell Source section

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Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

Allogeneic

HLA-identical Other Unrelatedsibling relative

Bone Peripheral Umbilicalmarrow Blood cord blood

Negative Positive Ex vivoselection selection expansion

Bone Peripheralmarrow blood

Negative Positive Ex vivoselection selection expansion

Donor

Collection

Manipulation

Autologous

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9

PrePre--TED Graft ManipulationTED Graft Manipulation

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Most Commonly Used Preparative Most Commonly Used Preparative Regimen AgentsRegimen Agents

TBI 52% 85% 25% Cytoxan 87% 91% 85%Busulfan 48% 17% 10%Etoposide 24% 19% 73% Ara-C 5% 10% 25%Thiotepa 4% 14% 8%Platinum* <1% <1% 7%Nitrosourea** 1% <1% 53%

HLA-ident Unrelated Auto-sib BMT- Donor BMT- HSCT

malignancy malignancy Lymphoma

* cis-Platinum / carboplatin ** BCNU / CCNU

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A Continuum of A Continuum of NonNon--myeloablativemyeloablative/Reduced /Reduced

Intensity Prep RegimensIntensity Prep Regimens

Gen

etic

Dis

parit

y

CLL / CML LCL AMLLGL MM

Aggressiveness Of Malignancy

Cy + ATG + Thymic XRTHaplo /T-cell Dep

MUD

Matchedsibling

Myelosuppression

Immunosuppression

TBI+CyTBI+F+TT

Bu16+Cy

BEAM

Bu8+F+ATGFMF+Cy

TBI 2Gy Flag-Ida

F+TBI2Gy

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10

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Allogeneic Transplants,Registered with the CIBMTR,

1998-2004

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

10,000

1998 1999 2000 2001 2002 2003 2004

Tra

nsp

lants

Reduced Intensity ConditioningTraditional

*

* Data incomplete

Slide 16

PrePre--TED Preparative RegimenTED Preparative Regimen

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Trends in Autologous TransplantsRecipient Age*

1993-2004

* Transplants for AML, ALL, NHL, Hodgkin disease, Multiple Myeloma

≤20 yrs21-40 yrs41-50 yrs51-60 yrs>60 yrs

0

20

40

60

80

100

1993-1996 1997-2000 2001-2004

Tra

nsp

lants

, %

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11

PrePre--TED CoTED Co--morbid Conditionsmorbid Conditions

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PrePre--TED Therapy TED Therapy PlannedPlanned as of Day 0as of Day 0

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PostPost--TEDTED

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Administer growth factors

G-CSF, GM-CSF

Monitor hematopoietic recovery

Cell number and type (granulocytes, platelets, etc.)

Marrow cellularity

Chimerism (X/Y, VNTR, HLA)

Enhance/Monitor RecoveryEnhance/Monitor Recovery

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ANC recoveryANC recovery(not engraftment)(not engraftment)

Report first of three consecutive days of ANC greater than 500

Usually not before 8-10 days for myeloablative HSCT

May never become neutropenic for reduced-intensity

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PostPost--TED ANC RecoveryTED ANC Recovery

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ComplicationsComplications

Graft rejection

Graft vs host disease

Relapse of disease

Infection

Regimen-related toxicity

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Graft vs Host Disease/Graft Rejection

GvHD

RejectionStem Cells

HLA differences stimulate detrimental immune responses

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Donor/Graft-relatedHLA-disparityFemale → MaleParityOlder ageT-cell doseAGVHD (for CGVHD)

Recipient-relatedOlder agePrior viral infection/exposureOther microbial infection

Treatment-relatedConditioning regimenInadequate immune suppression

Factors Influencing Risk Of GVHDFactors Influencing Risk Of GVHD

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Acute GVHD Acute GVHD GlucksbergGlucksberg Staging (organs) CriteriaStaging (organs) Criteria

Stage Skin Liver Intestinal tract*(Bilirubin) (Diarrhea)

None orStage 0 No rash <2.0 mg/dL or <500 ml/day or

<35 mmol/L <280 ml/m2/day

Maculopapular >500 butStage 1 rash, <25% 2.0-3.0 mg/dL or <1000 ml/day or

of body surface 35-52 mmol/L 280-555 ml/m2/day

Maculopapular >1000 butStage 2 rash, 25-50% 3.1-6.0 mg/dL or <1500 ml/day or

of body surface 53-103 mmol/L 556-833 ml/m2/day

Stage 3 Generalized 6.1-15.0 mg/dL or >1500 ml/day orerythroderma 104-236 mmol/L >833 ml/m2/day

Generalized Severe abdominalStage 4 erythroderma >15.0 mg/dL or pain, with or

with bullae >356 mmol/L without ileusformation anddesquamation

*use ml/day for adult patients and ml/m2/day for pediatric patients

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OverallOverall GradeGrade

Grade I Stage 1 to 2 skin rash; no gut involvement; no liver involvement; no decrease in clinical performance

Grade II Stage 1 to 3 skin rash; Stage 1 gut involvement or liver involvement (or both); mild decrease in clinical performance

Grade III Stage 2 to 3 rash; Stage 2 to 3 gut involvement or Stage 2 to 4 liver involvement (or both); marked decrease in clinical performance

Grade IV Similar to Grade II with Stage 2 to 4 organ involvement and extreme decrease in clinical performance

Thomas ED - N Engl J Med - 1975 Apr 24; 292(17):895-902

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Chronic GVHDChronic GVHD

Poorly understood late manifestationBoth alloimmune and autoimmune featuresIn part a failure of thymus function

Incidence~1/3 of matched sibs60-70% of matched unrelateHigher with mismatched

Risk factorsHLA disparity, patient age, prior aGvHD, graft source

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Chronic GVHD ClassificationChronic GVHD Classification(old but it(old but it’’s what wes what we’’ve got)ve got)

Limited

Either or both

Localized skin involvement

Hepatic dysfunction due to cGvHD

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Chronic GVHD ClassificationChronic GVHD Classificationcontinuedcontinued

ExtensiveGeneralized skin involvement, orLocalized skin involvement and/or hepatic dysfunction due to chronic GvHDOR

Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, orEye involvement (Schirmer test <5mm wet), orInvolvement of minor salivary glands/oral mucosaInvolvement of any other organ

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Manifestations Of Chronic GVHD (I)Manifestations Of Chronic GVHD (I)

Organ Definite manifestations Possible manifestationsSystem of Chronic GVHD of Chronic GVHD

Scleroderma (superficial or fasciitis), lichen planus, vitiligo, scarring alopecia, hyperkeratosis pilaris, contractures from skin immobility, nail bed dysplasia

Lichen planus, non-infectious ulcers, corneal erosions/non-fectious conjunctivities

Esophageal strictures, steatorrhea

None

Skin

Mucousmembranes

GI tract

Liver

Eczematoid rash, dry skin, maculopapular rash, hyperpigmentation, hair loss

Xerostomia, keratoconjunctivitis sicca

Anorexia, malabsorption, weight loss, diarrhea, abdominal pain

Elevation of alkaline phosphatase, transaminitis, cholangitis, hyperbilirubineamia

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Manifestations Of Chronic GVHD (II)Manifestations Of Chronic GVHD (II)

Organ Definite manifestations Possible manifestationsSystem of Chronic GVHD of Chronic GVHD

None

Vaginal stricture, lichen planus

Non-septic arthritix, myositis, myasthenia, polyserositis, contractures from joint immobilizationNone

Bronchiolitis obliterans

Liver

GU

Musculoskeleta1/Serosa

Hematologic

Lung

Elevation of alkaline phosphatase, transaminitis, cholangitis, hyperbilirubineamiaNon-infectious vaginitis, vaginal atrophyArthralgia

Thrombocytopenia, esinophilia, autoimmune cytopeniasBronchiolitis obliteranswith organizing pneumonia, interstitial pneumonitis

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PostPost--TED GVHDTED GVHD

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Evaluating PostEvaluating Post--HSCTHSCTDisease StatusDisease Status

Most frequent cause of treatment failure

Vigilance may affect rapidity of diagnosis

Method of detection really does matter

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Method of Detection of Method of Detection of DiseaseDisease

Molecular (most sensitive)Blood or marrowBcr/abl, bcl-2

Cytogenetic (mod. sensitive)Blood or marrowt(9:22), t(14:18)

Hematologic (least sensitive)Blood or marrow appearance

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PostPost--TED Disease AssessmentTED Disease Assessment

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Indications for DCIIndications for DCI

Relapse prophylaxis (“planned”)Treatment of relapse: CML, AMLTreatment of PTLD, EBV-LymTreatment of GVHDTreatment of Viral InfectionsChimerism

Stable or declining donor cellsOther emerging indications

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PostPost--TED DCITED DCI

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Causes of Death after Transplants Done in

1998-2002

HLAHLA--ID SIBID SIB

Infection(17%)

Other(13%)

Organ toxicity(13%)

Relapse (38%)

IPn (5%)

GVHD (14%)

AUTOAUTO

Infection (6%)

Other (9%)

Organ toxicity(8%)

Relapse (75%)

IPn (2%)

UNRELATEDUNRELATED

Infection (19%)

Other(17%)

Organ toxicity(11%)

Relapse (32%)

IPn (7%)

GVHD(14%)

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PostPost--TED SurvivalTED Survival

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Regimen-related toxicityCataractsNeurologicGonadalEndocrineGrowth & development

InfectionChronic GVHDRelapse of malignancy/New-2nd cancers

Late Complications of BMTLate Complications of BMT

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PostPost--TED Second CancerTED Second Cancer

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Diagnosis and stage of disease

Time from diagnosis to HSCT

Quality of HLA match

Ages of recipient/donor

Prior CMV exposure

Disease treatment

HSCT protocol

Factors AffectingFactors AffectingHSCT SuccessHSCT Success

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Information on persons treated under ordinary circumstances, with treatments selected by the recipients, by clinical judgements of physicians, or by nature rather than by experimental design.

Observational DatabaseObservational Database

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