Curs 4 - Imunologia Transplantului-TM

7/28/2019 Curs 4 - Imunologia Transplantului-TM

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Basics of Stem Cell

Transplant



Background

First successful transplants —late1960s

30,000-40,000 transplants performedyearly worldwide

>20,000 patients have survived >5

years

Lazarus HM. Autologous and allogeneic transplantation procedures for

hematologic malignancies. Manual of Clinical Hematology, 3rd edition2002:399-409



Graft Sources

Allogeneic: from another person

Syngeneic: from an identical twin

Autologous: from the patient

Choice of graft is based on diseasetype, patient condition, donorcompatibility and health



Graft Sources

Autologous Transplant

– No evidence of disease in the blood or

bone marrow – Transplant related mortality (TRM) lowest

with autos (<5%)

– Relapse rates are higher depending onthe disease

– Absence of graft versus tumor effects

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologicmalignancies. Manual of Clinical Hematology, 3rd edition 2002:399-409



Graft Sources

Allogeneic Transplants

– High TRM (30-50%)

– Lower relapse rates due to graft versus tumoreffects

– Graft versus host effects

Matched Related Donor (siblings)

– 25% chance a sibling will be a match

– The more siblings a patient has the betterchance for a match

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologicmalignancies. Manual of Clinical Hematology, 3rd edition 2002:399-409



HLA alleles

The considerable polymorphism of HLA is well-known.

HLA polymorphism is reflected by allelicsubstitution of many amino acid residues in thepolypeptide chains, especially the externaldomains which contain the peptide binding site.

This affects the spectrum of antigenic peptidespresented by the different allelic types of HLA molecules and the repertoire of responding T-cells.



The HLA genetics is complex

HLA polymorphism

Expression of HLA polymorphism –Typing

The transplanted graft represents a continuoussource of HLA alleles that can induce a rejectionresponse at any time post-transplant.

HLA matching can have a dualistic effect ontransplant outcome: it reduces rejection butconversely, it may promote other HLA-restrictedmechanisms of allograft injury.

Fundeni Centre for Immunogenetics and Virology



HLA Matching

6/6, 8/8, or 10/10

– HLA loci on chromosome 6

– HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ,HLA-DP

ABO incompatibility is not an exclusion


hematologic malignancies. Manual of Clinical Hematology, 3rd edition2002:399-409



Interpretation of results

Recipient D.F. Donor D.C.HLA HLA

A 02-24 A 02-24

B 18-18 B 18-18

C 07-07 C 07-07

DRB1 11-13 DRB1 11-13

DQB1 03-05 DQB1 03-05

KIR – B4 genotype KIR – B4 genotype

KIR –2DL1, 2DL2, 2DL4, 2DL5B, 2DS2,

2DS3, 2DS4004, 3DL2, 3DL3, 3DS1,

2DP1, 3DP1

KIR –2DL1, 2DL2, 2DL4, 2DL5B, 2DS2,

2DS3, 2DS4004, 3DL2, 3DL3, 3DS1,

2DP1, 3DP1


f



Recipient A.C. Donor C.R.

HLA HLA

A 03-24 A 03-24

B 18-44 B 18-44

C 05-12 C 05-12

DRB1 16-16 DRB1 16-16

DQB1 05-05 DQB1 05-05

DPB1 02-05 DPB1 02-05KIR – B4 genotype KIR – B4 genotype

KIR –2DL1, 2DL2, 2DL4, 2DL5B003-006,

2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,

3DP1003

KIR –2DL1, 2DL2, 2DL4, 2DL5B003-006,

2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,

3DP1003



F d i C f I i d Vi l




Recipient F.C. Donor F.E.

HLA HLA

A 02-03 A 02-03

B 07-40 B 07-40

C 01-03 C 01-03

DRB1 04-10 DRB1 04-10

DQB1 03-07 DQB1 03-07

KIR – A genotype KIR – A genotype

KIR – 2DL1, 2DL3, 2DL4, 2DS1, 3DL1,

3DL2, 3D33, 2DP1, 3DP1003

KIR – 2DL1, 2DL3, 2DL4, 2DS4, 3DL1,

3DL2, 3DL3, 2DP1, 3DP1003




Eligibility

Age < 65

– Autologous, mini-allo

Age < 55

– Myeloablative allogeneic

Exclusions

– CHF, uncontrolled diabetes mellitus,active infections, renal insufficiency



Indications Autologous

Transplant Multiple myeloma

NHL

Hodgkin’s disease AML

Neuroblastoma

Ovarian cancer Germ-cell tumors

Autoimmunedisorders

Amyloidosis

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

1826.



Indications for Allogeneic

Transplant AML

ALL

CML

MDS

MPD

NHL

Hodgkin’s Disease

CLL

Multiple myeloma

Juvenile CML

Aplastic anemia

PNH

Fanconi’s anemia

Blackfan-Diamond

Thalessemia major

Sickle cell anemia

SCID

Wiskott-Aldrich

Inborn errors of metabolism

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.



Preparative Regimens

Myeloablative

– High doses of chemotherapy +/- radiation

– 3 goals Eliminate malignancy

Immunosuppression to allow engraftment

Decrease graft versus host effects

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic malignancies.Manual of Clinical Hematology, 3rd edition 2002:399-409




Myeloablative Regimens


– Most common regimens

Cyclophosphamide/TBI Busulfan/Cyclophosphamide

Stem cells are essential to restore

marrow function

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic malignancies.Manual of Clinical Hematology, 3rd edition 2002:399-409





Therapy is based on disease

Other drugs

– Etoposide, BCNU, cytarabine, melphalan

Graft versus leukemia effects inallogeneic donors


1826.

Lazarus HM. Autologous and allogeneic transplantation procedures forhematologic malignancies. Manual of Clinical Hematology, 3rd edition2002:399-409



Umbilical Cord Blood

1st UCB transplant 16 years ago – Child with Fanconi’s anemia

Cell dose is given per recipient weight – Lower patient weights the high the cell dose

– 2 x 107 nucleated cells/kg

– 1.7 x 107 CD 34+ cells/kg

4/6 match UCB with sufficient cells has asimilar outcome to a matched or oneantigen mismatched MUD

Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord

Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.





– Cryopreserved

– Small number of stem cells

– Higher incidence of engraftment failure

Using more than one unit in adults

– Lower risk of GVHD – Degree of matching not as stringent

Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord Blood Transplants). AmSoc Hematol Ed Book. 2004:354-371.




Lower GVHD

TRM not different than MUD

Can be used with myeloablative ornonmyeloablative conditioning (on aclinical trial)

Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord

Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.



Complications

Early

– Mucositis

– Sinusoidal obstructive syndrome (VOD) Fluid retention, jaundice, hepatomegaly

– Transplant related infections

Damage to mouth, gut and skin Prolonged neutropenia


1826.



Complications

Early

– Pancytopenia

PRBC and platelet transfusions Broad spectrum antimicrobials

Antifungals if prolonged fevers 3-5 days

Lazarus HM. Autologous and allogeneic transplantation procedures forhematologic malignancies. Manual of Clinical Hematology, 3rd edition

2002:399-409



Complications

Early

– Graft Versus Host Disease

Acute GVHD to day 100 – Skin, GI tract, liver


hematologic malignancies. Manual of Clinical Hematology, 3rd

edition2002:399-409





GVHD In GVH diseases donor-derived immuno-competent lymphocytes

react with HLA incompatible recipient cells and induce inflammatoryresponses in host tissues such as the skin and gastrointestinal tract.

GVH disease seems more likely in cases whereby the donor is well

matched for the patient.

Direct and indirect HLA allorecognition mediate GVH reactions if immunocompetent donor cells recognize recipient incompatibilities.

During infection, microbial antigens are processed by APC andpresented via HLA molecules to T-cells that elicit cytotoxic and DTH-like inflammatory reactions in the allograft.




Complications

Early – Graft Rejection

Host versus graft Drug injury to marrow

Viral infections: CMV, HHV-6 & 8

– Interstitial Pneumonitis

Diffuse alveolar hemorrhage Too few donor stem cells

ARDS often caused by CMV



edition2002:399-409



Complications

Delayed

– Chronic GVHD

Scleroderma or Sjogrens syndrome Bronchiolitis

Keratoconjunctivitis

Malabsorption

Cholestasis

Esophageal stricture




Late Complications

Secondary Tumors – Acute leukemias, solid tumors, MDS – Months to years after transplant

– Increased incidence with TBI Late Infections

– Bacterial, viral fungal – Months after transplant

– Associated with GVHD – Need repeat vaccinations

Pneumovax, Hep B, Hemophilus influenza b, poliovirus,diphtheria/tetanus, flu



edition2002 399 409

Curs 4 - Imunologia Transplantului-TM

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