Introduction:

• Hematopoietic stem cell transplantation involves following steps
  • Conditioning- Administration of high dose chemotherapy and sometimes radiation to eradicate malignant disorder or poorly functioning bone marrow
  • GVHD prophylaxis- Administration of immune-suppressive, lymphotoxic chemotherapy to promote donor cell engraftment
  • Infusion of stem cells
  • Intense medical support- For patients to recover from the effects of conditioning regimen and complications associated with immunosuppression.
• Following are the types of HSCTs based on source of stem cells
  • Autologous- Patient’s own stem cells which are stored prior to conditioning are reinfused
  • Allogeneic- Stem are obtained from a donor
    • Matched related donor 
      • Syngeneic twin
      • Matched sibling donor (MSD)
      • Matched other relative- father/ mother/ son/ daughter
    • Matched unrelated donor (MUD)
    • Haploidentical donor- Patient’s father/ mother/ son/ daughter, by nature, are 50% HLA matched. They can also be used as donor.
    • Umbilical cord blood

Autologous HSCT- 

• Allows intensification in settings where there is correlation between dose and tumor response rate and hematopoietic toxicity is a limiting factor for dose intensification
• Principle- Very high doses of chemo is given with intent to kill all malignant cells. Lethal myelotoxic effect chemotherapy is later reversed by infusion of stem cells, which were stored earlier. (cryopreserved)
• Because of use of PBSC, engraftment is faster and there is decreased mortality
• 100 day mortality rate -<5%
• Conditioning regimens used
  • BEAM+/- Rituximab
  • High dose melphalan
• Tumor contamination in autograft leads to tumor relapse. Effective purging decreases contamination. Purging strategies include
  • Chemotherapy drugs: Commonly used agents – ifosfamide and cyclophosphamide. Stem cells express aldehydedehydrogenase with protects them from above agents. Purging is especially useful in AML auto grafts. Disadvantage is negative effect on hematopoietic stem cell recovery. Hence now largely been abandoned.
  • Monoclonal antibodies. Ex- Rituximab in B cell NHL
  • Stem cell (CD34+) cell selection from product: It has high cost and there are high chances of infection 

Allogeneic HCT: More complicated than auto SCT

• More pre transplant preparation is needed
• Greater risks of complications especially graft versus host disease.
• Higher non relapse mortality
• Considerably long post  transplant follow up
• Pre transplant chemo/ radiotherapy is required to eliminate tumor cells. This also eliminates recipient immunity otherwise infused donor cells are rejected 
• Eliminates tumor cells due to graft versus tumor effect.

Graft Vs Tumor Effect 

• Important mechanism of cancer eradication 
• Donor cells recognize residual host tumor cells and kill them
• Effector cells: 
  • CD8+ Cytotoxic T cells that recognize tumor associated antigens in context of class I microcytic hypochromic associated 
  • CD4+ T cells that recognize tumor associated antigens in context of class II microcytic hypochromic antigens 
  • NK cells and mediate their action via INF8 and IL2

Haploidentical donor

• Advantages
  • Immediately available donor.
  • Strong graft Vs tumor effect, hence less relapse.
• Disadvantages
  • GVHD in non T cell depleted product 
  • Graft rejection in T cell depleted product.
• Outcomes have improved after use of post transplant cyclophosphamide as GVHD prophylaxis

Indications for HSCT

Allogeneic:

• High risk, refractory and relapsed AML
• High risk, refractory and relapsed ALL
• MDS
• Aplastic anemia
• PRCA
• PNH
• Hemoglobinopathies
• Inherited immunodeficiency syndromes
• Osteopetrosis
• Genetic HLH
• Inherited metabolic disorders such as mucopolysacchridosis

Autologous:

• Myeloma
• Some NHL
• Relapsed/ refractory lymphoma
• Other tumors- Neuroblastoma, germ cell tumors
• Selected autoimmune disorders (Severe disease which is unresponsive to conventional therapies)- Multiple sclerosis, systemic sclerosis, SLE etc

Selection of candidates for transplantation

• Disease status at the time of transplant-Poor results with disease on board.Salvaging patients with advanced disease prior to transplant is needed.
• Performance score- ECOG performance score of 0-2 is needed to be eligible for transplant.
• Age-
  • Full dose allogeneic transplant -<55 years 
  • >55 years-Reduced intensity conditioning
• Comorbid medical conditions-Screen all potential transplant patients for heart and lung abnormalities and liver and kidney parameters and CMV, HBV, HCV, HIV
• Cardiac function- Ejection fraction must be >40%.
• Pulmonary function test- DLCO must be >40%
• Renal function- Creatinine clearance must be >40 cc/min
• Bilirubin must be <2-3 X ULN
• Histocompatible donors-Siblings are preferred. If not available-MUD. If MUD is not found haplotransplant.
• Psychosocial issues- It is necessary to assess risk of non-compliance, substance abuse, caregiver availability, financial aspects, and social support 

Immunogenetics:

• There are basically 2 forms of reactions in allogeneic stem cell transplant
  • Host versus Graft reaction (HVG)- Results in graft rejection
  • Graft versus Host response: Includes Graft versus host disease (GVHD) and Graft versus tumor effect.
• Antigens responsible for these reactions include
  • Human Leucocyte Antigens (HLA) /Major histocompatibility complex antigens (They function in antigen presentation in adaptive immunity. HLA system which includes more than 200 genes is located on chromosome 6)
    • HLA class I- A,B,C- They are found on all nucleated cells
    • HLA class II – DR, DQ, DP- They are found only on dendritic cells, B lymphocytes and macrophages.
    • HLA class III- Contains genes for complement factor and tumor necrosis factor
  • Minor histocompatibility antigens- 
    • HA-1, HA-2, HA-8, HY (coded by y chromosome)
    • They elicit weaker response
• T cell recognizes the peptide presented by antigen presented cell only if, it is presented along with same MHC molecule as encountered during priming. This concept is known as MHC restriction.
• Usually HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ are tested
• Common Definition in Human Leukocyte Antigen Genetics

HLA nomenclature

• Matching at A, B, C and DR-B1 (8/8) is considered critical.  Survival disadvantage by mismatch at any of these loci is same (Results of different studies are different). There is controversy regarding matching at HLA – DQ B1.
• Certain HLA mismatches produce good results and hence are termed “Permissive” mismatches. Uncovering such “Permissive “mismatches is incredibly complex due to polymorphic nature of HLA.

Non-HLA Genetic factors.

Even when HLA loci are identical GVHD and graft rejection can occur. This occurs because of other genetic factors which mediate transplant complications through various mechanisms. Such factors include.

• Killer immunoglobulin like receptors. 
• Cytokine, chemokine and immune response gene polymorphisms
• Minor histocompatibilityantigens .

Vector mismatching

• Presence of donor alleles not shared by recipient determines host versus graft allo recognition.
• Presence of recipient alleles not shared by donor provides the immunologic basis for GVH allo recognition.
• Bidirectional mismatching both HVG and GVH alleles are present at a given HLA locus.
• Unidirectional mismatching – situation in which either the donor or recipient is homozygous for the same allele at the mismatched locus.
• Unidirectional GVH vector mismatch occurs when the donor is homozygous and recipient is heterozygous and shares 1 allele with the donor.
• Unidirectional HVG vector mismatch is when patient is homozygous and donor is heterozygous and shares 1 allele with the patient.

KIR receptors

• Encoded on chromosome 19
• Present on NK cells
• Group A/ Inhibitory type are the predominant type
• If recipient is missing the appropriate ligand for donor NK cell inhibitory KIR (“Missing Ligand”), there is triggering of NK mediated killing of host target cells.
• Donor KIR ligand mismatching is associated with
  • No graft failure
  • No acute GVHD
  • 0% 5yr probability of relapse