HPC

Hematopoietic Progenitor Cell (HPC) Transplantation, often called stem cell transplant or bone marrow transplant, shares some principles with solid organ transplantation (like HLA matching), the immunology is fascinatingly different, with unique challenges like Graft-versus-Host Disease (GVHD) being a major focus

The Goal: Rebuilding the Blood and Immune System

• Why Transplant?: HPC transplantation aims to replace a patient’s diseased or damaged hematopoietic system (the bone marrow and the blood/immune cells it produces) with healthy progenitor cells. It’s used to treat:
  • Malignant Diseases: Leukemias (AML, ALL, CML, CLL), Lymphomas (Hodgkin, Non-Hodgkin), Multiple Myeloma. The goal is often to allow for high-dose chemotherapy/radiation to kill cancer cells (which also destroys the patient’s marrow) and then “rescue” the patient with new stem cells. Sometimes, the donor cells also exert a Graft-versus-Tumor (GvT) or Graft-versus-Leukemia (GvL) effect, where donor immune cells help eliminate residual cancer cells
  • Bone Marrow Failure Syndromes: Aplastic Anemia, Fanconi Anemia
  • Inherited Immune Deficiencies: Severe Combined Immunodeficiency (SCID), Wiskott-Aldrich Syndrome
  • Hemoglobinopathies: Severe Sickle Cell Disease, Thalassemia Major
  • Inherited Metabolic Disorders: Certain storage diseases
• The Cells: Hematopoietic Progenitor Cells (HPCs) are multipotent stem cells residing primarily in the bone marrow. They have the remarkable ability to self-renew and differentiate into all lineages of blood and immune cells (red cells, white cells of all types, platelets). They are often identified and quantified by the presence of the CD34 surface marker

Sources of HPCs

• Bone Marrow (BM): The traditional source. Collected via multiple aspirations from the donor’s posterior iliac crests under general or spinal anesthesia. Rich in stem cells but requires anesthesia and has some donor discomfort
• Peripheral Blood Stem Cells (PBSC): Most common source now. Donors receive injections of Granulocyte Colony-Stimulating Factor (G-CSF) +/- Plerixafor for several days. G-CSF “mobilizes” HPCs from the bone marrow into the peripheral circulation. The donor then undergoes apheresis (similar to platelet donation), where blood is drawn, passed through a machine to collect the CD34+ cells, and the remaining blood components are returned to the donor. Provides a higher yield of HPCs and usually faster engraftment than BM, with less donor discomfort than BM harvest
• Umbilical Cord Blood (UCB): Collected from the umbilical cord and placenta after birth. Contains a rich source of HPCs. Advantages include readily available (stored in cord blood banks), lower risk of transmitting infections, and less stringent HLA matching required due to the immunological naivety of cord blood T cells (leading to less Graft-versus-Host Disease). Disadvantages include lower cell dose (may be insufficient for larger adults), slower engraftment time, and inability to recall the donor for additional cells if needed

Types of HPC Transplants (Based on Donor)

• Autologous Transplant (“Auto”): The patient’s own HPCs are collected (usually PBSC) during a period of remission, stored (often cryopreserved), and then re-infused after the patient receives high-dose chemotherapy/radiation
  • Advantage: No risk of rejection or GVHD
  • Disadvantage: No Graft-versus-Tumor effect; higher risk of relapse if cancer cells were inadvertently collected with the stem cells
• Allogeneic Transplant (“Allo”): HPCs are collected from a donor other than the patient
  • Syngeneic: Donor is an identical twin (genetically identical). No GVHD risk, but also no GvT effect
  • Related Donor: Donor is usually an HLA-matched sibling. Historically the preferred donor type
  • Unrelated Donor (MUD - Matched Unrelated Donor): Donor found through international registries (like NMDP/Be The Match). Requires extensive HLA typing to find the best match
  • Haploidentical Donor (“Haplo”): Donor shares exactly one HLA haplotype (usually a parent, child, or half-matched sibling). Requires special techniques (like T-cell depletion or post-transplant cyclophosphamide) to manage the high risk of rejection and GVHD due to the significant HLA mismatch. Becoming more common due to donor availability
  • Cord Blood Donor: Uses unrelated UCB units
• Key Difference from “Auto”: Allogeneic transplants introduce a new immune system from the donor. This allows for the beneficial Graft-versus-Tumor effect but carries the major risk of Graft-versus-Host Disease (GVHD) and rejection

The Transplant Process

1. Conditioning Regimen Before receiving the HPC infusion, the patient undergoes intensive therapy
   • Goals
     • Eradicate the underlying disease (e.g., leukemia)
     • Provide sufficient immunosuppression to prevent the recipient’s immune system from rejecting the donor stem cells (critical for allogeneic)
     • Create physical “space” in the bone marrow for the new stem cells to engraft
   • Methods: High-dose chemotherapy, Total Body Irradiation (TBI), or a combination. Reduced-Intensity Conditioning (RIC) regimens use lower doses, relying more on the GvT effect, allowing older or less fit patients to undergo transplant
   • Consequence: Profound pancytopenia (low RBCs, WBCs, Platelets) and immunosuppression, making the patient highly vulnerable to infection and bleeding. Significant organ toxicities (mucositis, nausea, liver/kidney/lung damage) are common
2. HPC Infusion The collected HPC product (fresh or thawed cryopreserved) is infused intravenously into the recipient, much like a standard blood transfusion. This is often referred to as “Day 0”
3. Engraftment The infused HPCs travel (“home”) to the bone marrow niches, begin to proliferate, and differentiate. Engraftment is defined by the sustained recovery of blood counts, typically:
   • Neutrophil engraftment: ANC > 500/µL for 3 consecutive days (usually occurs ~10-21 days post-infusion, slower for cord blood)
   • Platelet engraftment: Platelet count > 20,000/µL without transfusion support (often takes longer than neutrophils)

Immune Complications: The Major Challenges of Allogeneic HCT

• Graft Rejection (Graft Failure): The recipient’s residual immune cells (especially T cells or NK cells) recognize the donor HPCs as foreign and destroy them. The graft fails to engraft, or engraftment is lost after initially occurring. More common with reduced-intensity conditioning, T-cell depleted grafts, or significant HLA mismatch. Leads to persistent pancytopenia
• Graft-versus-Host Disease (GVHD): The hallmark complication of allogeneic HCT. Occurs when mature, immunocompetent donor T lymphocytes (present in the HPC graft) recognize the recipient’s tissues as foreign (due to differences in HLA and minor histocompatibility antigens) and mount an immune attack against them
  • Acute GVHD (aGVHD): Typically occurs within the first 100 days post-transplant. Primarily affects:
    • Skin: Rash (maculopapular)
    • Liver: Jaundice, elevated liver enzymes
    • Gastrointestinal Tract: Diarrhea (often profuse, watery, or bloody), nausea, vomiting, abdominal pain
    • Severity is graded (I-IV). Can be life-threatening
  • Chronic GVHD (cGVHD): Usually occurs >100 days post-transplant (can occur earlier or evolve from acute GVHD). Can affect almost any organ system, often resembling autoimmune/collagen vascular diseases. Common features include skin changes (sclerosis, pigment changes), dry eyes/mouth (sicca syndrome), lung problems (bronchiolitis obliterans), liver dysfunction, joint contractures, GI issues. Major cause of late morbidity and mortality
  • Prevention/Treatment: Prophylactic immunosuppression (similar drugs to SOT: calcineurin inhibitors, methotrexate, mycophenolate, etc.) is standard. Treatment involves increasing immunosuppression (steroids first-line), potentially adding other agents (Rituximab, IVIg, ECP - extracorporeal photopheresis)

HLA Matching: Critical for Success

• Importance: Minimizing HLA differences between donor and recipient is paramount for allogeneic HCT to reduce the risk and severity of both GVHD and graft rejection
• Required Typing: High-resolution typing (identifying specific alleles) for HLA-A, -B, -C, and -DRB1 is considered essential. Matching at other loci (DQB1, DPB1) is increasingly considered
• Donor Hierarchy
  1. HLA-matched sibling (identical twin is perfect but rare)
  2. HLA-matched unrelated donor (MUD) (8/8 or 10/10 match preferred)
  3. HLA-mismatched unrelated donor
  4. Umbilical Cord Blood unit(s) (less stringent matching acceptable)
  5. Haploidentical relative

ABO Compatibility: Secondary but Important

• ABO antigens are not expressed strongly on HPCs themselves, so ABO incompatibility is not a barrier to performing the transplant (unlike SOT). However, it has significant implications for transfusion support and potential immune hemolysis during and after transplant
• Types of ABO Incompatibility
  • Major: Donor has ABO antigens recipient lacks (e.g., Group A donor -> Group O recipient). Recipient has pre-formed anti-A/anti-B (isohemagglutinins) that can attack donor RBCs produced after engraftment OR passenger lymphocytes in the graft making antibody. Risk of immediate or delayed hemolysis. HPC product may be plasma-reduced or RBC-depleted before infusion
  • Minor: Recipient has ABO antigens donor lacks (e.g., Group O donor -> Group A recipient). Donor graft contains plasma with anti-A/anti-B (isohemagglutinins) from the donor OR donor B cells that will produce anti-A/anti-B after engraftment. Risk of hemolysis of recipient RBCs shortly after infusion (“passenger lymphocyte syndrome”) or later as donor immune system takes over. HPC product may be plasma-reduced
  • Bidirectional: Both major and minor incompatibility exist (e.g., Group A donor -> Group B recipient). Risks of both scenarios
• Blood Bank Management: Requires careful planning for transfusion support around the time of transplant, often needing specific ABO group products depending on the incompatibility and phase of engraftment (e.g., using Group O RBCs and Group AB plasma initially for major incompatibility). Monitoring for hemolysis is crucial. Recipient’s blood type may eventually change to the donor’s type after full engraftment

Other Complications

• Infections: Profound and prolonged immunosuppression leads to high risk of bacterial, fungal, viral (CMV, EBV, Adenovirus, BK virus), and protozoal infections. Requires intensive monitoring and prophylactic/pre-emptive therapies
• Organ Toxicity: From conditioning regimens (mucositis, VOD/SOS - hepatic veno-occlusive disease/sinusoidal obstruction syndrome, lung injury, kidney injury, cardiotoxicity)
• Secondary Malignancies: Increased long-term risk due to radiation, chemotherapy, and chronic immunosuppression/GVHD
• Endocrine Issues: Hypothyroidism, hypogonadism, infertility, growth impairment in children
• Relapse: Return of the original underlying disease remains a major cause of treatment failure

Blood Bank Role: Essential Support

• HLA Typing Coordination: Working with specialized HLA laboratories
• Blood Product Support: Providing necessary RBCs and Platelets during the period of marrow aplasia post-conditioning. CRITICAL Requirements
  • Irradiation: Mandatory for all cellular components to prevent Transfusion-Associated GVHD (TA-GVHD) caused by viable donor lymphocytes in the blood product attacking the immunocompromised recipient
  • CMV-Safe: Leukocyte reduction or CMV-seronegative products are essential to prevent CMV transmission
  • Leukocyte Reduction: Standard practice
  • Managing ABO Incompatibility: Providing appropriate ABO group components pre- and post-engraftment based on the type of incompatibility (see above)
• Therapeutic Apheresis: Plasma exchange for TTP post-transplant, ECP for GVHD treatment
• HPC Collection/Processing/Cryopreservation: In centers where the Blood Bank/Transfusion Service manages the HPC laboratory. Includes CD34+ cell enumeration, processing (e.g., plasma reduction, RBC depletion), adding cryoprotectant (DMSO), controlled-rate freezing, and storage in liquid nitrogen. Thawing at the bedside prior to infusion

Key Terms

• Hematopoietic Progenitor Cells (HPCs): Multipotent stem cells that give rise to all blood cell lineages
• CD34: Surface marker commonly used to identify and quantify HPCs
• Mobilization: Process of stimulating HPCs to move from bone marrow into peripheral blood (using G-CSF)
• Apheresis: Procedure to collect specific blood components (like PBSCs) while returning the rest to the donor
• Conditioning Regimen: High-dose chemotherapy and/or radiation given before HPC infusion to eradicate disease and suppress the recipient’s immune system
• Engraftment: The process where infused HPCs establish themselves in the bone marrow and begin producing new blood cells
• Autologous Transplant: Using the patient’s own HPCs
• Allogeneic Transplant: Using HPCs from a donor
• Graft-versus-Host Disease (GVHD): Immune attack by donor T cells against recipient tissues; major complication of allogeneic HCT
• Graft-versus-Tumor (GvT) / Graft-versus-Leukemia (GvL): Beneficial effect where donor immune cells eliminate residual cancer cells in the recipient
• HLA Matching: Assessing compatibility of Human Leukocyte Antigens between donor and recipient; crucial for allogeneic HCT success
• Chimerism: The presence of cells from two genetically distinct individuals (donor and recipient) in one person after transplant
• Irradiation (Blood Products): Treatment to inactivate T lymphocytes in cellular blood components to prevent TA-GVHD
• Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome (SOS): Serious liver complication, often related to conditioning toxicity