chemo/radiation treatment: higher doses produce greater tumor killing, but also kill marrow
Þ transplant can circumvent this problem and allow more aggressive treatment (marrow ‘rescue’)
transplant can be used to completely replace non- or dysfunctional marrow (leukemias, multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphomas); can also be used in treatment of solid tumors (breast, ovarian, germ cell cancers)
also used in non-malignant conditions: myelodysplasia, aplastic anemia, congenital immune deficiency, hemoglobinopathies (sickle cell, thalassemias), storage diseases, autoimmune disorders (RA, MS - currently investigational)
Types of Transplant
allogenic
: best is a sibling with fully matched HLA antigens; due to codominant inheritance there is a 25% chance of any one sibling having an HLA match - chance of a match increases with number of siblings: 1-(3/4)N
unrelated HLA compatible donors
aren’t as good (2x risk of GVHD), but they work in a pinch and are getting more use; the National Marrow Donor Program is a catalog of about 4M people willing to donate if they are crossmatched to a needy patient
umbilical cord blood
: beginning to get more use (~ 800 done to date); is associated with a decreased risk of GVHD, EBV/CMV infection, levels the ethnic imbalance in current donor pool (most are white)
older donors are not as good, CMV+ donors also aren’t as good
syngenic
(identical twin): obviously the best match, but rare
autologous
(donate to self): stem cells are gathered from the patient and ‘good’ cells are isolated by various methods (including turmor-cell specific Ig); and these healthy cells can be re-infused into the patient
eliminates GVHD (mostly), but can cause relapse if malignant cells are infused
Mechanics of Transplant
direct harvest
: most common method currently; harvest is from the posterior iliac crest
peripheral blood
: cells are collected from peripheral blood via pheresis teqniques; recombinant growth factors can be used to increase the number of stem cells in the peripheral blood, or cells can be collected after rebound from chemo treatment
treatment after harvesting
: removal of immunocompetent cells (I.e. T-cells) to decrease GVHD; removal of malignant cells; positive selection of stem cells
Toxicities
opportunistic infections
: it takes several weeks for the infused cells to migrate to the marrow, set up shop, and render the host immunocomptent; supportive therapy during this interval period is very important to prevent infections and hemorrhagic problems
: more common in non-related donations or older donors
graft vs. host disease (GVHD)
: mediated by both cellular and humoral factors (cells produce cytokines)
wide spectrum of severity
acute
: occurs 20-100 days post-transplant; symptoms include skin, liver, GI; mediated by donor T-cells
chronic
: > 100 days post-transplant; symptoms more widespread (skin, liver, GI, MSI, lungs, eyes); mediated by stem cell progeny; more common in adults due to less functional thymus; kids have an active thymus and these new cells are better screened for self-identification
allogenic
: 40% with sibling matched donors; 80% with unrelated donors
autologous
: used to be thought impossible; can be induced with agents like cyclosporin
Post-Transplant Immunotherapy
allogenic: prevention of GVHD
autologous: attempt to induce graft vs. tumor
Mini-Transplant
(non-myeloablative): only part of the host cells are killed; the graft is made, making the recipient chimeric; once the graft has taken, CD8+ cells are infused which hopefully kill off the tumor and the rest of the host’s marrow