BMT

BMT timing:

Day –10 to –7: “conditioning” makes space for new cells, and immunosuppresses, gets rid of leukemia. Includes: total body radiation, cytoxan, VP16, busulphan, campath, and ATG (a T-cell suppressant) (see Medications). During this time, peripheral WBC drops to 0.

Day 0-14:

Low counts
Mucositis (from tongue to anus): diarrhea, loose stool, due to effects of chemo hitting rapidly dividing cells
VOD (day +2-3 to +27). Supportive tx, can give ATIII for increased clotting
Infection: reactivation of viral (HSV, adeno), bacterial, fungal
Hemorrhagic cystitis: acrolein binds to bladder wall. Mesna lines bladder and binds acrolein and other urotoxic metabolites of oxazaphosphorines (cyclophosphamide or ifosfamide) to form stable, non-urotoxic compounds. The half-life of mesna is shorter than the half-life of ifosfamide or cyclophosphamide, therefore multiple doses or continuous infusion of mesna, beyond the end of the oxazaphosphorine infusion is required to prevent urotoxicity.

+14 counts start to come up. First monocytes and segs, then lymphocytes

+30: should see engraftment (ANC >500 qd x 3 days, may recontaminate gut w/ yogurt or lactonex (lactobacillus) 1 packet tid x 2 days). Make platelets, blood, monocytes come back in. GVHD: where donor T-cells at day +30 attack. Acute GVHD (< +100), chronic GVHD > +100 days out). If no engraftment at day +30, may do BM aspirate to see. How to check engraftment? if donor is opposite sex, do FISH on sex chromosomes of host, and should see donor sex chromosomes ie. XX in an boy. If same sex donor, can do DNA fingerprinting i.e. Short tandem repeats

+20 to +60: higher risk of CMV (in white cells)

+100 and out: infection is unrelated to transplant, usually encapsulated organisms due to bad spleen

Complications of BMT:

Pancytopenia – tx: tranfusion, G-CSF (GM-csf would cause more reactions, due to monocyte stimulation and cytokine release), thrombopoietin, stem cell factor
Mucositis – all patients will experience ~. Mucosal disruption predisposes to infection/bleed
- Grading:
  - 1: erythema only
  - 2: ulceration
  - 3: confluent ulcers, epigastric/swallowing pain, substernal tenderness
  - 4: needs intubation, blood, emesis
VOD
GVHD – (see MHC also)
- Cutaneous: Looks maculopapular, morbilliform (like measles); also gut and liver disease
  - Why? Monocyte/macrophage type cells are destroyed by pre-chemo, and linger on, only to be attacked by the new graft. In skin (langerhans cells), in liver (kupffer cells) and endothelial type cells in liver.
- Need donor T-cells to do the rejecting AND an immunocompetent host
- This is why it is important to deplete T-cells from donor (irradiate, Cyclosporin, FK)
- Treatment: high dose steroids 2-10 mg/kg/d, CSA/FK506, ATG (anti-thymocyte globulin), MMF (cellcept), anti TAC Ab (zenapax), photopheresis
- Also: PUVA therapy (psoralen-UVA): give psoralen, it binds to DNA, and ‘sticky’ when exposed to UVA, so T-cells can’t divide.
- CHRONIC GVHD
  - Looks like autoimmune disease
    - Scleroderma, xeropthalmia, xerostomia, gut injury, malnutrition/infection, pulmonary dz (fibrosis, eo’s)
    - Any organ w/ immune reaction/activity
    - Autimmune hemolytic anemia or pancytopenia
  - Rx: cyclosporin, tacrolimus, prednisone, MMF, PUVA, campath Ab, rituximab ab (activates complement and cell lysis), thalidomide, topical retinoids
Graft failure: poor microenvironment, due to host cytotoxic t-cells, not enough stem cells
Graft rejection: pt not prepared intensely enough (not immunodepleted enough) or T-cells in graft are too depleted
Infection:
- Early: 0-+50: Neutropenia, therefore: bacterial gram pos/neg, HSV/adeno (may cause PNA, hem cystitis, bm supresssion, hepatitis), candida infections (due to no t-cells, and broad spectrum abx killing competitive flora)
- Mid: +30-100: white cells develop, acute GVHD and reaction, therefore: CMV occurs (needs white cells)… adeno, encapsulated organisms grow (no opsonizing agents), aspergillus appears (steroid treatment for GVHD paralyzes immune system (incl macrophages, neutrophils need to kill aspergillus). Non bacterial infections are more common, because neutrophils are becoming more numerous
- Late >+100-365: chronic GVHD. VZV develops at this time because immune function is necessary for this dz to break out.
- Post-transplant immunodeficiency occurs for about a year. Live virus vaccinations may be given 2 years post transplant. If GVHD occurs, the pt can never have live virus vax.

Terms:

MUD: matched, unrelated donor; 5-6 /6 match
UCBT: unrelated cord blood transplant
Histocompatible match: 6/6 match sib or related donor
Autogeneic
Allogeneic (MUD, sib, cord)
syngeneic (twin)

BMT indications:

Absolute

Relative

Leukemias, anemia, SCIDs, WAS

1) SCIDS (no T cells, +/- B or NK cells)

2) AML (during 1^st remission if sib donor)

3) Aplastic anemia: sib donor, transplant within 2 weeks? 90% survival. Rx: ATH, GCSF, Cyclosporin

4) Wiscott-Aldritch (small platelets): txp before age 6

5) ALL: if relapse on chemo, txp during 2^nd remission results in 50% survival for sib donors, 40% for unrelated. If txp 3^rd remission, 10% survival. 4^th remission: no indic for txp.

6) ALL: txp during 1^st remission IF philadelphia (t9,22)(+)

7) CML: BMT is the only cure (glivac)

Sickle cell

Thalassemias

Hurlers

Niemann pick

ALD (?) not many done

Neuroblastoma

Gauchers

Brain tumor

osteosarc

Transplantation

1) stem cells can be obtained from BM, peripheral blood stem cells (PBSC), cord blood

2) why txp?

Eliminate abnormal cells (leukemia, sickle, thal)

Provide missing cell lines (SCID, severe aplastic anemia)
To provide missing enzyme (glycogen storage dz)
To corrrect immune imbalance i.e. autoimmune dz, MS, scleroderma, lupus
For genetic, acquired immune deficiency
Malignant hematological dz
Malig solid tumor (as rescue after toxicity of chemo (autogeneic = take out BM 1^st, then give back later) (BM is destroyed by intensive chemo)

3) Most common indications for BM txp

Leukemia
Chronic leukemia
Lymphoma, other malig
Aplastic anemia
Other (scid, metabolic)

4) Bm txp = more accurately referred to as “hematopoeitic stem cell transplant” HSCT

Autologous – from BM, PBSC, or cord
allogeneic
HLA matched
1. sib donor, related, partially matched unrelated, MUD
2. haploidentical, related
syngeneic (twin)
xenogenic

Conditioning

may do without it
for myeloablation and immunosupression
a. total body radiation (1200-1500 centiGray)
b. busulphan, melphalan – for ablation; kills at stem cell level
c. VP-16, cytoxan, ATG, campath – for immunosuppresion
Reduced intensity
Non-myeloablative regimen
a. Fludarabine, campath, ATG, 200 cGy total body irrad. – immunosuppressive

Immunosuppression, pre and post txp

pre
cytoxan, ATG, campath, TBI, fludarabine
post
cyclosporin, ATG, MTX, steroid, tacrolimus (FK506), rapamune, campath, zenapex

Goal: to eliminate abnormal cells, make space, make recipient accept graft, prevent GVHD