REZVANI STANFORD 2018 – HEMATOPOIETIC STEM CELL TRANSPLANT (HCT)

Updated 12/18/19

Autologous – own cells

Allogeneic – someone else’s cells

MCC dx is Multiple Myeloma

  • these days we mostly do auto-transplants; not allo’s <- AML and ALL and MDS are the biggest indications for the allo’s

AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANT (less risky/less likely to be ICU) -> point is that you’re removing their cells to allow for much much higher chemo tx than would otherwise tolerate then giving them their cells back

  • remember the actual “taking the cells and giving them back” doesn’t do much -> it’s the ability to give them really really high chemo tx that they get while you take out the blood cells prior to giving them back
    • step 1) collect cells via IV
    • step 2) store them frozen
    • step 3) they get high dose chemo -> they get pancytopenia and mucositis
    • step 4) they get the cells back -> takes 10-14 days to engraft
  • bone marrow failure -> dose limiting the myelo-toxic doses via taking the stem cells out temporarily
    • can think about it as “high dose chemo”
  • need to hit up the “right” pt population -> choosing the population where the curative dose of chemo would lead to death via chemo <- so take out the cells temporarily
  • risk for MDS which is roughly 5% at 10 years out

multiple myeloma -> remember that autologous xplant isn’t curative; just prolonging remissions

  • there’s no way to avoid contamination of stem cell product w/ tumor cells

Lymphomas -> autologous xplant could be curative in this case

leukemias are less for autologous HCT b/c less curative

*bone marrow bx before and after collecting the cells

AUTO HCT -> mobilize via G-CSF, chemo, collection via apheresis, storage in DMSO/freezer

  • OP process
  • pancytopenia, mucositis side effects
  • conditioning chemo
  • median time to engraftment = 10 days
  • long term side effects -> MDS risk 5% at about 10 years

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT -> point for allo- as opposed to auto- is that you’re relying on the donor’s alloimmune attack against the residual malignancy. This is a form of immunotherapy; whereas the autotransplant above is form of chemotx.

  • different principle than auto
  • you’re getting the entire donor’s immune system <- that means you’re getting the donor’s entire immune system
    • “graft vs. tumor effects” whereby the alloimmune attack by donor cells on residual malignancy
  • main criteria is HLA matching
    • first choice = HLA-identical sibling
    • second choice = HLA-matched unrelated donor from National Marrow Donor Program

age limit in the unrelated donors, the cut off is about 60 yo -> ethics reasons

cord blood

  • collected from placenta at birth
  • rich in hematopoetic cells but low in T cells
  • b/c immunologically naive, you have greater tolerance for non-HLA matching…

can match peeps who are matched at 9/10 rather than 10/10 but your risk for GvHD goes up

umbilical cord blood has HSC

  • since these cells are more immunologically naive, you can get away with more HLA mismatching and still use them
  • typically you use two units and one will usually engraft -> 20 years ago, rates of non engraftment were very high b/c only used one unit

haploidentical family donor -> someone who shares half your HLA type

  • HLA disparity leads to GvHD
  • not having a fully-matched donor (i.e. when you’re haplo-identical), you have risk that the immune cells won’t fully attack the malignancy; there’s some concern that you may be at risk for long-term relapse

*few direct head-to-head comparisons with conditioning regimens

  • common elements -> total body radiation (TBI…small doses) and chemotherapy agents
  • “myeloablative” is the name of the game -> esp with autologous HCT, you’re using high dose during the conditioning regimen since you’re depending on the chem to cure the disease
    • carmustine, etoposide, cytoxin, etc are the common ones for myeloablative tx

concept of the allogenic HCT is that you’re relying on the immune GVT effect from donor cells

  • so conditioning regimen can be less “myeloablative” than the autologous
  • “reduced intensity,” “mini,” “non-myeloablative,” “reduced toxicity,” or “sub-myeloablative” terms
  • the more intensive the conditioning regimen = more likely to eradicate the disease = but you’re more likely to get side effects

POST TRANSPLANT COMPLICATIONS

usually related to conditioning chemo regimen

mucositis

fevers

pancytopenias

SOS – sinusoidal obstruction syndrome -> liver complication of obstruction from chemo

  • usually in the first couple of weeks post-TXP
  • TTP RUQ, ascites
  • can get hepatorenal syndrome

GvHD

  • allogenic tx
  • donor cells usually attack the malig; when it spills over and attacks the recipient, that’s GvHD
  • acute GvHD is usually within first 90d after transplant
  • skin rash
    • can try to get skin or EGD bx of GI tract
      • skin-only GVHD or upper-gut GVHD -> they tend to do well
      • lower-gut GVHD is dangerous/has large vol diarrhea usually
  • N/V/D
  • nonspecific rashes
  • ultimately, it’s a clinical dx; however, can try to use skin or endoscopic bx -> need to differentiate endoscopic dx (GvHD vs. CMV)

TREATMENT FOR ACUTE GVHD

  • prednisone -> usually 1-2 g/kg daily
    • can usually taper down after couple of weeks

STEROID-REFRACTORY GvHD is dangerous

      • 5-15% of people have steroid-refractory GvHD -> often fatal
      • once you destroy the crypt cells/gut stem cells, the gut epithelium is unlikely to repair
      • bacterial translocation/protein loss/malnutrition

IMMUNOSUPPRESSION

  • tacro (calcineurin inhibitor)
  • cyclosporin
  • HOWEVER, don’t need to be on immunosuppression lifelong -> donor cells will typically develop tolerance -> immunosuppression pulled back about 6w after HCT typically
  • GvHD is seen in 20-50% of patients
  • e.g., Stanford pt with initial tacro, but that was stopped 2/2 AKI; and, b/c of AKI they were never started on methotrexate
    • however, they were then started on mycophenolate mofetil (MMF) with reduced dose 2/2 AKI as well as sirolimus

CHRONIC GvHD (usually 90-100 days later) -> looks like Lupus or autoimmune diseases

  • various degrees of severity -> some mild, some debilitating

CAUSES OF DEATH

usually the primary problem that brought them in (i.e. not the GvHD) is the cause of death in these people

COMPLICATIONS

INFECTIOUS

  • ASPERGILLUS
    • suspicious looking lesions -> mold ppx
    • bronch
    • “halo sign” -> hazy infiltrate around fungal nodule
    • crescent sign -> cavitary lesion w/ air pocket around it
  • optimal tx is unknown -> concept seems to be keep them on mold control agent until they’re off their immunosuppression <- steroids seem to be arisk for this
    • voriconazole
    • posaconzaole
  • CMV
    • monitored weekly
    • MCC viral pathogen in BMT
    • 50% of BM pts have CMV reactivation (i.e. most people have been exposed to CMV in their life)
    • rely on timely/monthly CMV PCR
    • we probably overtreat for CMV
    • CMV pneumonitis is really high mortality
  • DIFFUSE ALVEOLAR HEMORRHAGE
    • in the ddx when there’s respiratory failure
    • usually in the first month after transplant
    • p/w progressive resp failure
    • very uncommon in autologous HCT
    • much more common after allo HCT
    • CXR similar to any diffuse alveolar disease -> b/l fine reticular opacities -> pulm edema/ARDS
    • bronch dx and then BAL returns with increasingly bloody lavages
      • tx with high dose steroids -> belief is that donor cells are causing inflammation
  • GI PCR panel
    • At Stanford, tests for Campylobacter, Plesiomonas, Salmonella enterica, Shiga-like toxin-producing E coli O157, Shigella, Vibrio cholerae, non-cholerae Vibrio species, Yersinia enterocolitica, Cryptosporidium, Cyclospora cayetenesis, Entamoeba histolytica, Giardia lamblia, Adenovirus, Astrovirus, Norovirus, Rotavirus, Sapovirus
  • Respiratory PCR panel
    • At Stanford, tests for Flu A, Flu B, RSV, Parainfluenza viruses 1-4, metapneumovirus, Rhinovirus/Enterovirus, Adenovirus, Coronavirus, Chlamydi pneumoniae, mycoplasma pneumoniae
  • CMV PCR quantitative
    • tests plasma
  • HSV 1/2 PCR
    • can look at blood or lesions if there are any
    • can look at swab/lesion, BAL, CSF, ocular fluid, or plasma
  • VZV PCR
    • can look at swab/lesion, BAL, CSF, ocular fluid, or plasma
  • AFB culture
    • lung tissue can be sent for AFB
  • Fungal culture or beta-D-glucan
    • can send lung tissue or blood
  • Viral culture and Adenovirus DNA PCR
    • can send tissue

IPS -> idiopathic PNA syndrome. This is a FIBROSING PROCESS.

    • catch-all term -> diffuse alveolar dmg
    • general term for diffuse alveolar injury for which cannot find an infection
    • multilobar opacities -> progressive hypoxic resp failure
    • usually in the first 4-6 months after HCT
    • not-great evidence, but treated w/ steroids -> usually 1g/kg glucocorticoids; sometimes they go pulse on them with 1g

BRONCHIOLITIS OBLITERANS -> how chronic GvHD presents itself. Defined by granulation tissue in the BRONCHIOLAR LUMEN.

    • they have severe airflow obstruction after allo-HCT
    • usually thought to be similar process as in lung xplant -> mismatch between the lung and the immune system
    • tx w/ inhaled and systemic steroids
    • azithro <- recent evidence that azithro could be harmful for these pts…not sure what study this was…
    • montelukast

ORGANIZING PNA (formerly BOOP) -> granulation tissue in DISTAL AIRSPACES. This is an INFLAMMATORY PROCESS.

    • many patchy infiltrates -> chest CT looks really bad out of proportion to sx
    • GGOs, nodules, bronchial wall thickening and patchy opacities

bone marrow xplant team categorizes pts at Stanford based upon their risk for ICU

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