GOALS

  • Elimination and replacement of diseased bone marrow, poorly functioning marrow, immunologically compromised marrow or metabolically compromised marrow
  • Protect against ultra-high doses of chemo
  • Establish immunologic platform

STEPS

  • conditioning -> preparing the recipient for txp
  • transplant -> day 0
  • engraftment -> waiting period while the marrow takes
  • recovery

DECISION TREE FOR TRANSPLANT -> disease, stage, and patient-specific decision

  • often a risk-benefit analysis taking into account the pt’s age, functional status and ability to tolerate the intervention (i.e. will they be able to tolerate receiving high-dose chemotherapy if auto-HCT? will the transplant appreciably affect their disease prognosis?)
    • age plays a huge role clinically in the prognostication/decision to do HCT; functional status also plays a large role
  • though, HCT is often for the ability to tolerate high-dose chemo or to achieve a graft-vs-tumor effect, there are certain malignancies where cure is not the goal (e.g., myeloma) but rather the goal is to prolong meaningful survival
  • in addition to knowing the specific primary malignancy, the team will often want to know the high-risk features (or specifically markers) of the disease -> often a specific gene mismatch or presence

AutoHCT

  • conditioning regimen: high/myeloablative
  • donor type: self, obviously
  • degree of match: perfect (duh, it’s your own cells)
  • source: bone marrow or peripheral blood
  • high doses of chemo and/or radiation designed to kill tumor -> therefore, autoHCT is really just stem cell rescue (not really a transplant); it allows you to use high-dose chemotherapy to wipe out the malignancy before rescuing the patient with the infusion of autoHCT

AlloHCT

  • conditioning regimen: high/myeloablative or reduced intensity
  • donor type: related or unrelated
  • degree of match: matched, mismatched, or highly mismatched (i.e. perfect match related donor (MRD) 10/10 HLA; matched unrelated donor (MUD); haploidentical (i.e. counterintuitively, you’re able to use half-matched cells from a family member–as long as you concomitantly infuse cytoxan, it works); mismatched unrelated (mmURD) or umbilical cord blood (UCB)
    • interestingly, the order above is the generally preferred order -> the haploidentical with cytoxan is more preferable than a mismatched unrelated donor even if they’re matching at 9/10 HLA
  • source: bone marrow, peripheral blood, or umbilical cord blood
  • two mechanisms for cure -> 1) immunologic via the graft vs. tumor effect and 2) chemo and/or radiation

PREPARATIVE/CONDITIONING REGIMEN

a combo of physical and chemical agents prior to stem cell transplant with purpose of reducing tumor burden and (in the case of the alloHCT) to allow engraftment of donor cells.

traditionally, the conditioning regimen was considered myeloablative

Myelosuppression -> physically to make space for the new marrow to reside

Immunosuppression -> to prevent rejection of the graft by the immune system of the recipient

MYELOABLATIVE CONDITIONING -> toxicity is higher but relapse is less -> long-term outcomes the same though (?survival) -> conceptually, you’d love to do a myeloablative everytime–minimize relapse potential and maximize ability for graft to attack tumor; in reality, this is too toxic for many pts

  • total body irradiation: 450 cGy single dose
  • total body irradiation: >/= 800 cGy fractionated +/- cyclophosphamide
  • standard busulfan/cyclophosphamide (“Bu/Cy”)
  • melphalan > 150mg/m^2 +/- other (“high dose melphalan”)-
  • Bu > 9mg/kg +/- other (“high dose busulfan”)

*anything other than the above 5 options is considered reduced intensity or non-myeloablative

NON-MYELOABLATIVE CONDITIONING -> less toxicity but higher relapse -> long-term outcomes the same though (?survival)

Reduced intensity

  • TBI > 200 but < 500 cGy single dose
  • TBI < 800 cGy fractionated +/- other
  • melphalan < 150mg/m^2 +/- other
  • busulfan < 9mg/kg +/- other

Non-myeloablative

  • TBI 200 cGy alone
  • fludarabine + TBI 200
  • fludarabine + cyclophosphamide

DONOR CHOICE

Matching the donor/recipient for HLA is the goal (the human leukocyte antigen molecule is the human version of the major histocompatibility complex)

Matching non-HLA loci are important -> not done as of 2013 lecture

HLA SYSTEM

Histocompatibility -> analogy is UPC code on cereal box

  • inherited histocompatibility for the HLA
  • sisters/brothers inherit the same possibility for HLA

Minor antigens -> different than major histocompatibility complex

  • they’re minor HLA antigens which aren’t taken into account (?)
  • therefore, the matched sibling donor is ALWAYS better than the “perfectly matched” unrelated donor

Mismatch -> there’s a benefit to mismatch (?) -> the greater the mismatch, the greater the graft vs. tumor effect which offsets the morbidity assoc with the also greater graft vs. host disease effect

SOURCE OF STEM CELLS

Mobilized peripheral blood -> less relapse, but higher chronic GvHD -> has more T cells

  • peripheral blood cells are hooked up to essentially a dialysis machine -> the cells are pheresed off the pt
  • also, better for pt’s with late stage cancer/advanced malignancy <- mobilized blood are activated cells
  • faster neutrophil and plt recovery with mobilized blood
  • less chance of graft failure (can think about this as you’re mobilizing blood from all over the body/it’s more robust than marrow aspiration)
  • req’s 12-15 days to engraft

Bone marrow -> higher relapse rate with bone marrow

  • marrow has higher rate of graft failure (think about this as you’re getting only a small, localized sample wherever you’re aspirating)
  • difficult to collect bone marrow -> ?general anesthesia required for pt
  • req’s 18-21 days to engraft (the period of neutropenia) -> quickest source to engraft

*no difference between peripheral blood and bone marrow with acute GvHD

*no difference between peripheral blood and bone marrow at 5y out -> similar survival, similar relapse

*?is marrow better though? -> marrow recipients have better psychological well being, less burdensome cGvHD (and therefore, less immunosuppressants)

*80% of transplants are still mobilized blood though -> ?should we switch back to marrow?

Umbilical cord blood -> less GvHD risk but higher risk for infectious complications (remember, the baby CD24/stem cells have not seen any antigens)

  • easiest of the stem cells to collect -> stored at time of delivery
  • longest time to engraft (~25d-4w), but highly variable time to engraft
  • has fewest number of T cells and they’re immature -> therefore, the recipients of umbilical cord blood are very immunocompromised
  • therefore, compared to peripheral blood and bone marrow, it is the lowest rates of GvHD
  • better graft vs. tumor effects w/ cord blood
  • b/c it immature from an immunologic standpoint, you can purposely mis-match cord blood
  • therefore, you can use 4 out of 6 matched units <- Cutler et al. uses 4/6 matches routinely w/ cord blood b/c it’s less immunogenic
  • also, if you could find more matched than 4 matches, you can probably find a matched adult donor and can use a matched adult donor instead of cord blood

OPTIMIZING HEMATOPOIETIC CELL TRANSPLANT

Treg and Tcon

  • Treg (regulatory T cells) are given on Day 0 while Tcon (or conventional T cells) are given on D +2
  • Treg are taken from the donor and infused into the host where they “teach” the infused HCT to tolerate the host tissues (i.e. avoiding GvHD)
  • this has allowed places like Stanford to test RCTs where pts get alloHCT and then randomized to no GvHD immunosuppressive ppx vs. GvHD immunosuppressive prophylaxis

NON-INFECTIOUS COMPLICATIONS OF TRANSPLANT

Checking for relapse or graft failure

Day +90 is ?standard day that check for relapse

  • check BMBx or PET scan
  • minimal residual disease (or, MRD) is saying that there’s no primary malignancy detectable -> at this point you can say CR1 or complete remission #1
    • they say minimal residual disease b/c it uses technological methods that stand in contrast to the traditional methods for determining relapse (i.e. looking at a path slide which is antiquated)

Post-Transplant Lymphoproliferative Disorder (PTLD)

  • B-cell proliferation due to therapeutic immunosuppression after transplant

Graft failure -> results in pan-cytopenia and high risk for infection or bleeding complications

  • could be reversed w/ additional donor cells (?kind of like a do-it-again approach?) -> donor lymphocyte infusion (?)
  • the major supportive measure w/ graft failure is transfusion support -> could also use myeloid growth factors (G-CSF, GM-CSF)
  • occurs by day 28 marked by pancytopenia, marrow aplasia, and ANC < 500

Graft rejection -> could be reversed with intensification of immunosuppression

  • also marked by pancytopenia
  • important that can use molecular chimerism to define graft failure vs. graft rejection
  • difficult to manage as difficult to tell if 1) pt req more immunosuppression (to inhibit immune-mediated rejection) or 2) less immunosuppression (to enhance the “graft vs. host” reaction of donor T cells against residual host cells
  • can provide more donor immunity via donor lymphocyte infusions (DLI)
  • can provide additional stem cells if concern is graft failure rather than immune-mediated rejection

GvHD

  • immunologic phenomenon; used to be defined by the temporal relationship to time of transplant
  • however, now, it is defined by the clinical features
  • interestingly, there’s an inverse relationship between probability of relapse and probability of GvHD
  • the greater the graft vs. tumor effect, the greater the potential for GvHD

Acute GvHD -> skin/liver/GI -> can occur anytime after initial engraftment but rarely beyond D+100

  • why skin/liver/GI? these are the cells that harbor a lot of antigen-presenting cells
  • 30% of pts with related-donor transplant
  • 50% of pts with unrelated-donor transplant
  • current standard of care as of 2013 was methotrexate and tacro/cyclosporine
  • skin w/ erythematous rash/desquamation, liver w/ transaminitis, GI with ileus/secretory diarrhea
  • about 50% of pts have skin findings only -> diffuse maculopapular rash w/ palms and soles involvement
  • ddx includes drug rash (but this will spare the palms and soles)
  • for liver involvement have to also include ddx of venoocclusive disease
  • will need biopsy for dx of GvHD liver
  • first line tx is 2 mg/kg methylprednisolone

Steroid-refractory GvHD -> progression after 3d of therapy or no response after 7d of therapy

  • second line tx is either biologics, TNF-alpha blockade, or chemo/phototherapy

Chronic GvHD -> resembes autoimmune disease -> 4 to 24 months post-Txp

  • generally, initial therapy is pred 1mg/kg/day AND either tacro 5-10ng/ml or cyclosporine 200-400ug/L
  • Graft failure -> the opposite of GvHD and much more rare
  • this is where the recipient’s immune system attacks the graft cells
  • typically, doesn’t happen 2/2 the immunosuppression the recipient is on
  • this is rare with HLA-matched donors -> if partially-matched graft, then you have a 5-10% risk for graft failure

Diagnostic criteria for bronchiolitis obliterans syndrome (BOS)

  • FEV1/VC < 70% or the 5th percentile of predicted
  • FEV1 < 75% predicted with > 10% decline (i.e. fast decline) over 2y
  • Absence of infection (this would disqualify it from being a “non-infectious complication of HCT”)
  • Air trapping supporting feature -> either A) air trapping on expiratory CT or small airway thickening or bronchiectasis by high-res chest CT or B) PFT air trapping (RV > 120% predicted or RV/TLC elevated over 90%

*current workup for BOS is currently an expiratory CT and PFTs; parametric mapping is currently under investigation -> therefore, should get a high resolution (i.e. helical) inspiratory and expiratory CT

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