Stem Cell Transplantation, ASPHO Flashcards
3 sources?
bone marrow, peripheral blood stem cells, cord blood
CD34 cell concentration to get good collection? Use what to get this?
> 20 cells/uL…GCSF (with or without chemo), plerixafor (–> peaks 5-11 hours later)
what if have ABO incompat with BONE MARROW donor?
need to do RBC depletion for major mismatches…plasma depletion for minor mismatches…PBSC generally have low RBC count so this is less of an issue
Role of cryopreservation?
done for autologus collections and cord blood, with DMSO.. smetimes needed for allogenic
what does DMSO do?
if you freeze a cell, it’s like a plate in a freezer and it can crack! DMSO –> membrane of cells–> keeps them flexible and less likely to break during freezing and thawing
CHallenge with DMSO?
room temp or warmed cells: can be toxic at high concentrations…infuse rapidly when thaw!
for what reason would you cryopreserve cells for allogenic transplant?
if cannot give cells to patient within 48-72 hours due to illness, etc–> need to cyropreserve the cells
problme with cyropreservation for AA pts?
could lead to increased rejection
sometimes do t-cell depletion, why?
decreased risk ofGVHD
2 ways to do t-cell depletion?
in vivo and in vitro
in vitro t-cell depeltion: hwo?
CD34+ selection OR CD3+ depeltion, CD3+/CD19+ depletion, alpha betaCD3+/19+depletion
problem with CD34 selection?
immune recovery very slow because ONLY have CD34 cells in your infusion
in vivo t-cell depletion how?
horse ATG
rabbit ATG
alemtuzumab
post-transplant cyclophosphamide
best to collect t-cells when?
early on, what high lymphocyte count, not too compromised from chemo
steps in car t cell prep?
collection, viral transduction, expansion, cryopreservation, infusion
how do you store stem cells for transplant?
fresh cells transpored cool; frozen cells in regulated shippers with continuous temp monitoring
stem cells stored how in lab?
liquid nitrogen tanks…viable for 30+ yrs
source for autologous transplant?
Peripheral cells!!!
source for allo transplant?
usually cord or marrow usually
t-cell count by source?
periphreal>BM>cord>t-cell depleted BM/periph
t-cell count affects?
time to neutrophil recovery faster with more t-cells…risk of graft rejection higher if few t-cells…gvhd high if lots of t-cells
CD34 count by source?
PBSC>BM>cord…higher if do t-cell depletion
early post HCT risk of infections by source?
highest in t-cell depleted>cord>BM>periphral
risk of graft rejection by source?
cord>BM>peripheral…higher if t-cell depleted
risk of acute GVHD by source?
peripheral=BM=cord…low if t-cell depleted
risk of chronic GVHD by source?
Peripheral>BM>cord…lower if t-cell depleted
target CD34 dose for BM adn PBSC transplant?
> 4-8x10^6 CD34 cells/kg recipient weight
target cells for cord blood transplant?
> 4 x 10^7 TNC/kg single unit…if mismatched, want >5 x 10^7…if 2 units, at least 3 x 10^7…more GVHD with 2 units though
if t-cell depleted/haploidentical cells, dose?
> 5-20 x 10^6 CD34 cells/kg recippient
also target <1x 10^5 CD3+ cells/kg recipient
allo trnasplant for leukemia: choose pbsc or cord if same match rate?
choose cord! don’t like to give unrelated donor peripheral cells in peds for allo
HLA: classes?
1 and 2
class I HLA compromised of?
A,B,C
class II HLA includes?
DR, DP, DQ
HLA antigens found where?
short arm of chrom 6
Class I HLA antigens found where?
almost all cells except some neurons
class II HLA antigens found where?
found on antigen-presenting cells, B cells
do we match for minotr antigens?
no
what does it mean to have a 6/6 match?
A,B,DRB1 matched
8/8 match=?
ABC and DRB1
10/10 match=?
ABC, DRB1, DQB1
12/12 match=?
A,B,C, DRB1, DQB1, DPB1
donor with respect to age consideration?
take the younger one!…most imp after HLA
what is the MOST important consideration for donor?
HLA
what the limit for unrelated donor mismatch BM/PBSC?
single allele/antigen mismatch…eg: 7/8
cord blood allowsfor waht level of mismatch?
4/6…although 6-7/8 better and high cell dose (>5 x 10^7) helps with mismatches
__ is preferred in peds over ___…data esp strong fron what?
BM; pbsc; non-malig disorders
PBSC –> ___ engraftment, __ GVHD
faster; more
when would you use PBSC?
used for high risk procedures (RIC, second trnaplants where need GVL effect)
need what from/to know what about peds donor?
- assent
- has relationship to recipient
- review of health conditoins
- screen fro HIV, HBV, HCV, syphilis, WNV, chagas
blood type matching ___; also want to match for?
helps (but not necessary)…CMV if possible
donor to avoid?
multiparous females (>1 preg), older female donor, donor who is much smaller than recipient
max volume you can take from donor?
20 ml/kg…goal of at least >4 x 10^6 CD34 cells/kg for recipient
ideal cord dose?
> 4 x 10^7 TNC/kg…at least 2.5 though!…and need >3 if 2 cords used…outcomes better with 1 cord (less GVHD)
best donor?
matched sibling
2 best donor?
matched unrelated donor, 8/8 or 10/10, BM preferred source
10/10 unrelated donor is similar to what?
single antigen mismatch sibling donor
fraternal or identical twin better donor?
FRATERNAL…identcal is like an auto transplant
reasons to not go forth with trnasplant?
-active infection/inflamm
-non-recovery of counts
-non-remission (TLS)
-MRD + (can still do but relapse risk higher)
-pulmonary function <50% FEV1, DLCOc
-LFTs>5x ULN
-Cardiac EF<50%
-GFR<70
-low Karonowsky score
-Psych disorder
some of these issues can be addressed with RIC
diff between non myeloablative, RIC, MA conditioning?
NMA: counts would eventually recover without transplant
RIC: may or may not eventually recover
MA: you would never recover
For AML/MDS, do you use MA or RIC?
MA…more relapse with RIC
conditioning for AML/RDS?
Busulfan-based: Bu/Cy, Bu/Fludarabine, Treosulfan/flu
Conditoning for ALL?
TBI-based!
decrease relapse by 21%, increase OS by 16% with TBI… give this >1200-13500cGy in 6-8 fractions + cy or VP 16 +/- thiotepa/fludarabine
conditoining for HLH?
RIC: flu/melphalan +/- thiotepa, bu/cy, treo/flu…and use serotherpay like rATG or campath to reduce GVHD
2 conditonsin with reduced prep?
FA (sensitive to TBI—> give min TBI, lower dose chemo), SCID (no prep!)
which disorders are hard to engraft?
SCD/thal
all autologous regimens are __ ___, ___ procedures
high dose, myeloablative
conditoning for NBL?
Carbo/Etop/Mel= CEM, tandem procedures
condtioning for CNS tumours?
Carbo/thio x 3 tandem, carbo/thio/etop x 1
conditioning for lymphoma?
BEAM (BCNU, Etop, Ara-C/Mel)
3 things in SCT that would prolong immune suppression?
use of cord blood
use of t-cell depletion
use of ATG
if you have prolonged immuen suppression, waht are you at risk for?
marked increase risk of viral reactivation/infection (CMV, adeno, EBV)…need surveillance for these!
other than prlonged immune suppression, what else increases risk of infection?
acute and chronic GVHD, particularly use of and dose of steroids = the critiical RF…best to use doses below 1 mg/kg and every other day
HLH pt who received RIC of alemtuzumab/flu/mel has a falling chimerism at day +55 (90 to 70%)…do what?
wean immune suppression rapidly and follow the chimerism
ways to measure chimerism?
FISH if sex mismatch, or short tandem repeats
in addition to whole blood chimerism can look at chimerism fo what?
t-cell (CD3)
if t-cell (or whole blood) chimerism of a normal (t-cell replete) transplant is falling what does this indicate?
may be rejecting
increased t cell chimerism from recipient in a malig case is associated with waht? what should you do?
relapse…wean immune suppression rapidly, consider donor leukocyte infusion
if rapid loss of t cell chimerism from recipinet in AA waht is this? do waht?
ongoing anti-marrow response; increase immune suppression (exception)
if no GVHD after tapering immunosuppression (in case of increased t cell chimerism from recipient in a malig case), do what next?
consider DLI
5 RFs for graft rejection
- NMA or RIC
- HLA mismatched donors
- cord blood/haploidnetial donors
- non-malig disordrse
- hyperinflamm/hyperprolif states
- infetion,viral reactivation
how to minimize risk fo graft rejection in NMA or RIC regimens?
use PBSC/agents like fludarabine
how to min risk of rejection in HLA mimatched donors?
avoid donor-specific abs
how to min rejection in cord blood/haploidentfical donors?
use intense, immunoablative regimens
how to min rejection in hyper-inflamm/prolif states?
calm down inflamm/prolif
how to min rejection in infection/viral reactivation?
control infection first, prevent viral reactivation if psosible
acute GVHD dx’ed when?
usually before day +100, but typically near time of engraftment
acute GVHD almost always invovles waht? and can involve what?
skin…intestine, liver, lung
of stages fo acute GVHD?
4
describe grading of skin aGVHD
1-rash <25%
2-25-50%
3->50%
4-generalized eyrhtroderma with bullae
describe liver grading of acute GVHD
1- bili 2-3 mg/dl
2- bili 3.1-6
3- bili 6.1-15
5- bili >15
describe gut grading of aGVHD
1-diarrhea 280-555 ml/m2/d
2-556-883
3->883
4- severe abdo pain
aGVHD grading IN GENERAL: how does skin translate?
skin grade 1-2–> grade one
skin grade 3–> grade three
skin grade 4- four
aGVHD grading in GENERAL: how does liver and gut translate?
liver or gut grade 1–> grade two
grade 2-3–> grade three
grade 4-> grade four
prevent GVHD how?
Calcinurin inhbitor like tacro or cyclosproin…mtx…ssome centres use mmf…others= sirolimus, ATG, pred, post-transplant cyclophos…..ALSO t-cell depletion! rATG, hATG, campath= alemtuzumab, CD34 selection, alpha beta CD3-CD19 depletion
t- cell dpletion increases risks of what?
infection
rejection
relapse
for mild GVHD (rash only), do what?
optimize levels of calcineurin inhibitor and give steroids topically
if progressive or multisystem GVHD,do what?
prednisolone 1-2 mg/kg/day
steroid refractory acute GVHD=?
no resposne at 3-7 days
do waht for steroid-refractory GVHD?
ruxolitinib for kids>12, also ECP, etanercept, infliximab, pentostatin…poor prog due to infectious complications
cGVHD diagnosed when?
usually after day +100
list 5 manifestations fo cGVHD
- vitiligo
- bronchiolitis obliterans
- vanishing bile ducts
- esoph strictures
- fat malabs
- poikiloderma
which SCT patients do best with GVHD?
- younger do better
- less adv disease do better
- good karofsky scores do better
- high plt counts
- matched sibling
tx for cGVHD?
pred 1 mg/kg/day…taper to 1 mg every other day over 6 weeks…most kids with more than mild disease require taco/siro/cyclosporine plus other meds…median duration of tx is 2 yrs for respondign patients
PTLD highly associated with waht?
t-cell depletion
4 ways to tx PTLD?
lower immune suppression
rituximab
cyclophosphamide
EBV_targeted cytotoxic t-lymphocytes
when does VOD present?
usually in the first 14 days after transpant, though can be through day +30
pathophys of VOD?
endothelial damage in hepatic venules–> plt deposition–> hepatic congestion–> cholestasis
which treatments are associated with VOD?
cy, busulfan, TBI….also sirolimus when used with tacro or cyclophos
list 5 signs/sx of VOD
- low plts (plt refractory)
- increased bili
- weight gain
- RUQ pain
- ascites
- renal insufficiency
- pulmonary edema
how to tx VOD?
- fluid management: diuresiss, keep fluid neg
- manage intravasc volume
- maage renal failure
- defibrotide
pathophys of transplant-associatd thrombotic microangiopathy?
endothelial damage from HSCT–> thrombosis nad fibirn depositonin the microcirc, with micoangiopathic HA and plt consuption
TA-TMA affects whihc organ mostly? others?
kidney…others= GI, neuro
How does TMA prseent?
low hgb low plts schistocytes increased LDH decreased haptoglobin
causes/associations fro TMA?
calcinuerin inhibitors (esp WITH sirolimus), TBI, high dose busulfan, infections
tx TMA how?
eculizimab can improve renal function; stop or lower calcineurin inhibitor
PRES stands for?
posteiror reversible encephalopathy syndrome
sx of PRES assocaited with what?
malignant hypertension
PRES linked to what tx?
calcineurin inhibitors
when does PRES occur?
days 30-100
how does PRES present?
headache, confuson, seizures, vision loss
Dx PRES how?
MRI imaging of brain
what do you see on MRI for PRES?
pattern of enhancement at post circulation
tx PRES how?
- control htn
- stop calcineurin inhibitors
most common problem 2 years after HCT?
relapse
list 5 late effects of HCT
cGVHD relapse secondary malig grwoth failure (TBI, CNS rad) hypot4 gonadal failure cardiomyoapthy from rad, anthra
what’s most dangerous, allo or auto trnasplant?
allo
GIve two disorders for which HCT can be used as gene therapy
Hurlier syndrome
X-linked adrenoleukodystrophy
indications for CAR T-cells?
-refractory B-ALL or second or higher relapse
% of pts who will either lose CARs and have CD 19 + relapse or CD 19 neg relapse?
30-35%, usually in first 6 months
in adult, CARs also used in?
NHL
AEs of CARs?
CRS, neuro events
