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Hematopoietic Stem Cell Transplantation
for Children: PHO Boards Prep
Michael Pulsipher, MD
Professor Of Pediatrics
Primary Children’s Hospital
Huntsman Cancer Institute/University of Utah School of Medicine
Chair, Pediatric Blood and Marrow Transplant Consortium
HLA and Donor Issues
An 18-month-old child with ALL in second remission is referred for
transplantation. Which would be the best donor for this child?
A.
The child’s own sorted cord blood (cell dose
5X10^6/kg)
B.
A 55-year-old female unrelated donor, 7/8 match
(willing to donate marrow or peripheral blood stem cells)
C.
A cord blood unit matched at 4/6 antigens: cell dose
5.4x106/kg
D.
A 40-year-old male unrelated donor matched at 8/8
loci (only willing to donate peripheral blood stem cells)
E.
A cord blood unit matched at 6/6 antigens (HLA A, B,
DRB1) with a cell dose of 4.0x106/kg
HLA and Donor Issues
An 18-month-old child with ALL in second remission is referred for
transplantation. Which would be the best donor for this child?
A.
The child’s own sotred cord blood (cell dose
5X10^6/kg)
B.
A 55-year-old female unrelated donor, 7/8 match
(willing to donate marrow or peripheral blood stem cells)
C.
A cord blood unit matched at 4/6 antigens: cell dose
5.4x106/kg
D.
A 40-year-old male unrelated donor matched at 8/8
loci (only willing to donate peripheral blood stem cells)
E.
A cord blood unit matched at 6/6 antigens (HLA A, B,
DRB1) with a cell dose of 4.0x106/kg
Human Leukocyte Antigen Groups
(HLA, Chromosome 6)
HLA Loci and Known Alleles
Class I (A, B, C)
Found on almost all cells (except some neurons)
 HLA-A
 HLA-B
 HLA-C
Class II (DR, DQ, DP)
Found on antigen-presenting cells, B cells
 DRB1
 DQB1
 DPB1
 DRB 3,4,5
2946
3693
2466
1684
712
472
58, 15, 21
Minor HLA Antigens—If it were only as simple
as HLA
Minor H Antigens Encoded by Autosomal Genes




HA-1 – HA-7
A2-1 – A2-4
B7-1 – B7-6
A3, A11, A29, B44, B65, Cw7
Minor H Antigens Encoded by the Y
chromosome




HLA-A2-HY
HLA-A1-HY
HLA-B7-HY
B8-1
Approach to HLA by Stem Cell Source
Table Level of Human Leukocyte Antigen (HLA) Typing Currently Used for
a,b
Different Hematopoietic Stem Cell Sources
Class I Antigens
Class II Antigens
Stem Cell Source
HLA A
HLA B
HLA C
HLA
DRB1
HLA
DQB1
HLA
DPB1
Matched Sibling
BM/PBSCs
Antigen
Antigen
Optional
Allele
Matched
Sibling/Other
Related Donorc
BM/PBSCs
Allele
Allele
Allele
Allele
Optional Optional
Unrelated Donor
BM/PBSCs
Allele
Allele
Allele
Allele
Optional Optional
Unrelated Donor
Cord Blood
Antigen
(Allele
Optional)
Antigen
(Allele
Optional)
Allele
Optional
Allele
Optional Optional
Stem Cell Sources—Different Ways to Grow a
New Bone Marrow
• Reported Sources
– Fetal Liver Cells
– Single or small numbers of “stem cells”
• iPSCs
– Umbilical Cord Blood (UCB)
– Bone Marrow (BM)
– Cytokine Mobilized Peripheral Blood
Mononuclear Cells (PBMC)
Bone Marrow—the Traditional
Source
Other Sources—Peripheral Blood Mononuclear
Cells and Umbilical Cord Blood
Hematopoietic Cell Sources—Content
of the Product Dictates Uses
• Autologous Transplant (High
Dose or Mega-Dose Therapy)
– Bone Marrow (risk with harvest)
– Cytokine Mobilized Peripheral
Blood Mononuclear Cells
(PBMC, quick engraftment)
– Manipulation of either source to
remove cancer cells or alter
immune response
Winner—PBMC!
• Allogeneic Transplant
– Umbilical Cord Blood (few Tcells, increased risk of rejection
and slow engraftment, can use
safely with more HLA
mismatches, less chronic GVHD)
– Bone Marrow (Intermediate Tcells numbers, intermediate
rejection and GVHD)
– PBMC (More T-cells, rapid
engraftment, less early transplant
morbidity, probably more chronic
GVHD)
Winner—?
Levels of Matching
Key Considerations Donor/HLA
• HLA match trumps everything
• Single allele/antigen mismatch is all that is
allowed for BM/PBSC (7/8)
• Cord Blood allows 4/6 matches
– 6-7/8 better, high cell dose helps with mismatches
• BM is preferred in pediatrics over PBSC
– Data especially strong for nonmalignant disorders
– PBSC results in faster engraftment, more GVHD, used
for reduced intensity regimens and second HCT
Screening a Donor
• Need Assent, beware parental bias
• Challenge if recipient unknown or difficult
relationship
• Avoid risks to donor health
– Donors with underlying disorders should be
assessed by experts to avoid risk
• Screened for transmissible diseases
– HIV, HBV, HCV, syphilis, WNV, Chagas, etc.
Other Considerations for Donor Choice
• Assent/Consent—if an 18+yo sib is equivalent to
younger, choose the adult
• Blood type matching helps/not necessary
• CMV negative donors for negative recipients
– Positive for positive may be better
• Gender match or male to female good: avoid
multiparous females
• Donor/recipient size mismatch can be a problem
– Max from donor 20mL/kg, goal CD34+/kg >3-5x10^6
• Cord dose >3x10^7 TNC/kg, can use 2 cords
– Outcomes better with 1 cord if dose OK (less GVHD)
Clinical Differences Between Stem Cell
Sources—T-cell Content Key
Table Comparison of Hematopoietic Stem Cell Products
PBSCs
BM
Cord
Blood
T-cell
Depleted
BM/PBSCs
Haploidentical
T-cell Depleted
BM/PBSCs
Very low
Very low
T-cell content
High
CD34+ content
Low (but
Moderate–
Moderate higher
high
potency)
Moderate–
high
Moderate–high
Time to
neutrophil
recovery
Rapid (13– Moderate Slow (16–
25 d)
(15–25 d) 55 d)
Moderate
(15–25 d)
Moderate (15–25
d)
Moderate Low
Early post-HCT
risk of
Low–
infections, EBV- moderate
LPD
Moderate High
Very High
Very High
Risk of graft
rejection
Low–
Moderate–
moderate high
Moderate–
high
Moderate–high
Low
Time to immune Rapid (6–
a
reconstitution
12 mo)
Moderate
Slow (6–24 Slow (6–24
(6–18
mo)
mo)
mo)
Slow (9–24 mo)
Risk of acute
GVHD
Moderate
Moderate Moderate
Low
Low
Risk of chronic
GVHD
High
Moderate Low
Low
Low
b
Which is syngeneic, which is
allogeneic, who is the better donor?
Major Increases in Risk occur with Pretransplant Comorbidities
• Active infection/inflammation
• Non-recovery of counts pre-HCT (prolonged
neutropenia)
• Non-remission
• Underlying organ damage
– Pulmonary, Hepatic, Cardiac, Renal—all risks
• Performance Status (low KS/LPS)
• Psychiatric Disorder requiring significant therapy
• Some of these issues can be addressed with
reduced intensity regimen approaches
Implications of Reduced Intensity
Current Practice: Preparative
Regimens
• Unpublished evidence suggests myeloablative
approaches superior to RIC for AML/MDS
– Busulfan-based regimens (adult data)
• Retrospective evidence suggests TBI-based approaches
better for ALL
– iBFM trial testing this
• Non-malignant disorder prep regimens vary
– RIC for HLH, RIC whenever possible
• Some disorders require reduced, minimal, or no prep
– FA—sensitive to TBI, chemotherapy
– SCID—Sib donors, no prep needed, URD, less prep may be
possible.
Allogeneic Conditioning Regimens
Preengraftment (Day +1 to +30)
Patient Presentation
• 6 yo female with h/o AML s/p MUD now day +9
• WBC 0.1 LFTs normal. BUN 13, Cr 0.2
• Temp 40C. RR 40s. O2 Sat 90%
• CXR: Fine patchy bilateral infiltrate
• BP: 100/50
Preengraftment (Day +1 to +30)
Case 1
Preengraftment (Day +1 to +30)
• Begins with conditioning until engraftment (day 30)
• Severe neutropenia (ANC <100)
• Severe lymphopenia (ALC <100)
• Hypogammaglobulinemia (IgG < 400)
• Severe GI mucosal disruption
Phases of Predictable Opportunistic Infections
Adapted from Van
Burik, Freifeld.
Clinical Oncology,
3rd Edition.
Philadelphia:
Churchill Livingstone;
2004:942)
Prevention & Prophylaxis
HSV/VZV
• Acyclovir 500 mg/m2 IV or PO tid
CMV
• If CMV quant-PCR elevated
1. GCV or foscarnet pre-emptive therapy
2. Prophylaxis strategies challenging
Fungal
• Fluconazole or voriconazole
Prevention & Prophylaxis
PJP
• Septra “load” pre-HCT
• Restart day +30
• Other meds
• Pentamidine
• Dapsone
• Atovaquone
Bacterial
• ? Antibiotics ? Levofloxacin
IVIG
• Replace for low IVIG levels <400mg/dL
Key Infection Considerations
• Transplant approach affects immune recovery
– Cord blood, T-cell Depl., ATG use= prolonged IS
– Marked increase in viral reactivation/infection
• CMV, Adeno, EBV, HHV-6, HSV—surveillance essential
• Occurrence of cGVHD adds to risk
– Use of and dose of steroids critical risk factor
– Doses <1mg/kg and qod dosing can decrease risk
Acute Graft-vs-Host Disease
•
•
•
•
•
Usually diagnosed before day +100
Typically occurs near time of engraftment
Almost always involves skin
Also involves intestine, liver, or lung
Substantial cause of morbidity and mortality
Palmar and Solar Erythema
Puritic Maculopapular Rash
Basal Keratinocyte Apoptosis
Basal Intestinal Crypt Apoptosis
Acute GVHD Staging
Stage
Skin
Liver
Gut
1
Rash on <25%
Bili 2-3 mg/dl
Diarrhea 280555ml/m2/d
2
Rash on
25-50%
Bili 3.1-6
mg/dl
Diarrhea 556883ml/m2/d
3
Rash on >50%
Bili 6.1-15
mg/dl
Diarrhea
>883ml/m2/d
4
Generalized
erythroderma
with bullae
Bili
>15 mg/dl
Severe
abdominal pain
Acute GVHD Grading
Grade
Skin
Liver
Gut
1
Stage I-II
none
none
2
Stage III
Stage I
Stage I
3
--------
Stage II-III
Stage II-III
4
Stage IV
Stage IV
Stage IV
EFS, OS by aGVHD Grade
Combined Effects of MRD and
GVHD on Relapse and EFS
Acute GVHD Prophylaxis
• Most use calcineurin inhibitors (tacro/CSP) +
– MTX given days 1,3, 6 +/- 11 for sib/URD BM/PBSC
– Or Mycophenylate mofetil (MMF) for cords
– Other agents in combination: sirolimus, ATG,
post-tx cyclophosphamide, T-cell depletion
• Complete removal of T-cells problematic
– Excess infections, rejection, relapse
Primary Acute GVHD Therapy
• Mild disease—limited skin rash alone
– Optimize tacro or CSP levels, topical steroids
• If progressive or multisystem
– Prednisilone 2mg/kg/d
• Steroid Refractory aGVHD (no response 3-7d)
– No clearly superior second regimen
– ECP, etanercept, infliximab, pentostatin
– Poor prognosis due to infectious complications
Case Scenario
An 8-year-old child with AML 6 months post-transplant comes
to clinic complaining of a maculo-papular rash on arms and
legs, dry, irritated eyes, and a persistent cough. His mother
has noticed that he gets winded much more quickly than he
used to. Which investigation is most likely to yield a diagnosis?
A.
Blood PCR for CMV
B.
Bronchiolar lavage to rule out pneumocystis
infection
C.
Pulmonary function tests and high resolution CT
D.
Galactomannan test for fungus
E.
Upper GI endoscopy
Chronic GVHD
• Diagnosed after day 100 (2m sometimes)
–
–
–
–
–
–
–
Immunodeficiency
Skin- lichen planus poikiloderma
Scleroderma
Sicca syndrome
Hepatic- vanishing bile ducts
Pulmonary- bronchiolitis obliterans
GI- esophageal strictures, fat malabsorption
Cumulative incidence of discontinuation of immune suppression after the diagnosis of
cGVHD shown with OS.
Jacobsohn D A et al. Blood 2011;118:4472-4479
©2011 by American Society of Hematology
OS by risk factors included in multivariate analysis.
Jacobsohn D A et al. Blood 2011;118:4472-4479
©2011 by American Society of Hematology
Standard Therapy for Chronic GVHD
• Prednisone 1 mg/kg/day
• Taper to 1 mg/kg/every other day over 6 weeks
• Prolonged course, usually tapered over one
year
• One half have resolution of GVHD
• Median duration of treatment is 2 years for
responding patients
Salvage treatment for chronic GVHD
•MMF
•FK506
•Thalidomide
•Plaquenil
•Pentostatin
•Methotrexate
•Rituximab
•PUVA
•photopheresis
Case Scenario
A 10 year old by undergoes stem cell transplantation for CML.
The graft is T-Cell depleted as part of an NIH sponsored IRB
approved research protocol. Day 145 post transplant the
patient develops severe cervical lymphadenopathy and
splenomegaly. The most likely diagnosis is:
A. Relapsed CML in accelerated phase.
B. Secondary Hodgkin disease.
C. PTLD.
D. Toxoplasmosis.
E. Transfusion acquired HIV.
Post-Tx Lymphoproliferative Disorder
• Occurs within a few months after BMT
• Highly associated with T-cell Depletion
– Product depletion techniques that preserve B-cells
• CD34+ selection
– In vivo depletion (ATG, less with campath)
– Therapy that is highly T-cell suppressive
• ATG for resistant GVHD
• Treatment
– IS withdrawal, rituxan, cyclophosphamide, EBVtargeted cytotoxic T-lymphocytes (CTLs)
Preengraftment (Day +1 to +30) - VOD
Venoocclusive Disease (VOD, also sinusoidal
obstruction syndrome, SOS)
• Typically in first 14 days of transplant, up through
day +30
• About 25% patients affected
• Caused by endothelial damage in the hepatic
venules  platelet deposition  hepatic
congestion  cholestasis
• Associated with Cy, Busulfan, and TBI
•New data show sirolimus use is a risk
Preengraftment (Day +1 to +30) - VOD
Venoocclusive Disease ctd.
• Signs and Sx:
1. Weight gain
2. RUQ pain (capsular distention)
3. Hyperbilirubinemia
4. Plt refractory
5. Ascites (capillary leak)
6. Renal Insufficiency
7. Pulmonary Edema
Preengraftment (Day +1 to +30) - VOD
Venoocclusive Disease ctd.
• Management:
1. Fluid management
2. Maintain intravascular volume
3. Manage renal failure
4. Consider antithrombotic agents (e.g.
defibrotide)
Postengraftment (Days 30-100)
Transplant-associated Thrombotic Microangiopathy (TA-TMA)
• Belongs to the family of thromobotic microangiopathies
including , HUS and TTP.
• Occurs when endothelial damage resulting from HCT causes
microangiopathic hemolytic anemia and platelet
consumption, resulting in thrombosis and fibrin deposition in
the microcirculation.
• The kidney is most commonly affected.
• Patients present with anemia; thrombocytopenia; often
schistocytes on blood smear; elevated LDH and decreased
haptoglobin
• Calcineurin inhibitors (especially + sirolimus), TBI, high-dose
busulfan, and infections increase risk
Patient Presentation
• 6 year old day +64 out from TBI-based
allogeneic transplant
– Presents to the ER with confusion
– Short tonic-clinic seizure witnessed in the ED
– Loss of vision noted
– What are key clinical facts you need to know?
Postengraftment (Days 30-100)
Postengraftment (Days 30-100)
Posterior Reversible Encephalopathy Syndrome
(PRES)
• Headache, confusion, seizures, and visual loss and most
often caused by malignant hypertension.
• In HSCT patients, the intractable hypertension and the
associated PRES have been linked to the use of calcineurininhibitors (tacrolimus and cyclosporine).
• The diagnosis of PRES is typically made on MRI imaging of
the brain, which reveals a characteristic pattern of
enhancement, commonly in the posterior circulation, which
may be seen, but poorly on CT
Late Issues after HCT
• Two years after BMT, most common problem?
– Relapse
• Non-relapse events
– Second malignancies
• 2-6%, higher in FA patients, associated with XRT
– Growth failure
• Rare, associated with TBI + CNS XRT
– Endocrine issues
• Hypothyroidism
• Gonadal failure
• Sequelae of pre-HCT Rx and GVHD
– Cardiac related to XRT and anthracylines
– GVHD effect on lungs, QoL
• Emerging Evidence of TBI effect on children < 3 at HCT
Hematopoietic Cell Transplantation:
Current Indications
• Cancer Treatment
– Allows high dose chemotherapy
– Immunological platform
• Replacement or “Resetting”of a Dysfunctional
Hematopoietic/Immune System
– Absent vs. aberrant function
• Gene Therapy
– Only useful if the gene can be delivered by hematopoietic
cells
The Big Decisions: Chemotherapy vs.
Transplant—Auto vs. Allo
• Autologous: TRM <1% at most centers.
– CR1 if better outcome/ difficult salvage
– Fertility/ immune suppression/ late effects
• Allogeneic: TRM 5-20%
– GVHD morbidity/QOL chief concerns
– Would want a 15% advantage over
chemotherapy/autologous options
Indications for ALL HCT (Allo only)
• CR1
– Primary induction failure
– Hypodiploidy (<44 chromosomes)
– Persistent MRD after consolidation
• CR2
– Early BM relapse (<36m from dx, esp if on rx)
– Late BM relapse if MRD+ after reinduction
– Any T-cell or Ph+ BM relapse
• CR3—any relapse
Indications for AML HCT
• CR1
–
–
–
–
Induction failure
Mono-7, Mono-5, Del 5q, High AR flt-3/ITD+
Persistent MRD after induction (experimental)
Most recent approach
• Sibling donor, pt with intermediate/HR disease
• CR2, CR3—any relapse
• Auto BMT?
– CBF or M3 AML with late relapse (>12m from dx) and
clean marrow (PCR negative)
Indications for CML/MDS/JMML HCT
• CML
– Resistance/failure of TKIs
– Good donor with strong family preference
• Significant growth failure with TKIs
– Advanced phase
• MDS
– Any child with MDS
– Adults “low risk” MDS: wait until progression
• JMML
– Trying to define “better actors”, currently omit Noonan’s
syndrome (germline mut PTPN11)
– Careful with NF1 pts, they may have CNS tumors, peripheral
nerve sheath tumors
Indications for Lymphoma
• NHL
– Relapsed Disease (attempt auto)
– For lymphoblastic treat similar to ALL (allo)
– Allo role for resistant or relapse after auto
• HL
– Auto for relapsed/resistant disease
– Allo can salvage auto failures if disease responsive
Figure 2
Biology of Blood and Marrow Transplant 2010 16, 223-230DOI: (10.1016/j.bbmt.2009.09.021)
Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions
Indications for Solid Tumors
• Neuroblastoma
– Documented Improvement for High Risk CR1 patients
• Brain Tumors
– Good data for use in <3yo to avoid XRT
– Data in medulloblastoma, CNS germ cell tumors for
relapsed disease
• Responsiveness, resectability, XRT important
• Other Tumors
– Role for Ewings, relapsed HR Wilm’s, Rhabdo unsure
– Responsive HR germ cell tumors (relapsed) and HR
retinoblastoma, some evidence of benefit with auto
Indications for Non-malignant
Disorders
• BM failure or lineage insufficiency
– Severe aplastic anemia, Fanconi Anemia, SDS, DC,
CAMT, TAR, DBA, others
– RBC: SSD, Thalassemia
– WBC: KS, LAD
• Immune Deficiencies/Dysregulation
– SCID, WAS, CD40L def (hyper IgM), CGD, IPEX,
others
– HLH, CA-EBV
HCT as Gene Therapy
• Inborn Errors of Metabolism
– Hurler Syndrome MPS-IH
– X-Adrenoleukodystrophy (X-ALD)
– Metachromatic Leukodystrophy
– Many others
Best of Luck on your Test!
• Future of HCT
– Targeting cellular therapies
•
•
•
•
CART
NK Cells
BiTE
BiNK
– Combined therapies with immunomodulators
• Cells can cure cancer