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1
Q

Rationale for HSCT -auto

A

 Dose intensify chemotherapy

 Stem cell rescue from myeloablative chemotherapy

 Non-hematopoietic organ toxicity becomes dose-limiting

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2
Q

Rationale for HSCT -allo

A

 Stem cell rescue from myeloablative chemotherapy

 Establish a graft-versus- malignancy effect to destroy recipient cancer cells

 Replace missing or abnormal hematopoietic component

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3
Q

Types of Transplant - anatomical source

A

 Bone marrow (BMT)

 Peripheral blood (PBSCT)

 Umbilical cord blood (UCB

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4
Q

Types of Transplant - immunologic source

A 
 Allogeneic
   Matched related donor (MRD)
   Mismatched related donor (MMRD) or haploidentical
   Matched unrelated donor (MUD)
   Mismatched unrelated donor (MMUD)

 Syngeneic

 Autologous

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5
Q

Selection of HSC Source - Recipient Factors -4

A

 Type and stage of recipient disease

 Donor availability

 Age

 Performance status

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6
Q

Selection of HSC Source - Donor Factors -7

A

 HLA match

 Age

 Sex

 Number pregnancies in female donor

 Blood type and ABO compatibility

 Serologic status for cytomegalovirus

 Matched race

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7
Q

HLA Matching -serology vs DNA

A

S: Identifies HLA molecules on the cell surface using antigen specific anti-sera

D: Identifies HLA molecules by defining the DNA code in the cell nucleus

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8
Q

slide 5C

A

&&&

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9
Q

Umbilical Cord Blood Stem Cells - Advantages -5

A

 Ease of procurement & faster availability than MUD

 Lower immunogenicity in cord blood leading to lower rates of severe GVHD (permitting 1-2 antigen-mismatch)

 Advantage of a lower transmission rate of infectious and genetic diseases

 Increased units for ethnic minorities and patients with rare haplotypes

 Frozen in small volumes; DMSO content is minimized

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10
Q

Umbilical Cord Blood Stem Cells - Disdvantages -5

A

 Low number of stem cells in cord units

 Cost

 Lack of donor lymphocyte infusions

 Lack of experience and long-term
outcomes

 High rate of acquired infection

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11
Q

slide 6B

A

&&&

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12
Q

most common source of marrow

A

kids: BM
adults: peri blood

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13
Q

Adult Acute Lymphoblastic Leukemia (ALL) Timing of Transplant Consultation -3

OS early tx 40%

what are high risk feautures -5

A

 CR1 up to age 35 for standard risk

 CR1 over age 35 if high risk
 Poor-risk cytogenetics (e.g., (t(9;22 or 11q23))
 High WBC (>30-50 x 109/L) at diagnosis
 CNS or testicular leukemia
 No CR within 4 weeks of initial treatment
 Induction failure

 CR2 and beyond

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14
Q

Adult ALL Key Recommendations -5

A

 Allogeneic HSCT is recommended in CR1 for all risk groups based on a survival benefit &&&

 Autologous HSCT is an alternative if there is no allogeneic donor (similar survival to maintenance chemo with shorter treatment duration)

 Imatinib therapy before and after allogeneic HSCT should be considered

 TBI based conditioning may be preferred

 RIC only if they unsuitable for myeloablative

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15
Q

Adult Acute Myeloid Leukemia (AML) Timing of Transplant Consultation -3

OS early 50%

AML high risk feautures -3

A

 High-risk AML including
 Antecedent hematological disease (e.g., myelodysplastic syndromes)
 Treatment-related leukemia
 Induction failure

 CR1 with poor-risk cytogenetics or molecular
markers

 CR2 and beyond

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16
Q

Adult AML Key Recommendations -3

what about low risk cytogenetics? -1

intermediate risk? -1

A

 Allogeneic HCST in CR1 confers a survival benefit over conventional chemotherapy in high-risk cytogenetics if patient < 55 years old
 No survival advantage if low-risk cytogenetics
 Unclear in intermediate risk cytogenetics

 No advantage to autologous HSCT in CR1 over
conventional chemotherapy

 Allogeneic HSCT in CR2 is recommended
 Insufficient data to recommend a MUD over autologous HSCT

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17
Q

Myelodysplastic Syndrome (MDS) Timing of Transplant Consultation -3

OS early 40%

A

 Intermediate-1 (INT-1), intermediate-2 (INT-2)
or high IPSS score which includes either:
 > 5% marrow blasts
 Other than good risk cytogenetics (good risk includes 5q- or normal)
 > 1 lineage cytopenia

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18
Q

MDS Key Recommendations -2

A

 Autologous is only recommended as part of a clinical trial

 Allogeneic HSCT early in the disease course is recommended for
 IPSS score of intermediate-2 or high risk
 Have a suitable donor
 Meet HSCT criteria
 IPSS score of Intermediate -1 who have poor prognostic features not included in IPSS (older age, refractory cytopenias)

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19
Q

Chronic Myeloid Leukemia (CML)
Timing of Transplant Consultation -5

OS CP 70%
OS AP 40-45%

A

 No hematologic or minor cytogenetic response 3 months post-imatinib initiation

 No complete cytogenetic response 6-12 months post imatinib initiation

 2nd Relapse

 Accelerated phase

 Blast crisis (myeloid or lymphoid)

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20
Q

CML Key Recommendations -1

&&&may be more- panotumib update

A

 CML – Accelerated phase and blast crisis
 Allogeneic HSCT as soon as CML – CP can be
achieved with TKI and/or chemotherapy

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21
Q

CLL Key Recommendations - 3

OS 40% (does not really flatten out)

def high risk CLL -3

A

 Autologous HSCT
 2 prospective RCT show improved EFS, but no
impact on overall survival (NOT DONE)

 Allogeneic HSCT
 Myeloablative conditioning generally not recommended because of high TRM (NOT DONE)
 RIC considered for patients with high-risk CLL
1. Deletion 17p or 11q;
2. refractory to chemoimmunotherapy
3. who develop recurrence within 12 months after purine analog treatment

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22
Q

Non Hodgkin’s Lymphoma (NHL) Timing of Transplant Consultation - Diffuse large B-cell lymphoma -3
50% OS vs 30% with chemo insensitive dz (same as chemo)

A

 At 1st or subsequent relapse

 CR1 for patients with high or high-intermediate IPI risk

 No CR with initial treatment

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23
Q

Non Hodgkin’s Lymphoma (NHL) Timing of Transplant Consultation - Follicular -4

A

 Poor response to initial treatment

 Initial remission duration < 12 months

 Second relapse

 Transformation to diffuse large B cell lymphoma

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24
Q

Non Hodgkin’s Lymphoma (NHL) Timing of Transplant Consultation - Mantle Cell Lymphoma -3

A

 Following initial therapy

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25
Q

NHL Key Recommendations - DLBCL -2

A

 Autologous HSCT recommended in 1st
chemosensitive relapse as it improves survival

 Not recommended in 1st CR for any IPI risk or in partial remission after 3 cycles of chemotherapy

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26
Q

NHL Key Recommendations - FL -4

A

 Autologous HSCT recommended for transformed follicular lymphoma

 Autologous HSCT NOT recommended in CR1
 No overall survival benefit
 No comparative data with rituximab-containing regimens
 Higher incidence of therapy related AML/MDS

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27
Q

NHL Key Recommendations - mantle cell -1

A

Many experts recommend autologous HSCT in CR1

PROBABLY NOT TESTABLE

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28
Q

Hodgkin’s Disease Timing of Transplant Consultation -2
OS CR 70%
OS not CR sens 60%
OS not CR insens 40%

A

 No initial CR

 1st or subsequent relapse

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29
Q

Hodgkin’s Disease Key Recommendations -3

A

 Autologous HSCT is recommended in 1st chemosensitive relapse -outcomes improved over conventional therapy in randomized trials

 Autologous HSCT is recommended in patients with refractory disease- outcomes improved over conventional therapy

 RIC Allogeneic considered in eligible patients with no other options (including clinical trials)

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30
Q

Multiple Myeloma Timing of Transplant Consultation -2

no cure, OS 45% at 6yr

A

 After initiation of therapy

 At first progression

31
Q

Multiple Myeloma Key Recommendations -8

A

 Single Autologous HSCT
 RCT demonstrated improved EFS over conventional chemotherapy
 3 of 7 RCT demonstrated a benefit in OS
 Considered standard of care

 Tandem Autologous HSCT
 3 RCT demonstrated an improvement in EFS
 Only 1 RCT demonstrated a benefit in OS
 Tandem autologous HSCT considered in patients with less than a very good partial response to 1st HSCT

 Allogeneic
 Comparative studies demonstrate similar or worse survival in myeloablative allogeneic HSCT compared with autologous HSCT -high TRM with myeloablative conditioning
 1 of 3 RCT demonstrated improvement in survival with autologous HSCT followed by a RIC allogeneic HSCT compared with a tandem autologous HSCT

32
Q

Severe Aplastic Anemia (SAA) Key Recommendations -2

OS MRD 70-87%
OS MUD 50-67%

A

 Matched related donor BMT
 Recommended for initial therapy for newly diagnosed patients if they have severe or very SAA and are <50 years old (or 50–60 years old with good performance status), and has failed at least one course of antithymocyte globulin and cyclosporine

33
Q

Solid Tumor Key Recommendations - Germ Cell Tumors

A

Autologous HSCT recommended for relapsed

disease- may be curative

34
Q

Solid Tumor Key Recommendations - High-Risk Neuroblastoma

A

Autologous HSCT recommended as part of first line

therapy (current trial comparing single vs. tandem)

35
Q

HSCT Pre-transplant Process - Patient Evaluation -10

A

 Appropriateness of HSCT
• Disease and stage, age, PS, organ function
• Chemosensitivity

 Patient evaluation
  •	History & Physical 
  •	CBC + chemistries 
  •	Virology 
  •	Blood & HLA typing 
  • Cardiac/Pulmonary
  •	CXR; Labs 
  •	CT scans; Disease evaluation 
  •	Urinalysis; Pregnancy
36
Q

HSCT Pre-transplant Process - Donor Evaluation -8

A
  • HLA typing
  • History & Physical
  • CBC + chemistries
  • PT/ APTT
  • Blood type
  • Virology
  • Cardiac studies
  • Pregnancy test
37
Q

Stem Cell Collection -Bone marrow harvest -3

A

 Multiple aspirations of posterior iliac crest

 Requires general anesthesia; Limited by health of donor;
Serious adverse event rate < 0.3%

 10-20 mL/kg recipient weight = TNC 2 - 4 x 108/kg

38
Q

Stem Cell Collection -Peripheral blood stem cell harvest =3

A

 Requires “mobilization” of cells

 No anesthesia; may require multiple apheresis

 Minimal risks:  dec Ca2+, anemia, thrombocytopenia, hypotension, thrombosis

39
Q

Stem Cell Collection -Umbilical cord blood

A

Collected before or after placental delivery

40
Q

slide 19C

41
Q

Stem Cell Mobilization - allo -1

A

Filgrastim alone

42
Q

Stem Cell Mobilization - auto -4

A

 Colony stimulating factor alone (filgrastim or sargramostim or both)

 Colony stimulating factor + chemotherapy

 Colony stimulating factor + plerixafor

 Colony stimulating factor + chemotherapy + plerixafor

43
Q

Factors Negatively Affecting Stem Cell Mobilization -7

A

 Tumor infiltration of bone marrow

 Fibrotic bone marrow

 Pelvic or abdominal irradiation

 Marrow hypocellularity

 Prior exposure to stem cell toxin
 Alkylating agents; nitrosoureas; fludarabine; lenalidomide
 Number of prior regimens; duration of exposure, short
interval since last chemotherapy

 Age > 60 – 70 years

 Baseline platelet count < 150 x 109/L

44
Q

Plerixafor + filgrastim

A

more cells collected, fewer median apheresis sessions, less mobilization failures than filgrastim alone

45
Q

slide 20C-21A

46
Q

HSCT Conditioning Regimens -ALLO MALIGNANT -4

A

immunosuppress (anti-graft rejection)

make space (ablate)

eradicate dz (anti-tumor)

avoid overlapping toxicities

47
Q

HSCT Conditioning Regimens -ALLO NON-MALIGNANT -3

A

immunosuppress (anti-graft rejection)

make space (ablate)

avoid overlapping toxicities

48
Q

HSCT Conditioning Regimens -AUTO -3

A

make space (ablate)

eradicate dz (anti-tumor)

avoid overlapping toxicities

49
Q

22C

A

study slide!!! ADR

50
Q

Dz Sensitivity to GVT Effects

A

CLL, low-grade NHL, CML, Mantle cell NHL (CAN USE NON-MYELOABLATIVE) >

Intermediate- grade NHL, AML, MM, HD >

High grade- NHL, ALL

51
Q

HSCT Conditioning Regimen Intensity Defined - Myeloablative (MA) regimens

A

Irreversible cytopenia and stem cell support is mandatory

52
Q

HSCT Conditioning Regimen Intensity Defined - Nonmyeloablative (NMA) regimens

A

 Minimal cytopenia; given with or without stem cell support

 Rely on immunosuppression to allow engraftment

 Tumor eradication depends on GVT effects

 Low dose total body irradiation and immunosuppressive chemotherapy

53
Q

HSCT Conditioning Regimen Intensity Defined -RIC regimens do not fit criteria for MA or NMA

A

Cytopenia of variable duration, should be given with stem cell support

54
Q

“High-dose” TBI

A

800-1320 cGy

55
Q

“Low-dose” TBI

A

200-400 cGy

56
Q

myeloablative ex regimen

A

Cy/TBI, BEAM

57
Q

RIC ex regimen

A

Flu/Bu/ATG (Bu is 1mg/kg q6h), Flu/melphalan

58
Q

NON-myeloablative ex regimen

A

Flu/low dose TBI

59
Q

Comparing RIC/NMA to

Myeloablative Conditioning

A

 Risk of NRM is lower with RIC/NMA
 Fewer inpatient hospital days
 Reduced need for transfusion
 Shorter duration of neutropenia & dec bacterial infections

 Risk of relapse is higher with RIC/NMA

 Risk of PFS (? and OS) is similar (because need for GVT effect)

 Risk of acute GVHD before day 100 may be lower, but patients develop late-onset acute GVHD

 Incidence of chronic GVHD is similar

60
Q

Causes of Death after Transplants performed in 2008-2009 - primary dz

A

MRD: 33
MUD: 47
auto: 73

61
Q

Causes of Death after Transplants performed in 2008-2009 - GVHD

A

MRD: 14
MUD: 19
auto: 0

62
Q

Causes of Death after Transplants performed in 2008-2009 - infection

A

MRD: 12
MUD: 16
auto: 8

63
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -BUSULFAN

A

hepatotoxicity

pulmonary tox

GI

64
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -CARBOPLATIN

A

nephrotox

ototoxicity

pulmonary tox

65
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -CARMUSTINE

A

pulmonary tox

hepatotoxicity

66
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -CYCLOPHOS

67
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -CYTARABINE

68
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -ETOPOSIDE

69
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -FLUDARABINE

70
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -IFOS

A

nephrotox

neurotox

bladder tox

71
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -MELPHALAN

72
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -THIOTEPA

A

neurotox

mucositis

73
Q

HSCT Preparative Chemotherapy Non-Hematologic DLT -TBI

A

pulmonary tox

hepatotoxicity

GI

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