8/27- Tx of Hematologic Malignancies/HSC Transplantation Flashcards Preview

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Flashcards in 8/27- Tx of Hematologic Malignancies/HSC Transplantation Deck (46):
1

What are the treatment phases of acute leukemia?

Induction:

- "Remission induction" with standard chemo

Consolidation/Intensification: Elimination of residual disease

- Standard chemo

- (High dose) chemo/HSC transplant

Maintenance: Prevention of recurrence

- Low dose standard chemo

**So no such thing as urgent HSC transplant; it's not 1st step/1st line

2

What is the rationale for HSCT/principle behind it?

Replace defective marrow with normal marrow

Allow dose intensification of chemotherapy

- Kill residual tumor cells

- Rescue hematopoiesis with normal cells

Induce graft vs. tumor effect

3

What are the types of donors/transplants?

- Autologous (self)

- Syngeneic (identical twin)

- Allogeneic

4

What is the point of autologous transplants?

Able to sustain high dose chemo

5

Fill out

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6

What is an allogeneic transplant (sources)?

- Matched sibling

- Closely matched unrelated donor (fully matched, >/= 1 mismatches)

- Haploidentical family member

7

What are sources of HSCs?

- Bone marrow

- Peripheral blood

- Cord blood

8

The graft includes stem cells and what else?

T cells?????

9

What is the process of bone marrow harvest?

- BM is harvested and pooled by passing through series of filters and into collection bag

- Filters remove bone fragments and platelet clots

10

How are peripheral blood stem cells collected? Process?

Apheresis

- Peripheral blood removed form donor

- As it passes through centrifuge channel a mononuclear rich portion of the blood is collected while the remainder of the plasma and RBCs are returned to the donor

11

PBSC versus bone marrow

- Priming required

- Number of collections

- Anesthesia required

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12

How is cord blood collected/stored?

- Taken at birth/delivery

- HSCs may be infused fresh or cryopreserved (cord blood itself is cryopreserved?)

13

What are indications/uses for autologous SC transplantation?

Malignant diseases:

- Myeloma

- Non-Hodgkin Lymphoma

- Hodgkin lymphoma

- Acute leukemia

(Autoimmune diseases- reboots the system)

14

What are indications/current uses for allogeneic SC transplantation?

Hematological malignancies:

- AML

- ALL

- CML

- (CLL)

- (Myeloma)

- (Lymphoma)

Non-malignant disorders:

- Aplastic anemia

- Immunodeficiencies

- Hemoglobinopathies

- Metabolic storage diseases

- (Autoimmune diseases)

15

What are the most common indications for overall HSCT in the US? Autologous? Allogeneic?

1. Myeloma/PCD

2. NHL

Autologous: Myeloma/PCD

Allogeneic: AML (also ALL, MDS/MPD)

16

What preparative regimens does the HSC recipient need to undergo?

Chemo +/- radiation

- Busulfan, cyclophosphamide

Immunosuppressive agents:

- ATG (anti-thymocyte globulin)

- Monoclonal Abs (e.g. Campath: Anti-CD52)

17

What are the goals of conditioning regimens for the recipient?

- Ablate host immune system to ensure engraftment (not rejected)

- Eradicate malignancy to prevent relapse (leads to myeloablation)

- Minimize toxicity

18

What are "mini" transplants?

- Use reduced intensity or on-myeloablative conditioning regimens

- Initial mixed chimerism (i.e. donor and recipient hematopoiesis) is followed by conversion to full chimerism allowing graft vs. tumor effect (get host hematopoiesis to go away)

- Less toxicity in older pts

- Different sensitivity of different tumors

19

What is the process of HSC infusion?

- HSC product infused into blood stream

- HSCs home to marrow and engraft over 10-30 days

20

What is the best HSC product to use?

Depends on available choices and clinical scenario

21

Peripheral blood vs. marrow

- Speed of engraftment

- GVHD

Peripheral blood SCs:

- Faster engraftment (10-14 d vs. 20-26)

- No increase in acute GVHD

- Increased incidence of chronic GVHD

----Maybe better disease free survival in poor risk pts, but for unrelated donors, may not always be the best

22

What are the pros/cons of cord blood as an HSC source?

Pros:

- Available immediately

- May induce less GVHD

Cons:

- Cell numbers may be limiting for larger pts

- Slower engraftment (up to 1 mo)

Initial studies on outcome are promising, but no long term data available yet

23

What is the primary type/source of HSCs in autologous transplants? Allogeneic?

Autologous: peripheral blood

Allogeneic: Peripheral blood (but significantly more of the other types than autologous)

24

What are the major risks of HSCT?

Autologous and Allogeneic:

- Relapse of primary disease (graft contamination or residual disease)

- Regimen related toxicity

- Immunosuppression/infection

Allogeneic only:

- Graft rejection ("host vs. graft")

- Graft vs. host disease

25

What are some regimen related toxicities?

- Mucositis

- Veno-occlusive disease

- Interstitial pneumonitis

- Hemorrhagic cystitis

- Cardiomyopathy

26

Immune system recovery after HSCT is dependent on what?

What makes it slower?

- Conditioning regimen destroys recipient’s immune and hematopoietic system

- Recovery dependent on engraftment

Slower when:

- Allogeneic transplant

- GVHD and immunosuppression

27

What are some opportunistic pathogens to be aware of pre-engraftment? Risk factors?

Risk factors:

- Similar for autologous and allogeneic recipients

- Break in mucocutaneous barriers

- Neutropenia

Prevalent pathogens:

- Line infections/oral mucosa (Gm+)

- Gram negatvies from GIT

- Candida or Aspergillus

28

What are some opportunistic pathogens to be aware of post-engraftment? Risk factors?

Risk factors:

- Higher risk for allogeneic transplants

- Impaired cell mediated and humoral immunity

Prevalent pathogens:

- Herpes viruses

- Aspergillus

- Encapsulated bacteria

- Pneumocystis

29

What are some risks specific to allogeneic BMT?

Complication of alloreactivity:

- Graft rejection

- Graft vs. Host disease (GVHD)

30

What antigens are considered in transplantation?

- Major histocompatibility complex (human leukocyte antigens, many loci)

- Minor histocompatibility antigens (foreign peptides)

- B-cell antigens (Ab mediated, e.g. ABO)

**ABO match is not critical for HSCT!

31

What are the effects of donation from an unrelated/mismatched family member vs. matched related donor?

With unrelated/mismatched related, you have increased alloreactivity due to:

- Mismatches at MHC antigens

- Increased disparity at minor histocompatibility antigens

32

What causes rejection?

- Risk

- Methods

- Residual recipient immune system rejects donor cells (MHC, minor antigens)

- Overall risk is

- Higher risk in cord blood and mini transplants

33

What are prerequisites for GVHD?

- Graft contains immunocompetent cells

- Recipient expresses tissue antigens not present in donor (MHC, minor antigens)

- Recipient immunosuppressed and unable to reject immunocompetent donor cells

34

What are manifestations of acute GVHD?

Skin

- Maculopapular rash (tend to be reversible, can affect palms/soles)

Gastrointestinal tract

- Diarrhea

- Abdominal pain

- Nausea

Liver

- Cholestasis

Fever

35

What is seen here 

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Acute GVHD of skin

36

How can you prepare for GVHD?

Acute GVHD Prophylaxis I: block activation and expansion of T cells

- Steroids: Lympholytic

- Methotrexate: Prevent division and expansion

- Cyclosporin/tacrolimus: Block cytokine synthesis and prevent activation

Acute GVHD Prophylaxis II:

Deplete mature alloreactive T cell ex vivo

- DD34 selection (select SCs)

- T cell monoclonal Abs (deplete T cells)

Deplete T cells in vivo

- Campath

- ATG

37

What is acute GVHD therapy?

(Less effective than prophylaxis)

- Steroids are first line

- ATG

- T cell antibodies

----Daclizumab (anti-CD25)

- Anti cytokine antibodies

----Infliximab (anti-TNF)

- Mycophenolate mofetil (MMF)

- Pentostatin

38

What is the pathophysiology of GVHD?

Shares features with autoimmune diseases:

- Epithelial injury

- Autoantibodies

- Fibrosis

39

What are target organs of GVHD? Symptoms?

Skin (dyspigmentation, lichen, sclerosis, nail dystrophy)

Mouth (xerostomia, ulcers, lichen, sclerosis)

Eyes (xerophthalmia, conjunctivitis)

Musculo-skeletal (fasciitis, myositis, contractures)

GI tract (malabsorption, esophageal strictures)

Liver (cholestasis, hepatitis)

Lung (bronchiolitis obliterans, effusions)

Heart (pericarditis) Bone marrow (cytopenias)

Kidney (nephrotic syndrome)

Genital (vaginal sclerosis, ulcerations)

40

What is seen here? 

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Chronic GVHD of the skin and mucosa

41

What is seen here? 

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Chronic GVHD

42

What is treatment for GVHD?

- Cyclosporin and Prednisone

- Tacrolimus and Prednisone

- MMF

- Rapamycin

- Azathioprine

43

What are HSC transplant outcomes?

Varies with indication; composite effect of:

Relapse, related to:

- Disease & stage/status at time of HSCT

Non-relapse complications, including:

- Infections, related to degree of immunosuppression & GVHD

- Regimen related toxicities, related to type of conditioning regimen & co-morbidities

44

Which of the following conditions may be an indication for allogeneic HSC transpantation?

A. Anemia due to beta-thalassemia

B. Folate deficiency anemia due to poor diet

C. Iron deficiency anemia 2' to gastrointestinal bleeding due to colon cancer

D. Iron deficiency anemia secondary to iron malabsorption due to celiac disease

E. Vitamin B12 deficiency due to pernicious anemia

Which of the following conditions may be an indication for allogeneic HSC transpantation?

A. Anemia due to beta-thalassemia 

B. Folate deficiency anemia due to poor diet 

C. Iron deficiency anemia 2' to gastrointestinal bleeding due to colon cancer 

D. Iron deficiency anemia secondary to iron malabsorption due to celiac disease 

E. Vitamin B12 deficiency due to pernicious anemia

- B -> E are all 2' causes of BM issues

45

The risk of severe GVHD is greatest in which of the following HSC transplantation settings?

A. Allogeneic transplantation from an HLA-matched sibling donor for AML in 1st remission

B. Allogeneic transplantation from an HLA-matched unrelated donor for ALL in 2nd remission

C. Autologous transplantation for NHL

D. Syngeneic transplantation for HL

The risk of severe GVHD is greatest in which of the following HSC transplantation settings?

A. Allogeneic transplantation from an HLA-matched sibling donor for AML in 1st remission 

B. Allogeneic transplantation from an HLA-matched unrelated donor for ALL in 2nd remission

C. Autologous transplantation for NHL 

D. Syngeneic transplantation for HL

- Depends more on type of donor than type of disease 

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46

A 34 yo male develops acute GVHD 30 days after an allogeneic transplant for refractory AML. Which of the following manifestations would you LEAST expect to be present?

A. Diarrhea

B. Fever

C. Jaundice

D. Maculopapular skin rash

E. Skin fibrosis (Scleroderma-like changes)

A 34 yo male develops acute GVHD 30 days after an allogeneic transplant for refractory AML. Which of the following manifestations would you LEAST expect to be present? 

A. Diarrhea

B. Fever 

C. Jaundice 

D. Maculopapular skin rash

E. Skin fibrosis (Scleroderma-like changes)

- Most of the acute GVHD symptoms are reversible - The skin fibrosis is more of a chronic process