8/27- Tx of Hematologic Malignancies/HSC Transplantation Flashcards
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
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
What are the types of donors/transplants?
- Autologous (self)
- Syngeneic (identical twin)
- Allogeneic
What is the point of autologous transplants?
Able to sustain high dose chemo
Fill out
What is an allogeneic transplant (sources)?
- Matched sibling
- Closely matched unrelated donor (fully matched, >/= 1 mismatches)
- Haploidentical family member
What are sources of HSCs?
- Bone marrow
- Peripheral blood
- Cord blood
The graft includes stem cells and what else?
T cells?????
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
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
PBSC versus bone marrow
- Priming required
- Number of collections
- Anesthesia required
How is cord blood collected/stored?
- Taken at birth/delivery
- HSCs may be infused fresh or cryopreserved (cord blood itself is cryopreserved?)
What are indications/uses for autologous SC transplantation?
Malignant diseases:
- Myeloma
- Non-Hodgkin Lymphoma
- Hodgkin lymphoma
- Acute leukemia
(Autoimmune diseases- reboots the system)
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)
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)
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)
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
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
What is the process of HSC infusion?
- HSC product infused into blood stream
- HSCs home to marrow and engraft over 10-30 days
What is the best HSC product to use?
Depends on available choices and clinical scenario
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
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
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)
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
What are some regimen related toxicities?
- Mucositis
- Veno-occlusive disease
- Interstitial pneumonitis
- Hemorrhagic cystitis
- Cardiomyopathy
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
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
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
What are some risks specific to allogeneic BMT?
Complication of alloreactivity:
- Graft rejection
- Graft vs. Host disease (GVHD)
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!
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
What causes rejection?
- Risk
- Methods
- Residual recipient immune system rejects donor cells (MHC, minor antigens)
- Overall risk is < 5%
- Higher risk in cord blood and mini transplants
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
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
What is seen here
Acute GVHD of skin
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
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
What is the pathophysiology of GVHD?
Shares features with autoimmune diseases:
- Epithelial injury
- Autoantibodies
- Fibrosis
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)
What is seen here?
Chronic GVHD of the skin and mucosa
What is seen here?
Chronic GVHD
What is treatment for GVHD?
- Cyclosporin and Prednisone
- Tacrolimus and Prednisone
- MMF
- Rapamycin
- Azathioprine
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
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
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
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
