Bone Marrow Transplantation Stem Cell Transplantation

1
Bone Marrow Transplantation (Stem Cell
Transplantation)

• Introduction
• 1950 first in marrow transplantation
• 1990, Edward Donnall Thomas Joseph Edward
  Murray, winners of the Nobel prize
• Allogenic BMT
• Autologous BMT
• peripheral blood stem cell transplantation
• umbilical cord blood transplantation
• minitransplantation (non-myeloablative)
• over 200 transplant centers worldwide

2
Sources of Stem Cell

• Syngeneic
• Allogeneic
• Autologous
• Bone marrow
• PB
• Umbilical cord

3
Antigen differences between the donor and the
recipient

• Human leukocyte antigen (serotyping or molecular
  typing)
• major histocompatibility complex (MHC) several
  closely linked gene loci on 6p
• Class I A, B, C
• Class II DR, DRW, DQ, DP
• other minor antigens HY

4
Stem Cell Transplantation(Indications in
malignant diseases)

• acute leukemia
• high grade lymphoma, Hodgkins disease, sensitive
  relapse
• chronic myelogenous leukemia
• multiple myeloma (allogeneic)
• solid tumor (breast ca, germ cell tumor,
  neuroblastoma) ?

5
Stem Cell Transplantation (Indications in
non-malignant diseases)

• aplastic anemia
• severe thalalssemia
• congenital immune deficiency
• storage disease

6
Allogeneic Stem Cell Transplantation

• eradicates of the marrow cells (marrow-ablating
  C/T or R/T)
• implantation of allogenic stem cells
• homing of the stem cells to the marrow cavity
• growth of the stem cells and recovery of the
  blood cells

7
Preconditioning Regimens

• Ablate recipients immunity
• Provide space for engraftment
• Regimens
• TBI 175 cGy x 6 d CTX 60 mg/Kg x 2 d mesna 60
  mg/Kg iv 24h x 2 d.
• Non-myeloablative CTX 60 mg/Kg x 2 d mesna 60
  mg/Kg iv 24h x 2 d fludarabine 25 mg/m2 iv x 5
  d

8
Doses of Stem Cell Transplantation

• Allogeneic 1-5 x 108 nucleated cells/Kg
• Syngeneic 1-5 x 107 nucleated cells/Kg
• PBSCT 3-4 x 106 CD34 cells/Kg
• Autologous 1-2 x 106 CD34 cells/Kg
• 2-4 weeks for recovery, PBSCT more rapid recovery
  of PMN and platelets

9
Choice of Donors

• 1st choice syngeneic or matched sibling
• Partial matched relative, MUD (30-40 available)
  if gt 2 HLA mismatch T-cell depletion
• UCB (umbilical cord blood) less GVHD but cell
  counts usually too low, high graft failure rate,
  should be considered only if with 1.5-3 x 107
  nucleated cells/Kg

10
Non-myeloablative transplantion

• Use non-myeloablative conditioning agents
• Reduce toxicities
• Exploit Acute GVHD (graft versus host disease)
• Disadvantage graft failure, GVHD

11
Complications of SCT

• rejection, graft failure
• GVHD (graft-versus-host disease)
• infection
• VOD
• obliterative bronchiolitis
• sepsis
• relapse of disease

12
Complications of Cytoreductive Chemotherapy

• infection
• bacterial infection 50 of recipients
• aspergilloisis, candida
• risk factors Catheter, neutropenia,
  immunosuppressant, mucositis (within 3 wks),
  aspiration
• cardiomyopathy CTX, anthracycline
• CNS complications, GB syndrome, neuropathy
  cytarabine
• hemorrhagic cystitis CTX, IFX
• tumor lysis syndrome

13
Relapse and Rejection

• Rejection
• lt 1 in HLA-identical TBI
• incidence increases in increasing HLA disparity,
  heavily transfused patients
• Recurrence of primary malignancy
• early stage leukemia 20
• advanced leukemia 5070
• Second transplantation may be successful, but
  mortality high

14
GVHD (Graft versus Host Disease)

• Immunologic reaction of donor lymphocytes to
  foreign antigens present on the surface of host
  cells
• foreign antigens
• HLA antigens
• minor antigens not detected by current typing
  techniques

15
Acute GVHD (1) incidence

• Within the first 3 months after BMT
• 2050 of HLA-identical, 80 of HLA non-identical
  recipients
• Mortality 50
• incidence increases with
• patient age
• degree of HLA disparity

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Acute GVHD (2)manifestations

• Histology lymphocytic infiltration of the
  epidermis and GI tract
• fever
• dermatitis diffuse macular dermatitis, bullas,
  desquamation
• enteritis cramping abdominal pain, watery to
  bloody diarrhea
• hepatitis jaundice, cholestasis, hepatocellular
  necrosis
• infection frequently related to mortality
• hyperacute GVHD (no prophylaxis) 7 days after
  BMT exfoliative dermatitis, shock, hyperpyrexia

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Acute GVHD (3) immunology

• Effector cells donor cytotoxic T lymphocytes
• in response to host histocompatibility antigens
• lymphokines recruit mononuclear cells
• Donor T lymphocyte removal can lessen GVHD but
  increase graft rejection and recurrent malignancy

18
Chronic GVHD (1) incidence

• develops gt 3 months after BMT
• 2050 of allografts, usually following acute
  GVHD
• 2030 develops de novo, without prior acute GVHD

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Chronic GVHD (2) manifestations like collagen
diseases

• skin pigmentation, sclerosis
• mucosa lichenoid oral plaque, esophagitis,
  polyserositis, oral and eye sicca syndrome
• liver elevated ALP and GOT in 90 cases
• chronic wasting due to anorexia
• chronic pulmonary disease 1020 (diffuse
  interstitial pnuemonitis and obliterative
  bronchiloitis)
• death usually caused by infection, low mortality
  related to de novo onset less tissue
  involvement.

20
Chronic GVHD (3) immunology

• minor histocompatibility antigen difference and
  deficient thymic function
• increase in nonspecific suppressor lymphocyte
  function
• lack specific suppression of cytotoxic reactivity
  to host alloantigens
• cytokine mediators propagate autoimmune-like
  tissue injury
• chronic immunodeficiency, increases opportunistic
  and other fatal infection

21
GVHD Prophylaxis

• Prevention is of paramount importance, no
  prevention ? 100 develop acute GVHD
• GVHD may lead to fatal hepatic failure, GI
  bleeding, diffuse exfoliative dermatitis,
  increase CMV enteritis, pneumonia, bacterial and
  fungal infection
• prophylaxis with MTX cyclosporine or
  tacrolimus? acute GVHD decreases to 25

22
GVHD management

• Diagnosis needs biopsy of skin, liver or GI tract
• Treatment is difficult methylprednisolone 2
  mg/Kg/day, ATG, continue MTX cyclosporine,
  anti-T lymphocyte monoclonal antibodies
• surveillance for infection, prophylactic
  antibiotics
• adequate nutrition TPN. Opiate for cramping pain
  and diarrhea
• care for bleeding, especially GI bleeding

23
Hepatic Veno-occusive Disease (1) incidence

• lt 2 of BMT without TBI
• 2060 of BMT with C/T and TBI
• higher rate in older age and prior hepatitis
• mortality 30, no effective treatment

24
Hepatic Veno-occusive Disease (2) presentation

• occurs within 2 weeks of BMT
• weight gain with peripheral edema
• increased GOT, GPT, jaundice
• ascites
• painful hepatomegaly
• metabolic encephalopathy and coma
• hepatorenal syndrome

25
Hepatic Failure (diagnosis)

• hepatic VOD, GVHD (majority), drugs toxicity
  (cyclosporine, antibiotics, antimetabolites),
  infections (hepatitis B, C, CMV, HSV, EBV, and
  bacterial, fungal)
• VOD GOT peaks within 2 weeks
• GVHD occur after day 20, ALP much higher than in
  VOD
• Dx by image studies, biopsy, culture

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Hepatic Failure (management)

• VOD
• restriction of fluid and Na, judicious use of
  loop diuretics (decrease ascites but avoid
  compromising renal perfusion) blood products
  transfusion, hemodialysis may be needed
• anticoagulant or thrombolytic therapy risk in
  thrombocytopenia
• GVHD treatment of GVHD, management of hepatic
  encephalopathy

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Pneumonia (Incidence and Pathogenesis)

• 4060 of recipients
• infectious pneumonia (50)
• bacteria
• fungi (aspergillus, candida )
• CMV ( 60) 30150 days after BMT
• HSV, VZV, effectively prevented by acyclovir PCP
  by bactrim
• noninfectious lung infiltrates
• pulmonary hemorrhage, edema, ARDS, idiopathic
  interstitial pneumonia, thromboemboli, leukemia

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Pneumonia (Presentation-1)

• within 30 days
• Focal patchy infiltrates bacterial or fungal
  infection
• Diffuse infiltrates pulmonary edema, ARDS,
  hemorrhage, acute GVHD, often progress to
  respiratory failure

29
Pneumonia (Presentation-2)

• beyond 30 days viral pneumonia (CMV), idiopathic
  interstitial pneumonia, PCP, often progress to
  respiratory failure
• late gt 100 days chronic GVHD, (CMV, VZV, PCP
  less frequent), idiopathic pneumonia due to late
  radiation or cyclophosphamide

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Obliterative Bronchiloitis

• 10 of recipients
• among long term survival of chronic GVHD
• manifestations
• PFT airway obstruction, CXR may be normal
• insidious progression of DOE, wheezing, often
  progresses to respiratory failure and death.
• progression rate predicts the outcome,
• mx control of chronic GVHD

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Pneumonia (diagnostic approach 1)

• Diffuse infiltrate
• Early 30 days ? empiric broad-spectrum
  antibiotics, diuresis and Na restriction (may
  guided by pulmonary artery wedge measurement)
  correction of bleeding disorder. If deteriorates
  ?bronchoscopy BAL
• After 30 days bronchoscopy BAL, detection for
  viral, especially CMV, bacterial, fungal, and
  cytologic stains, culture. Thoracotomy is
  reserved for nondiagnostic BAL with high risk of
  infection.

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Pneumonia (diagnostic approach 2)

• Focal lesion
• High probability of bacterial or fungal
  infection.
• Bronchopheumonia ?bronchoscopy BAL, peripheral
  lesions ? percutaneous needle aspiration biopsy,
  open lung biopsy or complete surgical resection

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Pneumonia (treatment 1)

• Bacterial
• high prevalence of coagulase - staphylococcus
• late (chronic GVHD) pneumococcal, needs PCN or
  bactrim.
• Viral CMV pneumonia fatal in gt 85, treated with
  ganciclovir 2.5 mg/Kg q8h for gt2 weeks,
  cytotect 400500 mg/Kg 35 times weekly for 23
  weeks.

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Pneumonia (treatment 2)

• Other herpes viruses ?iv acyclovir 500 mg/m2 q8h
  for gt7 days
• RSV and parainfluenza ?aerosolized ribavirin
• Fungal aspergillus, mucor, rhizopus high
  mortality, candida (common) ? iv amphotericin B
  10 mg/Kg/d until resolution. Surgical resection
  of localized lesion.
• Other infections PCP, legionella, nocardia,
  treatment same as in usual patients

35
Idiopathic pneumonia

• Early idiopathic pneumonia
• no proven treatment
• biopsy diffuse alveolar damage
• Late idiopathic interstitial pneumonia
• pathology mononuclear cells interstitial
  infiltrates, may be immunologically mediated
  process
• management same as managing idiopathic pulmonary
  fibrosis, immunosuppression to control the GVHD

36
Infection Control

• oral bactrim for the 2 weeks prior to BMT, twice
  weekly after PMN engraftment
• laminar airflow (LAF) environment for neutropenia
  (reduce infection, but reduce mortality only in
  aplastic anemia)
• oral nonabsorbable antibiotics for GI
  decontamination (eliminate G(), not G(-))
• LAF decreases incidence of acute GVHD
• prophylactic acyclovir after BMT suppress HSV
  infection

37
Sepsis Syndrome

• bacteremia in 50 marrow recipients
• G(-), G() coagulase - staphylococci, yeast
  (candida)
• viral infection (CMV) seen in previous infected
  patients who develop acute GVHD. CMV viremia
  high cardiac output, low SVR, sepsis syndrome
• coexist with acute GVHD
• empiric antibiotic coverage, modified with
  culture results and endemic infection and
  resistance pattern
• careful iv volume expansion