Autologous stem cell transplant (ASCT)

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Autologous stem cell transplant (ASCT)

• Dr. Herman Liu

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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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Levels of treatment (HA)

• 5 levels of care
• Level 1 palliative
• Level 2 mild chemotherapy
• Level 3 intensive chemotherapy (all 7 clusters)
• Level 4 auto transplant (QMH/PWH/QEH/TMH/PYNEH/PM
  H)
• Level 5 allo transplant (QMH)

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PYNEH

• F5 ward
• 2 isolation rooms with HEPA filter
• 10 auto-transplants in 2011/2012
• Multiple Myeloma
• Non Hodgkins Lymphoma

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Transplant capacity at QMHwas saturated
since 2002
No. of SCT at QMH (n 1708)
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Mean Waiting Time (days) for HSCT in QMH
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No. of HSCTService Demand, Throughput Drop-out
Total Referral
No. of Transplant Done
Drop out rate preferably lt15
Drop out (Consented but never had the SCT and
died)
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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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• Nobel Prize 1990
• E. Donnall Thomas
• 1st successful HSCT in acute leukaemia
• NEJM 1957

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Types of HSCT

• Allogeneic
• Siblings
• Matched Unrelated Donors (MUD)
• Syngeneic
• Identical twins
• Autologus

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Stem cells characteristics

• Stem cells are able
• (1) to divide for indefinite period
• (2) to self renew
• (3) to generate a functional progeny of highly
  specialised cells

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Haematopoietic stem cells

• 1/25000-100000 of bone marrow cells
• Characteristics
• CD34
• CD133
• Lin
• C-kit (CD117)
• BCRP

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Source of Stem Cell

• Bone Marrow
• Peripheral Stem Cell Blood
• Umbilical Cord Blood

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BMT Team

• Red Cross / Blood Bank
• Medical Social Worker
• Psychologist
• Radiologist
• ICU

• Haematologist
• Haematology nurses
• Microbiologist
• Dentist
• Dietitian
• Pharmacist

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Exclusion

• 1. Age gt65
• 2. Limited life expectancy for other reasons
• 3. Severe renal, hepatic, cardiac impairment
• 4. Seriously infected patents especially
  deep-seated fungal infections
• 5. Psychologically unstable patients

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Preparation

• Disease control
• Family conference
• Doctor / nurse liaise with patient and their
  family members
• Consent

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Work up (1)

• Blood tests
• CBC, ret, ESR, PT/APTT/fibrinogen, G6PD, Hb
  pattern
• L/RFT, Ca, PO4, LDH, urate, sugar
• Immunology
• ANA, Anti DNA, RF, C3
• Anti ENA, anti smooth muscle Ab, AMA
• ABO, Rh blood group

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Work up (2)

• Viral study
• CMV, toxoplasma, herpes simplex, herpes zoster
  titre
• EBV, VDRL
• HIV-Ab, HTLV-1
• HBsAg/Ab, HBeAg/Ab, HBcAb, Anti HCV
• HBV DNA (if HBsAg)
• Surveillance culture
• 1. MSU, sputum, nasal swab C/ST
• 2. throat swab, rectal swab, stool C/ST
• 3. stool for ova, cyst, parasite (label for
  strongyloides)

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Work up (3)

• Dietitian
• Dental for fitness for BMT
• Cardiopulmonary assessment CXR, ECG, lung
  function test with DLCO (corrected for Hct),
  Echocardiogram, MUGA scan
• Renal assessment 24 hour for CrCl, protein
• Endocrine evaluation

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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Infusion of stem cells
• 6. Post transplant care
• 7. Potential complications

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Mobilisation agents

• High dose Cyclophosphamide G-CSF
• Collect stem cells from peripheral blood via a
  cell separator
• No risk of GA effect and wound complications

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Mobilisation protocol(high dose Cyclophosphamide
G-CSF)

• Cyclophosphamide 1000mg/m2 x 3
• During cyclophosphamide administration (day 0)
• IV hydration
• Ask patient to void as frequent as possible, not
  to hold bladder
• I/O chart Q4H
• Urine-stix for RBC Q6H for 2 days

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Medication during cyclophosphamide administration

• Zofran/navoban before 1st dose of
  cyclophosphamide
• Maxalon 10-20mg ivi Q4H prn
• Benztrophine 2mg iv bolus if maxalon-induced
  dystonia
• Lorazepam 1-2mg BD oral/SL, if severe nausea or
  vomiting not controlled with maxalon
• Lasix 20mg iv prn if u/o lt400ml/4h or 1kg weight
  gain

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Day 1

• Stop iv hydration after mobilization scheduled
  finished
• Encourage fluid intake
• Stop anti-emetic if no symptom
• Commence G-CSF 5ugkg/day SC BDstarting 24 hours
  after cyclophosphamide
• Continue G-CSF BD till completion of
  leukopheresis
• Home leave if possible

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Day 2-7

• G-CSF BDcheck WBC, neutrophil, peripheral film
  on day 3,5,6
• Reserve irradiated platelet conc for weekend till
  day 7 (Monday)
• Day 7 (Monday)
• Continue G-CSF BD
• Insert renal dialysis catheter the day before
  harvest
• Reserve irradiated platelet conc for day 8 till
  10
• CD34 count (3 ml EDTA blood) (HKBTC) at 9am

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Day 8 and onward

• Urgent CBC at 7am, trace result before 9am
• Continue G-CSF daily till completion of apheresis
• CD34 count
• Harvest on D8 if
• (1) WBC gt 8.0 x 109/L or
• (2) Appearance of blast or
• (3) CD34gt15-20/ul
• Harvest daily until satisfactory stem cells
  obtained

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• If CD34 numbers persistently do not meet minimum
  requirement once WBC recovered, double the dose
  of G-CSF patient is receiving daily
• If after 2-3 days on double dose G-CSF? no
  improvement in CD34 numbers ? abandon procedure

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• Insert renal dialysis catheter the day before
  harvest (usually on Monday)
• Harvest daily for consecutively 2 days for every
  patient
• Platelet count must be at a safe level gt50x 109/L
  for apheresis (transfusion with irradiated
  platelet if necessary, before procedure)
• The usual processed volume is 2 times whole blood
  volume or 10L, whichever is less

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Continue G-CSF and daily apheresis till the
following minimum target achieved

• Minimum CD34 for autologous PBSCT
• 2 x 106 /kg

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Harvesting Stem Cell
Stem Cell Bag
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PBSC APHERESIS TOXICITY GRADING SCALES

• Citrate Toxicity Symptom Scale
• Grade 0 no complaints
• Grade 1 peri-oral tingling
• Grade 2 nausea, vomiting
• Grade 3 carpopedal spasm
• Grade 4 cardiac dysrhythmias
• Fluid Management Toxicity
• Grade 0 no clinical problems, no change in weight
• Grade 1 weight gain 10
• Grade 2 weight gain of 20
• Grade 3 pulmonary edema
• Grade 4 apheresis session ended earlier than
  scheduled

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PBSC APHERESIS TOXICITY GRADING SCALES

• Patient Comfort
• Grade 0 no complaints of discomfort
• Grade 1 mild discomfort
• Grade 2 requires sedation
• Grade 3 apheresis interrupted due to discomfort
• Grade 4 apheresis session ended earlier than
  scheduled
• Growth Factor Discomfort
• Grade 0 no bone pain
• Grade 1 bone pain requiring paracetamol
• Grade 2 bone pain requiring codeine
• Grade 3 pain requiring a decrease in dose
• Grade 4 next dose of growth factor aborted

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Liquid Nitrogen Tank (-196C)(for storage of
cryopreserved stem cell)
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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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Pre-Transplant Conditioning Regimen

• Goals
• Effective destruction of residual tumor cells
• Suppress or ablate the host immune system
• Make room in the bone marrow for the stem cells
  to grow

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Conditioning Chemotherapy

• Multiple Myeloma
• High dose melphalan

• Lymphoma
• Big CBV
• Cyclophosphamide
• VP-16 ( etoposide )
• BCNU ( carmustine )
• BEAM
• BCNU
• Etoposide
• Intermediate/ high dose araC ( cytarabine)
• High dose melphalan

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Melphalan (200) or (140 for renal impairment)

• D -9 cyclophosphamide 300mg/m2 ___mg iv bolus
• D -2 900am Monitor urine output
• 930am start forced diuresis NS 500ml NS
  20mmol KCL in 30min
• 1000am Lasix 20mg iv, NS 500ml20mmol KCl in
  30 min
• Aim for urine output gt8ml/kg/hr
• 1030am Melphalan (200mg/m2) ___mg iv in 100ml
  NS over 30 min
• Delay Melphalan by 1/2 to 1hour
  and give further NS and lasix
• If urine output is
  unsatisfactory
• 1100am- 500mlNS 10 mmol KCL hourly X3
• 2pm Lasix 20mg iv hourlyX3
• Aim for hourly urine output500ml
• Give further lasix if ve balance
• 200pm- 500ml 1/21/2 Q4H X5
• mane maintain fluid balance6
• Check Na/K at 3pm and 10pm
• D 0 stem cell infusion
• Give anti-emetic regimen (D -2)

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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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Stem cell infusion
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Fluid management

• Hydration with an intravenous fluid appropriate
  for the patient (½ ½ solution) should
• (a) begin 4 hours prior to the infusion
• (b) continued for at least 4 hours following
  infusion.
• Intravenous fluids on the day of PBSC infusion,
  excluding the volume of cells infused, should
  total 3000 ml/m2/24 hours.

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Pre-medications

• Hydrocortisone
• Benadryl should be given before infusion (due to
  DMSO cryoprotectant).
• Careful intake and output measurements should be
  documented hourly during the hydration and
  infusion times. Diuretics are frequently
  required to avoid fluid overload.
• Mannitol is used to increase renal output and
  flush out the RBC fragments and Hgb present in
  the thawed PBSC product

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Water Bath
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Thawing of Cryopreserved Stem Cell
2
1
4
3
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Thawing of PBSC

• The patient identity must be checked with the
  identifiers on the containers of PBSC prior to
  thawing.
• PBSC are thawed in a 37?C waterbath which is
  monitored with a mercury thermometer to ensure
  temperature does not rise above 40?C.
• Only one bag of PBSC should be thawed at a time.
  Each frozen bag should be removed from the metal
  canister, and the identity of the bag is verified
  as per procedure.
• In the event of bag breakage, every effort is
  made to maintain sterility and salvage the PBSC
  component using a syringe with a large bore
  needle.
• When the infusion of one bag is completed, the
  next bag should be thawed.

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Stem cell infusion

• Thawed PBSC should be infused as rapidly as
  tolerated through a central venous catheter.
• No blood component filter is recommended.
• The unit may be infused by gravity, or the cells
  may be drawn up into a syringe and pushed by
  trained personnel.
• When the final bag of PBSC has been infused, the
  IV tubing should be flushed with normal saline.

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Stem Cell Infusion
Blood Warmer
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Precipitating Factor Possible Symptoms
Haemolysed red cells Fever, chills, haemoglobinuria
Cellular clumps and debris Chest pain, hypoxia, hypertension
Cold 10 DMSO Nausea, headache
Microbial contamination Fever, chills, hypotension
Plasma proteins Urticaria
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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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Routine charting

• 1. Each Day -
• 4 hourly temperature, pulse, blood pressure and
  respirations.
• SaO2 monitoring Q12, Q4H if febrile.
• Body weight - 0800 1800
• Strict fluid balance chart
• Ø maintain progressive 1-2 hourly total of
  patients input output
• Ø ensure oral. Net IV are charted separately
• Ø chart bowel fluid loss
• Daily skin check - document report
  abnormalities, swab any lesions. Examine areas
• not readily visible
• Daily line insertion site check - document
  condition.
• Daily oral mucosa check document
• Daily urinalysis
• Assess Document Pain
• Daily ECOG score
• Document daily nutritional source (oral,
  naso-enteric, TPN or fasting)
• Document bowel actions B.D.

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General hygiene

• may reduce the risk of skin and mouth flora
  causing severe infections
• 1. Shower daily. Particular attention is paid to
  skin folds, perineum and axilla.
• 2. Encourage patient in general hygiene measures
  i.e. hand washing pre meals after toileting
• 3. Maintain dressing / care of lines as per
  protocol
• 4. Encourage regular mouth care as per protocol
• 5. Bed linen to be changed daily
• 6. Visitors are not to use the patients bathroom
  facilities
• 7. If patient is experiencing diarrhoea,
  encourage keeping perineum clean use of sitz
  baths etc

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Natural course of ASCT

• Pre-engraftment
• Usually 2-4 weeks
• BM suppression and suffering from treatment
  related toxicity
• Engraftment
• ANC gt0.5 g/dl for 3 consecutive days
• Followed by rise in platelet and red cell count
• Verified by bone marrow aspiration and biopsy

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Criteria For Discharge

• Satisfactory neutrophil and platelet count
• Afebrile
• Off IV medication
• Satisfactory oral intakegt 1000 calories/day
• Emesis controlled
• Diarrhoea lt 500ml/day
• Good exercise tolerance
• Understand expected outcomes, home care and
  monitor complications

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Home Environment (1)

• Avoid contact with substances that are toxic to
  bone marrow
• gasoline, cleansing products, solvents, paint
  fumes, gardening fertilizers and pesticides
• Not to handle or breathe the fumes associated
  with cleansing products
• have someone to do cleansing if possible

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Home Environment (2)

• Avoid exposure to animals, plants and soil
• Avoid cleaning up after pets and coming into
  contact with barnyard animals for 6 months to a
  year post-transplant
• Plants carry harmful bacteria primarily in the
  soil
• Can keep indoor plants which require little care
• Gardening and repotting of plants should be
  avoided for at least three months post-transplant

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Reimmunization schedule

• Except for live virus vaccine, all patients
  should be vaccinated
• 1. Pneumococcal vaccine administer at 7 months
  and 24 months post-BMT
• 2. Haemophilus influenzae type b conjugate
  vaccine starting at 7 month, administer 3 doses,
  6 months apart
• 3. Diptheria toxoid administer at 12 months
• 4. Tetanus toxoid administer at 12 months
• 5. Enhanced inactivate poliovirus vaccine
  administer 3 doses, at one-month intervals
• 6. Hepatits B vaccine same as poliovirus vaccine
• 7. MMR vaccine administer at 2 years

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Supportive care

• All packed cells and platelets (except marrow) to
  be irradiated (2,500 cGy) irrespective of state
  of engraftment.
• Irradiation of blood products for at least
  12 months post transplant

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Anti-microbial protocol prophylaxis

• Oral decontaminant regimen (on admission)
• Bactidol mouth washes 30ml (30 sec) qid
• Fluconazole 200mg daily qd or Itraconazole 200mg
  daily
• Ciprofloxacin 500mg q12h po or Levofloxacin 500mg
  daily
• Prophylactic systemic antibiotics (PSA)
• Begin when neutrophil lt0.5 x109/L and continue
  until recovery gt0.5 x109/L
• As long as oral tolerated, continue oral
  ciprofloxacin or levofloxacin, no need for IV
  medication if afebrile

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Anti-microbial protocol prophylaxis

• Prophylactic co-trimoxazole (D30-100), if WBC
  allows
• Septrin 2 tab bd three times/week
• If side effect after septrin, inhalational
  pentamidine 300mg once every 3 to 4 weeks
• Alternative to use pentamidine when engrafted,
  then substitute with septrin when WBC allows
• Prophylactic acyclovir (D0-D30) for HSV
• 5mg/kg q8h over 1 hour if orally tolerated, give
  acyclovir 200mg tds po

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Selected patients (1)

• Prophylactic systemic anti-fungal (from
  conditioning till neutrophil gt1.0 x 109/L)
• For patient with history of documented serious
  fungal infection pre-BMT
• Amphotericin B 0.3mg/kg/day for history of
  hepatospenic/ visceral candidiasis
• Amphotericin B 0.5-1 mg/kg/day for mould and deep
  mycosis

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Selected patients (2)

• Prophylactic anti-TB therapy
• (1) Old TB changes in CXR, culture negative, no
  history of treatment
• Continue INAH 300mg qd and rifampicin 450mg daily
  from pre-BMT to at least 6 months post-transplant
• (2) Old TB changes in CXR, culture negative,
  history of complete anti-TB treatment
  (documented)
• Oral ciprofloxacin 500mg q12h po
• (3) ? active/ documented active disease
• Full anti-TB treatment treated for 9 months
• Continue anti-TB treatment till all
  immunosuppression taken off after at least 9
  months therapy

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Selected patients (3)

• Stool positive for strongyloides
• Thiabenazole 25mg/kg BD for 2 days pre-BMT

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Areas of discussion

• 1. Transplant service in HK
• 2. Introduction to SCT
• 3. Mobilisation and collection of stem cells
• 4. Conditioning
• 5. Stem cell infusion
• 6. Post transplant care
• 7. Potential complications

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Myelosuppression Infection/ bleeding

• Infection
• Neutropenic fever
• Treat promptly with antibiotics with
  antipseudomonal effect
• Risks of septic shock
• In that case resuscitate consult ICU
• Give also antifungal/ vancomycin/ G-CSF

• Bleeding
• Give plt conc/ FFP / cryoprecipitate etc
  accordingly
• See site of bleeding and treat accordingly

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Hemorrhagic cystitis (1)

• A serious complication of high dose
  cyclophosphamide t
• Initiated by a urotoxic metabolite of
  cyclophosphamide ( acrolein )
• May develop during the first few days after
  cyclophosphamide infusion or later
• May persist for weeks and even months
• Incidence reduced by
• Forced diuresis ( 200-250ml/hr )
• Bladder irrigation
• Mesna

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Hemorrhagic cystitis (2)

• Other treatment
• Spasmolytic ( eg oxybutynin ) or analgesics
• Continue bladder irrigation via Foley catheter
• Some persistent cystitis may need cauterisation
  of bleeding mucosa with formaldehyde via
  cystoscopy
• Maintain platelet gt 50

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Hemorrhagic cystitis (3)

• If develop later after transplantation ( ie weeks
  to months )
• Suspect infectious causes rather than drug
  induced
• Viral infections ( more common in allo transplant
  )
• Adenovirus/ polyoma virus/ BK virus
• Polyvalent Ig may be given ( iv )

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Other side effects of cyclophosphamide

• Cardiotoxicity
• At gt 200mg/kg
• Endothelial damage associated with myocardial
  necrosis
• Potentially lethal CHF
• Pulmonary toxicity and VOD
• SIADH ( Renal tubular injury )

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Veno-occlusive disease (VOD) of liver

• Early complications of conditioning therapy
• Endothelial cell injury
• Intrahepatic venous clotting occurs
• Then postsinusoidal obstruction to portal flow
• If severe liver failure

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Hepatic dysfunction -- VOD of liver

• The most common liver disease in the first month
  post-transplant
• Suspected if
• BW increase due to fluid retention
• Painful hepatomegaly
• Increasing bilirubin

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Management

• Transfuse RBC
• Keep hematocrit gt 0.30 / Hb gt 10
• RBC helps in increase osmotic load/ supply O2 to
  liver cells and renal tubules
• Spironolactone/ lasix
• Abdominal tap if severe ascites
• tPA/ heparin in selected patients

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Liver VOD DDx

• Congestive heart failure
• Viral hepatitis
• Hep B/C
• CMV
• (less often ) adenovirus/ varicella zoster/ HSV
• Sepsis with reactive change
• Drug induced cholestasis

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High dose melphalan

• Mucositis
• GI muscosal injury limits dose escalation to gt
  200mg/m2 as single agents
• VOD
• Diffuse pulmonary alveolitis ( like other
  alkylating agents )
• Stimulate SIADH

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Interstitial pneumonitis

• Mild restrictive ventilatory defects in 20 post
  transplant ( most severe effect noted at 1 year )

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Interstitial pneumonitis

• BCNU
• Acute ( or semi-acute ) interstitial pneumonitis
• A restrictive pulmonary syndrome that can occur
  typically at 4-8 wks after transplant
• Start systemic steroid promptly
• BAL to exclude infective process

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DDx Diffuse alveolar hemorrhage

• Mimic interstitial pneumonitis ( noted esp in
  auto patients )
• Short course high-dose corticosteroids is often
  life-saving

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DMSO toxicity

• Rare anaphylactic reaction during the initial
  infusion of thawed cells
• Treatment of anaphylactic reactions /
  resuscitation
• The remainder of the cells may be administered
  cautiously
• Non-allergic profound hypotension
• Likely from histamine-induced vasodilatation
• Skin flusing, dyspnea, abdominal cramping, mausea
  and diarrhoea can occur ( DMSO induced histamine
  release? )
• Headache ( 70)

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Thank you