Transcript Bone Marow Transplantation

Blood and Marrow Transplantation
Francisco F. Lopez, MD
Hematology and Medical Oncology
Bone Marrow Transplantation
1st BMT Reunion (January 2004)
Outline
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History
Definition
Rationale
Procedure
Indications
Our data
Summary
History of Blood and Marrow
Transplantation in the Philippines
1990
1st marrow transplant at the NKTI
2001
1st peripheral blood stem cell transplant
at NKTI
2002
St Luke’s Medical Center (SLMC)
2002
Asian Hospital Medical Center (AHMC)
2005
1st autologous stem cell transplant at
AHMC
2005
1st cord blood transplant at SLMC
The transfusion of the immature
progenitor stem cells derived from a
donor to the recipient (allogeneic); OR
stem cells previously harvested from
the patient (autologous).
It is NOT an operation / surgical
procedure.
“Let’s crack your bones wide open!”
Stem cells
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Young immature cells that make up 0.5%
to 5% of the marrow cells.
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Express CD34+
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Progenitor cells: self-renew and divide to
become red and white cells, and
platelets.
Stem cells
Bone marrow
2 to 5 x 108 TNC/kg weight of recipient with the maximum volume dictated by
the weight of the donor (20ml BM aspirate/kg)
can be stored at room temperature for up to 24hrs until infusion into the
recipient or cryopreserved
Peripheral blood
2.0 to 5.0 x 106 CD34+ cells/kg for auto/allo transplants
can be stored at 4 C overnight or cryopreserved with dimethyl sulfoxide
(DSMO)
Umbilical cord
3.7 x 106 TNC/kg recipient body weight
can be stored at 4 C or 25 C for up to three days or cryopreserved with DSMO
Rationale
Two kinds
• Allogeneic: Donor
– Matched or partially mismatched sibling
– Unrelated
– Cord blood
• Autologous: No donor
– Stem cells are harvested from patient
Allogeneic transplant
• involves the transfer of stem cells from
donor to recipient to permanently replace
all hematopoietic cells
• eradicate malignant cells with high dose
chemotherapy +/- radiotherapy
• sufficient immunosuppression of the
host to allow growth of the allograft
• immune mediated graft vs
leukemia/lymphoma or graft vs tumor
effect
Human Leukocyte Antigen (HLA) typing
Autologous transplant
• Increasing the dose of some
chemotherapeutic agents may result in
large increase in tumor cell kill
• Transfusing previously harvested stem
cells of the patient will guarantee bone
marrow recovery
Procedure
Allogeneic transplant
Schema
-8 admit to hospital
-7 Total body Irradiation
-6 Total body Irradiation
-5 Total body Irradiation
-4 Total body Irradiation; Donor starts GCSF
-3 Cytoxan (60mg/kg)
-2 Cytoxan (60mg/kg)
-1 Rest day and start cyclosporine IV
0 Harvest and infusion of stem cells
+1 Methotrexate 15mg/mm
+3 Methotrexate 10mg/mm
+6 Methotrexate 10mg/mm
+11 Methotrexate 10mg/mm
WBC from day of transplant to
recovery
5
4.5
4
3.5
3
2.5
WBC
2
1.5
1
0.5
0
-11 -9 -7 -5 -3 -1 0
1
3
5
7
9 11 13 15 17
Procedure
Autologous transplant
Procedure: The Harvest
D –10 Cyclophosphamide 1.5gm/mm
D – 7 Start GCSF 10mcg/kg
D–6
D–5
D–4
D–3
D–2
D–1
D 0 Harvest using apheresis machine (collect 2.5
x 106 / kgBW CD 34+ cells)
The transplant
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Day
Day
Day
Day
Day
Day
Day
Day
Day
Day
Day
-8 admit
-7 Total body irradiation
-6 Total Body irradiation
-5 Total body irradiation
-4 etoposide 60mg/kg IV
-3 rest
-2 cytoxan 100mg/kg IV
-1 rest
0 infusion of stem cells
+5 begin GSCF 5mg/kg/day
+10 marrow recovery or engraftment
Transfusion of stem cells
Indications and Timing of
Transplant
Allogeneic Transplant
Malignant
• Acute and chronic leukemias
– AML, ALL, CML
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Myelodysplastic syndrome (MDS)
Lymphomas (failed chemotherapy)
Multiple myeloma
Myeloproliferative diseases
Allogeneic Transplant
Non malignant
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Aplastic anemia
Thalassemia
Immune disorders
Paroxysmal nocturnal hemoglobinuria
(PNH)
Autologous Transplant
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Multiple Myeloma
Non-Hodgkins Lymphoma
Hodgkins Disease
Solid Tumors
Autoimmune diseases (multiple sclerosis)
Allogeneic BMT in Pediatric AML
Indications: All except
Down’s syndrome
t(8;21)
t(15;17)
inv 16
80
70
60
50
40
30
20
10
0
chemo
1st CR
> 1st CR
Allogneic BMT in Pediatric ALL
Indications:
t(9;22)
t(4,11)
3rd CR or higher
relapse on therapy or
w/in 12 months of
end of therapy
May be offered:
> 28 days to achieve CR
2nd CR, relapse > 12
months of end of therapy
90
80
70
chemo
good
risk
1st CR
high risk
60
50
chemo
high risk
40
30
2nd CR
20
10
> 2nd CR
0
chemo
Severe Aplastic Anemia
80
70
60
50
IST
BMT
40
30
20
10
0
OS
>40y/o
<40y/o
Allogneic BMT in adult ALL
Poor risk features
• WBC > 25,000
• T(9;22) t(8;14) t(4;11)
• Age > 30y/o
• Extramedullary
disease
• Requiring more than
4 weeks to achieve a
CR
60
50
40
30
20
10
0
chemo
1st CR
> 1st CR
Allogeneic BMT in adult AML
Prognostic indicators that
predict outcome of
standard chemotherapy
based on cytogenetic
abnormalities.
favorable: t(8;21) t(15;17)
inv 16
Intermediate: del y; normal
karyotype; 11q23
Poor: all others
70
chemo
60
50
1st CR
40
30
20
10
0
1st
relapse/
2nd CR
induct
fail/ >2nd
relapse
2nd BMT Reunion (January 2005)
Complications During BMT
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Nausea and Vomiting
Nutrition
Mouth Sores
Diarrhea
Infection
Renal complications
Veno-Occlusive disease of the liver (VOD)
Pancytopenia
Graft Rejection
Acute Graft vs Host Disease
Rash
Pulmonary complications
Death
• Nausea and Vomiting
– More common during the early part of
transplant
– Round the clock anti emetic medications
– During the recovery phase, nausea / vomiting
/ abdominal pain (cramps) / diarrhea, the
patient may have graft vs host disease
(GVHD).
• Nutrition
– Low bacteria diet: no fresh fruit and
vegetables; served hot; no left over; tray
should be clean;
– Appetite diminishes after chemotherapy
– Total parenteral nutrition until patient can eat.
• Mouth Sores
– Mouth wash (nystatin and biotene)
– Morphine pushes or drip when severe (face
will be swollen)
– Thrush
• Diarrhea
– Chemotherapy induced (Cuclophosphamide)
– Infection: Clostridium Defficile
– GVHD (graft vs host disease)
– Food induced (avoid creamy, milk, oily food)
• Bacterial Infections
– Gram negative
– Gram positive (central line or skin); patient should
shower or sponge bath daily.
– Antibiotics: third generation cephalosporin and
vancomycin
• Fungal
– Pulmonary (aspergillus)
– Yeast
– Amphoteric B prophylaxis
• Viral
– Herpes zoster
– Acyclovir IV
Prevention
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Isolation room : positive pressure
Strict hand washing
Mask
No need for gown or gloves unless patient
is positive for clostridum defficile
• Renal Complications
– Renal insufficiency
– Drugs: cyclosporine, vancomycin,
amphotericin B)
– Monitor I & 0 accurately every 12 hours.
Balance fluid I & 0. lasix IV given prn.
• Liver Complications
– Veno-Occlusive disease of the liver (VOD)
• Water retention
• Tender liver
• Elevated bilirubin
• Elevation in bilirubin and SGPT and SGOT
– Medications: cyclosporine, TPN
– GVHD
• Pancytopenia
– Blood and platelet transfusion
– Platelet apheresis is always used
– Blood and platelets should always be
available, filtered and irradiated.
• Graft rejection
– Engraftment occurs between two to three
weeks after transfusion of stem cells
– Recipient develops antibodies against the
HLA antigen of the donor.
– Incidence increases in heavily transfused
patients.
– Prior transfusions without filter and random
donor platelets used
• Graft versus host disease
– Occurs when donor stem cells recognizes the
body of the recipient as foreign and attacks
the body.
– Acute GVHD occurs during engraftment:
diarrhea, elevated bilirubin and rash
– GVHD prophylaxis: cyclosporine IV,
methotrexate IV
• Rash
– Drug
– GVHD
– infection
• Pulmonary complications
– Pneumonia
– Pulmonary congestion
• Total fluid per day 3L to 4L
– Engraftment syndrome
• Mortality
– Infection
– GVHD
– Relapse
3rd BMT Reunion (January 2006)
Bone Marrow
Transplant Data
BMT Data:
27 patients since December 2002
5
4.5
4
3.5
3
2.5
allogeneic
2
1.5
1
0.5
0
2002
2003
2004
2005
2006
2007
BMT Data
• December 2002 to April 2007
• 27 stem cell transplants
– 22 allogeneic
– 5 autologous
• Ages: 8 months to 66 years old
• Sex: 17M and 10F
• Transplant Regimen:
– Chemotherapy only: 21
– Fractionated total body irradiation + chemo: 6
• GVHD prophylaxis:
– CSA + Methotrexate 17
– CSA + Cellcept 5
BMT Data: Donor
• Sex
– Same sex: 10
– Opposite sex: 12
• HLA match
– Full sibling: 21
– Mismatch: 1(HLA 4/6 from father)
BMT Data
• 22 allogeneic
– Acute myelogenous Leukemia 10
• 1st CR 7
• 2nd CR 1
• Induction failure 2
– Acute lymphoblastic leukemia 4
• 1st CR 1
• > 1st CR 3
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Myelodysplastic syndrome 4
Chronic myelogenous leukemia 1
Severe aplastic anemia 1
Thalassemia 1
Metastatic (lung & bones) renal cell cancer 1
BMT Data
• 5 Autologous
– 3 multiple myeloma
– 1 relapsed hodgkin’s disease
– 1 acute myelogenous leukemia in 2nd CR
Results
Allogeneic
• Harvested stem cells: mean 7 x 106 CD34+ cells
/ kg BW of patient
• Range: 2.9 to 23.6 x 106 CD34+ cells
• Days of harvest: mean 2 days
• Range 1 to 4 days
Autologous
• Harvested stem cells: mean 5.1 x 106 CD34+
cells / kg BW of patient
• Range: 3.2 to 8.1 x 106 CD34+ cells
• Days of harvest: mean 2 days
• Range 1 to 4 days
Results
• Engraftment (allo and auto)
– Mean 13 days
– Range: 10 to 18 days
Morbidity
Rejection
Acute: Patient with AML 1st CR did not
engraft at all. Positive antibodies against
HLA. Was salvaged with a second
transplant using same donor.
Currently doing well and off immuno drugs
Delayed: Patient with thalassemia. Graft
rejection after 1 year. Autologous recovery
of marrow. Transfusion dependent.
Acute Graft Vs Host Disease
(AGVHD) in BMT
• Manifestation of alloreactivity and occurs
when mature T cells are transferred to
hosts expressing histocompatibility
differences
• Donor CD4+ and CD8+ target major
tissues of the skin, liver and intestinal tract
Acute Graft vs Host Disease
(GVHD) n = 15/22
Grade
1
2
3
4
# of pts
5
7
2
1
Causes of GVHD
Causes
• HLA disparity
• Conditioning regimen
• Sex mismatch
• Age
• Parous donor
• Peripheral blood vs marrow
Infection
• 8 had either gram (+) or gram (-) bacterial
infection
• 1 had recurrence of PTB during transplant.
He was an auto transplant patient with
relapsed hodgkin’s disease, (+) history of
treated PTB
• 4 had herpes zoster, months after
• 1 had anal warts, months after
Cytomegalovirus (CMV)
• 9/14 developed (+) CMV blood culture within
100 days of transplant.
• They were successfully treated with ganciclovir
for six weeks.
• Risks of developing CMV:
– HLA mismatch
– AGVHD
– (+) serum CMV antibody
Mortality n = 11
• Infection (Gm negative septic shock) 2
– 10 and 11 days post transplant
– history of prior infections
– poor performance status
• Severe AGVHD of the GIT 1
• Relapse disease 8
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2 ALL > 1st CR
3 myelodysplastic syndrome
1 AML induction failure
1 AML auto
1 multiple myeloma auto
survival
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Allogeneic: 13/22
Autologous: 3/5
16/27 survivors
1st patient transplanted is now 4yrs and 5
months post transplant
• Data may change in time
– wait for 2 to 3 years
Survival
100
90
80
OS
36
33
30
27
24
21
18
15
12
9
6
DFS
3
0
70
60
50
40
30
20
10
0
Improve outcome
• Education and information
– Can be done in our country
– Dispel myths
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Not a surgical procedure
Harvesting stem cells is not a painful procedure
Maximum hospital stay 6 weeks
Live a normal life
• Screen candidates
• Early transplant and not later on (not a last
resort)
Burst my bubble!
Kicking leukemia away!
Survival
Cost
Cost
Factors
– Age
– Disease and status of disease
– Weight
– Complications
– Regimen used
Cost
• Range (Php 0.8M to Php 3M)
– Adult (Php 1.7M)
– Pediatric (Php 1.4M)
• Beyond what most Filipinos can afford
• The cost of BMT abroad is more
expensive
– Israel US$ 100,000
– USA $250,000 to $500,000
4rd BMT Reunion (February 2007)