Blood and Marrow Transplantation
Francisco F. Lopez, MD
Hematology and Medical Oncology
Bone Marrow Transplantation
1st BMT Reunion (January 2004)
Outline
• 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
• Young immature cells that make up 0.5% to 5% of the marrow cells.
• Express CD34+
• Progenitor cells: self-renew and divide to become red and white cells, and platelets.
Stem cellsBone marrow2 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 blood2.0 to 5.0 x 106 CD34+ cells/kg for auto/allo transplantscan be stored at 4 C overnight or cryopreserved with dimethyl sulfoxide
(DSMO)
Umbilical cord3.7 x 106 TNC/kg recipient body weightcan 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
ProcedureAllogeneic 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
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
-11 -9 -7 -5 -3 -1 0 1 3 5 7 9 11 13 15 17
WBC
ProcedureAutologous transplant
Procedure: The Harvest
D –10 Cyclophosphamide 1.5gm/mm D – 7 Start GCSF 10mcg/kgD – 6 D – 5D – 4D – 3D – 2D – 1 D 0 Harvest using apheresis machine (collect 2.5
x 106 / kgBW CD 34+ cells)
The transplant
• Day -8 admit• Day -7 Total body irradiation• Day -6 Total Body irradiation• Day -5 Total body irradiation• Day -4 etoposide 60mg/kg IV• Day -3 rest• Day -2 cytoxan 100mg/kg IV• Day -1 rest• Day 0 infusion of stem cells• Day +5 begin GSCF 5mg/kg/day• Day +10 marrow recovery or engraftment
Transfusion of stem cells
Indications and Timing of Transplant
Allogeneic TransplantMalignant
• Acute and chronic leukemias– AML, ALL, CML
• Myelodysplastic syndrome (MDS)
• Lymphomas (failed chemotherapy)
• Multiple myeloma
• Myeloproliferative diseases
Allogeneic TransplantNon malignant
• Aplastic anemia
• Thalassemia
• Immune disorders
• Paroxysmal nocturnal hemoglobinuria (PNH)
Autologous Transplant
• 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
0
10
20
30
40
50
60
70
80
chemo
1st CR
> 1st CR
Allogneic BMT in Pediatric ALLIndications:
t(9;22) t(4,11)3rd CR or higherrelapse on therapy or
w/in 12 months of end of therapy
May be offered:> 28 days to achieve CR2nd CR, relapse > 12 months of end of therapy
0
10
20
30
40
50
60
70
80
90chemogoodrisk
1st CRhigh risk
chemohigh risk
2nd CR
> 2nd CR
chemo
Severe Aplastic Anemia
0
10
20
30
40
50
60
70
80
OS >40y/o <40y/o
IST
BMT
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 0
10
20
30
40
50
60
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 others0
10
20
30
40
50
60
70chemo
1st CR
1strelapse/2nd CR
inductfail/ >2ndrelapse
2nd BMT Reunion (January 2005)
Complications During BMT
• 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
• 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 MarrowTransplant Data
BMT Data: 27 patients since December 2002
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
2002 2003 2004 2005 2006 2007
allogeneic
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
– 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
ResultsAllogeneic• 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 daysAutologous• 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 # of pts1 52 73 24 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
– 2 ALL > 1st CR– 3 myelodysplastic syndrome– 1 AML induction failure– 1 AML auto – 1 multiple myeloma auto
survival
• 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
0
10
20
30
40
50
60
70
80
90
100
OS
DFS
Improve outcome
• Education and information– Can be done in our country– Dispel myths
• 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)