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)