1. Blood and Marrow Transplantation Francisco F. Lopez, MD Hematology and Medical Oncology Bone Marrow Transplantation

2. 1 st BMT Reunion (January 2004)

3. Outline History Definition Rationale Procedure Indications Our data Summary

4. History of Blood and Marrow Transplantation in the Philippines 1990 1 st marrow transplant at the NKTI 2001 1 st peripheral blood stem cell transplant at NKTI 2002 St Luke’s Medical Center (SLMC) 2002 Asian Hospital Medical Center (AHMC) 2005 1 st autologous stem cell transplant at AHMC 2005 1 st cord blood transplant at SLMC

5. 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.

6. “Let’s crack your bones wide open!”

7. 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.

9. Stem cells Bone marrow 2 to 5 x 10 8 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 10 6 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 10 6 TNC/kg recipient body weight can be stored at 4 C or 25 C for up to three days or cryopreserved with DSMO

10. Rationale

11. Two kinds Allogeneic: Donor –Matched or partially mismatched sibling –Unrelated –Cord blood Autologous: No donor –Stem cells are harvested from patient

12. 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

13. Human Leukocyte Antigen (HLA) typing

14. 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

16. Procedure Allogeneic transplant

20. 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

23. WBC from day of transplant to recovery

24. Procedure Autologous transplant

25. 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 10 6 / kgBW CD 34 + cells)

28. 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

29. Transfusion of stem cells

30. Indications and Timing of Transplant

31. Allogeneic Transplant Malignant Acute and chronic leukemias –AML, ALL, CML Myelodysplastic syndrome (MDS) Lymphomas (failed chemotherapy) Multiple myeloma Myeloproliferative diseases

32. Allogeneic Transplant Non malignant Aplastic anemia Thalassemia Immune disorders Paroxysmal nocturnal hemoglobinuria (PNH)

33. Autologous Transplant Multiple Myeloma Non-Hodgkins Lymphoma Hodgkins Disease Solid Tumors Autoimmune diseases (multiple sclerosis)

34. Allogeneic BMT in Pediatric AML Indications: All except Down’s syndrome t(8;21) t(15;17) inv 16

35. Allogneic BMT in Pediatric ALL Indications: t(9;22)t(4,11) 3 rd CR or higher relapse on therapy or w/in 12 months of end of therapy May be offered: > 28 days to achieve CR 2 nd CR, relapse > 12 months of end of therapy

36. Severe Aplastic Anemia

37. 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

38. 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

39. 2 nd BMT Reunion (January 2005)

40. Complications During BMT

41. 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

42. 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).

43. 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.

44. Mouth Sores –Mouth wash (nystatin and biotene) –Morphine pushes or drip when severe (face will be swollen) –Thrush

45. Diarrhea –Chemotherapy induced (Cuclophosphamide) –Infection: Clostridium Defficile –GVHD (graft vs host disease) –Food induced (avoid creamy, milk, oily food)

46. 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

47. Prevention Isolation room : positive pressure Strict hand washing Mask No need for gown or gloves unless patient is positive for clostridum defficile

48. Renal Complications –Renal insufficiency –Drugs: cyclosporine, vancomycin, amphotericin B) –Monitor I & 0 accurately every 12 hours. Balance fluid I & 0. lasix IV given prn.

49. 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

50. Pancytopenia –Blood and platelet transfusion –Platelet apheresis is always used –Blood and platelets should always be available, filtered and irradiated.

51. 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

52. 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

53. Rash –Drug –GVHD –infection

54. Pulmonary complications –Pneumonia –Pulmonary congestion Total fluid per day 3L to 4L –Engraftment syndrome

55. Mortality –Infection –GVHD –Relapse

56. 3 rd BMT Reunion (January 2006)

57. Bone Marrow Transplant Data

58. BMT Data: 27 patients since December 2002

59. 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

60. BMT Data: Donor Sex –Same sex: 10 –Opposite sex: 12 HLA match –Full sibling: 21 –Mismatch: 1(HLA 4/6 from father)

61. BMT Data 22 allogeneic –Acute myelogenous Leukemia 10 1 st CR 7 2 nd CR 1 Induction failure 2 –Acute lymphoblastic leukemia 4 1 st CR 1 > 1 st CR 3 –Myelodysplastic syndrome 4 –Chronic myelogenous leukemia 1 –Severe aplastic anemia 1 –Thalassemia 1 –Metastatic (lung & bones) renal cell cancer 1

62. BMT Data 5 Autologous –3 multiple myeloma –1 relapsed hodgkin’s disease –1 acute myelogenous leukemia in 2 nd CR

63. Results Allogeneic Harvested stem cells: mean 7 x 10 6 CD34 + cells / kg BW of patient Range: 2.9 to 23.6 x 10 6 CD34 + cells Days of harvest: mean 2 days Range 1 to 4 days Autologous Harvested stem cells: mean 5.1 x 10 6 CD34 + cells / kg BW of patient Range: 3.2 to 8.1 x 10 6 CD34 + cells Days of harvest: mean 2 days Range 1 to 4 days

64. Results Engraftment (allo and auto) –Mean 13 days –Range: 10 to 18 days

65. Morbidity

66. Rejection Acute: Patient with AML 1 st 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.

67. 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

69. Acute Graft vs Host Disease (GVHD) n = 15/22 Grade# of pts 15 27 32 41

70. Causes of GVHD Causes HLA disparity Conditioning regimen Sex mismatch Age Parous donor Peripheral blood vs marrow

71. 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

72. 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

73. 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 > 1 st CR –3 myelodysplastic syndrome –1 AML induction failure –1 AML auto –1 multiple myeloma auto

74. survival Allogeneic: 13/22 Autologous: 3/5 16/27 survivors 1 st patient transplanted is now 4yrs and 5 months post transplant Data may change in time –wait for 2 to 3 years

75. Survival

76. 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)

77. Burst my bubble!

78. Kicking leukemia away!

79. Survival

80. Cost

81. Factors –Age –Disease and status of disease –Weight –Complications –Regimen used

82. 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

83. 4 rd BMT Reunion (February 2007)