Bone Marrow Transplantation in pediatrics

Bonr marrow transplantation

1. Bone Marrow/Stem Cell Transplantation

2. Objectives Introduction Stem Cell And Its Sources Types Of BMT Indications Of BMT HLA Matching Transplant Process Adverse Effects Of BMT Graft Rejection (GVHD) Post BMT Care BMT In Different Conditions

3. Bone Marrow Bone Marrow is the soft spongy tissue that fills the cores of larger bones. It serves an active function in the body by producing all three types of blood cells; RBCs; Having oxygen carrying capacity. Platelets; Role in blood coagulation. WBCs; Support immune system.

4. Bone Marrow Transplantation(BMT) Bone Marrow Transplantation is a procedure used to treat patients with life-threatening blood, immune or genetic disorders. A Bone Marrow Transplant replaces the unhealthy blood-forming cells with healthy ones. Healthy bone marrow stem cells are harvested from matching bone marrow donors.

5. Cont… The immunology of HSCT is distinct from that of other types of transplant because, in addition to stem cells, the graft contains mature blood cells of donor origin, including T cells, B cells, natural killer cells,and dendritic cells. These cells repopulate the recipient’s lymphohematopoietic system and give rise to a new immune system, which helps eliminate residual leukemia cells that survive the conditioning regimen.

6. Cont… This effect is known as the graft-versus-leukemia (GVL) effect. The first MBT was performed in 1968 in a child with an inherited immune disorder.

7. Stem Cell & Its Sources Stem cells are immature cells in the bone marrow that give rise to all your blood cells . Stem Cell Transplants can come from three sources : Peripheral Blood ( Aphereses) Marrow ( Bone Marrow Harvest) Umbilical Cord Fetal Liver

8. Types Of BMT There are two types of Bone Marrow Transplants on the basis of source of Stem Cells; Autologous Transplant; Patient’s own HSCs from bone marrow or peripheral blood. Allogeniec Transplant; HSCs from another person.

9. Cont… Types of Bone Marrow Transplant on the basis of Donor are; Isograft; From identical twin Optimal Donor-Identical Tissue Typing; Usually a sibling 25% Partially-matched Donor; A biologic parent is always half-matched or Haplocompatible. There is 50% chance that any sibling will be half-matched with any other sibling. Umbilical Cord Blood

10. Advantages & Disadvantages Of HSC Collection Methods

11. Haplo-identical HSCT Advantages Nearly all patients have a donor. Share major(HLA-C) & Minor histocompatability antigens. Disadvantages HLA barriers; Graft rejection. GVHD. Immune dysregulation.

12. Cord Blood Transplantation Advantages Waste product of normal deliveries. Readily available. Decreased transmission of viruses e.g CMV Disadvantages One unit rescues one patient. Theoretical risk of genetic disease transmission. Theoretical risk of maternal cell contamination(GVHD)

13. Indications Of BMT Non-cancerous Conditions/Stem Cells Defects; Aplastic Anemia Thalassemia Major Sickle Cell Disease SCID Wiskott-Aldrich Sydrome Fanconi Anemia Chronic Granulomatous Disease

14. Cont… Cancerous Conditions; Leukemia Lymphoma Neuroblastoma Medulloblastoma Sarcoma

15. Cont… Genetic Diseases; Thalassemia Major Sickle Cell Disease SCID Inborn Errors Of Metabolism; Hurler’s Syndrome Fanconi’s Syndrome Adrenoleukodystrophy Metachromatic Leukodystrophy Osteopetrosis

16. HLA Matching HLA are proteins or markers on most cells in the body specially WBCs. Immune System uses HLA to recognize which cells belong to body and which do not. These antigens are also known as the major histocompatibility complex (MHC) and occupy the short arm of chromosome 6. This genetic region has been divided into chromosomal regions, called classes.

17. Cont… Class I; is made up of  HLA-A ,  HLA-B , and  HLA-C , as well as genes that are less frequently discussed (eg,  HLA-E ,  HLA-F , and  HLA-G ). Class II; is made up of  HLA-DR ,  HLA-DP , and  HLA-DQ , as well as variations on these genes.  Traditionally, the loci critical for matching are  HLA-A ,  HLA-B , and  HLA-DR .

18. Cont… HLA-C  and  HLA-DQ  are also now considered when determining the appropriateness of a donor. For unrelated transplants(MUD) 6 of 8 HLA markers must be matched. For haploidentical or half-matched transplants, donors match exactly half or 5 of 10 HLA markers. A cord blood transplant must match at least 4 of 6 markers.

19. Transplant Process A successful transplant requires an expert medical team- doctors, nurses, and support staff( pharmacist, dietician, social worker, physiotherapist, psychologist and occupational therapist) The Transplant Process consists of 5 main steps; Conditioning Phase Stem Cell Infusion Neutropenic Phase Engraftment Phase Post-engraftment Period.

20. Conditioning Phase A period of several days of chemotherapy and/or radiation, before the transplant can go ahead. It typically lasts for 7-10 days. The purposes of Conditioning Regimen are; To eliminate malignancy To provide immune suppression to prevent rejection of new stem cells To create space for the new cells

21. Cont… Strategy of Conditioning Regimen is; Myelo-Ablative Therapy Reduced-intensity Therapy

22. Stem Cell Infusion Stem Cells are transfused through a central line called Hickman’s Cathetar , in a way much like blood transfusion. It usually takes 20min to an hour depending on the amount transfused. The crucial thing is not the volume, but the number of stem cells it contains i.e Total Nucleated Cell count, or TNC. When treating cancer, the transplant dose should be at least 25 million TNC per kilogram of patient body weight (1 kilogram equals 2.2 pounds).

23. Cont… Stem Cell products are cryopreserved at -40ºC with Dimethyl Sulfoxide (DMSO) as a preservative . The stem cells may be processed before infusion to remove T cells to prevent GVHD. Premedication with acetaminophen and diphenhydramine to prevent reactions.

24. Neutropenic Phase During this period (2-4 wk), the patient essentially has no effective immune system. Healing is poor, and the patient is very susceptible to infection. Supportive care and empiric antibiotic therapy are the mainstays of successful passage through this phase. Whole blood and platelet transfusion is done to prevent infections and bleeding.

25. Engraftment Phase The new stem cells will take 10-28 days to ‘Bed Down’ and start producing new cells. This recovery of normal levels of cells is called Engraftment. Neutrophil engraftment is important ; GCSF may be given to accelerate the process. Platelets are the next to return with red cells last.

26. Cont… During this period, the healing process begins with resolution of mucositis and other lesions acquired. In addition, fever begins to subside, and infections often begin to clear. The greatest challenges at this time are management of GVHD and prevention of viral infections (especially CMV).

27. Post-engraftment Phase This period lasts for months to years. Hallmarks of this phase include; The gradual development of tolerance. Weaning off of immunosuppression. Management of chronic GVHD. Documentation of immune reconstitution.

28. Adverse Effects Of BMT Early Effects; (0-30 Days) Mucositis; is the most common short-term complication of myeloablative preparatory regimens (common with etoposide -containing regimens) and methotrexate used to prevent GVHD. Intestinal mucositis results in nausea, abdominal cramping, and diarrhea and requires total parenteral nutrition (TPN) to maintain caloric requirements.

29. Cont… Hemorrhagic cystitis; is a disorder that manifests as dysuria and hematuria, with the hematuria being microscopic or gross. Medications used in conditioning (especially cyclophosphamide) are well known to be associated with hemorrhagic cystitis.

30. Cont… Prolonged and severe pancytopenia; Severe (< 500/µL but often < 100/µL), prolonged (up to 4 wk) neutropenia is common after transplantation and invariably requires the use of empiric broad-spectrum antimicrobials until recovery of the neutrophils. Serious infections (eg, pneumonia, bacteremia, fungemia, viremia) may occur in up to 50% of patients after transplantation.

31. Cont… Infections; One to 3 months after transplantation, T-cell dysfunction, hypogammaglobulinemia, and acute GVHD predispose to infections with the following: Encapsulated bacteria (eg, pneumococcus,  Haemophilus influenzae ) Viruses (eg, cytomegalovirus [CMV]) Pneumocystis jiroveci   Molds (eg,  Aspergillus,   Zygomycetes ) Candida  species.

32. Cont.. Graft Failure; graft failure results from failure to establish hematologic engraftment after transplantation. The greater the degree of HLA mismatch, the greater the risk of graft rejection.   Other risk factors for failure include the following: Aplastic anemia. T-cell depletion of the donor graft (loss of helper T cells, which help in engraftment).

33. Cont… Infusion of lower number of hematopoietic stem cells - As in cord blood transplants Nonmyeloablative transplants GVHD Splenomegaly Use of methotrexate, mycophenolate mofetil, antithymocyte globulin, and ganciclovir.

34. Cont… Pulmonary Complications; Transplantation-related lung injury(TRLI) is an acute inflammatory response. In patients receiving Allografts, interstitial pneumonitis is frequently fatal. A diffuse alveolar hemorrhage is sometimes observed in the autograft setting.

35. Cont… Hepatic Veno-occlusive Disease; More accurately termed as Sinusoidal Obstruction Syndrome, is very common after HSCT. Clinically it is characterized by; Weight gain. Fluid retention. Tender hepatomegaly. Jaundice & ascites. Can progress to fulminant hepatic failure.

36. Cont… Transplantation-associated Thrombotic Microangiopathy; is a microangiopathic hemolytic anemia. Characterized by; Hemolytic Anemia. Platelet consumption. Fibrin/Thrombosis in microcirculation i.e Kidneys .

37. Late Effects; Late onset problems can occur months after transplantation usually allograft. Late effects include; Chronic GVHD. Ocular Effects; Posterior Subcapsular Cataract, Keratoconjunctivitis Sicca & Infectious Retinitis. Cont…

38. Cont… Endocrine Problems; Infertility both in males & females is common following HSCT. Options to preserve fertility are sperm cryopreservation & oocyte retrieval & cryopreservation. Other endocrine problems include growth & development impairment and hypothyroidism.

39. Cont… Pulmonary Effects; Pulmonary infiltrates which can be; Infectious; CMV, P jiroveci & Aspergillus. Non-infectious; Restrictive lung disease,COPD( Bronchiolitis Obliterans), CHF, Hemorrhagic alveolitis, Aspiration & Pulmonary embolism.

40. Cont… Neurocognitive & Neuropsychological Effects; Low IQ scores. Sleep disorders. Fatigue. Memory problems. Developmental delays.

41. Cont… Immune Effects; is suppressed for months to years after HSCT usually allograft. Musculoskeletal Effects; Osteopenia Osteoporosis Avascular necrosis

42. Graft Versus Host Disease(GVHD) Major cause of mortality and morbidity after allogeneic HSCT. Caused by engraftment of immunocompetent donor T lymphocytes in an immunologically compromised host which show histocompatibility differences with the donor.

43. Cont… GVHD is subdivided into; Acute GVHD; Occurs within 3 months or 100 days after transplantation. Chronic GVHD; Occurs after 3 months or 100 days of transplantation.

44. Cont… Acute GVHD; It occurs within the first 100 days after the procedure. Pathogenesis; Type IV Hypersensitivity Reaction: Delayed type. 30% incidence.

45. Cont… A three-step process generates the clinical syndrome. Step 1; Conditioning-induced tissue damage activates recipient antigen-presenting cells. Step 2; Donor T cells become activated, proliferate, expand, and generate cytokines such as tumor necrosis factor-α, interleukin (IL)-2, and interferon-γ. Step 3; T hese cytokines cause tissue damage through cytotoxic CD8 + T cells.

46. Cont… Clinical Manifestations; Erythematous maculopapular rash. Persistent anorexia. Vomiting and/or diarrhea. Liver disease with deranged LFFTs.

47. Cont… Stages/Grades of Acute GVHD;   is graded as per Glucksberg Criteria.  Stage I disease is confined to the skin and is mild.  Stage II-IV have systemic involvement. Stage III and IV acute GVHD carry a grave prognosis.

48. Cont… Risk Factors;   HLA-mismatched grafts( Most common)   MUD grafts Advanced patient age Grafts from a parous female donor

49. Cont… Prophylaxis; T-cell depletion of the graft. Using immunosuppressive agents against donor cytotoxic lymphocytes.  Cyclosporine Tacrolimus Methotrexate Sirolimus Mycophenolate mofetil

50. Cont… Treatment;   High-dose steroids Antithymocyte globulin (ATG)

51. Cont… Chronic GVHD; Occurs after 100 days of HSCT. Pathogenesis; A disorder of immune regulation characterized by; Autoantibody production Increased collagen deposition Fibrosis Cytokines involved are IL-4, IL-5, and IL-13. 25% incidence.

52. Cont… Clinical Manifestations; C linical symptoms are similar to those seen in autoimmune diseases. Lichenoid and sclerodermatous skin lesions Malar rash Sicca syndrome Arthritis Joint contractures Obliterative bronchiolitis Bile duct degeneration with cholestasis.

53. Cont… Risk Factors; Acute GVHD(Most common)   Peripheral blood stem cell transplants  HLA-mismatched grafts  MUD grafts Advanced patient age Second transplant

54. Cont… Treatment; Immunosuppression is the mainstay of treatment. Prednisone   Tacrolimus Mycophenolate mofetil  Extracorporeal phototherapy   Pentostatin

55. Post-BMT Care Discharge Criteria; Adequate ANC No infection or fever Infrequent requirement for blood & platelet transfusion. Instructions For Caregivers; How to care for catheter Special isolation precautions Medication distribution Schedule of follow-up visits

56. Cont… Diet requirements Housekeeping precautions Follow-up Visits; Initially weekly then Monthly for 1 st 6 months Every 3 months until 2 years after HSCT Eventually every 6-12 months thereafter. At regular intervals blood is withdrawn to evaluate new immune system & degree of engraftment.

57. BMT In Different Conditions & Success Rate Acute Lymphoblastic Leukemia(ALL); Most common indication of BMT In 1 st complete remission or in 2 nd or further complete remission after previous marrow relapse. Event-free survival rate, transplanted in 1 st or 2 nd complete remission is 60-70% and 40-60% respectively.

58. Cont… Acute Myeloid Leukemia(AML); Best results when transplant done in 1 st remission. Probability of event-free survival is in order of 70%.

59. Cont… Chronic Myelogenous Leukemia (CML)/ Philadelphia+; Best results when transplantation done in chronic phase from HLA-matched identical sibling within 1 year from diagnosis. Leukemia-free survival of ML after an allograft is 45-80%.

60. Cont… Juvenile Myelomonocytic Leukemia; Rare hematopoietic malignancy accounting for only 2-3% of pediatric leukemias. Characterized by hepatosplenomegaly & organ infiltration with excessive proliferation of monocyte & granulocyte lineages. Aggressive clinical course with mean survival of <12% from time of diagnosis. HSCT cure approximately 50-60% of the patients.

61. Cont… Myelodysplastic Syndromes; Heterogeneous group of clonal disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenia & propensity to evolve into AML. HSCT is the treatment of choice for these patients. Probability of survival is 60% while that for refractory cytopenia is as high as 80%.

62. Cont… Non-Hodgkin Lymphoma & Hodgkin Disease; These are sensitive to chemotherapy but some are at risk of relapse. HSCT can cure these patients with relapse if offered early. Event free survival rate is 50-60%.

63. Cont… Acquired Aplastic Anemia; HSCT is the treatment of choice for severe acquired aplastic anemia which is defined as; Platelets <20000/mm³ ANC <500/mm³ OR Retic count <1% when anemia is present with hypoplastic bone marrow ( <20% total cellularity). Survival rate is < 85-90% with younger patients having better outcomes.

64. Cont… Thalassemia Major; HSCT remains the only curative treatment for thalassemia patients. There are 3 classes on the basis of 3 parameters; Quality of iron chelation Liver enlargement Portal fibrosis.

65. Cont… Class 1; Good compliance of iron chelation without liver disease & it has survival rate of >90% with transfusion independence. Class 2; One or two adverse criteria & it has survival rate of >82%. Class 3; All three adverse criteria & it has survival rate of 60%.

66. Cont… Sickle Cell Disease ; Indications of HSCT in sickle cell disease are; History of strokes. MRI of CNS lesions. Failure to respond to Hydroxyurea as shown by recurrent chest syndromes.

67. Cont… ± Vasooclussive crisis. ± Severe anemia. ± Osteonecrosis. HSCT can cure Homozygous S Disease and probability of survival is 80-90%.

68. Cont… Immunodeficiency Disorders; HSCT is the treatment of choice for children with severe immunodeficiecny as well as immunodeficiency disorders i.e Wiskott-Aldrich Syndrome. Leukocyte Adhesion Defect Chronic Granulomatous Disease. Survival approaches 100% with HLA identical donor.