The document provides an overview of bone marrow and stem cell transplantation (BMT), detailing its objectives, processes, types, and indications, along with the roles of stem cells and HLA matching. It explains the transplant process in detail, including pre-transplant conditioning, stem cell infusion, and post-engraftment care, while also addressing potential complications such as graft-versus-host disease (GVHD) and adverse effects. Additionally, it discusses BMT success rates for various blood disorders, emphasizing the importance of matching donors and the complex care required post-transplant.

2. Bone Marrow/Stem
Cell Transplantation

3. 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

4. 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;
I. RBCs; Having oxygen carrying capacity.
II. Platelets; Role in blood coagulation.
III. WBCs; Support immune system.

6. 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.

7. 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.

8. 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.

9. 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:
I. Peripheral Blood ( Aphereses)
II. Marrow ( Bone Marrow Harvest)
III. Umbilical Cord
o Fetal Liver

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

12. Cont…
 Types of Bone Marrow Transplant on the basis of Donor
are;
I. Isograft; From identical twin
II. Optimal Donor-Identical Tissue Typing; Usually a sibling
25%
III. 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.
IV. Umbilical Cord Blood

14. Advantages & Disadvantages Of HSC Collection
Methods

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

16. 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)

17. Indications Of BMT
Non-cancerous Conditions/Stem Cells
Defects;
oAplastic Anemia
oThalassemia Major
oSickle Cell Disease
oSCID
oWiskott-Aldrich Sydrome
oFanconi Anemia
oChronic Granulomatous Disease

18. Cont…
 Cancerous Conditions;
o Leukemia
o Lymphoma
o Neuroblastoma
o Medulloblastoma
o Sarcoma

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

20. 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.

21. 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.

22. 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.

23. 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;
(1) Conditioning Phase
(2) Stem Cell Infusion
(3) Neutropenic Phase
(4) Engraftment Phase
(5) Post-engraftment Period.

24. 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

25. Cont…
 Strategy of Conditioning Regimen is;
I. Myelo-Ablative Therapy
II. Reduced-intensity Therapy

26. 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).

27. 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.

28. 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.

29. 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.

30. 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).

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

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

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

36. Cont…
III. 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.
o Serious infections (eg, pneumonia, bacteremia,
fungemia,
viremia) may occur in up to 50% of patients after
transplantation.

37. Cont…
IV. 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.

38. Cont..
V. Graft Failure; graft failure results from failure to
establish hematologic engraftment after transplantation.
o The greater the degree of HLA mismatch, the greater the
risk of graft rejection.
o 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).

39. 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.

40. Cont…
VI. 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.

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

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

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

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

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

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

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

48. 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.

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

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

51. 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; These cytokines cause tissue damage through
cytotoxic CD8+ T cells.

52. Cont…
 Clinical Manifestations;
I. Erythematous maculopapular rash.
II. Persistent anorexia.
III. Vomiting and/or diarrhea.
IV. Liver disease with deranged LFFTs.

53. 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.

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

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

57. Cont…
 Treatment;
o High-dose steroids
o Antithymocyte globulin (ATG)

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

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

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

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

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

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

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

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

68. 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%.

69. 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.

70. 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%.

71. 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%.

72. 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.

73. 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.

74. 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%.

75. 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.

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

77. 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.