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TABLE OF CONTENTS:

BONE MARROW TRANSPLANT AND ITS TYPES AND AS A CURATIVE

TREATMENT FOR THALASEMIA .........................................................................2

INTRODUCTION: ...................................................................................................... 2

BONE MARROW: .......................................................................................................3

STEM CELLS: .............................................................................................................4

BONE MARROW TRANSPLANT (BMT) ............................................................... 5

DEFINITION: .............................................................................................................. 5

TYPES OF BONE MARROW TRANSPLANT: .......................................................5

STEM CELL TRANSPLANT INDICATIONS: ........................................................7

PATIENT ASSESSMENT BEFORE TRANSPLANT ..............................................9

DONOR SELECTION FOR TRANSPLANT ......................................................... 11

THE TRANSPLANT PROCESS .............................................................................. 15

NEUTROPENIC PHASE: .........................................................................................18

ENGRAFTMENT PHASE: ....................................................................................... 18

PROCEDURE OF AUTOLOGOUS SCT ................................................................ 19

Table 1.4 ALLOGENEIC SCT advantages and disadvantages: ............................ 20

PROCEDURE OF ALLOGENEIC STEM CELL TRANSPLANT ...................... 20

BONE MARROW TRANSPLANT AS A CURATIVE TREATMENT FOR

THALASEMIA .......................................................................................................... 21

TRANSPLANT PROCEDURE: ............................................................................... 22

MIXED CHIMERISM: ............................................................................................. 23

CONCLUSION ........................................................................................................... 24

Hamilton HC, Foxcroft DR. Central venous access sites for the prevention of

venous thrombosis, stenosis and infection in patients requiring long-term

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intravenous therapy. Cochrane Database Syst Rev. 2007 Jul 18 ;( 3):CD004084 25

BONE MARROW TRANSPLANT AND ITS TYPES

AND AS A CURATIVE TREATMENT FOR

THALASEMIA

INTRODUCTION:

Over past four decades, hematopoietic stem cell transplantation (HSCT) and bone

marrow transplantation (BMT) have increasingly been used to treat various non-

malignant and malignant disorders. After Second World War the nuclear radiation

effects on human body developed interest in study of this field.

Primitive studies on animals showed bone marrow as the most sensitive organ to the

lethal radiation effects. In irradiated animals marrow cells were re-infused to save

those animals. In 1950, for leukaemia treatment fatal irradiation doses were given to

patients. Even though many had recovery after the treatment, all patients sooner or

later entered into relapse phase of malignancy or developed infections. Between

1950-1960 nearly 200 allogeneic bone marrow transplants were carried out in humans

but there were no long lasting success. Though, in this time, transplantation using

donors like identical twin showed reasonable success and laid a foundation for further

clinical research.

In 1959, french oncologist George Math carried out first bone marrow transplant on

five nuclear workers but all were rejected. He later pioneered application of BM

transplants in leukaemia treatment. E. Donnall Thomas received Nobel Prize in 1990

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for the first successful hematopoietic stem cell transplantation in acute leukaemias

treatment1. The first successful bone marrow transplant on non-malignant disease was

performed by Robert A. Good in 1968.

BONE MARROW:

It is fundamental part of human body. It is soft and spongy tissue, present in the

central part of bone. Bone marrow most commonly in the breast bone, ribs, spine,

skull and hips contain cells which produce bodys blood forming cells. The three

common types of hematopoietic cells formed in bone marrow are:

1. White blood cells (WBC) : also called leukocytes, fight against infection and

help in immune system.

2. Red blood cells (RBC) : also called erythrocytes, functions in oxygen transport

in the body.

3. Platelets: helps in primary hemostasis.

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FIG 1.1 Hematopoietic and stromal cell differentiation

STEM CELLS:

These are immature primitive cells, also known as hematopoietic stem cells or blood

forming cells, which are capable:

1. Of self renewal.

2. To divide indefinitely.

3. Produce progeny of highly specified functional cells.

Most blood forming cells are present in bone marrow but some are present in blood

stream. These are known as peripheral blood stem cells (PBSC). Hematopoietic stem

cells are also found in umbilical cord blood.

SOURCES OF STEM CELLS:

Main sources for stem cells are;

1. Bone marrow

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2. Peripheral blood

3. Umbilical cord blood

4. Fetus liver

Table 1.1 characteristics of HSCs

CHARATERISTICS OF HEMATOPOEITIC STEM CELLS

POSITIVE LOW POSITIVE NEGATIVE

CD34

AC133

Aldehyde dehydrogenase

Thy 1

c-KIT

CD38

CD33

T- and B-cell markers

CD71

HLA-DR

BONE MARROW TRANSPLANT (BMT)

DEFINITION:

It is defined as a procedure in which damaged or diseased hematopoietic stem cells

are substituted with non-malignant stem cells in order to repopulate or replace

hematopoietic system as a whole or in parts, so that it can develop healthy new cells.

BMT is generally used when malignancy treatments have damaged the normal bone

marrow stem cells. BMT can also be performed when healing chances are low after

treatment with chemotherapy alone.

TYPES OF BONE MARROW TRANSPLANT:

The two main types of bone marrow transplant are;

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1. AUTOLOGOUS TRANSPLANT: it is also known as self transplant. It

involves gathering of patients own bone marrow cells. These are calculated,

evaluated and then stored and frozen for later on use. It is most frequently

carried out for multiple myeloma, lymphoma and associated diseases. Less

frequently it is performed for leukaemias treatment as well.

TANDEM TRANSPLANT: it is a form of autologous transplant. In a

number of clinical trials, it has been studied for the management of

different forms of cancers. During tandem transplant, a patient gets two

chronological courses of the high-dose chemotherapy by means of stem

cell transplant. The duration of two courses is weeks to months apart.

Researchers anticipate that by this method cancer recurrence can be

prevented later on.

2. ALLOGENEIC TRANSPLANT: for this type of transplant, stem cells are

obtained from a donor who could be a relative (sibling) or any other donor

(volunteer unrelated donor) or umbilical cord blood. But the tissue type of

donor should closely match with the patient. The probability of sister or

brother to be a suitable match is 1 in 4. The odds of other members of family

as a suitable match are less. Such transplants are commonly recommended for

leukaemias. Other than that allogeneic transplant also indicated for bone

marrow and immuno-deficiency disorders.

SYNGENEIC TRANSPLANT: it is also called as identical twin transplant.

Identical twin is the perfect donor since the genetic individuality between

donor and recipient. The cells are identical to own cells apart from the

fact that they are healthy cells and not damaged by earlier chemotherapy.

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MINI TRANSPLANT: it is one of the forms of allogeneic transplant and

also called as low intensity or non-myeloablative transplant. In mini-

transplant less lethal quantity of chemotherapy and/or radiation therapy is

used for preparation of patient. Low dose therapy removes some of the

patient bone marrow, leaving rest intact. It also lowers cancer cells and

restrains the immune system of the patient to prevent transplant rejection.

After mini transplant both the patient and donor cells co exist in patients

body for some time. So once engraftment occur, this result in graft versus

tumor effect and destroy the remaining cancerous cells left after therapy.

To enhance this graft versus tumor effect, patient is given donors WBC

injection. This method is called donor lymphocyte infusion.

STEM CELL TRANSPLANT INDICATIONS:

Table 1.2 indications for SCT

AUTO STEM

CELL

TRANSPLANT

ALLO STEM CELL TRANSPLANT

RELATED

(SIBLING)

UNRELATED

(VUD)AML with 1st CR

Good cytogenetics NR NR NR

Standard cytogenetic R R NR

Poor cytogenetics R R R

AML with 2ndCR R R R

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ALL with 1st CR D R NR

ALL t(9;22) 1stCR R R R

ALL with 2ndCR R R R

CML with 1stCP NR R(after imatinib

trial)

R(after imatinib

trial)

MYELOMA R R D

MDS NR R R

HD with 1stCR NR NR NR

HD relapsed R R D

NHL with DLBCL 1st

CR

D D D

NHL with DLBCL

relapsed

R R D

Follicular NHL D R D

AA(Aplastic anemia) NR R D

Haemoglobinopathie

s

NR R D

AML: acute myeloid leukaemia ALL: acute lymphoblastic leukaemia

CR: complete remission CML: chronic myeloid leukaemia

MDS: myelodysplastic syndrome DLBCL: diffuse large B-cell lymphoma

NHL: non-Hodgkin lymphoma VUD: volunteer unrelated donor

R: recommended NR: not recommended D: developmental

STEM CELL TRANSPLANT is indicated for both the malignant/premalignant

disorders as well as the non-malignant disorders. The malignant diseases mainly

include all leukaemias that is, AML, ALL, CML and the immature myelomonocytic

leukaemia. Other malignant conditions include disorders of plasma cell, the

myelodysplastic syndrome and non-Hodgkin and Hodgkin lymphomas. The non-

malignant conditions include a variety of disorders like:

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Inherited metabolic diseases: hurler syndrome, osteoporosis,

Acquired immuno-deficiency disorders: like HIV (a HIV patient having AML

was treated by allogeneic BMT used from a donor lacking CCR5 surface

proteins. These are important for HIV access to human cells. In the final

report, patient was responding well and stayed off of antiretroviral treatment

for 2 years after BMT2,3

Inherited immune diseases: Wiskott-Aldrich syndrome etc

Inherited RBC disorders: -thalasemia, SCD, pure red cell aplasia.

Auto-immune disorders: rheumatoid arthritis, crohns disease, systemic

sclerosis, multiple sclerosis and SLE etc4,5

Marrow failure conditions: Fanconi anemia, aplastic anemia and other

disorders.

PATIENT ASSESSMENT BEFORE TRANSPLANT

The most crucial step in assessment is the tissue typing as HLA mismatching poses

serious problems during transplant. A complete medical history showed be taken and

general physical examination along with specific systemic examination should be

carried out to assess the conditions of patient. Transplant may sound a terrifying

procedure for the patients and therefore emotional and psychological support should

be provided through out the procedure. Before the procedure, different laboratory

tests and other tests are carried out for patient assessment. These include:

Biopsy of bone marrow

Computed tomography scan

Magnetic resonance imaging

Cardiac function analysis

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Electrocardiogram

Echocardiogram

Respiratory system analysis

Pulmonary function tests(PFTs)

CXR(chest x-ray)

Hematological tests

Complete blood count(CBC)

Viral screening

HIV

HBV

CMV

CENTRAL VENOUS ACCESS (CVA) IN BMT:

For CVA a large bore catheter is inserted into the vein in neck, femoral area or upper

chest area. It is mainly used for drugs administration which otherwise cannot be given

conveniently by mouth or by a cannula in arm. Two authors carried relevant studies

to evaluate which route presents as lower frequencies of venous stenosis, venous

thrombosis and central venous catheter related infections.6 The studies showed that

subclavian access is preferred over femoral access because of less association with

complications in long term therapy6. In auto transplant CVC is also used for stem cell

harvesting for apheresis.

ELIGIBILITY CRITERIA FOR TRANSPLANT:

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Younger individuals, in early phase of disease or those people who donot have already

gone through a number of treatments, show better results with transplant.

Some centers for transplant set an age limit. For example, some donot allow

allogeneic transplant for patients over 50 years of age while for autologous transplant,

transplant is not allowed in those people who are over 60-65 years old. Some people

are excluded from transplant, if there are other major medical problems are present,

such as lung, heart and kidney or liver diseases. In such cases mini-transplant can be

an alternative option.

DONOR SELECTION FOR TRANSPLANT

Matched donor selection is the most crucial part in stem cell transplant. The

lymphocytes and hematopoietic progenitor cells of the donor when infused into

patient result in the activation of immunological responses in otherwise immuno-

suppressed recipient. The different forms of resulting reaction include host versus

graft (HVG) reaction which is rare and the major graft versus host (GVH) reaction.

The HVG can lead to graft rejection, which ultimately can result in graft failure.

While GVH can be evident as graft versus host disease or graft versus leukaemic

response. These complications are mainly associated with allogeneic transplantation.

While in autologous transplantation these responses are missing.

The antigens aligned with GVH and HVG reactions include:

Major HLA antigen complex which is present on chromosome 6

Minor H antigens (i-e histocompatibility antigens). These are programmed by

number of unrelated genes which are present exterior to HLA system.

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The HLA complex consist of six major antigens and a match is consider 6/6 match if

all the major elements are present and thus regarded as best match. These antigens

are:

HLA-A

HLA-B

HLA-C

HLA-DR

HLA-DQ

HLA-DP

Thus the different probable sources for these are:

A sibling, related or the unrelated donor. Thus the donor is either HLA

identical, haploidentical or can be mismatched. This is for Allo transplant

Identical twin results in syngeneic transplant and is always HLA identical

Patient can also be a donor as in Auto transplant and therefore HLA identical

Blood from umbilical cord can also be used in Allo transplant and therefore it

may be identical or mismatched or even haploidentical.

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FIG 1.2 selections of donors for immediate allogeneic transplant in case of absent

sibling donor

DIFFERENT CONSIDERATIONS CONCERNING THE OPTIONS

FOR UNRELATED DONORS (UD):

HLA-A, -B, -C, -DRB1, -DQB1 matching i-e 10/10 matching7, 8, 9

Mismatch of single allele can be tolerated and thus overall survival (OS) in

long term is obvious

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Individual loci mismatches show different results

mismatch for HLA-A is usually well tolerated

mismatch for HLA-B shows considerably worse OS and thus be

avoided

mismatch for HLA-C shows tolerance in term of overall survival but

shows increase frequency regarding acute and chronic GVHD

mismatch for KIR ligand shows increased transplant-related mortality

(TRM), also poor OS. Therefore if possible better to avoid

In short, if mismatch for class 1 antigens is unavoidable then A mismatch

is preferred, then C mismatch is chosen next and finally B mismatch or a C

with KIR GVH mismatch

Mismatching for multiple allele showed considerably impaired OS.

In spite of the fewer single mismatches for class II or mixed mismatches for

class I and II, the best approach is to avoid these due to major rise in severe

GVHD, TRM and following poorer OS.

HLA-DPB1 matching10

If a donor is DP-B1 matched then irrespective of the HLA matching status,

there is increased chance of relapse. Particularly in disorders like CML and

ALL.

Therefore DP-B1 typing should be done before every transplant and

incompatible DP-B1 donor is preferred over compatible one.

Observation of individual loci mismatching shows:

mismatch of HLA-DPB1 at region D which is hyper variable and

mismatch at amino acid location 65 or 57 results in increased TRM

and poorer OS

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Other permissive mismatches for DPB1 may also exist.

THE TRANSPLANT PROCESS

The transplant procedure in general can be divided into following phases: harvesting

or cell mobilization phase, conditioning, stem cell infusion, cytopenic phase,

engraftment and post-engraftment phase.

HARVESTING PHASE:

This is also called as cell mobilization phase. In this phase different growth factors

and chemotherapeutic agents are used foe stem cell proliferation and for mobilization

of stem cells from bone marrow to blood stream. Through apheresis process, these

cells are harvested and later used for the replacement of stem cells that are destroyed

through conditioning therapy. G-CSF is most commonly used for cell mobilization

and is given alone or following myelosuppressive chemotherapy.

The hematopoietic stem cells and the progenitor cells are localized inside marrow

cavity by binding through certain adhesion molecules, these include VLA4 and

CXCR4. G-CSF mainly acts by disrupting this binding. Harvesting is done on 5th and

6th day. G-CSF alone is given as 4 daily injections given subcutaneously. The

minimum target cells harvested in more than 90% cases with G-CSF therapy is

2 x 106 CD34+ cells per Kg. Common adverse effects include bone pain, myalgia and

headache.

CONDITIONING PHASE:

During this phase the bone marrow and immune system are prepared for the

previously harvested cells, by conditioning with high-dose therapy, which include

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either total body irradiation (TBI) or a mixture of chemotherapy and radiotherapy. The

conditioning phase lasts for 7-10 days. The main purpose is to eliminate malignancy,

avoid elimination of new stem cells and generate space for new cells.

A. MYELOABLATIVE CONDITIONING:

IN AUTOLOGOUS STEM CELL TRANSPLANT:

In autologous transplant, the conditioning regimens are planned with dose

amplification but the main limitation to it is the extramedullary toxicity including

mucositis and gastrointestinal toxicities. Common conditioning regimes include:

Myeloma Autografts: Melphalan 200mg/m2 is used

Lymphoma : BEAM (carmustine, Etoposide, cytarabine, Melphalan)

AML and ALL: auto transplants rarely indicated but both

cyclophosphamide/TBI or busulfan preparation can b used

Solid tumors: different combinations including busulfan, thiotepa and

Melphalan are used.

IN ALLOGENEIC STEM CELL TRANSPLANT:

The most frequently used conditioning regimens consist of TBI/Cyclophosphamide

combination or Cyclophosphamide/Busulfan combination.

Cyclophosphamide: It is an alkylating agent. Dose is 120-200mg/kg. It has

both immunosuppressive and anti-leukaemic characteristics. The main dose

related complications are hemorrhagic cystitis and cardiac toxicity.

TBI (total body irradiation): the therapeutic dose is 12-14.4Gy but for

decreased toxicity the general dose is decreased or administered in small

proportions like 14.4Gy in divided doses of 8 parts over 4 days. The early

complications with TBI are nausea, vomiting, diarrhea and parotitis and these

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can be symptomatically treated. Amplified doses of TBI can result in

pneumonitis or veno-occlusive disease of the liver (VOD) and both are life

threatening complications. The long term complication manifest as

hypothyroidism, cataract formation, growth retardation in children and

infertility.

Busulfan: it is an alkylating agent. It is the central element of both Allo and

auto transplant. Dose is 14-16mg/kg orally administered 6 hourly for 4 days.

Major complications include VOD, CNS toxicity and pulmonary toxicity.

Other combinations include various drugs in addition to the above mentioned

regimens. These are fludarabine, Melphalan, cytarabine, Etoposide and

thiotepa. Also ATG (antithymocyte globulin) can be used in addition to above

regimens to reduce graft rejection.

B. REDUCED-INTENSITY CONDITIONING:

LOW-DOSE TBI BASED REGIMEN:

This include TBI dose of 200-450cGy in combination with ciclosporin and

mycophenolate mofetil.

NON-TBI BASED REGIMENS:

It includes combination of fludarabine and alkylating agents like, Melphalan,

cyclophosphamide and busulfan.

C. GVHD PROPHYLAXIS:

After myeloablative conditioning the common form of GVHD prophylaxis is post

transplant immunosuppression by ciclosporin, methotrexate, prednisolone and

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mycophenolate mofetil. T-cell depletion (TCD) is also very effective way of

decreasing the possibility of both acute and chronic GVHD.

NEUTROPENIC PHASE:

Duration of neutropenia is 2-4 weeks. During this time the patient is devoid of any

effectual immune system and present with poor healing and prone to infection. The

main management during this phase is by supportive care and also empirical antibiotic

therapy. The potential pathogens are herpes simplex virus (HSV) and the endogenous

flora. Nosocomial infections pose greatest risk and are more frequently resistant to

typical antibiotic therapy.

ENGRAFTMENT PHASE:

This process may take several weeks. In this process the stem cells are engrafted back in the

patient body to re develop the immune process. Occasionally purging techniques can be used

to remove any residual tumor cells earlier to engraftment to shortly after that. Different

clinical factors influence stem cell engraftment, these are:

IN AUTOLOGOUS AND SYNGENEIC TRANSPLANT:

The main determining factor is stem cell dose. Graft failures are rare if stem

cell dose transplanted is 2 x 106 CD34+ cells per kg.

IN ALLOGENEIC TRANSPLANT:

The main determining factors are:

Intensity of conditioning regimen induced immunosuppression

T-cell depletion

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Level of genetic inequality between donor and recipient

PROCEDURE OF AUTOLOGOUS SCT

FIG 1.3 autologous transplant process

Table 1.3 AUTOLOGOUS SCT advantages and disadvantages:

ADVANTAGES DISADVANTAGESIncreased dose therapy earlier to

harvesting and following engraftment

may :

Reduces recurrence risk

Curing destructive component of

disease

Chances of contamination of engrafted

cells with disease.

Higher risk for secondary AML or for

MDS.

Increased incidence of TRM and this may

be because of:

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Produce long lasting remission

Avoid GVHD.

Regimen associated toxicity

Infections during the different

stages of transplant process

Table 1.4 ALLOGENEIC SCT advantages and disadvantages:

ADAVNTAGES DISADVANTAGES

Tumor excluded graft.

Unharmed stem cells.

Secondary AML/MDS are avoided.

(GVL) Graft versus leukaemic effect is

produced.

Lack of availability of matched donor.

Increased incidence of TRM related with:

Regimen associated toxicity

Infections

GVHD

PROCEDURE OF ALLOGENEIC STEM CELL

TRANSPLANT

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FIG 1.4 allogeneic transplant process

BONE MARROW TRANSPLANT AS A CURATIVE

TREATMENT FOR THALASEMIA

Thalasemia is the most common inherited single gene disorder, characterized by

increased RBC disorder and therefore require regular blood transfusion to cure the

anemia. However regular transfusion results in increased iron load as well, which

ultimately causes multiple organ damage. Therefore the only major treatment for

thalasemia in present times is correction of the genetic fault and that is carried out

with HSCT.

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Table 1.5 Risk factors for BMT in thalasemia:

RISK FACTORS FOR BMT IN THALASEMIA

Chelation Regular vs irregularHepatomegaly Absent vs present

Liver fibrosis Absent vs present

Table 1.6 Pesaro classifications11

RISK CLASSES FOR BMT IN THALASEMIA

CHELATION HEPATOMEGALY FIBROSIS

CLASS 1 Regular Absent Absent

CLASS 2 Regular / irregular Absent / present Absent / present

CLASS 3 Irregular Present Present

TRANSPLANT PROCEDURE:

The first step is search for the donor that is HLA identical. Then according to the

Pesaro classification, patient is assigned to one of the three risk classes. The transplant

procedure for 1st two classes, i-e class 1 and class 2 is same, while class 3 shows more

progressive disease and therefore needs time and skill. The protocol for treatment is:

Busulfan 14mg/kg total dose is given and then followed by cyclophosphamide

200mg/kg total dose.

When Allo graft starts to reproduce inside patient, immunological GVH

response develops. Thus prophylactic treatment is given for GVHD with

Cyclosporin

Methotrexate 3-4 doses together with cyclosporin in start 15 days

following transplant.

Then bone marrow is injected in peripheral vein in 4-6 hours

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Patient isolation as important as he is having aplastic marrow and therefore

should receive

Platelet transfusion

RBC transfusion

Prophylactic management with anti-fungal, anti-bacterial and anti-viral

drugs

Prophylactic management for GVHD

Medical examination and blood tests are initially performed twice every week

till patient is back home

Class 1 and class 2 patients return home around day 70 or plus

Class 3 patients can return home by day 90 or plus

Cyclosporin is continued for a year following treatment with steadily

tapering dose

MIXED CHIMERISM:

To create conditions for absolute marrow engraftment, patients stem cells should

Be completely ablated. This condition is called as complete chimerism (CC).

Using PCR, short tandem repeats were analyzed for marrow engraftment evaluation.

A total of 93 thalassemic patients who had received BMT were evaluated12. All these

patients were selected from Asian countries and from Middle East. Early mixed

chimerism following BMT was observed in 46% patients. Further analysis revealed

that, out of 27 patients with complete engraftment, 7 patients presented with graft

rejection while 8 showed mixed chimerism. Out of those 7 patients, 5 patients showed

presence 25% of residual host cells before the commencement of transplant12

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CONCLUSION

Developments in supportive management, anti-biotic therapy and HLA typing have

produce important role in improving overall survival and life quality after transplant.

In broad spectrum, patients with steady disease or in remission state have improved

outcome compared to those who are transplanted during advanced disease phase and

those with disease relapse. Young age present with favourable outcome. CMV-

negative class of donor and recipient increases the probability of overall survival. A

large dose of hematopoietic cells speed up engraftment and results in better outcome

but also enhances the chances of GVHD. Non-malignant disorders show more

favourable results.

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