Leukaemia’s

Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia (AML) is an acute onset leukaemia involving clonal expansion of myeloid cell line derived blast cells (precursors of polymorphonuclear leukocytes). The World Health Organisation (WHO) defines AML as leukaemia with bone marrow or peripheral blood blast percentage of more than 20%.

Patients often present with chromosomal abnormalities in marrow cells and maturational arrest of bone marrow myeloid cells in the earliest stages of development. AML manifests as pancytopenia, megaloblastic bone marrow and nucleated red cells in peripheral marrow.

AML commonly occurs following a prior hematologic disorder such as MDS, familial syndromes (germline mutations), environmental and drug exposures such as to alkylating agents used in treatment of a prior disorder.

If transplant indicated (intermediate or adverse risk AML), it is usually needed urgently with allo-HSCT the standard of care. High resolution HLA typing of patient and sibs, WMDA search and early initiation of the full search without waiting for related donors to all be typed may be required. Wherever possible, it is recommended that the laboratory always have x2 potential donors identified and ready to be called.

Acute Lymphocytic Leukemia (ALL)

Acute Lymphocytic Leukemia (ALL) is an acute onset leukaemia characterised by clonal expansion of lymphoid cell line derived blast cells in the bone marrow replacing the normal hematopoietic cells. Lymphoid precursor cells (i.e. B and T lymphoblasts) that are arrested in an early stage of development. ALL includes the precursor B lymphoblastic leukaemia and precursor T lymphoblastic leukaemia.

ALL is the most common childhood cancer. It also accounts for approximately 20 percent of adult acute leukaemia. Childhood B-cell precursor ALL has a multifactorial aetiology, with a two-step process of genetic mutation and exposure to infection playing a prominent role. Less is known about the aetiology of other ALLs.

HSCT is the standard of care for high risk patient in first complete remission and in other relapsed patients or patients who fail induction.

Chronic Myeloid Leukemia (CML)

Chronic Myeloid Leukemia (CML) is the most common of the chronic onset myeloproliferative disorders and is typically a disease of the middle-aged or elderly. It is characterised by clonal expansion of the granulocytic cell line without the loss of their capacity to differentiate.

CML progresses through three phases – chronic, accelerated and blast. In the chronic phase mature cells proliferate. In the accelerated phase, additional cytogenetic abnormalities occur and in the blast phase, immature cells rapidly proliferate.

CML is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)] – the Philadelphia (Ph1) chromosome.

Use of stem cell transplantation for CML patients is reduced in the Imatinib era.

Chronic Lymphocytic Leukemia (CLL)

Chronic Lymphocytic Leukemia (CLL) is the most common form of chronic lymphoid leukaemia. It is a monoclonal disorder characterized by morphologically mature but immunologically immature lymphocytes which slowly accumulate in the blood, bone marrow and lymphatic tissue.

CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes.

CLL is usually an adult onset disease with the majority of patients diagnosed being males over 50 years of age. Many people with CLL lead normal and active lives for many years. Stem cell transplantation is therefore rarely used as a first-line treatment due to its associated risks.

Allo-HSCT is indicated for high risk patient and for patients who fail induction.

Myelodysplastic Syndrome (MDS)

Myelodysplastic Syndrome (MDS) is a clonal haematopoietic disorder characterized by a hypercellular bone marrow with dysplasia (abnormality of development) and ineffective haematopoiesis in one or more cell lines. This may be accompanied by up to 20% myeloblasts.

MDS manifests as progressive cytopenia that occurs over months to years resulting from clonal expansion of mutant cells, predominating in the bone marrow, suppressing healthy stem cells.

MDS may occur de-novo or following exposure to alkylating agents and/or radiotherapy.

HSCT (Allo) is only indicated in high risk patients.

Myelofibrosis

Myelofibrosis is a myeloproliferative disorder in which the bone marrow is replaced by fibrous tissue.

The fibrosis impairs the ability to generate new blood cells, leading to pancytopenia. The fibrosis also leads to blood forming in other organs such as the spleen and liver, leading to the classic symptoms of Myelofibrosis which include splenomegally and some degree of hepatomegaly.

Stem cell transplantation is generally not recommended for low risk patients but is the standard of care for high risk patient below the age of 45.

Adult T-Cell Leukemia/Lymphoma (ATLL)

Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive T-cell lymphoma with a poor prognosis.

Patients present with generalized swelling of the lymph nodes hepatomegaly and splenomegaly accompanied by fatigue and anorexia. Patients may also have hypercalcemia, constipation and general weakness.

ATLL is linked to infection by the human T-cell lymphotropic virus 1 (HTLV-1). All potential live related donors must be tested for HTLV-1.

Juvenile Myelomonocytic Leukemia (JMML)

Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of early childhood caused by excessive proliferation of monocyte and granulocyte cell lineages.

JMML is characterized by overproduction of monocytic and granulocytic cells that infiltrate different organs, including the spleen, liver, lung and gastrointestinal tract. Affected children usually have pallor, fever and skin bleeding, which result from anaemia, leucocytosis and thrombocytopenia.

Approximately 90% of patients carry either somatic or germline mutations of PTPN-11, K-RAS, N-RAS, CBL or NF1 in their leukemic cells.

HSCT remains the only curative treatment for JMML. The urgency of transplant favours use of cord blood.

Lymphoproliferative Disorders

Hodgkins Lymphoma (HL)

Hodgkin’s disease is a potentially curable malignant lymphoma. It is characterized by the presence of Reed-Sternberg cells (large, multi-nucleated cells, with prominent eosin staining inclusions in the nucleus). Hodgkin’s patients experience progressive enlargement of the lymph nodes, spleen and general lymphoid tissue. Hodgkin’s disease is sometimes accompanied by symptoms such as fever, weight loss, fatigue and night sweats.

Hodgkin’s disease occurrence is bimodal with incidence peaks in young adults (15-35) and older persons (over 55’s).

Autologous transplantation is the standard of care relapsed/refractory Hodgkin’s patients.

Non-Hodgkins Lymphoma’s

NHL comprises of all lymphomas except Hodgkin’s lymphoma. NLH are a diverse group of diseases which have been divided into several subtypes based on whether the disease is indolent or aggressive and whether T or B cells are involved. Subtypes of NHL include Diffuse B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Burkitt Lymphoma, Peripheral T Cell Lymphoma and Adult T Cell Lymphoma.

Burkitt Non-Hodgkin Lymphoma

Burkitt NHL is a highly aggressive B-cell non-Hodgkin lymphoma characterized by the translocation and deregulation of the c-myc gene on chromosome 8. It occurs at a high frequency in patients with immunodeficiencies and in HIV positive patients.

The exact cause of Burkitt NHL is unknown. Theories include Epstein-Barr virus (EBV) and malaria infection as well as C-myc oncogene activation.

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoproliferative, non-Hodgkin lymphomas, derived from a subset of naive pregerminal center cells localized in primary lymphoid follicles or in the mantle region of secondary lymphoid follicles. It is characterized by the chromosomal translocation t(11;14)(q13;q32).

The cause of MCL is unknown but is thought to be associated with viral infection (Ebstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpesvirus 6), environmental factors (pesticides, hair dyes) and primary and secondary immunodeficiency.

Follicular Lymphoma

Follicular lymphoma is a type of non-Hodgkin lymphoma that most commonly presents as a painless, slowly progressive adenopathy (swelling of tear, sweat, hormonal and other glands).

The t(14;18) chromosomal translocation is a hallmark of follicular lymphoma.

Viruses, including the EBV, HTLV-1 and the herpesvirus associated with Kaposi sarcoma have been implicated in the aetiology.

First line treatment of Follicular lymphoma is chemotherapy including use of Rituximab. Reduced Intensity Conditioning (RIC) followed by Allo-HST has been shown to be effective in older patients and in patients who had previously undergone an Auto transplant as a bridge to Allo.

Multiple Myeloma (MM)

Multiple Myeloma (MM) is a bone marrow based plasma cell neoplasm (bone marrow plasma cells > 10%) characterized by high production of serum monoclonal protein (most commonly IgG) in the bone marrow and skeletal destruction causing bone lesions, fractures, bone pain, hypocalcaemia and anaemia.

MM is characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein) and can present as a single lesion (plasmacytoma) or multiple lesions.

The precise aetiology of MM is not established. Roles have been suggested for a variety of factors, including genetic causes, environmental or occupational causes, radiation, chronic inflammation and infection.

Current treatment involve treatment with the triple agents thalidomide, lenalidomide and bortezomib to CR potentially followed by Auto HSCT.

Haemoglobinopathies

Thalassaemia

The Thalassemia’s are a heterogeneous group of hereditary autosomal recessive haemolytic anaemia’s which have in common a decreased rate of synthesis of one or more haemoglobin polypeptide chains, resulting in anaemia.

Allo-HSCT with a matched related donor remains the only curative treatment.

Sickle Cell

Sickle cell disease is a group of inherited disorders, the most serious of which is sickle cell anaemia, in which there is reduced oxygen carrying capacity of red blood cells due to a ‘sickling’ effect.

Sickle cell is a disease characterized by chronic haemolytic anaemia, episodic painful crises and pathological involvement of many organs.

Sickle Cell Disease is an autosomal recessive disease, its genetic basis being the homozygous expression of haemoglobin S.

First line treatment is with immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine.  Allogeneic stem cell transplantation is considered usually only if there is a matched sibling donor.

Langerhans Cell Histiocytosis (LCH)

Langerhans Cell Histiocytosis (LCH) is a group of idiopathic disorders characterized by the excessive production of Langerhans cells, a type of white cell found mostly in skin and lymph nodes which are involved in preventing infections.

If the cells multiply and remain mostly in the skin, the result often is localized to the skin. In children this can manifest as rashes. When the cells migrate to other parts of the body, the symptoms are much more widespread and serious and the disorder can be life-threatening.

The aetiology of LCH is unknown. Langerhans cell proliferation may be induced by a viral infection, a defect in intercellular communication (T cell–macrophage interaction) and/or a cytokine-driven process mediated by tumour necrosis factor, IL-11 and leukemia inhibitory factor.

Bone Marrow Failure Syndromes

Aplastic Anaemia (AA)

Aplastic Anaemia (AA) is a serious disorder of the bone marrow characterised by pancytopenia and a hypocellular bone marrow. AA can be idiopathic or secondary due to bone marrow damage by toxins, radiation, or immunologic factors.

Specific treatment of aplasia involves either immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine or allogeneic stem cell transplantation with a matched related donor for Severe Aplastic Anaemia (SAA). Where HSCT is required, the preferred source of stem cells is bone marrow (BM) rather than peripheral blood stem ells (PBSC). Use of PBSC for transplants in SAA has been associated with significantly inferior survival with a concurrent two-fold increase in GvHD across all age groups but especially so in young patients. The lack of a need to eradicate an underlying malignancy means that non-myeloablative regimens can be used for SAA patients without the need for the increased cell dose obtained from PBSC, resulting in reduced GvHD with BM as the stem cell source.

Fanconi’s Anaemia (FA)

Fanconi’s anaemia is the most common of the inherited bone marrow failure syndrome (IBMFS) with pancytopenia. Patients present with combination of aplastic anaemia and physical anomalies including skin pigmentation and upper limb, gonadal and skeletal abnormalities.

Fanconi’s anaemia is an autosomal recessive disease in more than 99% of patients (FANCB is X-linked recessive). Patient are homozygous for mutations in one of the 15 genes that cause Fanconi’s anaemia. HSCT is indicated in patients who are transfusion dependent or who have severe neutropenia and in patients with myelodysplasia or leukemia.

Diamond-Blackfan Anaemia (DBA)

Diamond-Blackfan anaemia is a rare inherited bone marrow failure syndrome (IBMFS) that manifests with pure red cell aplasia. The anaemia is usually macrocytic (large cells), with elevated foetal haemoglobin and increased red cell adenosine deaminase.

Diamond-Blackfan anaemia is (usually) an autosomal dominant disease caused by mutations in the genes that provide instructions for making several ribosomal proteins.

Indications for HSCT include nonresponse to steroids, transfusion dependency, progressive pancytopenia or MDS/AML.

Immunodeficiencies

Severe Combined Immunodeficiency (SCID)

SCID is a heritable immunodeficiency syndrome arising as a result of defects to several genes in the B and T cell arms of the adaptive immune response. Sufferers are extremely vulnerable to infectious diseases.

SCID arises as a result of defects to several genes in the B and T cell arms of the adaptive immune response.

Sibling HSCT has an overall survival rate of 90%. Transplantation may proceed without conditioning of GvHD prophylaxis given the severe immunocompromised state of the patient. In the absence of sibling haploidentical parents may also be an option for transplantation.

Inborn Errors in Metabolism (IEM)

Inborn Errors in Metabolisms (IEMs) are a large group of rare genetic diseases that generally result from a defect in an enzyme or transport protein which results in a block in a metabolic pathway. Most of the disorders are inherited as autosomal recessive genes though autosomal dominant and X-linked disorders are also present.

Hurler Syndrome

Hurler syndrome (Mucopolysaccharidosis – MPS IH), is a genetic disorder which causes a deficiency of alpha-L iduronidase, an enzyme responsible for the degradation of glycosaminoglycans (GAGs) in lysosomes. Hurler syndrome is therefore known as a lysosomal storage disorder (LSD).

Hurler syndrome results in the build-up of GAGs (also known as mucopolysaccharides). Symptoms present at 3-6 months and include a large head with prominent frontal bones, elongated skull, flattened nasal bridge, widely spaced eye sockets and eyes that may protrude from the skull.

Hurler syndrome is an autosomal recessive resulting from two defective copies of the IDUA gene which encodes for the protein iduronidase. The gene has been mapped to the 4p16.3 site on chromosome 4.

Early HSCT is indicated to prevent multiple organ dysfunction and death.

Scheie Syndrome

Scheie syndrome (Mucopolysaccharidosis – MPS IS), is a genetic disorder which causes a deficiency of iduronidase.

Scheie syndrome results in the build-up of glycosaminoglycans. It has milder symptoms compared to Hurler syndrome.

Scheie Syndrome is an autosomal recessive resulting from two defective copies of the IDUA gene which encodes for the protein iduronidase. The gene has been mapped to the 4p16.3 site on chromosome 4.

Hurler-Scheie Syndrome

Hurler-Scheie syndrome (Mucopolysaccharidosis – MPS IH/S), is a genetic disorder which causes a deficiency of iduronidase.

Hurler-Scheie syndrome results in the build-up of glycosaminoglycans. It has symptoms intermediate between Scheie and Hurler syndromes.

Hurler-Scheie Syndrome is an autosomal recessive resulting from two defective copies of the IDUA gene which encodes for the protein iduronidase. The gene has been mapped to the 4p16.3 site on chromosome 4.

Hunters Syndrome

Hunters syndrome (Mucopolysaccharidosis – MPS II), is an X-linked recessive genetic disorder which causes a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S).

Hunters syndrome results in the build-up of the glycosaminoglycans heparan sulphate and dermatan sulphate in lysosomes of all body tissues.

Hunters syndrome is an X-linked recessive genetic disorder which preferentially affects males who inherit a defective X chromosome from the mother and do not have another X chromosome to compensate for the mutant gene.

Mannosidosis

Mannosidosis (classified as alpha and beta) is a lysosomal storage disorder, caused by a deficiency in alpha-mannosidase, a major exoglycosidase in the glycoprotein degradation pathway.

Mannosidosis is characterised by progressive lysosomal accumulation of mannose-rich oligosaccharides in all tissues, resulting in impaired cellular function and apoptosis.

Alpha Mannosidosis is caused by mutations in the MAN2B1 gene (short arm of chromosome 19) and Beta Mannosidosis is caused by mutations in the MANBA gene (long arm of chromosome 4).

Leukodystrophy

Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Patient have an inability to degrade sulphated glycolipids and/or a deficiency in the lysosomal enzyme sulfatide sulfatase resulting in accumulation of sulfatide compounds in neural and in nonneural tissue, such as the kidneys and gallbladder.

Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain.

Autoimmune Diseases

Autoimmune Diseases comprise a large group of disorders characterized by pathologic immune reactions to autologous tissue. Autoimmune Diseases may be systemic (e.g. Systemic Lupus Erythematosus) or they may be organ specific, (e.g. Thyroiditis).

A small number of Auto-HSCTs have been performed for patients with Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and childhood Crohn’s with promising results.

Solid Tumors

Germ Cell

Germinal Tumours are neoplasms of the ovary and other uterine tissue or testis. The neoplasms may be benign or malignant.

Neuroblastoma

Neuroblastoma is a metastatic malignant neoplasm often originating in the adrenal gland before spreading to other parts of the body. It is often asymptomatic before metastases. It has a characteristically early onset.

Ewing’s Sarcoma

Ewing Sarcoma is a rare malignant neoplasm of bone and articular cartilage. The most frequently affected sites are the pelvis, femur, humerus, ribs and clavicle. Ewing Sarcoma is more common in young males, presenting between the ages of 10 to 20.

Breast Cancer, Overy Cancer, Small Cell Lung Cancer and Renal Cell Carcenoma

Breast Cancer is a metastatic malignant neoplasm originating in breast tissue. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.