Bone Marrow Failure Syndrome

Bone Marrow Failure Syndrome

• A clinical condition where peripheral blood pancytopenia arises from a specific failure of bone marrow precursor cells to produce mature cells.
• This failure is not due to the production of abnormal cells with shortened survival, or normal cells subjected to an abnormal environment.
• There is no abnormality of the stroma in bone marrow failure.

Bone Marrow Failure

• Remaining marrow cells appear morphologically normal or near normal, showing minor changes from 'marrow stress'.
• Mild increase in dyserythropoietic forms such as macrocytosis of red cells may occur.
• Classified into two main types: Aplastic anemias and Single-cell cytopenias.
• Aplastic anemias involve failure in the pluripotent stem cell.
• Single-cell cytopenias involve failure in one of the committed cell lines.

Bone Marrow Failure Overlap

• Single-cell failure can progress to total marrow failure.
• Aplastic anemia may continue with single-cell deficiency after partial recovery.

Bone Marrow Failure Classification

• Bone marrow failure can be inherited or acquired

Inherited bone marrow failure examples:

• Fanconi's anemia: Auto recessive, impacts Pancytopenia, onset 0-50, can result in Leukaemia, Sq carcinoma,and Hepatocellular carcinoma
• Dyskeratosis congenita: X-linked recessive/Auto dominant/Auto recessive, impacts pancytopenia, onset 0.3-50, can cause leukoplakia
• Shwachman-Diamond: Auto recessive, impacts Neutropaenia, Anaemia and Thrombocytopaenia / Pancytopenia, onset 0-15, and can result in Leukaemia
• Diamond-blackfan anaemia: Sporadic, impacts pure red cell aplasia, onset 0-35, can cause Leukaemia
• Kostmann's: Auto recessive, impacts Neutropaenia, onset 0-4, can result in Leukaemia
• Thrombocytopaenia with absent radii: Aut recessive, impacts Thrombocytopaenia, onset 0-0.6, can cause Leukaemia Amegakaryocytic thrombocytopaenia: X-linked aut recessive, impacts Thrombocytopaenia

Acquired Bone Marrow Failure

• Can include these conditions
• Aplastic Anemia
• Myelodysplastic syndrome
• Megaloblastic Anemia
• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Myelofibrosis
• Multiple Myeloma
• Viral infections e.g. HIV

Differential Diagnosis of Pancytopaenia

• Pancytopaenia is characterized by Anaemia, Neutropaenia and Thrombocytaenia
• Conditions associated with pancytopaenia Hypocellular Myelodysplastic Syndrome, Hypocellular Acute Myeloid Leukaemia, Hypocellular Acute Lymphoblastic Leukaemia, Hairy Cell Leukaemia, Lymphoma, Myelofibrosis, Mycobacterial Infections, Hypersplenism, Megaloblastic Anaemia, HIV Infection

Aplastic Anaemia

• Defined by pancytopenia in peripheral blood and a hypocellular marrow where normal haemopoietic marrow has been replaced by fat cells.
• Abnormal cells are not found in either the peripheral blood or the bone marrow.
• Diagnosis is based on the absence of cells, not on the presence of any characteristic feature.

Diagnosing Aplastic Anaemia

• This requires at least two of the following in addition to a hypocellular marrow:
• Haemoglobin < 10 g/dl
• Platelet count < 100 × 10^9/L
• Neutrophil count < 1.5 × 10^9/L

Aetiology Examples and Clinical Course

• Inevitable: Caused by Ionizing radiation and Cytotoxic drugs, with a Predictable clinical course and Recovery being usual
• Idiosyncratic: Causes include Idiopathic, Drug induced, Viral, Commercial solvents, with a Prolonged clinical course which is Unpredictable
• Inherited: Causes include Fanconi's anaemia and Dyskeratosis congenita, with a Usually progressive clinical course and increased malignancy
• Industrial: Caused by Benzene, the clinical course is Dose dependent with Proliferative disorders being more common
• Immune: Caused by Drug induced Viruses EBV SLE the clinical course is Spontaneous recovery
• Malignant: Causes include ALL, Hypoplastic AML and Hypoplastic MDS and is Usually is seen in Children

Idiosyncratic Acquired Aplastic Anaemia

• May occur spontaneously or after exposure to drugs or viruses that do not usually cause marrow failure.
• Characterized by unpredictable onset and prolonged course.
• Death usually results from deficiency of granulocytes or platelets and failure in support measures.

Incidence

• Incidence in Western countries is about 2-5 per million of the population per year.
• Incidence in the East is about 5-10 fold higher.
• The difference between the East and West is attributed to environmental factors

Aetiology - Aplastic Anaemia

• In approximately one-third of acquired aplastic anaemia cases, a specific agent can be identified, such as a drug, chemical, or virus.
• In at least two-thirds of cases, no agent can be identified, classifying them as idiopathic aplastic anaemia.
• Drugs with a reported link to ‘causing’ aplastic anaemia is long, but mostly only a single or a few cases have been reported for each drug, and the evidence against many of the reported drugs is slim.

Drugs Associated with Idiosyncratic Acquired Aplastic Anaemia

• Antibiotics: Chloramphenicol, Sulphonamides, Cotrimoxazole
• Antimalarials: Chloroquine
• Anti-inflammatory: Phenylbutazon, Indomethacin, Naproxen, Diclofenac, Ibuprofen, Piroxicam
• Antirheumatics: Gold salt, d-Penicillamine
• Antithyroids: Carbimazole, Methylthiouracil, Methimazole, Propylthiouracil
• Psychotropic/antidepressants: Phenothiazines, Mianserin and Dothiepin
• Anticonvulsants: Carbamazepine, Phenytoin
• Antidiabetics: Chlorpropamide
• Carbonic anhydrase inhibitors: Acetazolamide, Methazolamide
• Miscellaneous: Allopurinol

Viruses Associated with Aplastic Anaemia

• Hepatitis is a precursor to aplastic anaemia in 5–10% of cases in the West; it is perhaps double that in the Far East
• In most patients, no specific hepatitis virus is identified; the association is based on clinical grounds and liver function tests.
• The delay between clinical hepatitis and pancytopaenia is 6-12 weeks, similar to drug exposure and aplasia.
• Parvovirus B19 infection in non-immune individuals may lead to transient pure red cell aplasia in those with hemolytic anaemia.
• Epstein barr virus can produce neutropaenia and thrombocytopaenia.

Pathogenesis

• The way the agents produce aplastic anaemia is largely unknown.
• There may be an unidentified underlying genetic predisposition.
• Human leucocyte antigen (HLA) DR2, specifically the DR15 split, have been linked with acquired aplastic anaemia.
• The primary defect may be in the haemopoietic stem cell itself or result from environmental factors, like immunological attack.
• There is evidence of both quantitative and qualitative stem cell defects in aplastic anaemia and increased apoptosis of remaining haemopoietic progenitor cells.
• Cytotoxic suppressor T lymphocytes release cytokines, such as interferon-γ and tumour necrosis factor α (TNF-α), that are inhibitory to haemopoietic progenitor cells.
• TNF-α up-regulates Fas antigen expression on CD34+ cells, potentially reducing the survival of aplastic anaemia marrow progenitor cells.

Haematological Findings

• Peripheral blood film shows pancytopenia without gross morphological abnormalities in circulating cells.
• Macrocytosis of remaining red cells is possible, usually with absolute reticulocytopenia. Possibility of paroxysmal nocturnal haemoglobinuria (PNH) should be considered in some patients.
• Increased staining of granules (toxic granulation) is seen Granulocytes in neutropenia,.

Haematological Findings cont

• Monocytes are usually reduced in proportion to granulocytes.
• Lymphocyte count reduction varies; it may be normal/increased but is commonly reduced.
• Abnormal cells are typically not seen.
• Bone marrow aspirate is typically easily obtained and hypocellular and exhibits increased lymphocytes, plasma cells, and other non-haemopoietic forms

Clinical Presentation

• derived from the decrease in peripheral blood cells and are non-specific.
• Weakness, fatigue due to Anaemia
• Easy bruising or petechiae and bleeding episodes
• Infection, less frequent than bleeding in idiosyncratic aplastic anaemia
• Spleen, liver, and lymph nodes are typically not enlarged
• Jaundice may be present in post-hepatitis aplasia patients with a prolonged cholestatic phase.

Clinical Course and Characteristics

• Modified by transfusion support and antibiotic therapy.
• Interruptions to the clinical course may occur, apart from low platelet counts and neutropenia.
• Reduced marrow proliferative capacity may mean unstable marrow, may cause abnormal clones of cells, PNH, myelodysplasia or leukaemia may appear during the disease, sometimes all three in the same

Stable, Progressive and Unstable Variants

• Stable aplastic anaemia: Presents with a degree of pancytopaenia remaining over a long period. Greater degree of pancytopaenia means worse the prognosis. Progressive or fluctuating aplasia: Small degree of pancytopaenia occurs of deficiency, in a cell line but over the succeeding months or year the aplasia is becomes more profound
• Unstable aplasia: may show an improvement in peripheral counts associated with abnormal clones. PNH clones appear in 10-20% of patients with prolonged aplasia

Criteria for Severe Aplastic Anaemia

• Requires two out of three of the following:
• Neutrophils < 0.5 × 10^9/L
• Platelets < 20 × 10^9/L
• Reticulocytes < 20 × 10^9/L (1%)
• Bone marrow trephine:
• Markedly hypocellular < 25%, normal cellularity
• Moderately hypocellular 25–50%, normal cellularity with < 30% remaining cells haemopoetic

Treatment Approach

• Total support for the patient while awaiting bone marrow recovery.
• Attempts to accelerate bone marrow recovery.
• Support and reassurance needed.
• Patients, relatives, and staff need help in maintaining morale.

Support for the Aplastic Anaemia Patient

• Providing blood product support.
• Protecting patients from infection.
• Isolating patients from sources of infection
• Use of antibiotics, both prophylactic and therapeutic.
• Blood product support is mainly with packed red cells and transfusions, to maintain a safe blood count.
• Patients are usually transfused with packed cells as required

Clinical Management

• Prophylactic platelet transfusions are given when the platelet count is < 10 × 10/L. Splenectomy.
• Maintaining Good mouth with chlorhexidine mouthwash. Reverse-barrier isolation is of benefit.
• Fever and signs of infection should be treated immediately with broad-spectrum intravenous antibiotics, particularly those active against Gram-negative organisms.
• Antibiotics are continued for at least 72 hours after normal temperature is reached, with regular monitoring.
• The need for specific antibiotics is driven from taking appropriate samples for microbiology.
• Growth factors G-CSF and GM-CSF enhance neutrophil function and combat infection.
• These factors tend to have weakest effect in patients with most severly aplastic patients

Antilymphocyte Globulin

• It should only be prescribed by physicians familiar with the drug, it needs to be taken in hospital only
• Cyclosporin has been used both with ALG and alone in the treatment of aplastic anaemia and it accelerates recovery in blood counts

Androgen

• A dose of Oxymetholone 2.5 mg/kg per day may be used to treat the condition
• Side-effects include Virilization, Salt retention, Prostatic enlargement, Hepatotoxicity
• Including the development of peliosis hepatitis and/or Hepatocellular carcinoma after prolonged usage
• Allogeneic Bone Marrow Transplantation Allogeneic bone marrow transplantation (BMT) for aplastic anaemia was first introduced in 1969.
• BMT transplant of of peripheral blood stem cells (PBSC) is the treatment of choice for young patients with SAA who have an HLA-identical sibling donor.
• Overall survival is around 60-80%. Transplant is the youger BMT has a better long term survival compared to immono suppresive drugs

Bone Marrow Transplantation

• The youger patient must be 20 years or younger with severe aplastic anaemia, especially if their neutrophil count is <0.2×109/l
• The risk of relapse and new clonal disease is much less with successful transplants
• Allogeneic PBSC transfusion can be an alternative to BMT.
• Major causes of BMT failure in aplastic anaemia are graft failure and post-graft infection.
• Patients with aplastic anaemia are immunocompetent apart from neutropaenia and may be immunostimulated by infections and blood transfusion.
• Chronic GVHD occurs in about 25% of successful transplants.