Bone Marrow Failure – Causes, Symptoms, Treatment

Bone Marrow Failure (BMF) refers to the decreased production of one or more major hematopoietic lineages which leads to diminished or absent hematopoietic precursors in the bone marrow and attendant cytopenias. It can be divided into two categories: acquired and inherited. This activity will review the inherited forms in greater detail while briefly mentioning the acquired forms (they are covered more thoroughly under each specific topic).

Inherited bone marrow failure (IBMF) is bone marrow failure that occurs from germline mutations passed down from parents or arising de novo. In addition to symptoms associated with aplastic anemia such as fatigue, hemorrhage, and recurrent bacterial infections, patients often have extra-marrow features unique to each syndrome.

The most common inherited bone marrow failure syndromes (IBMFSs) are Fanconi anemia (FA), dyskeratosis congenital (DC), Shwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia (CAMT), Blackfan-Diamond anemia (BDA), and reticular dysgenesis (RD). Others are less common and share features with the inherited bone marrow failure syndromes listed, for example, short telomerase.[rx][rx][rx][rx][rx][rx]

Pathophysiology

Many steps occur for the development of inherited bone marrow failure syndromes. There are critical points in hematopoietic lineage pathways. The highly penetrating, specific mutant alleles isolated are of genes that directly affect cell survival and function (routes essential for normal hematopoiesis), in addition to other genetic modifying processes such as cytokine signaling hyperactivity isolated in the pathogenesis of acquired autoimmune aplastic anemia. Lineages most affected are those with frequent division (hematopoietic, gastrointestinal, and integumentary cells), providing the basis behind marrow and extra-marrow pathology observed in inherited bone marrow failure syndromes.

Fanconi anemia involves genomic instability due to mutations in genes coding for DNA damage repair proteins. DNA repair proteins are not oncogenic; however, DNA repair is important in maintaining the integrity of the genome, and any abnormalities allow mutations in other genes during the process of normal cell division. Fanconi anemia is part of a group of autosomal recessive disorders characterized by hypersensitivity to other DNA damaging agents (others include Bloom syndrome and ataxia-telangiectasia, both of which are sensitive to ionizing radiation). Of the 13 genes that make up the  Fanconi anemia complex, FANC is the most common mutation. A subset of patients has BRCA2 mutations (FANCD1, FANCG, FANCJ, FANCP), associated with an increased risk of breast and ovarian cancer. These proteins are responsible for DNA damage repair via homologous recombination of intrastrand and interstrand DNA crosslinks due to chemical crosslinking agents. When these genes are mutated, crosslinks remain unrepaired, and when they are exposed upon strand separation during cell replication, the chromosomes break. These exposed ends lead to the activation of salvage nonhomologous end-joining pathways, bridge-fusion-breakage cycles, and massive aneuploidy. Some proteins also participate in the stem cell survival pathways in a direct or indirect manner, further influencing cell survival.[rx][rx]

Dyskeratosis congenita has mutations in genes responsible for encoding proteins and RNAs involved in telomere maintenance (DKC1, TERC, TERT, NOLA2, NOLA3, WRAP53,) These are only half of the genes found in patients. Other less commonly inherited bone marrow failure syndromes and 5% to 10% of adult-onset aplastic anemia have mutated telomerase enzymes. Telomerase is involved in cell replication; defects in telomerase result in short telomeres, leading to premature hematopoietic stem cell exhaustion and marrow aplasia. Moreover, short telomeres are present in half of all patients with aplastic anemia due to a combination of mutated telomerase or excessive stem cell replication.[rx]

Shwachman-Diamond syndrome involves mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, responsible for proteins implicated in ribosome biogenesis and mitotic spindle function.

Congenital amegakaryocytic thrombocytopenia is not associated with chromosome fragility; however, mutations in MPL (myeloproliferative leukemia virus) oncogene leads to thrombocytopenia from absent or reduced megakaryocytes in bone marrow. MPL is responsible for coding thrombopoietin receptor c-MPL, a regulator of megakaryocytopoiesis and platelet production.[rx]

Blackfan-Diamond anemia includes mutations in gene families RPL and RPS. They are responsible for ribosomal proteins involved in ribosome biogenesis. Similar to those in dyskeratosis congenital, they account for only half of the genes found in patients.[rx]

Reticular dysgenesis is one of the rarest and most severe forms of severe common immunodeficiency (SCID) and occurs from a mutation in mitochondrial adenylate kinase 2 (AK2). Patients develop profound leukopenia, especially neutropenia.[rx]

Causes of Bone Marrow Failure

Inherited bone marrow failures occur secondary to germline mutations passed down from parents or arising de novo. Most are inherited in an autosomal recessive manner (Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, reticular dysgenesis) while a small subset is inherited in X-linked recessive (dyskeratosis congenita, 2% of FC) or autosomal dominant patterns (Blackfan-Diamond anemia, reticular dysgenesis).[rx][rx][rx][rx][rx][rx]

It isn’t clear what causes bone marrow cancer. Contributing factors may include

• exposure to toxic chemicals in solvents, fuels, engine exhaust, certain cleaning products, or agricultural products
• exposure to atomic radiation
• certain viruses, including HIV, hepatitis, some retroviruses, and some herpes viruses
• suppressed immune system or plasma disorder
• genetic disorders or family history of bone marrow cancer
• previous chemotherapy or radiation therapy
• smoking
• obesity

Symptoms of Bone Marrow Failure

Signs and symptoms of Bone Marrow Failure may include:

• weakness and fatigue due to a shortage of red blood cells (anemia)
• bleeding and bruising due to low blood platelets (thrombocytopenia)
• infections due to a shortage of normal white blood cells (leukopenia)
• extreme thirst
• frequent urination
• dehydration
• abdominal pain
• loss of appetite
• drowsiness
• confusion due to high levels of calcium in the blood (hypercalcemia)
• bone pain or weakened bones
• kidney damage or kidney failure
• peripheral neuropathy, or tingling, due to nerve damage
• fever and chills
• weakness and fatigue
• frequent or severe infections
• unexplained weight loss
• swollen lymph nodes
• enlarged liver or spleen
• bruising or bleeding easily, including frequent nosebleeds
• tiny red dots on the skin (petechiae)
• excessive sweating
• night sweats
• bone pain

Some signs and symptoms of lymphoma are:

• swelling in the neck, underarm, arm, leg, or groin
• enlarged lymph nodes
• nerve pain, numbness, tingling
• feeling of fullness in the stomach
• unexplained weight loss
• night sweats
• fever and chills
• low energy
• chest or lower back pain
• rash or itching

Diagnosis of Bone Marrow Failure

Histopathology

Bone marrow biopsy from patients with inherited bone marrow failure syndromes who have aplastic anemia will be markedly hypocellular. Fat and fibrotic stroma fill up the remaining marrow space (see image). Any residual hematopoietic cells are predominantly lymphocytes. There may be dysplastic features such as hyponucleated small megakaryocytes, multinucleated red cells, or hypolobulated or hypogranular myeloid cells, none of which are malignant. Some inherited bone marrow failure syndromes affect only one lineage (other lines are well-represented and functional).

History and Physical

Common symptoms of inherited bone marrow failure syndromes are related to aplastic anemia. They include fatigue and pallor due to anemia, hemorrhage secondary to thrombocytopenia, and fevers, mucosal ulcerations, and bacterial infections from neutropenia. Many patients have extra-marrow features specific to each syndrome; however, clinicians cannot rely on the absence of such findings to exclude inherited bone marrow failure syndromes because many patients do not have them.

Fanconi anemia presents in children more often than adults. Patients will have:

• Low birthweight
• Cafe au lait spots
• Short stature
• Microcephaly
• Renal or cardiac malformations
• Hypogonadism
• Absent radii and thumbs
• Histories of bone marrow failure or malignancies, specifically, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), squamous cell carcinoma (SCC), at younger ages (younger than 40 years) in the patient or family members. [rx][rx]

Dyskeratosis congenita also presents in children more often than adults. While dyskeratosis congenital shares many features with Fanconi anemia (short stature, low birth weight, hypogonadism, and histories of premature malignancies including MDS/AML and SCC), it has the following differences:

• Lacy reticulated skin pigmentation with telangiectasias affecting the upper body,
• Maldentition,
• Alopecia,
• Premature graying of hair,
• Dystrophic nails,
• Hyperhidrosis of glabrous skin
• Pulmonary fibrosis. [rx]

Blackfan-Diamond anemia presents in all ages with bone marrow failure (predominantly neutropenia), exocrine pancreatic dysfunction, and skeletal abnormalities.[rx] Congenital amegakaryocytic thrombocytopenia patients have histories of thrombocytopenia in infancy (bleeding involving the skin, gut, and mucosal surfaces) progressing to aplastic anemia in later childhood, and increased risk of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).[rx] Blackfan-Diamond anemia presents early in life with isolated erythroid failure more commonly than aplastic anemia and other findings such as low birth weight, bony deformities (triphalangeal thumbs), and short stature. Patients with reticular dysgenesis will have early onset of infections, profound neutropenia, and decreased T and NK cells with absent to low B cells.[rx]

Evaluation

In patients with pancytopenia, the first step is to examine the peripheral blood smear for abnormalities including B12 and/or folate deficiency (hypersegmented neutrophils and oval macrocytes). Next, perform a bone marrow biopsy and aspirate to look for any evidence of myelodysplastic morphology or clonal cytogenic abnormalities. Rule out acquired bone marrow failure by stopping suspected medications, treating active infections, and testing for hepatitis, pregnancy, or paroxysmal nocturnal hemoglobinuria (PNH). Patients who have bone marrow failure with a positive family history of MDS/AML or SCC, extra-marrow findings associated with inherited bone marrow failure syndromes, or age less than 40 years need to be evaluated for inherited bone marrow failure syndromes. It is imperative not to discount these conditions in adults.[rx][rx]

Screen for Fanconi anemia by the presence of abnormal chromosome breakage in metaphase preparations of lymphocytes or skin fibroblasts cultured with phytohemagglutinin (PHA) dosed with bifunctional DNA interstrand crosslinking agents such as diepoxybutane (DEB) or mitomycin C (MMC). An alternative screening test involves complement analysis using flow cytometry analysis of G arrest in melphalan-dosed cells after transduction. Confirm with gene sequencing.[rx][rx][rx]

The screening test for dyskeratosis congenital is a quantitative analysis of lymphocytic telomere length using flow fluorescence in situ hybridization (FISH). Because it is similar to FA, simultaneously test for chromosomal fragility. Confirm with gene sequencing.[rx]

Gene sequencing in other disorders (Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, DBA, reticular dysgenesis) is mandatory because there are no screening tests. Blackfan-Diamond anemia is associated with increased serum adenosine deaminase (ADA) levels. [rx][rx][rx][rx][rx]

Other causes of bone marrow failure are acquired. The most common forms occur from drugs, chemicals, radiation, viral infections, immune disorders, MDS, PNH, or large granular lymphocytic leukemia.

Treatment of Bone Marrow Failure

The definitive treatment for marrow disease associated with inherited bone marrow failure syndromes is a hematopoietic stem cell transplant (HSCT). Immunosuppressive therapy plays no role. Gene cell therapy may promise a cure in the future.[rx][rx]

Before undergoing hematopoietic stem cell transplant, it is important to consider the following: inherited bone marrow failure syndromes are associated with increased mortality using conventional regimens. Patients with FA are highly intolerant of radiation therapy and crosslinking agents in conditioning regimens.

Dyskeratosis congenital and Shwachman-Diamond syndrome individuals suffer excess post-transplant morbidity and mortality including severe pulmonary and hepatic toxicity. Nonmyeloablative regimens including fludarabine are preferred, though data is sparse. Before the transplant, clinicians must not overlook the diagnosis of inherited bone marrow failure syndromes in siblings who have HLA-matches because the recipient will die. The hematopoietic stem cell transplant will provide no benefit, and the conditioning regimen will be too toxic. Therefore, screen all first-degree relatives of patients with inherited bone marrow failure syndromes upon diagnosis and refer for genetic counseling as needed.[rx][rx]

The exception to treatment is DBA. It is more tolerant of standard conventional treatment and more apt to respond to glucocorticoid treatment (up to 80% of patients). Start with 2 mg/kg/day then taper after hemoglobin reaches 10 mg/dL and reduce to every other day or discontinue altogether (15% of patients will remain disease-free off steroids).

Supportive care includes infection prophylaxis/treatment and transfusions (leukoreduced red blood cells for Hb less than 7 mg/dL or platelets less than 10,000/microliter or less than 50,000/microlitler for active blood loss). Avoid blood products from family members because of the risk of alloimmunization increases. Monitor for secondary hemochromatosis and if needed, administer iron chelators. It is not recommended to use growth factors such as erythropoietin or granulocyte colony-stimulating factors because there are not enough precursor cells to generate satisfactory responses.

The main treatments are:

• Chemotherapy (Chemo) – Doctors inject cancer-fighting drugs into your body, or you take them by mouth. They may be used with radiation or other drugs.
• Immunotherapy – This treatment boosts your immune system. It may also use man-made versions of your immune system to kill cancer cells or slow their growth.
• Targeted therapy drugs – These drugs pinpoint the changes that happen in your body’s cells to cause cancer. They often have less severe side effects than chemo.
• Radiation – Special x-rays and gamma rays are used to attack and shrink tumors. Radiation kills cancer cells by destroying their DNA.
• Biological therapy – This therapy uses your own immune system to kill cancer cells.
• Targeted therapy drugs – These drugs attack specific types of cancer cells in a precise manner. Unlike chemotherapy, they prevent damage to healthy cells.
• Stem cell transplant – During chemo, cancerous bone marrow cells are killed off. In high-dose chemo, the stem cells that form blood in your bone marrow are also destroyed. A stem cell transplant — also called a bone marrow transplant creates more of the cells that grow in your marrow. After chemo or radiation, you’ll get them through an IV, an injection into your veins.

For patients wishing to have children, in vitro fertilization is successful and transplanted cord blood from unaffected offspring shows promise in the treatment of Fanconi anemia.[rx]

References