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WHAT IS IT
Aplastic anemia is a rare and serious disease characterized by the failure of the bone marrow to produce enough blood cells. In the presence of bone marrow aplasia, a simultaneous reduction of red blood cells, white blood cells and platelets is observed.
Aplastic anemia is not an oncological disease, but it is a disease of the bone marrow and blood cells characterized by the lack of cell production by the marrow. In the definition of this disease, the term "aplasia" indicates in fact the inability of the marrow - the organ responsible for producing red blood cells, white blood cells and platelets to be released into the bloodstream - to produce blood cells adequately. Most patients develop "pancytopenia" that is, all three series (red blood cells, white blood cells and platelets) are decreased, and the marrow is "empty": aplastic anemia is therefore a bone marrow failure syndrome.
HOW DO WE RECOGNIZE IT
Aplastic anemia should be suspected in patients with pancytopenia (depression of white blood cell, red blood cell and platelet counts) and hypo-cellular (ie empty) bone marrow. Typical symptoms include fatigue and easy bruising or bleeding; infections may be present, but there is generally no long-standing history of the disease.
The disease can come on suddenly or progress slowly over weeks or months. There is a well-known distribution with respect to age of onset with a peak in mid-late childhood and another in the elderly: it can develop at any age, but it is more common in adolescents and young adults (20-25 years) and in people over 50 years old. It affects men and women equally. The estimated annual incidence of aplastic anemia is about 2 cases per million in Europe and North America, with a 2-3 times higher incidence in East Asia.
The disease is divided into two forms: acquired and present at birth (congenital). The congenital forms (20%) usually represent the terminal phase of the evolution of a genetic disease (for example, Fanconi's anemia or congenital dyskeratosis).
Acquired disease is the most frequent and is estimated to account for 80% of medullary aplasias.
The acquired form can be distinguished according to the origin of the disease into:
- idiopathic medullary aplasia (when the causes are unknown, 80% of cases
- secondary medullary aplasia (when the causes are known, 20%)
In ~ 10% of patients, a history of non-viral hepatitis may precede the onset of aplastic anemia; An uncommon association with eosinophilic fasciitis has also been reported. With rare exceptions, such as chloramphenicol, antiepileptics, and the emerging link to immunotherapies, it can be difficult to establish a causal relationship with drugs or toxins.
CAUSESThe three main causes that determine an "empty marrow" are:
- direct marrow damage: drugs, such as chemotherapy, and radiation can cause a transient, dose-dependent lowering of counts, which undergoes spontaneous recovery; some molecules, on the other hand, due to exposure to toxic molecules (such as benzene) can develop early bone marrow failure;
- constitutional syndromes: bone marrow failure derives from mutations - generally hereditary - of the DNA of the germ cell; Fanconi's anemia, dyskeratosis congenita, or GATA2 disease, etc. belong to this group. Constitutional syndromes classically occur in childhood and can be associated with physical anomalies;
- immune-mediated aplastic anemia (almost all cases of sporadic aplastic anemia, especially if severe and acute, appear to be of the immune-mediated type) or there is an altered response of the immune system which leads to damage to the marrow and therefore to pancytopenia. Factors that can temporarily or permanently damage the bone marrow and impair the production of blood cells include radiotherapy and chemotherapy, toxic chemicals, drugs, autoimmune diseases, viral infections, pregnancy, unknown factors.
DIAGNOSIS
Diagnosis is based on excluding other disorders that can cause pancytopenia. To make a diagnosis, the following exams are carried out:
- peripheral blood investigations - sampling
- bone marrow blood tests
- bone marrow biopsy
The diagnosis of aplastic anemia is confirmed according to the "Camitta criteria":
- cellularity of bone marrow biopsy <25%
- 2 out of 3 of the following criteria: or hemoglobin <10 g / dL, or reticulocytes <50 × 109 / L or <1%; or platelets <50 × 109 / L;
- neutrophilic leukocytes (ANC) <1.5 × 109 / L.
HOW IT IS TREATED
In the treatment of aplastic anemia, two levels must be distinguished: supportive therapy (aimed not at treating the disease but at managing symptoms and avoiding complications) and curative treatment.
Treatments with curative purposes:
- Bone marrow transplant. Stem cell transplantation is the process of replacing a diseased bone marrow with a healthy one obtained from a donor to restore normal blood cell production. This is the option of choice for young patients who have an identical HLA family donor (molecules that determine the compatibility between donor and recipient) and can therefore quickly access the transplant option. Transplantation is limited by its complications such as graft rejection and graft versus host disease (GVHD), as well as the availability of suitable donors. Where there is no compatible HLA sibling available, then the search for a donor in the IBMDR registry is initiated. Young age is a favorable factor for unrelated HLA compatible transplantation. Further possibilities - to be considered in the absence of response to drug therapy alone (see below) and the unavailability of family or registry donors with full compatibility - are the transplantation of cord units or from a family donor with compatibility of 50%.
- Immunosuppression. Since aplastic anemia is a disease based on an immune-mediated mechanism, the use of immunosuppression strategies (drugs that suppress / inhibit / eliminate the patient's immune system by inducing a reorganization of the same) has given satisfactory results.
For people who cannot undergo a bone marrow transplant and for those who have bone marrow aplasia caused by an autoimmune disease, treatment involves the use of drugs that suppress the immune system, so-called immunosuppressive drugs, such as for example cyclosporine and anti-thymocyte globulin. These drugs block the activity of the immune cells that are destroying the bone marrow and cause it to start making new blood cells. Immunosuppressive therapy is less arduous than transplantation and is available to all patients, but late disease relapses can occur.
The combination of ATG + cyclosporine is today a recognized standard in the immunosuppressive therapy of aplastic anemia. Another growth factor - eltrombopag, a synthetic mimetic of thrombopoietin - has proved useful in refractory aplastic anemia.
FOLLOW-UP
Once the treatment process is completed, the patient enters the follow-up program (post therapy monitoring). The patient who has received a donor transplant will follow the specific post-transplant follow-up program. This is a potentially cured patient.
PREVENTION
Generally, no prevention is possible for most cases of acquired bone marrow aplasia as the underlying cause is not known. However, a small percentage of cases develop following exposure to chemicals. So, avoiding exposure to insecticides, herbicides, organic solvents, paint thinners, and other toxic chemicals can lower your risk of getting sick.
WHAT DO WE DO AT SAN RAFFAELE HOSPITAL?
The above (from diagnosis to immunosuppressive treatment, transplant treatment, short and long-term follow-up) is offered as an integral and structured part of the Hematology and Transplant Unit - UOE-TMO activity of the Stem Cell Program, JACIE certified.
We are a center for Acquired Aplastic Anemia in the Rare Diseases network.
We are active in EBMT (European Group of Bone Marrow Transplant) in the Aplastic Anemia Working-Party.
We actively collaborate with national and international centers that, like us, deal with Acquired Aplastic Anemia.
References- Istituto Superiore di Sanità
- Young NS. Aplastic Anemia. N Engl J Med. 2018; 379 (17): 1643 – 1656. doi: 10.1056 / NEJMra 1413485 • Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017; 129 (11): 1428 – 1436. doi:10.1182/blood-2016-08-693481
- Peslak SA, Olson T, Babushok DV. Diagnosis and Treatment of Aplastic Anemia. Curr Treat Options Oncol. 2017; 18 (12): 70. Published 2017 Nov 16. doi:10.1007/s11864-017-0511-z
REFERRING DOCTORS for this deseaseat Ospedale San Raffaele
