Aplastic Anemia

A syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia.

A rare hematologic disorder marked by pancytopenia and a hypocellular marrow.

AA is characterized by pancytopenia and loss of hematopoietic stem cells, progenitor cells, and precursor cells in the bone marrow.

Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes.

A heterogeneous disorder characterized by hematopoetic stem cell deficiency and bone marrow hypoplasia, with significant reductions of red and white cells and platelet counts.

Acquired or congenital.

AA results from one of three mechanisms: damage by extrinsic factors, manifestations of familial genetic mutations, and autoimmune attack on hematopoietic stem cells and progenitor cells.

Up to 70% of cases occur sporadically, from a sudden onset of T cell mediated destruction of hematopoietic stem cells and progenitor cells.

Most cases are designated as idiopathic because the triggers for immune hematopoetic attack remain obscure.

Inherited bone marrow failure can be caused by germline defects in telomere biology, ribosomal function, or DNA repair.

Acquired type associated with pancytopenia and an empty bone marrow.

Acquired AA is caused by immune mediated destruction in hematopoietic stem cells and progenitor cells.

In immune aplastic anemia, activated T cells produce pro inflammatory cytokines and proteins associated with the lack of immune regulation that results in the recognition and elimination  of hematopoietic stem cells.

Extrinsic causes of AA are usually apparent and include: major accidental or therapeutic exposure to radiation, chemotherapy, or massive exposure to benzene or pesticides such as organochlorines and organophosphates.

Medication have been infrequently associated with AA.

There are known associations with eosinphilic fasciitis and thymoma.

CD34+ cells and early progenitors are reduced in aplastic anemia.

Basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment.

Hematopoietic precursor cells in the bone marrow replaced by fat, resulting in pancytopenia.

The genetic disorder most commonly associated with AA is Fanconi anemia, with a DNA repair defect resulting from mutation in one of at least 15 known genes.

The incidence is 0.6-6.1 cases per million population.

The annual incidence of aplastic anemia in Europe is 2 cases per million population.

More common in Asia than in the West.

The incidence is 4 cases per million population in Bangkok, but it may be closer to 6 cases per million population in the rural areas of Thailand.

The increased incidence is not observed in people of Asian ancestry living in the United States.

Incidence as high as 14 cases per million population in Japan.

No racial predisposition is reported in the United States, but the prevalence is increased in the Far East.

2-3 fold incidence increase in Asia.

More common in adolescents and young adults between the age of 10-25 years as well as adults over age 60.

Rare in children, affecting 1 per million for year.

Approximately 750 new cases will be reported in the US in 2017.

The male-to-female ratio for acquired aplastic anemia is approximately 1:1 in the US.

Occurs in all age groups, with a small peak in the incidence in childhood because of the inclusion of inherited marrow-failure syndromes.

Most cases are acquired are the consequence of immune mediated destruction of hematopoiesis.

Some cases are idiopathic occurring with no established chemical or drug exposure or viral infection.

Other forms are iatrogenic and constitutional.

Iatrogenic aplastic anemia occurs following cytotoxic chemotherapy or radiation therapy.

Drug-related and chemically related aplastic anemias account for 11% to 20% of all cases.

Ionizing radiation is well documented cause.

Certain chemicals or physical agents can injure proliferating and hematopoetic cells, damaging DNA and leading to apoptosis.

Such agents include benzene and benzene derivatives, trinitrotoluene, insecticides and weedkillers.

The incidence peaks in people aged 20-25 years, and a subsequent peak is observed in people older than 60 years.

Clinical presentation is insidious, and the initial symptom is related to anemia, bleeding, or fever.

Patients may manifest with pallor, headache, palpitations, dyspnea, fatigue, or edema as a result of anemia.

Thrombocytopenia may cause mucosal and gingival bleeding or petechial rashes.

Neutropenia may manifest as infections, recurrent infections, or mouth and pharyngeal ulcerations.

Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.

Most experts initiate antifungal prophylaxis in patients with severe aplastic anemia with voriconazole or posaconazole, especially for patients who have received ATG or undergone HSCT.

For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.

Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus prophylaxis.

Patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic processes..

History of solvent and radiation exposure

Examination may show signs pallor, tachycardia, and petechiae, purpura, or ecchymoses.

In idiopathic disease bone marrow suppression results from immune processes that involves overproduction of γ-interferon and tumor necrosis factor myelosuppressive cytokines.

Abnormally activated T cells overproduce γ-IFN.

Patients who had shorter telomeres at the start of therapy and therefore more exhausted bone marrow were less likely to respond.

More than 80% of cases are acquired.

Congenital or inherited causes of aplastic anemia account for 20% of cases.

Acquired aplastic anemia, suggested to be an autoimmune disease.

The bone marrow appears to be devoid of hematopoietic elements.

FDA has expanded the approval of eltrombopag in combination with standard immunosuppressive therapy to include newly diagnosed adult and pediatric patients 2 years and older with severe aplastic anemia.

Eltromopag addition to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously owned treated patients with severe aplastic anemia, without additional toxic effects.

Eltrombopag, the thrombopoietin receptor agonist in conjunction with cyclosporine A and ATG demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.

Iron overload is another complication in the setting of increased transfusions in aplastic anemia patients, and iron chelation therapy using deferasirox is effective at reducing serum f2242itin levels in patients with aplastic anemia.

Flow cytometry studies reveal that the CD34 cell population, which contains the stem cells and the early committed progenitors, is substantially reduced.

Hematopoietic progenitors are unresponsive even to high levels of hematopoietic growth factors.

The bone marrow microenvironment is usually normal.

In approximately 70% of patients with acquired aplastic anemia immunosuppressive therapy improves marrow function.

Human leukocyte antigen (HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia, and its presence is predictive of a better response to cyclosporine.

Suppression of hematopoiesis is likely mediated by an expanded population of cytotoxic T lymphocytes (CTLs): CD8 and HLA-DR+, which are detectable in both the blood and bone marrow of patients with aplastic anemia.

These cells produce inhibitory cytokines, such as gamma-interferon and tumor necrosis factor, which can suppressing progenitor cell growth by affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis.

These cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic cells.

Tbet, a transcriptional regulator that is critical to Th1 polarization, occurs in a majority of aplastic anemia patients.

The major causes of morbidity and mortality from aplastic anemia include infection and bleeding.

Because infection is a common cause of morbidity and mortality in patients with aplastic anemia due to prolonged neutropenia, patients should receive broad-spectrum antibiotics with antipseudomonal coverage.

Survival is decreased in patients with who delay initiation of therapy, and therefore prompt ref2242al for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Current standards of care recommend HLA-matched sibling donor transplant for patients who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes.

IN AA as many as 55% of all patient deaths are attributed to secondary infections in patients receiving immunosuppressive therapy.

G-CSF in patients receiving immunosuppressive therapy did not result in an overall survival benefit although the risk of infection is decreased.

Pulmonary aspergillosis and Zygomycetes are a major cause of mortality related to opportunistic mycotic infections in patients with aplastic anemia.

The infectious risk is directly related to the duration and severity of neutropenia.

Approximately one third of patients do not respond to immunosuppressive therapy.

For patients that survive there is an increased risk of PNH and myelodysplastic syndrome.

Some patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.

Acquired causes of aplastic anemia usually idiopathic, but may be associated with Infectious causes, such as hepatitis viruses, EB virus, human immunodeficiency virus (HIV), parvovirus, and mycobacteria.

Associated with exposure to radiation and chemicals, such as benzene, and drugs such as chloramphenicol, phenylbutazone, and gold.

Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation.

Intracellular γ-IFN levels in circulating and bone marrow T cells may predict response of immunosuppressive therapy and onset of relapse.

5-10% of cases follow an episode of seronegative hepatitis in which immune activation is suggested by pattern of T cell activation:this is the most common known trigger for aplastic anemia, preceding it by approximately 2 to 3 months.

The median age at the onset of hepatitis associated aplastic anemia is 20 years.

AA is also thought to occur following infection with common hepatitis viruses and other viruses including HIV and parvovirus B19.

There is speculation that Covid-19 may be a trigger factor for aplastic anemia.

Benzene rarely responsible, in the West and medical drugs have a extremely small role in Asia.

Incidence is 2 per million people, about 2-3 times higher in Asia.

Infectious origin suggested in rural Thailand.

Kinectin protein bound to sera antibodies in 40% of patients.

Diazepam binding protein antigen bound to antibodies in a small number of patients.

Relevance of autoantibodies presently, unclear.

The responsiveness of this process to immunosuppressive drugs is the best evidence of underlying immune etiology.

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT).

The main treatment options include allogeneic bone marrow transplant and immunosuppression.

Factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age.

Studies indicate identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients. supporting recommendations for upfront unrelated donor transplantation for aplastic anemia.

The backbone of therapy is anti-thymocyte globulin (ATG), which is composed of serum containing polyclonal xenogenic antibodies obtained from animals that have been sensitized to human T cells.

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy with ATG and cyclosporine A are the first-line therapy.

2/3 of patients have a response to standard immunosuppressive treatment with horse ATG plus cyclosporine.

Horse ATG is preferred over rabbit ATG, demonstrating improved survival.

ATG should be used in combination with cyclosporine A to optimize outcomes.

The development of myeloid cancers remains a troublesome complication if the immuno suppressive therapy in accounts for 10 to 15% of late treatment failures.

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an inherited marrow failure syndrome, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy.

The risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL.

Transfusion carries the risk of alloimmunization and transfusion-related graft versus host disease, and should be minimized when possible.

All blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and transfusion related GVHD.

Screening for Rh and Kell antibodies to reduce the risk of allo-immunization is recommended.

Majority of patients have hematologic improvement with T cell depletion by antithymocyte globulin therapy and many patients respond to low doses of cyclosporine.

Immunosuppression induced by infusion of antithymocyte globulin, polyclonal antibodies generated in animals, by inoculation with thymocytes is as effective as stem cell transplantation from a histocompatible sibling.

Rabbit ATG is inferior to horse ATG as a first treatment for severe aplastic anemia (Scheinberg P et al).

Immunosuppression with ATG and cyclosporine is often the first treatment offered for severe aplastic anemia, since most patients lack a histocompatible sibling donor or are not suitable candidates for stem cell transplantation because of age, coexisting morbidity or lack of access to such a treatment.

Children show higher rates of recovery and survival with immunosuppressive therapy.

80 to 90% expected long-term survival with matched related donor Hematopoetic stem cell transplant.

Matched unrelated donor HSCT results in long-term survival between 39-64%.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.

Among patients with anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.

In inherited marrow failure syndromes patients, the donor cell type may affect the choice of conditioning regimen, with reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation.

Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival compared to cyclophosphamide conditioning.

Total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.

Current conditioning regimens typically use a combination of cyclophosphamide and ATG with or without fludarabine.

The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure

Longer donor leukocyte telomere length is associated with increased 5 year survival in patients who receive allogeneic hematopoietic transplantatio, while patient leukocyte telomere length is not associated with survival (Gadalla SM et al).

As survival has improved due to bone marrow transplant or immunosuppressive therapy the late development of myelodysplastic syndrome, acute myeloid leukemia is noted in about 15% of patients: this is called clonal evolution.

Overall survival for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures.

In patients with refractory disease to immunosuppressive therapy who lack a matched sibling donor, matched unrelated donor HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing.

With use of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating matched unrelated donor HSCT in the treatment plan for patients without a matched sibling donor

Eltrombopag stimulates stem cells and mimics the actions of a natural growth substance for marrow stem cells while suppressing the immune system improving the likelihood, quality and speed of recovery in aplastic anemia patients.

The target of eltrombopag, the MPL receptor, can also be found on blood stem cells.

These rates are about 20% higher than the response rates in our patients treated historically with ATG and cyclosporine alone.

Patients who had shorter telomeres at the start of therapy and therefore more exhausted bone marrow were less likely to respond.

Stimulating remaining stem cells with a drug mimicking the actions of a natural growth substance for marrow stem cells while suppressing the immune system improves the likelihood, quality and speed of recovery in seriously ill patients.

It is a promising therapy for patients with severe aplastic anemia who do not have a stem cell transplantation option or for whom transplantation is too risky.

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