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58АКТУАЛЬНОСТЬ ЛЕЧЕНИЯ АПЛАСТИЧЕСКОЙ АНЕМИИ
Салиева Минара Джалалов Равшанбек Абдурахимов Абдухалим Нугманов Озодбек
Андижанский государственный медицинский институт
Андижан, Узбекистан
Апластическая анемия - это заболевание, при котором костный мозг не производит достаточного количества клеток крови. Дефицит всех типов клеток крови - белых кровяных телец (лейкоцитов), красных кровяных телец (эритроцитов) и тромбоцитов - может привести к образованию заболевания, называемого панцитопенией. Лечение этого заболевания очень актуально. Об этом и пойдет речь в этой статье.
Ключевые слова: апластическая анемия, эритроцит, тромбоцит, лейкоцит, панцитопения, гипоплазия костного мозга, нормостеническая анемия, эритропоэз, периферическая цитопения, гемоглобин, нейтрофилы, трансплантация.
APLASTIK ANEMIYANI DAVOLASHNING DOLZARBLIGI
Aplastik anemiya bu suyak iligi yetarli miqdordagi qon hujayralarini ishlab chiqarmasligi bilan kechadigan kasallik. Barcha qon hujayra turlarining yetishmasligi kelib chiqishi mumkin - oq qon hujayralari (leykotsitlar), qizil qon hujayralari (eritrotsitlar) va trombotsitlar - bu pansitopeniya deb ataladigan kasallikning shakllanishiga olib keladi. Ushbu kasallikni davolash juda dolzarbdir. Bu esa ushbu maqolada muhokama qilinadi.
Kalit so'zlar: Aplastik anemiya, eritrotsit, trombotsit, leykotsit, pansitopeniya, ilik gipoplaziyasi, normostenik anemiya, eritropoez, periferik sitopeniya, gemoglobin, neytrofil, transplantatsiya.
THE RELEVANCE OF THE TREATMENT OF APLASTIC ANEMIA
Aplastic anemia is a disease in which the bone marrow does not produce enough blood cells. Deficiency of all blood cell types - white blood cells (leukocytes), red blood cells (erythrocytes) and platelets - can lead to the formation of a disease called pancytopenia. For the treatment of aplastic anemia, medications, blood transfusions, or bone marrow transplants (stem cell transplants) are performed. Treatment of this disease is very topical. This will be discussed in this article.
Keywords: Aplastic anemia, erythrocyte, platelet, leukocyte, pancytopenia, bone marrow hypoplasia, normosthenic anemia, erythropoiesis, peripheral cytopenia, hemoglobin, neutrophils, transplantation.
DOI: 10.24411/2181-0443/2020-10078
Introduction: Treatments for aplastic anemia, which will depend on the severity of your condition and your age, might include observation, blood transfusions, medications, or bone marrow transplantation. Severe aplastic anemia, in which your blood cell counts are extremely low, is life-threatening and requires immediate hospitalization. Blood transfusions. According to scientists at the Mayo Clinic: [1,2] Although not a cure for aplastic anemia, blood transfusions can control bleeding and relieve symptoms by
providing blood cells your bone marrow isn't producing. You might receive: Red blood cells. These raise red blood cell counts and help relieve anemia and fatigue. Platelets. These help prevent excessive bleeding. While there's generally no limit to the number of blood transfusions you can have, complications can sometimes arise with multiple transfusions. Transfused red blood cells contain iron that can accumulate in your body and can damage vital organs if an iron overload isn't treated. Medications can help rid your body of excess iron. Over time your body can develop antibodies to transfused blood cells, making them less effective at relieving symptoms. The use of immunosuppressant medication makes this complication less likely.
Immunosuppressants. According to scientists at the Mayo Clinic: [2,3] For people who can't undergo a bone marrow transplant or for those whose aplastic anemia is due to an autoimmune disorder, treatment can involve drugs that alter or suppress the immune system (immunosuppressants). Drugs such as cyclosporine (Gengraf, Neoral, Sandimmune) and anti-thymocyte globulin suppress the activity of immune cells that are damaging your bone marrow. This helps your bone marrow recover and generate new blood cells. Cyclosporine and anti-thymocyte globulin are often used together. Corticosteroids, such as methylprednisolone (Medrol, Solu-Medrol), are often used with these drugs. Although effective, these drugs further weaken your immune system. It's also possible for anemia to return after you stop these drugs.
Antithymocyte globulin (ATG) and cyclosporine (combined or intensive immunosuppression). For aplastic anemia that is severe, as defined by peripheral-blood counts, definitive therapies are immunosuppression or stem-cell transplantation; immunosuppressive therapies are most widely used because of lack of histocompatible sibling donors, patient age, and the immediate cost of transplantation. Even in responding patients, blood counts often remain below normal but adequate to avoid transfusion and to prevent infection. Most specialists use an ATG-based regimen in combination with cyclosporine, based on the outcomes of relatively large studies performed in the 1990s (Table 1). The larger experience is with ATG produced in horses, although a rabbit ATG, recently approved for use in the United States, is more potent by weight and in the treatment of graft rejection after solid organ transplantations (a current NIH trial is directly comparing these 2 ATGs as first therapy in severe aplastic anemia). ATG is cytolytic: lymphocyte numbers consistently decline during the first few days of infusion and then return to pretreatment levels in a week or 2. ATGs are produced by immunizing animals against human thymocytes, not lymphocytes, and the mix of antibody specificities plus direct experimentation suggests that ATG may be immunomodulatory as well as lymphocytotoxic, perhaps producing a state of tolerance by preferential depletion of activated T cells. The toxicity of ATG is allergic, related to administration of a heterologous protein, and there is little added infection risk beyond the neutropenia intrinsic to the disease. ATG doses and regimens are empiric and traditional. By administration of a larger dose over fewer days, immune complex formation and consequent serum sickness are minimized, as patients usually do not produce their own antibodies to the foreign protein until a week or 10 days after exposure [4].
Only studies of more than 20 enrolled patients are tabulated. Responses to immunosuppressive therapy are usually partial; blood counts may not become normal but transfusions are no longer required and the neutrophil count is adequate to prevent infection. Relapse is usually responsive to further immunosuppressive therapies. Clonal evolution is to dysplastic bone marrow changes and/or cytogenetic abnormalities. For details, see "Immunosuppression"
* With androgens and ± G-CSF; t With mycophenolate mofetil.
Table 1. Intensive immunosuppression (ATG plus cyclosporine) for severe aplastic anemia.
Cyclosporine's selective effect on T-cell function is due to direct inhibition on the expression of nuclear regulatory proteins, resulting in reduced T-cell proliferation and activation. While severe aplastic anemia can respond to cyclosporine alone, it is less effective than either ATG alone or ATG plus cyclosporine. [5,6] As with ATG, doses and length of treatment have not been formally established. Cyclosporine has many side effects, but most are manageable by dose reduction; permanent kidney damage is unusual with monitoring (to maintain blood levels at nadir of about 200 ng/mL). Maintenance of blood counts may be achieved with very low doses of cyclosporine, such that drug levels in blood are undetectable and toxicity is minimal, even with years of treatment.
Outcomes of combined immunosuppressive therapy. Reported hematologic response rates vary, at least in part due to lack of consensus on parameters (transfusion independence, absolute or relative improvement in blood counts) and defined landmarks. In our experience, improvement of blood counts so that the criteria for severity are no longer met highly correlates with termination of transfusions, freedom from neutropenic infection, and better survival. By this standard, about 60% of patients are responders at 3 or 6 months after initiation of horse ATG. [8] Comparable figures for hematologic response rates have come from Europe [7] and Japan. [9] Responders have much better survival prospects than do nonresponders. Long-term prognosis is predicted by the robustness of the early blood count response (defined as either platelets or reticulocytes > 50 x 109/L [50 000/^L] 3 months after treatment): about 50% of patients who are treated with horse ATG have a robust response and almost all of them will survive long term. Outcomes of immunosuppressive therapy are related to patient age: 5-year survival of more than 90% of children has been reported in recent German, [10] Japanese, and Chinese [11] trials, compared with about 50% survival for adults older than 60 years in the collective European experience [12].
Relapse, defined conservatively as a requirement for additional immunosuppression and not necessarily recurrent pancytopenia, is not uncommon, occurring in 30% to 40% of responding patients. Relapse defined by renewed need for transfusion was estimated at 12% of European patients at 3 years, but prolonged cyclosporine dependency among all patients was common. [7] Reinstitution of cyclosporine usually reverses declining blood counts, but when required, a second round of horse [13] or rabbit [14] ATG is usually effective. In our experience, relapse does not confer a poor prognosis, but it is obviously inconvenient and may not always be remediable. Molecular analysis of the T-cell response in aplastic anemia, discussed in "Pathophysiology," suggests that the major reason for relapse is incomplete eradication of pathogenic clones by ATG.
More serious than relapse is evolution of aplastic anemia to another clonal hematologic disease, PNH, myelodysplasia, and leukemia. Small PNH clones present at diagnosis usually remain stable over time but may expand sufficiently to produce symptomatic hemolysis. For myelodysplasia and leukemia, the cumulative long-term rate of clonal evolution is about 15%; [15] evolution is not inevitable in aplastic anemia, and some cytogenetic abnormalities may be transient or, as with trisomy 8, responsive to immunosuppressive treatments. As discussed in "Clonal evolution," emergence of monosomy 7 may be favored in severely neutropenic patients who require chronic G-CSF therapy.
Improving on ATG and cyclosporine.Growth factors. Historically, intensification of immunosuppression has increased response rates. However, attempts to improve on ATG plus cyclosporine have been frustratingly disappointing. Megadoses of methylprednisolone only added toxicities. Small pilots of GM-CSF [16] and much larger, randomized studies of G-CSF [9,17] as routine additions to ATG and cyclosporine have been negative to date; improved neutrophil counts did not translate into a higher rate of recovery or even less infection. A very large ongoing European study of G-CSF should definitively answer efficacy and safety concerns.
Other immunosuppressive drugs. As the addition of cyclosporine clearly improved outcomes compared with the use of ATG alone, other immunosuppressive drugs might be predicted, based on their mode of action, animal studies, and experience in other human diseases and with organ transplantation, to be effective. Mycophenolate mofetil is a tolerizing agent, as it selectively depletes activated cells by inhibition of inosine monophosphate dehydrogenase, a critical enzyme of the purine salvage pathway, therefore blocking activated lymphocyte proliferation. Nonetheless, its addition to ATG and cyclosporine in an NIH trial of 104 patients did not change hematologic response (about 62%), relapse (37%), or evolution rates; at best, there was a modest sparing of cyclosporine usage. The 4-year survival rate for all treated patients was 80%—almost certainly due to better supportive care rather than any new drug effect. Sirolimus, which blocks the serine-threonine kinase known as mammalian target of rapamycin is synergistic with cyclosporine in tissue culture and in clinical transplantation. Again, when tested in a randomized protocol in combination with ATG and cyclosporine in aplastic anemia, results were not superior to these agents only.
Cyclophosphamide. As with ATG, recovery of blood counts can occur after a failed bone marrow transplantation preceded by conditioning with cyclophosphamide. High-dose cyclophosphamide was used intermittently by investigators at Johns Hopkins University (Baltimore, MD) in the 1980s during periods in which ATG apparently was not available to them; in their most recent update, of 38 previously untreated patients, the response rate was 74% and survival estimated at 86% [18,19]. In contrast, an NIH randomized study was halted early due to the development of fungal infections and a much higher death rate in the cyclophosphamide arm, and both relapse and cytogenetic evolution were observed. The major toxicity of high-dose cyclophosphamide, prolonged neutropenia with concomitant susceptibility to infection, is now addressed by the Baltimore investigators by routine antimicrobial prophylaxis and prolonged G-CSF administration. Cyclophosphamide therapy does not eradicate PNH clones, and relapses now have been observed in Baltimore. [19] In the absence of another randomized trial, comparison of data from a small, singlecenter pilot with historical and more general results is problematic; it is especially difficult to exclude biased patient selection, both explicit (such as exclusion of those unlikely to respond or with a generally poor prognosis or older patients) and implicit (inability to treat uninsured individuals or foreign citizens).
Stem cell transplant. According to scientists at the Mayo Clinic: [20] A stem cell transplant to rebuild the bone marrow with stem cells from a donor might be the only successful treatment option for people with severe aplastic anemia. A stem cell transplant,
also called a bone marrow transplant, is generally the treatment of choice for people who are younger and have a matching donor — most often a sibling. If a donor is found, your diseased bone marrow is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected intravenously into your bloodstream, where they migrate to the bone marrow cavities and begin creating new blood cells. The procedure requires a lengthy hospital stay. After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells. A stem cell transplant carries risks. Your body may reject the transplant, leading to life-threatening complications. In addition, not everyone is a candidate for transplantation or can find a suitable donor.
[21] Daratumumab is an effective and safe therapeutic option for treatment of PRCA post-transplant. Earlier use of daratumumab should be considered to prevent repeated blood transfusions and unnecessary exposure of other less effective therapies thereby minimizing toxicity.
According to a group of scientists: [22] Aplastic anemia encompasses a heterogeneous group of diseases with distinct pathophysiologies and a common clinical endpoint of marrow failure. Patients with severe aplastic anemia can be treated with immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT). Over the last 30 years, advances in both treatment modalities have significantly improved the prognosis for this disease; yet this evolution complicates the central therapeutic question in aplastic anemia: which patients should receive IST and which ones should receive HSCT as front-line therapy? In this review, we describe the major improvements that have occurred in transplantation for aplastic anemia in the last 3 decades. We then outline a framework for deciding which patients should be considered for upfront transplantation. And according to their conclusion: [22] The last 30 years have brought great progress both in our understanding of AA and in its treatment, so much so that the majority of patients can be cured with current therapies. Nonetheless, choosing the right treatment for an individual patient is a challenging task that begins with ruling out the presence of an inherited marrow failure syndrome. For patients with acquired severe AA, the choice of treatment depends principally on the patient's age and the availability of a matched donor. Assuming transplantation eligibility, we would consider this modality as front-line therapy for any patient with an available syngeneic donor, for patients up to the age of 55 or so with a matched sibling donor, and for patients up to the age of 21 or so with an allele-level HLA-matched unrelated donor. For all other patients, we would recommend IST as initial treatment. If history is a guide, the coming years will bring new developments in this field, requiring further reexamination of this question, and will continue to improve the prognosis of patients with this fascinating disease.
Conclusion: In conclusion, aplastic anemia is a very dangerous and topical disease, and there are still a number of difficulties in its treatment. Nevertheless, this article has shed some light on the treatment of this type of anemia and the difficulties in this process. We hope that more in-depth research will be conducted in this regard.
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