What happens when ATG is given over a long period?
If a skin reaction occurs, the infusion of ATG is typically given over a longer period of time or a desensitization to ATG may be performed ATG can potentially cause a condition known as serum sickness. A corticosteroid such as prednisone is typically given during the first 10 days of treatment to help prevent serum sickness.
Is a complete ATG course possible with this approach?
With this approach, a complete ATG course is accomplished in nearly all patients in our experience. Cyclosporine.
How long does it take for platelets to return after ATG?
The majority of responses (90%) occur within the first 3 months, with fewer patients responding between 3 and 6 months or after. 99 After ATG treatment, the threshold for prophylactic platelet transfusion is reduced to 10 000/μL (or for bleeding).
How many doses of ATG are in a course of treatment?
Only one treatment course (a total of 4 doses) with ATG is usually given. ATG is often given in the hospital, but can be given in an outpatient infusion center (if well-tolerated), allowing the person to go home afterwards. Cyclosporine may be taken in the hospital or at home.
How often do aplastic anemia patients need blood transfusions?
In SAA patients, transfusions may be required more than once per week [33]. The reliance on blood transfusions has been found to impact quality of life due to the time required, inconvenience, and the risk of side effects in patients with SAA as reported through patient focus group discussions.
What is the success rate of ATG treatment?
Immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine is the standard treatment for patients with severe aplastic anemia who do not have a human leukocyte antigen-matched related donor; it leads to a response rate of 60 to 70%.
Can aplastic anemia go into remission?
Results: Eighteen (13%) of 136 patients satisfied the criteria for spontaneous remission at median 14 days (range, 4-332) from the diagnosis of aplastic anemia. In fifteen (83%) of 18 patients, spontaneous remission occurred within 50 days. Spontaneous remission was complete in fourteen patients (78%).
What lab value is high in aplastic anemia?
Aplastic anemia is suspected in patients, particularly young patients, with pancytopenia. Severe aplastic anemia is defined by a bone marrow with < 30% cellularity (hypocellularity) and the presence of ≥ 2 of the following: Absolute neutrophil count < 500/microL (< 0.5 × 10 9/L)
Can ATG cure aplastic anemia?
Anti-Thymocyte Globulin (ATG) ATG is approved in the U.S. to treat acquired aplastic anemia and to reduce the chance of organ rejection after a kidney or other organ transplant. It may also be used to treat MDS or reduce rejection after a bone marrow transplant.
How long does aplastic anemia last?
Aplastic anemia is a life-threatening condition with very high death rates (about 70% within 1 year) if untreated. The overall five-year survival rate is about 80% for patients under age 20. In recent years, the long-term outcomes of aplastic anemia patients have been continuously improving.
Can aplastic anemia relapse?
The cumulative incidence of relapse was 11.9% at 10 years and the median time from diagnosis to relapse was 21 months (range, 6 to 138 months). The median time from response to antithymocyte globulin therapy to relapse was 22 months (range, 2 to 135 months).
Is aplastic anemia serious?
Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells. The condition leaves you fatigued and more prone to infections and uncontrolled bleeding. A rare and serious condition, aplastic anemia can develop at any age.
What is remission in aplastic anemia?
A remission is a partial or complete disappearance of the symptoms and characteristics of a disease, usually as a result of treatment. A complete remission means that there is no evidence of the disease. A partial remission means that the disease has improved, but the symptoms and characteristics of the disease remain.
What is the lowest WBC count?
The definition of low white blood cell count varies from one medical practice to another. In general, for adults a count lower than 4,000 white blood cells per microliter of blood is considered a low white blood cell count. For children, that threshold varies with age.
Is hemoglobin low in aplastic anemia?
Aplastic anemia occurs when your bone marrow doesn't make enough red and white blood cells, and platelets. Having fewer red blood cells causes hemoglobin to drop.
Does aplastic anemia cause low white blood cell count?
In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). Symptoms of aplastic anemia are those of anemia, bleeding, and infection.
Why use G-CSF after ATG?
The rationale for using G-CSF after ATG + CSA is to attempt to reduce the risk of infection during the 3 months before neutrophil response is expected and to possibly improve response. However, prolonged use of growth factors may increase the risk of late clonal disorders, as shown by a retrospective EBMT WPSAA study. 39 No study has ever shown an increase in trilineage response by the use of G-CSF. In a prospective Japanese study, the risk of relapse after response was decreased in the G-CSF arm. In a recent EBMT study, the association of ATG + CSA with G-CSF was associated with higher neutrophil counts, and less infection and hospitalization for the duration of G-CSF administration. 19 Given these conflicting data, the EBMT WPSAA currently recommends to limit the use of G-CSF after ATG + CSA to patients with neutropenic infection.
What is aplastic anemia?
Aplastic anemia (AA) is defined as pancytopenia with a hypocellular marrow. The incidence of acquired AA in the Western hemisphere is around 2 per million population per year and higher in East Asia. Age distribution shows peaks in children and young adults and again in patients age > 60 years. AA is, in most cases, an acquired autoimmune disorder; congenital AA is not the topic of this review. Patients with AA commonly present with anemia and hemorrhage and, more rarely, neutropenic infection. Severe AA (SAA) is defined by at least two of the following: reticulocytes < 50 × 10 9 /L (or 20 × 10 9 /L by manual counting), platelet count < 20 × 10 9 /L, and neutrophil count < 0.5 × 10 9 /L. In very severe SAA (vSAA) neutrophil counts are < 0.2 × 10 9 /L. Often, the diagnosis is not very clear at the outset. Marrow cellularity is not always easy to assess and varies with age (ie, a normocellular marrow in an octagenerian is considered hypocellular in a child). In healthy older patients, subcortical marrow tends to be acellular. In general hypocellularity by biopsy is more reliable than by cytology. Patients may require more than one biopsy to confirm the diagnosis. Treatment decisions are complex; a watch and wait strategy is often used initially in a case of unexplained pancytopenia, but an interval from diagnosis to treatment of more than 1 to 2 months may be associated with worse outcome. 1 Prior to treatment, the patient should be stable in terms of controlling bleeding and treating infection. Spontaneous recovery is rare. Once the patient is clinically stable, the disease is confirmed, disease severity is assessed, and family typing done. It is usually time to initiate treatment rapidly.
What blood transfusions are needed for AA?
Red cell and platelet transfusions are essential for patients with AA to maintain safe blood counts. Platelet transfusions should be given prophylactically when platelet count is < 10 × ·10 9 /L or < 20 × ·10 9 /L in the presence of fever. A common problem in multitransfused patients with AA is that they may develop alloimmunization to leukocytes present in red cell and platelet transfusions by generating anti HLA- (or non-HLA) antibodies. This can result in platelet refractoriness, as well as an increased risk of graft rejection after allogeneic BMT. Apart from transfusional support, practical measures to help prevent bleeding include dental hygiene, oral tranexamic acid, and control of menorrhagia with progestagens. Although there are no data on transfusion-induced GVHD in recipients of IST, experts recommend to universally use irradiated blood products during and after ATG therapy. 37 There is, however, no consensus for how long after treatment to maintain this recommendation.
What is the survival rate of IST?
IST, using the combination of ATG + CSA, is associated with response rates of 60% to 80%, with current 5-year survival rates of around 75% . 12–16 Survival is better in younger than in older patients, as shown in Figure 4. Response definition includes a confirmation by two or more blood counts at least 4 weeks apart, in patients not receiving growth factors. Partial response is defined by transfusion independence, whereas normalization of blood counts is required for complete remission. 17 Following ATG + CSA, patients should be followed for response, relapse, and late clonal disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and acute myeloid leukemia. There are no good predictors of response to IST, although a recent study by the National Institutes of Health (NIH) has shown that response at 6 months is associated with age, absolute reticulocyte count, and absolute lymphocyte count. 18 In a recent EBMT study randomizing patients between concomitant treatment with G-CSF versus none, neutrophil response to G-CSF was associated with better survival in a post-hoc analysis. 19 These factors are interpreted as reflecting disease severity moreso than the true autoimmune nature of the disease. Patients failing a first course of IST or relapsing after initial response may respond to a second course. 20, 21 A second course should not be initiated earlier than 4 to 6 months after the first course, because it usually takes more than 3 months before a response occurs. There is a 30% to 60% chance of response to a second course. There are patients refractory to two courses of IST who will not respond to a 3 rd and who are considered true IST refractory cases. 22 In these patients, the pathophysiology of the disease may be different, although there are no tools at this point in time to distinguish them from responding AA patients. Early identification of IST refractory cases is obviously needed, because these patients may be treated by other means (eg, alternative donor stem cell transplantation).
What is rabbit antithymocyte globulin?
Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimula ting factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia.
Can androgens be used for AA?
Androgens were used extensively in the treatment of AA for many decades before the availability of immunosupressants. In some patients, oxymetholone can stimulate erythropoiesis and rarely can produce a trilineage response; recent work has shown that androgens increase telomerase by indirect upregulation of the TERT (telomere reverse transcriptase) promoter. 40 In combination with ATG, they increase response, but are hepatotoxic. Because of virilization, they are often unacceptable to women. The value of androgens in this disease, especially in refractory patients who are not candidates for alternative donor transplantation, needs to be reassessed in the current era.
How has survival in severe aplastic anemia improved?
Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute.
What is the standard initial IST for horses?
Standard initial IST is horse ATG and CsA, which produces hematologic recovery in 60% to 70% of cases and excellent long-term survival among responders, as shown in several large prospective studies in the United States, Europe, and Japan. 1, 62-66 Despite the use of different horse ATG preparations, the rates, time course, and patterns of hematologic recovery have been consistent across studies, which argues against significant lot variations affecting outcomes. As the addition of CsA to ATG increased the hematologic response rate, further attempts have been made to intensify immunosuppression and thus improve on this standard regimen. The addition of mycophenolate mofetil, 67 growth factors, or sirolimus 68 to horse ATG/CsA did not improve rates of response, relapse, or clonal evolution ( Table 2 ). The use of tacrolimus as an alternative to CsA has not been systematically examined in SAA, and the experience is limited to case reports and small case series that suggest activity. 69, 70
What is the pathophysiology of marrow cell destruction?
The pathophysiology responsible for marrow cell destruction and peripheral blood pancytopenia has itself been inferred from the results of treatment in humans, with substantial in vitro and animal model support. The reader is referred to more didactic textbook chapters and formal reviews on these topics. 1-4 The success of HSCT in restoring hematopoiesis in SAA patients implicated a deficiency of HSCs. Hematologic improvement after immunosuppressive therapy (IST), initially in the context of rejected allogeneic grafts and then in patients receiving only IST, implicated the immune system in destruction of marrow stem and progenitor cells. Immune-mediated marrow failure can be modeled in the mouse by the “runt” version of GVHD, with HSC depletion and hematopoietic failure induced by infusion of lymphocytes mismatched at major or minor histocompatibility loci. 5, 6
What does marked hemophagocytosis mean?
Marked hemophagocytosis, obvious dysplasia, or increased blasts indicate other diseases, although differentiation of hypocellular myelodysplastic syndrome (seen in ∼ 20% of myelodysplastic syndrome [MDS] cases) from aplastic anemia can be difficult.
Is aplastic anemia a thrombocytopenia?
For aplastic anemia patients who present with thrombocytopenia alone, standard therapies for immune thrombocytopenia are usually ineffective, and eventually a diagnosis of marrow failure follow s from the finding of a hypocellular marrow with reduced megakaryocytes.
Is severe aplastic anemia fatal?
Until the 1970s, severe aplastic anemia (SAA) was almost uniformly fatal, but in the early 21st century most patients can be effectively treated and can expect long-term survival. Nevertheless, making a diagnosis and selecting among treatment options are not straightforward, and both physicians and patients face serious decision points at the outset of their disease to years after its presentation. We summarize our approach to SAA, with recommendations based on decades of experience in the clinic as well as a critical review of the literature. Unfortunately, as a rare disease, there are few large trials of any kind and even fewer randomized controlled studies, which usually provide the best evidence to guide practice in the clinic.
Is peripheral blood a source of stem cells?
In general, mobilized peripheral blood as a source of stem cells for transplant ation has supplanted bone marrow because of higher stem cell doses and donor and physician preference because of ease of collection. Distinctively in SAA, peripheral blood stem cell results have been inferior to grafts of bone marrow origin. In a retrospective analysis, the rate of chronic GVHD was greater with peripheral blood (27%) compared with bone marrow stem cell grafts (12%) in patients younger than 20 years. 38 In a subsequent retrospective analysis, similar higher rates of chronic GVHD were observed for patients of all ages undergoing HSCT with peripheral blood compared with bone marrow derived stem cell grafts. 39 For unrelated donor transplants, bone marrow source of stem cells was associated with lower rates of acute GVHD (31%) compared with peripheral blood-derived CD34 + cells (48%), and better overall survival (76% vs 61%, respectively). 40 In contrast to allogeneic transplantation undertaken for malignancies, where GVHD may offer graft-versus-tumor benefits, in SAA GVHD is unequivocally to be avoided, and its occurrence decreases survival and long-term quality of life. Thus, except for experimental clinical research, bone marrow is preferred as the source of stem cells in SAA.
How many doses of ATG are given?
Pre-medications and I.V. fluids, such as hydration, may add more time. Only one treatment course (a total of 4 doses) with ATG is usually given.
How long does it take to get ATGAM?
Estimated total infusion time for this treatment: As short as 4 hours, or up to 24 hours for each ATG treatment.
How long does it take for ATGAM to cause nausea?
Serum sickness from ATGAM, when it occurs, is reported to happen within 6 to 18 days of receiving the first dose. Importantly, not all people who experience a side effect from ATGAM (horse) + Cyclosporine (Gengraf® or Neoral®) will experience it in the same way.
How long does it take to infuse antithymocyte globulin?
Antithymocyte globulin (ATG) intravenous (I.V.) infusion over 4 to 24 hours on Days 1, 2, 3, and 4. Cyclosporine (typically 2 to 6 oral capsules) by mouth twice daily. Your dose may need to be changed several times during therapy to achieve the target blood levels of cyclosporine.
What is the purpose of horse antibodies?
The antibodies are collected from the horse, purified, and then used to treat humans with overactive lymphocytes thought to cause aplastic anemia.
How long does it take for a cytosporine to respond to a stem cell transplant?
Although some patients may need to wait longer, the majority of patients have a response within the first 3 months. In some cases, after therapy with Cyclosporine + ATG, a bone marrow transplant (stem cell transplant) may be performed with the goal of cure.
Can ATGAM cause low platelet count?
Ear infection (2%) *A low platelet count may be from having aplastic anemia, however, ATGAM has also been associated with a low platelet count (thrombocytopenia). Platelet transfusions may be needed after receiving ATGAM in order to increase the platelet count and reduce the risk of bleeding.
What is the primary approach to acquired aplastic anemia?
The primary therapeutic approach to acquired aplastic anemia (AA) in older adults differs from the primary approach used in children and younger adults because in the former group, the results of allogeneic bone marrow transplantation (BMT) are less favorable. With increasing age of the patients, immunosuppressive therapy with antithymocyte ...
How old do you have to be to get BMT?
The age limit for the primary choice of BMT has not been fully established, and in patients older than 30–35 years, intense IS may be selected as a first attempt, with BMT used as salvage therapy for non-responders.
What is AA in medical terms?
Typical acquired aplastic anemia (AA) is a disease of young adults, but a second peak in incidence has been reported in the fifth or sixth decade of life. In older adults the differential diagnosis of AA includes hypocellular myelodysplastic syndrome (MDS), which may be difficult to distinguish due to the insufficient marrow cellularity often precluding morphologic evaluation and successful chromosome analysis. As a normal karyotype common in MDS and some elderly cases of AA may represent misdiagnosed MDS, clues to the recognition of MDS include micromegakaryocytes, myeloid dysplasia and residual blasts.
What are the complications of BMT?
Late clonal complications of conservatively treated patients include evolution to myelodysplasia and paroxysmal nocturnal hemoglobinuria and may develop in 20% of the patients. However, BMT also has several sequelae including an increased frequency of solid tumors.
Is cyclosporine better than BMT?
With increasing age of the patients, immunosuppressive therapy with antithymocyte globulin (ATG ) and cyclosporine (CsA) constitutes the primary treatment option and may be better than BMT. There are very few clinical clues as to the selection of patients likely to respond to immunosuppression.
Can AA occur during pregnancy?
Pregnancy seems to predispose to AA but this issue remains controversial. The mechanism that triggers AA in pregnancy remains unclear, but AA often resolves with the termination of pregnancy and can recur during subsequent pregnancies. Even if the initial presentation of AA was not associated with pregnancy, women with a recent history of successfully treated AA should be counseled to not get pregnant. However, successful pregnancies have been described and in the majority of case series most of the women had positive outcomes. 12 The therapy of pregnancy-associated AA depends on the gestational age of the fetus. The baby of a mother with severe AA may delivered, if it is close to term, a measure which may result in improvement. Earlier in pregnancy, supportive measures are most commonly used, but ATG has been also administered to women with severely depressed counts, especially low ANC.
Is AA cytogenetics?
However, in many reports, cases of “AA with abnormal cytogenetics” have often been included . Certain karyotypic abnormalities such as trisomy 8 may be more common in these cases, and cytogenetic evaluation may show only a portion of affected metaphases and likely may just reflect oligoclonal hematopoiesis.
What is the best treatment for aplastic anemia?
Mainstays for treatment for aplastic anemia remain HSCT, the only curative therapy to date, and immunosuppressive therapy (IST). HSCT continues to be the recommended first-line therapy for individuals with severe or very severe aplastic anemia who have a matched sibling donor. 1–4 The upper limit of age for this recommendation has been 40 years, although there is increasing variation in this regard, especially with use of less-aggressive conditioning regimens. Results of matched sibling HSCT have improved over time. A large, recent retrospective review found a significantly inferior overall survival rate of 73% (n = 614) in those patients receiving transplantations between 1991 and 1996 compared with 80% (n = 550) in those receiving transplantations between 1997 and 2002. 24 Survival of children in the latter cohort was even higher at 91%. Indeed, younger age, year of transplantation, and decreased interval from diagnosis to transplantation all contributed to improved outcome in this European registry report. Conditioning regimens for matched sibling HSCT have historically been limited in their reliance on radiation, a trend that has become more pronounced. For example, 24% compared with 8% of matched sibling HSCT incorporated radiation into the conditioning regimen in the above 2 time periods, respectively, and irradiation was inversely correlated with survival. 24 The mainstay of conditioning has remained cyclophosphamide with or without additional agents.
Why is it important to take a history of BM aplasia?
One goal of history taking is to elicit evidence of any drug or toxin exposures that have been associated with BM aplasia.
What are the long term complications of HSCT?
The long-term complications of HSCT (somewhat independent of underlying disease) are increasingly well appreciated, 49 and long term survivors of IST 1, 29 are also at risk for a multiplicity of complications. Some of these complications become obvious only with prolonged followup. Moreover, these data are imperfect because both the characteristics of specific patient cohorts and regimens influence outcome. One might expect that as patients with different diseases, particularly IBMFS, are removed from the “aplastic anemia” cohort and as regimens alter (certainly toward less radiation and potentially to alternative IST), the challenges faced by survivors will also change.
Is HSCT a sibling therapy?
HSCT remains the mainstay of therapy for those with matched sibling donors, and results have improved even further in recent years. For those without a sibling donor, the high response and overall survival rates of combined immunosuppressive therapy (IST) have proven robust.
Is aplastic anemia confined to peripheral blood?
Aplastic anemia remains a disorder confined by conventions that specify a combination of low peripheral blood counts with specific appearances of the BM itself. The most common conventions, modified by severity criteria, are shown in Table 1.
Can BM failure be ascertained?
Unfortunately, no tests permit ascertainment of causal relationships between any specific exposure and subsequent BM failure. From the perspective of the individual patient, any associations therefore remain presumptive, and the utility is simply in removing any ongoing exposure.
Is aplastic anemia a diagnosis of exclusion?
Aplastic anemia remains a diagnosis of exclusion. Our ability to reliably diagnose, and therefore exclude, a variety of inherited or acquired diseases with similar phenotypes has improved markedly. An efficient diagnostic plan is important because time from diagnosis to treatment is related to outcome regardless of the therapeutic option chosen. HSCT remains the mainstay of therapy for those with matched sibling donors, and results have improved even further in recent years. For those without a sibling donor, the high response and overall survival rates of combined immunosuppressive therapy (IST) have proven robust. Nonetheless, incomplete response, relapse, and progression to myelodysplasia/leukemia have more clearly emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Best practices in this regard are not yet clearly established and may vary by a variety of demographic and treatment-specific factors. Regardless of the type of therapeutic approach, patients require ongoing monitoring for occurrence of disease and/or therapy-related side effects.