Aplastic Anemia Treatment & Management

Aplastic anemia has a mortality rate of greater than 70% with supportive care alone. It is a hematologic emergency, and care should be instituted promptly.

The specific medications administered depend on the choice of therapy and whether it is supportive care only, immunosuppressive therapy, or BMT.

Inpatient care for patients with aplastic anemia may be needed during periods of infection and for specific therapies, such as antithymocyte globulin (ATG) or BMT.

As previously stated, with immunosuppression, aplastic anemia in approximately one third of patients does not respond. For the responders, relapse and late-onset clonal disease, such as PNH, MDS, and leukemia, are risks.^{[8, 21, 22, 23, 24]}

Go to Anemia, Chronic Anemia, Megaloblastic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

Transfer considerations

Patients with aplastic anemia should be treated by physicians who are experts in the care of immunocompromised patients and in consultation with a BMT physician for patients younger than age 65 years.

Diet, activity, consultations, and follow-up

The diet for the patient with aplastic anemia who has neutropenia or who is receiving immunosuppressive therapy should be tailored carefully to exclude raw meats, dairy products, or fruits and vegetables that are likely to be colonized with bacteria, fungus, or molds. Furthermore, a salt-limited diet is recommended during therapy with steroids or CSA.

The patient should avoid any activity that increases the risk of trauma during periods of thrombocytopenia.

The risk of community-acquired infections increases during periods of neutropenia.

Consult a hematologist and/or a BMT specialist.

Frequent outpatient follow-up of patients with aplastic anemia is needed to monitor blood counts and adverse effects of various drugs.

Transfusions of packed RBCs and platelets are administered on an outpatient basis.

Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted.

For patients in whom BMT may be attempted, transfusions should be used judiciously, because minimally transfused subjects have achieved superior therapeutic outcomes.

Avoiding transfusions from family members is important because of possible sensitization against non-HLA tissue antigens of the donors.

In considering blood-bank support, attempt to minimize the risk of CMV infection. If possible, the blood products should undergo leukocyte reduction to prevent alloimmunization and CMV transmission, and they should be irradiated to prevent alloimmunization as wells as transfusion-associated graft versus host disease (GVHD) in BMT candidates.

Judicious use of blood products is essential, and transfusion in conditions that are not life threatening should be performed in consultation with a physician who is experienced in the management of aplastic anemia.

Infections are a major cause of mortality.^{[27, 28]}

Risk factors include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal infections, especially those due to Aspergillus species, pose a major risk.

Empirical antibiotic therapy should be broad based, with gram-negative and staphylococcal coverage based on local microbial sensitivities. Especially consider including antipseudomonal coverage at the start of treatment for patients with febrile neutropenia, and consider early introduction of antifungal agents for those with persistent fever.

Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections, although this therapy should be weighed against cost and efficacy.^{[2, 29, 30, 31]}

Central venous catheter placement is required before the administration of BMT.

Bone marrow transplantation using an HLA-matched sibling donor

HLA-matched sibling-donor BMT is the treatment of choice for a young patient with SAA (controversial but generally accepted for those aged < 40 y).

One of the major problems of BMT in aplastic anemia is the high (10%) rate of rejection (range, 5-50%), and this is positively correlated with the number of transfusions and duration of disease before undergoing transplantation.

For the initial few years, the conditioning regimen used was only cyclophosphamide. These transplantations were complicated by almost 35% risk of graft rejection (35%).^{[32, 33]} A major risk factor for graft rejection was prior transfusion therapy.^{[34, 35]} The conditioning regimen as well as transfusion practices were modified subsequently to eliminate graft rejections. The practice of using only irradiated blood products significantly lowered graft rejection.^[36]

A higher stem cell dose, as well as the addition of total body irradiation to cyclophosphamide conditioning, were tried and were associated with a reduced incidence of graft rejection, but the benefit was negated by high transplant-related mortality (TRM) because of more graft versus host disease (GVHD). The addition of ATG to cyclophosphamide for conditioning resulted in infrequent graft rejections as well as improved overall survival.^{[10, 29, 30, 37]} Thus, currently, ATG with cyclophosphamide is a commonly used conditioning regimen for transplantations in aplastic anemia.

Fludarabine- and cyclophosphamide-based reduced intensity conditioning (RIC) regimens +/– ATG reduced rejection and improved outcome in Indian patients undergoing allogeneic stem cell transplantation for SAA.^[38] When compared with 26 patients previously transplanted using cyclophosphamide/antilymphocyte globulin, there was faster neutrophil engraftment (12 vs 16 days), with significantly lower rejection rates (2.9% vs 30.7%) and a superior event-free (82.8% vs 38.4%) and overall survival (82.8% vs 46.1%) rate.^[38]

The occurrence of GVHD as a complication of BMT is positively correlated with increasing age of the patient. Grafts depleted of T cells reduce the risk of GVHD but increase the risk of graft failure.

The addition of CSA along with methotrexate has substantially reduced the incidence of GVHD.^[37]

Bone marrow transplantation using an unrelated donor

BMT using an unrelated donor was associated with very high mortality due to the high rate of graft failure and GVHD. Most of earlier papers reported a 5-year survival rate of only 29-36% after unrelated transplantation. This poor outcome was mainly due to less stringent HLA matching. Recent reports suggest a better outcome after unrelated transplants, and this improvement is mainly due to high-resolution HLA testing, optimization of the conditioning regimen, and better supportive care, as well as better management of GVHD. A recent retrospective study of comparative data from Japan indicated similar overall survival in children and young adults with aplastic anemia who received transplants from either a sibling or an unrelated donor, although rates of acute and chronic GVHD were significantly higher in the group receiving unrelated transplants.^[39] Due to significantly higher rates of GVHD, unrelated donor transplants are still not preferred over immunosuppressive therapy.

Unrelated-donor BMT is currently justified only if the donor is a full match and only if immunosuppressive therapy or treatment as part of a clinical trial fails. Early referral to a transplantation center at diagnosis is recommended in all young patients, even if they lack a suitable related donor.^[11]

Increased graft rejection and increased GVHD remain obstacles to success for unrelated-donor BMT for patients with SAA.^[17]

The probability of graft failure at 100 days after using a 1-antigen mismatched, related donor was 21%, while the probability was 25% for a greater-than-1-antigen mismatched, related donor; 15% for a matched, unrelated donor; and 18% for a mismatched, unrelated donor.^[11]

Partial T-cell depletion may decrease the risk of severe GVHD while still maintaining sufficient donor T lymphocytes to ensure engraftment.^[17]

In unrelated-donor transplantation, radiation, along with cyclophosphamide, may be used to reduce graft rejection. Fludarabine-based conditioning regimens have been tried,^[18] along with ATG and cyclophosphamide.

Unrelated-donor BMT using high resolution allelic matching has improved outcome, especially in younger patients.

A study by Maury et al indicated that the survival of patients after unrelated-donor stem cell transplantation for SAA has improved significantly in the past 15 years mainly because of better HLA matching. Maury et al found that results for young patients who are fully HLA-matched at the allelic level with their donor are comparable to those observed after stem cell transplantation from a related donor.^[40] An earlier Japanese study appeared to reach a similar conclusion.^[41]

A study by Chan et al suggested that unrelated-donor BMT is a feasible treatment strategy for children with refractory SAA who lack a well-matched, adult donor.^[16] The investigators evaluated 9 children with refractory SAA (all had had at least 1 unsuccessful course of immunosuppression) who underwent such a transfusion with increasingly immunosuppressive preparative regimens.

Donor/recipient HLA matching was 6 of 6 (n = 1), 5 of 6 (n = 2), and 4 of 6 (n = 6). The median nucleated cell dose infused was 5.7 x 10⁷ cells/kg (range 3.5-20 x 10⁷ cells/kg). Six patients were engrafted after the first unrelated-donor BMT, and 2 of the 3 patients without hematopoietic reconstitution were engrafted after a second transfusion. All children who received 120 mg/kg or more of cyclophosphamide in the preparative regimen were engrafted. The median time to myeloid engraftment was 25 days.^[16]

Two patients developed acute GVHD, and 5 developed chronic GVHD. Five patients developed EBV viremia posttransplant (lymphoproliferative disorder in 3 patients). At a median follow-up of 34 months, 7 patients were alive and transfusion independent.^[16]

In current practice, umbilical cord blood transplantation (CBT) constitutes approximately 10% of unrelated donor transplants for aplastic anemia. Cord blood lymphocytes are naïve, and allotransplantation with HLA disparity is feasible without a significantly higher rates of GVHD. CBTs have also been used for malignant diseases, with encouraging results. Results of CBT in aplastic anemia are not encouraging owing to high rates of graft failure, and the 2-year overall survival rate is approximately 40% in most of the reported case series. An acceptable way of HLA matching for CBT is serological testing for HLA-A and HLA-B (class 1) and allele-level matching for DRB1 (class 2). Out of these 6 antigens, up to 2-antigen mismatch is acceptable in most of data. Important determinants of successful engraftment are HLA matching and cell dose.

CBT is not yet recommended as first- or second-line therapy and should be used as experimental therapy for patients who do not have an HLA-matched donor and have failed 1-2 courses of immunosuppressive therapy. Controlled trials are needed to better define the role and timing of CBT in aplastic anemia.^{[42, 43, 44]}

Immunosuppressive therapy (IST) using antithymocyte globulin (ATG) and cyclosporine-A (CSA) is associated with an overall response rate of 60-80% and a 5-year survival rate of 75% in most of reports, but event-free survival rates are in range of 35-50%.

ATG has 2 origins, horse and rabbit. Most of the data are with horse ATG as first-line IST for aplastic anemia although now rabbit ATG is being increasingly used in certain parts of world; although data are scarce for its first-line use. However, a study by Scheinberg et al involving 120 patients with aplastic anemia may influence this trend. Participants were randomized in a 1:1 ratio to receive either horse-derived or rabbit-derived ATG. The primary end point was hematologic response at 6 months, which was defined as no longer meeting severe aplastic anemia criteria. Secondary end points included robustness of hematologic recovery, relapse, response rate both at 3 months and annually, clonal evolution, and overall survival.^[45]

A large difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56-80) as compared with rabbit ATG (37%; 95% CI, 24-49; P< 0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90-100) in the horse-ATG group compared with 76% (95% CI, 61-95) in the rabbit-ATG group (P = 0.04) when data were censored at the time of stem-cell transplantation and 94% (95% CI, 88-100) compared with 70% (95% CI, 56-86; P = 0.008) in the respective groups when stem-cell–transplantation events were not censored.

In other studies of ATG, responses have been defined as complete responses (CRs)when all blood counts return to normal , and partial responses (PRs), have been defined as improvement in blood counts with transfusion independence. In these analyses, response to ATG is slow, and it usually takes 3-6 months for a response to occur. If patient has not responded to a first course of ATG, then a second course may be given 4-6 months after the first course, using either the same preparation or another one. Of patients, 30-60% may even respond to a second course of ATG.

IST using ATG plus CSA is being used as first-line therapy for patients older than 40 years and as second-line therapy in younger patients if a matched sibling donor is not available. Central venous catheter placement is required before the administration of IST. Patients also require intense platelet support during ATG therapy.

In one study, response rates to CSA alone were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate aplastic anemia.^[46] Therefore, the only predictor of response to CSA was an absolute neutrophil count (ANC) of less than 200/mm³. Adding G-CSF to ATG and CSA in patients with an ANC of over 200/mm³ does not produce any additional advantage in reducing the infection rate or in increasing survival or therapeutic responses.

The response in aplastic anemia, unlike in other autoimmune diseases, is slow. At least 4-12 weeks is usually needed to observe early improvement, and the patient continues to improve only slowly thereafter. About 50% of patients respond by 3 months after ATG administration, and about 75% respond by 6 months. Most patients improve and become transfusion independent, but many still have evidence of a hypoproliferative bone marrow.

Although the initial response rate is good, relapses are common, and continued immune suppression is often needed. Approximately one third of patients have a relapse, most of whom have a relapse at the time of CSA taper. About one third of responders are CSA dependent. Of patients whose conditions have no response or who relapse, 40-50% respond to a second course of immunosuppressive therapy.

In rare cases, full hematologic recovery is observed, but most patients improve to a functional hematologic recovery that obviates further transfusion support. Furthermore, the risk of some form of clonal disease other than PNH is 15-30% and may be due to the inability of these therapies to completely correct bone marrow function, due to a missed diagnosis of MDS, or due to the fact that the stem cells under proliferative stress may be more prone than other cells to mutation.

Preliminary data suggested that high-dose cyclophosphamide may result in durable remissions in some patients with aplastic anemia. However, some of these patients develop PNH and cytogenetic abnormalities on follow-up. Based on this preliminary report, a prospective randomized study was conducted using cyclophosphamide versus ATG plus CSA. This study was terminated early because of very high mortality and fungal infections in the cyclophosphamide arm.^{[47, 48]} At present, the use of high-dose cyclophosphamide should be limited to clinical trials.

Other promising investigational IST include alemtuzumab (monoclonal anti CD52 antibody) and daclizumab (anti-interleukin 2 receptor or CD-25 antibody). Mycophenolate mofetil and sirolimus were also used, but without responses.