eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Aplastic Anemia: Treatment & Medication

Author: Sameer Bakhshi, MD, Associate Professor of Pediatric Oncology, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, India
Coauthor(s): Esteban Abella, MD, Consulting Staff, Arizona Pediatric Hematology/Oncology, PLLC
Contributor Information and Disclosures

Updated: Oct 4, 2009

Treatment

Medical Care

• Transfusions
  • Patients with aplastic anemia require transfusion support until the diagnosis is established and until 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 leukopoor reduction to prevent alloimmunization, and they should be irradiated to prevent third-party 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.
• Treatment of infections^24,25
  • Infections are a major cause of mortality.
  • 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 anti-pseudomonal 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.^2,26,27,28
• BMT with 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 <60 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.
  • The conditioning regimen most often used includes a combination of antithymocyte globulin (ATG), cyclosporin (CSA), and cyclophosphamide.^{19,29,30,31,32} The addition of ATG and CSA to the conditioning regimen has resulted in reduction of graft rejection.^8,26,27,33 When radiation was used as part of the conditioning regimen, the incidence of graft rejection was <5%, but the incidence of chronic GVHD, interstitial pneumonitis, and malignant disease was increased; no survival advantage resulted.
  • 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.³⁴ When compared with 26 patients previously transplanted using cyclophosphamide/antilymphocyte globulin, there was faster neutrophil engraftment (12 vs 16 days; P = 0.002) with significantly lower rejection rates (2.9% vs 30.7%; P = 0.003) and a superior event-free (82.8% vs 38.4%; P = 0.001) and overall survival (82.8% vs 46.1%; P = 0.005).³⁴
  • GVHD is a complication of BMT. It 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.³³
• BMT with an unrelated donor
  • BMT with an unrelated donor is associated with a high mortality rate.
  • Unrelated-donor BMT is probably 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.⁹
  • Both increased graft rejection and increased GVHD remain obstacles to success for unrelated-donor BMT for patients with SAA.¹³ The probability of graft failure at 100 days after 1-antigen mismatched related donor was 21% 25% for >1-antigen mismatched related donor, 15% for matched unrelated donor, 18% for mismatched unrelated donor transplants.⁹ Partial T-cell depletion may decrease the risk of severe GVHD while still maintaining sufficient donor T lymphocytes to ensure engraftment.¹³
  • In unrelated-donor transplantation, radiation along with cyclophosphamide may be used to reduce graft rejection. Fludarabine-based conditioning regimens have been tried,¹⁴ 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 the increased survival of patients after unrelated-done stem cell transplantation for SAA has improved significantly in the past 15 years mainly due to 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.³⁵ An earlier Japanese study appeared to have reached a similar conclusion.³⁶
    • A study by Chan et al suggests that unrelated-donor BMT is a feasible treatment strategy for children with refractory SAA who lack a well-matched adult donor.¹² 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 of cyclophosphamide in the preparative regimen were engrafted. The median time to myeloid engraftment was 25 (17-59 days) days.¹²

Two patients developed acute GVHD, and 5 developed chronic GVHD. Five patients developed EBV viremia post transplant (lymphoproliferative disorder in 3 patients). At a median follow-up of 34 months, 7 patients were alive and transfusion independent.¹²

• Immunosuppressive therapy
  • Immune suppression is especially useful if a matched sibling donor for BMT is not available or if the patient is older than 60 years.
  • Options include combination therapy, including ATG, CSA, and methylprednisolone, with or without cytokine support. ATG and CSA alone may also produce a response in aplastic anemia, but the combination improves the likelihood of a response.
  • In 1 study, response rates to CSA alone were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate aplastic anemia.²⁹ Therefore, the only predictor of response to CSA was an absolute neutrophil count (ANC) of <200/mm³. Adding G-CSF to ATG and CSA in patients with an ANC of >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 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% 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. At present, the use of high-dose cyclophosphamide should be limited to clinical trials.

Surgical Care

A central venous catheter placement is required before the administration of immunosuppressive therapy or BMT.

Consultations

Consult a hematologist and/or BMT specialist.

Diet

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.

Activity

• 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.

Medication

The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity, prevent complications, and eradicate malignancy.

Immunosuppressive Agents

The merits of additional immunosuppression versus the increased risk and cost should be considered. Data from a randomized prospective study indicated that an increased proportion of patients responded to the addition of CSA to ATG, but this did not translate into a long-term survival advantage.

For patients who cannot tolerate equine-based products, use of the commercially available rabbit-based ATG product (Thymoglobulin) may be considered. This product is currently approved in the United States and has been used for the treatment of aplastic anemia in Europe (although note the different dose schedule).

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease) for a variety of organs.

For children and adults, base the dosing on the ideal body weight. Frequent monitoring of drug levels is needed. To convert to the PO dose, use a IV-to-PO correction factor of 1:4. Dosage and duration of therapy may vary with different protocols.

Methylprednisolone (Medrol, Solu-Medrol)

Steroids ameliorate the delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis. In severe serum sickness (mediated by immune complexes), parenteral steroids may reduce the inflammatory effects. Hence, used with ATG to decrease the adverse effects (eg, allergic reactions, serum sickness). Also an additional immunosuppressive. High doses or long duration may be needed if serum sickness occurs with ATG. The doses and duration may vary with different protocols.

Lymphocyte immune globulin, equine (Atgam)

Inhibits cell-mediated immune response by altering T-cell function or eliminating antigen-reactive cells.
There is little prospective randomized data to suggest a single schedule superior, but experience suggests that a short infusion is best tolerated.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells. Monitor carefully; used only on an investigational basis.

Lymphocyte immune globulin, rabbit (Thymoglobulin)

May modify T-cell function and possibly eliminate antigen-reactive T lymphocytes in peripheral blood. The dose and duration of therapy vary with the investigational protocols.

Cytokines

Several preliminary studies have demonstrated that the addition of cytokines (eg, G-CSF, GM-CSF) may hasten the neutrophil recovery and that these agents may improve the response rate and survival, although long-term use may increase the risk of clonal evolution.

Sargramostim (Leukine, Prokine)

Recombinant human GM-CSF. Can activate mature granulocytes and macrophages. The dose and frequency of administration vary with the investigational protocol.

Filgrastim (Neupogen)

G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.

Antineoplastic Agent, Antimetabolite (purine)

Antimetabolites are antineoplastic agent that inhibit cell growth and proliferation.

Fludarabine (Fludara)

Contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A) that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Inhibits DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase. This inhibits RNA function, RNA processing, and mRNA translation. Also activates apoptosis.

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