Equine antithymocyte globulin preferable for immunosuppressive therapy in aplastic anemia

Aplastic anemia is a rare disease caused by a failure of the bone marrow stem cells. Pancytopenia, including anemia, is characteristic of the disorder. Patients are at risk of infection due to neutropenia and bleeding due to thrombocytopenia, as well as fatigue caused by anemia. Without treatment, more than 70% of those patients will die within the first year of diagnosis from complications of cytopenias.

In most patients with AA, the disease is considered to be immune mediated, due to T-cell mediated destruction of the bone marrow elements. Hence, the most common treatment options are hematopoietic stem cell transplantation and immunosuppressive therapy. Aplastic anemia can be divided into three categories: moderate (or non-severe) AA, severe AA (SAA) and very severe AA (vSAA). Treatment should be offered to patients with transfusion-dependent moderate AA and all patients with SAA or vSAA.

Patients with SAA under the age of 40 years with a matched sibling donor should be offered a HSCT as first-line therapy with curative intent. Long-term survival can exceed 75% in such patents. Survival after HSCT tends to decrease with increasing age. Outcomes also remain superior with matched sibling donors compared to unrelated donors, although this survival advantage has grown smaller over time.

Debbie Blamble

The standard conditioning regimen is a combination of cyclophosphamide (Cy) and antithymocyte globulin (ATG). The standard stem cell source is from bone marrow stem cells harvested from the matched sibling. Notably, using peripheral blood as a stem cell source has shown to decrease survival after HSCT, likely due to the adverse effects of chronic graft vs. host disease (cGVHD). The occurrence of GVHD does not improve outcomes in AA compared with hematologic malignancies. HSCT may still be an option for older patients, those without a matched sibling donor, as well as relapsed patients using different conditioning regimens and/or stem cell sources — all of which are under investigation to determine the best approach.

Immunosuppressive therapy

Immunosuppressive therapy is the treatment of choice for all patients who are not eligible for HSCT as first-line therapy. Five-year survival is about 75% for IST. However, IST is not curative in many patients; only about two-thirds of patients respond and relapse occurs in up to one-third of patients. Responses, should they occur, happen in the first 3 to 6 months after therapy. Patients receiving IST are also at risk of late complications, such as development of paroxysmal nocturnal hemoglobinuria (PNH); myelodysplastic syndrome (MDS); and acute myeloid leukemia (AML); as well as solid tumors.

The standard IST regimen is the combination of ATG and cyclosporine (CsA). CsA is administered at a dose of 5 mg/kg/day for at least the first 6 months. Cyclosporine frequently needs to be continued long term to prevent relapse. High-dose corticosteroids, used as prophylaxis against serum sickness, are administered in the short term and tapered off during the first month.

Several additions have been made to the ATG/CsA regimen in an attempt to improve outcomes. The addition of daily filgrastim for 3 months after ATG/CsA does not appear to improve outcomes such as survival or response rates. There is concern that the prolonged use of filgrastim in these patients may increase the risk of developing MDS or AML. Currently, filgrastim should be reserved for adjunct use in the management of infections. Additional immunosuppressive agents have been studied. The addition of sirolimus and mycophenololate mofetil did not improve response rates. Single agents have shown responses in the treatment of AA and warrant further investigation, including high-dose cyclophosphamide, alemtuzumab and daclizumab.

There are two different ATG products available in the US, horse (equine) ATG (Atgam) and rabbit ATG (Thymoglobulin) (See Table). Most first-line clinical trials have used horse ATG; some first-line data with rabbit ATG have been reported. Any differences from the standard dosing listed in the table will be noted in the study description.

Comparative studies

The Severe Aplastic Anemia Studying Group in China conducted a four-arm open-label randomized study of either horse ATG alone [Lymphoglobuline at 12 mg/kg/day] (regimen 1);horse ATG + CsA (regimen 2); horse ATG + CsA + GM-CSF + erythropoietin (regimen 3); or rabbit ATG [ATG-Fresenius] + CsA + GM-CSF + erythropoietin (regimen 4).

One-hundred forty-two patients were randomized between 1991 and 2000. Overall response rates were 58% for regimen 1, 79% for regimen 2, 73% for regimen 3 and 53% for regimen 4. This study confirmed that the addition of growth factors does not improve response rates. The authors also concluded that results obtained with the rabbit ATG preparation were inferior for the treatment of SAA.

Investigators in Russia conducted a prospective, double-blind randomized study of two ATG products for the treatment of AA in pediatric patients. From 2000 to 2003, 32 patients were randomized to either horse ATG (N=15) or rabbit ATG (at a total course dose of 40 mg/kg, N=17) with methylprednisolone and CsA. Patients not responding at 6 months were crossed over to the alternative agent. The response rate was 93% in the horse ATG group and 47% in the rabbit ATG group. There was one early death in the horse ATG group due to infection. No differences in adverse effects were noted. The authors concluded that the horse ATG product remains the agent of choice.

Investigators from Spain performed a retrospective review of the use of horse ATG (Lymphoglobuline) and rabbit ATG (Thymoglobuline) from 2003-2008. Both products were available in Spain at that time and physicians could chose from either product. One-hundred and one patients received therapy; 29 received the horse ATG product and 72 received a rabbit ATG product (2.5 mg/kg/day x 5 days). All patients also received CsA and methylprednisolone. Patients who did not achieve a CR could receive either a second course of IST, second line therapy or no further therapy. The CR rate and PR rate were 38% vs. 22% and 10% vs. 24% for horse ATG (ORR = 48 %) and rabbit ATG (ORR = 46%) respectively. If a second course of IST therapy was given (N = 31), the response rates were 80% (N = 4 of 5) vs. 73% (N = 19 of 26) for horse ATG and rabbit ATG respectively. No differences were noted in adverse events. The investigators found no significant difference in outcomes based on the type of ATG used in their study.

Investigators in Brazil also conducted a retrospective analysis of all AA patients who received ATG from 2000 to 2008. Patients from 2000 – 2005 were treated with horse ATG (Lymphoglobuline). When that product became unavailable, patients received rabbit ATG (Thymoglobuline at 2.5 mg/kg/day) starting from 2006 until study completion. Seventy-one patients were evaluated; 42 received horse ATG and 29 received rabbit ATG. The groups were comparable with the exception that the horse ATG group had more patients that received greater than 4 weeks of corticosteroids. The overall response rate at 6 months was 59.5% in the horse ATG group and 34.5% in the rabbit ATG group. Patients receiving rabbit ATG relapsed more quickly after IST and had poorer survival compared to the horse ATG group. The authors concluded that horse ATG is superior in terms of response rates and survival as first line therapy for SAA.

At last year’s American Society of Hematology (ASH) meeting, investigators from the National Institutes of Health (NIH) presented a late-breaking abstract of results from a randomized trial of horse ATG (Atgam) versus rabbit ATG (Thymoglobulin) in SAA. Between December 2005 and July 2010, consecutive patients were randomized between the two ATG products. All patients also received CsA for at least 6 months. One-hundred twenty patients were randomized. The hematologic response rate at 3 months was 62% for horse ATG and 33% for rabbit ATG which was significantly different. Six month response rates were 69% for horse ATG and 35% for rabbit ATG (statistical significance was not calculated as not all patients were yet evaluable). More deaths have occurred in the rabbit ATG arm leading to separation of the survival curves. The authors concluded that results with rabbit ATG are inferior to horse ATG as first line therapy in SAA.

In summary, aplastic anemia is a rare, life-threatening disease that manifests as profound cytopenias. Patients with a matched sibling donor who are under the age of 40 years should be offered HSCT as first-line therapy. HSCT can be curative in a high number of patients. Patients not eligible for HSCT should be offered IST. Immunosuppressive therapy will produce responses in the majority of patients but is less likely to be curative compared with HSCT.

Which ATG product does one choose for IST? Even excluding the Chinese and Russian studies in which a pharmacologically different rabbit ATG preparation was used, the remaining studies suggest that rabbit ATG is not better than, and is likely inferior to, horse ATG in the first-line treatment of AA. Therefore, the standard of care first-line IST for AA remains horse ATG + CsA.

Debbie Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center. She may be reached at dblamble@mdanderson.org. She reports no relevant financial disclosures.

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