Salvage Therapies for Aplastic Anemia: An Updated Perspective

Catherine Floroff, PharmD
PGY1 Pharmacy Practice Resident
Medical University of South Carolina, Charleston, SC

A 67-year-old woman was diagnosed with aplastic anemia in August 2012. In June of that same year, she originally complained of fatigue, shortness of breath, and tachycardia. A complete blood count (CBC) revealed a white blood cell (WBC) count of 1.5 K/mL, hemoglobin count of 5.1 g/dL, and platelet count of 7 K/mL. She was referred to a private oncologist the first week of July, at which time a bone marrow biopsy revealed hypocellular bone marrow with erythroid hyperplasia, profound anemia, and marked leukopenia. A repeat bone marrow biopsy was performed at our clinic later that month and revealed 5% cellularity with decreased myeloid and erythroid lineage. Serum testing for hepatitis B and C as well as HIV was negative. Upon diagnosis with aplastic anemia, she was treated with a 5-day course of horse antithymocyte globulin (hATG), cyclosporine (CsA), and prednisone. She started maintenance therapy with CsA. From this, she obtained a complete response but then relapsed in June 2013. It was decided to begin treatment with eltrombopag 50 mg daily, which was increased to 75 mg daily on week 5 because of persistent thrombocytopenia. She was hospitalized again in December 2013 due to acute kidney injury and continued pancytopenia. What salvage therapies should be considered as a next course of treatment?

Aplastic anemia is a rare disorder that occurs when the bone marrow fails to produce hematopoietic precursor cells, resulting in pancytopenia.1 Immunosuppressive therapy with hATG and CsA is the standard treatment for aplastic anemia in patients older than 40 years old and those younger than 40 years without a human leukocyte antigen (HLA) compatible sibling donor.1 Refractory aplastic anemia occurs in about one-third of patients and is defined as a lack of response after one course of immunosuppression with persistence of severe pancytopenia observed at 6 months following therapy.2,3 Additionally, approximately one-third of responders are anticipated to relapse after initial immunosuppressive therapy.4 Predictors of nonresponse to immunosuppression include older age, low absolute reticulocyte count (<20 K/mL), low lymphocyte count (<1 K/mL), and disease severity.1,5 Matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) may be considered for patients younger than 50 years old or patients who are 50–60 years old with good performance status and are refractory to a first course of immunosuppression.1 Unfortunately, 20%–40% of patients are ineligible for HSCT and continue to have severe cytopenias that put them at risk for hemorrhage from thrombocytopenia and infections from neutropenia.

No standard treatment, other than supportive care measures, is recommended for patients with refractory aplastic anemia or relapsed disease who are ineligible for HSCT and do not respond to immunosuppressive therapies. Intensification of the immunosuppressive regimen with more potent agents, such as rabbit antithymocyte globulin (rATG), sirolimus, or mycophenolate mofetil (MMF), have not shown an improvement in the response rate.5 Patients with relapsed disease show a higher hematologic response rate to immunosuppression compared to HSCT.6 Therefore, HSCT is usually not recommended for treatment of older patients with relapsed aplastic anemia. Readministration of immunosuppressive therapy, an alternative immunosuppressive drug or novel agent, or experimental forms of transplantation are potential options to consider.

ATG-Based Regimens

Few studies have investigated salvage therapy with rATG for patients who fail to respond to an initial course of hATG. A second course of immunosuppression with rATG/CsA is associated with a variable response rate between 22% and 77%.7-8 A randomized controlled trial that compared rATG and CsA (n = 27) versus alemtuzumab (n = 27) in refractory disease found a comparable 6-month response rate (33% versus 37%, p = 0.78).9 Repeated treatment with hATG in 43 patients who did not respond to initial treatment or who relapsed after initial response was evaluated.10 Without resulting in increased risks of side effects, transfusion- independent hematopoiesis was achieved in 63% of patients with a survival probability of 52%

± 8% at 10 years. Standard hATG plus CsA in patients who were refractory to initial rATG/ CsA or cyclophosphamide (CY)/CsA resulted in a hematologic response in four of 19 (21%) patients who received rATG, compared to no patients in the CY group, by 3 months and in only one of six (17%) patients who received CY at 6 months.11 These results suggest that the overall response rate is likely to be lower when hATG is used as salvage treatment compared to initial therapy. Administration of a third course of ATG, regardless of the animal source, was found to be ineffective in patients with refractory aplastic anemia.12

Further augmentation of response rates has been investigated with the addition of a third immunosuppressive agent or growth factor. Administration of rATG/CsA plus G-CSF at a dose of 5 mcg/ kg on days 1–90 as salvage therapy after failed hATG/CsA in 30 cases resulted in a complete response rate of 30%, and transfusion independence was achieved in 77% of patients.7 A prospective randomized trial examined the addition of sirolimus to the combination of hATG/CSA, but there was no improvement in response rates observed in these patients.13 Other immunosuppressive agents such as MMF have been added to the ATG/CsA regimen, but no improvement in response or relapse rates have been observed when compared to ATG/CsA alone.14

Alternative Immunosuppressive Regimens

High-dose CY administered intravenously at 50 mg/ kg for 4 days with intravenous mesna for prophylaxis of hemorrhagic cystitis or alemtuzumab given at various doses and schedules have been used as alterative immunosuppressive therapies in the treatment of refractory aplastic anemia. One study suggested high-dose CY showed comparable responses to hATG/CSA with fewer relapses; however, the 10-year follow-up data were disappointing as overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively.15-16 Furthermore, a prospective study comparing high-dose CY with ATG/CsA in treatment-naïve patients was terminated prematurely due to excess deaths and increased incidence of fungal infections in patients treated with CY.17 Alemtuzumab, a humanized anti-CD52 IgG1 monoclonal antibody, was evaluated in a prospective clinical trial that included 25 patients with severe aplastic anemia (n = 11), pure red cell (PRCA; n = 12), or pure white cell aplasia (PWCA; n = 2).18 A response rate of 58% was observed when alemtuzumab was administered subcutaneously in a single course over 5 consecutive days at escalating doses of 3–10–30–30–30 mg to patients with severe aplastic anemia. Low-dose CsA (1 mg/ kg) followed from day 7 and then adjusted according to blood levels. Early relapse rates were seen in five out of 11 patients with severe aplastic anemia, but three out of five patients achieved a complete response with retreatment of alemtuzumab. Alemtuzumab (60 mg and 90 mg) in combination with CsA was examined in a dose-escalation study.19 A total of 19 patients were enrolled: 14 patients with severe/very severe aplastic anemia, three with transfusion-dependency, one with hypoplastic myelodysplastic syndrome (MDS), and one with PRCA. Response occurred in 35% (6 of 17) of patients with aplastic anemia, and all responses occurred in the 60-mg arm.

There have been several strategies aimed at preventing relapse after initial therapy with hATG/CsA. Continuation of full-dose CsA for 6–12 months with a slow taper afterward is a possible approach. A small retrospective study of 42 pediatric patients examined a CsA taper regiment that varied between patients.20 Relapse was 7.6% in the “slower” CsA taper group (0.4–0.7 mg/ kg/month) compared to 60% in the “rapid” taper group (0.8 mg/ kg/month). A larger study found that 102 patients who received a hATG-based regimen achieved a cumulative incidence of relapse of 29% when the CsA dose was tapered by 25% every 3 months.21 The relapse rate was slightly higher at 32% when CsA was discontinued at 6 months.

Eltrombopag and Androgens

Eltrombopag (Promacta®) is an oral thrombopoietin agonist that increases platelet counts by binding to and activating the receptor c-MPL on megakaryocytes, resulting in platelet maturation and release.22 Eltrombopag produced hematologic responses in 11 of 25 refractory patients (44%) at 12 weeks with minimal toxic effects.21 Furthermore, eltrombopag may reduce transfusion requirements in patients with platelet transfusion-dependent aplastic anemia.23-24 The starting dose was 50 mg/day with doses increased in 25-mg increments in nonresponders every 2 weeks if the platelet count had not increased by 20 L/cumm up to a maximum dose of 150 mg/day. An additional 18 patients were included in long-term follow up, and the overall response rate was 40% (17 of 43 patients) at 3–4 months, including tri- and bi-lineage responses.25 In the extension arm of responders remaining on eltrombopag, 14 of 17 patients continued to show hematologic improvement and seven eventually achieved significant increases in neutrophil, red blood cell, and platelet lineages.

Androgens, such as oxymetholone and danazol, have been studied and were used before ATG/CsA became the standard treatment of aplastic anemia.26-27 The results of these studies have not shown a significant impact on response or relapse rates or clonal growth. A recent study was conducted of 12 refractory and four relapsed patients who were alternately administered CsA (3 mg/ kg and 5 mg/ kg per day in adults and children, respectively) and levamisole (150 mg per day in adults or 2.5 mg/ kg per day in children weighing less than 40 kg in three divided doses) every other day for 12 months, followed by a slow taper.28 Of the 16 patients, five achieved a complete response at the last follow-up of a median 28 (range 4–53.5) months. Furthermore, CsA alternately combined with levamisole has promising results in patients with moderate aplastic anemia based on a recent study.29 

How Much Do You Know About Treating Aplastic Anemia?

Test your knowledge of aplastic anemia therapy by answering the following questions. The correct answers are provided on the next page.

  1. What is not a predictor of nonresponse to immunosuppressive therapy in a patient with refractory aplastic anemia?
    a. Young age
    b. Low absolute reticulocyte count
    c. Low lymphocyte count
    d. Disease severity
  2. What is not a consideration when deciding whether to advise a transplant or nontransplant approach in a patient with refractory aplastic anemia or relapsed disease?
    a. Patient age and comorbidities
    b. Performance status
    c. Availability of a suitably matched donor d. Supportive care regimen
  3. What is the standard treatment for patients with refractory aplastic anemia or relapsed disease who are ineligible for HSCT?
    a. rATG+ CsA
    b. Alemtuzumab
    c. High-dose CY
    d. There is no standard approach, and the treatments may be challenging.
  4. What is the general dosing strategy for patients with refractory aplastic anemia who are treated with eltrombopag?
    a. Initial dose is 25 mg once daily up to a maximum dose of 150 mg once daily, and dosage adjustment is based on platelet response after 2 weeks.
    b. Initial dose is 50 mg once daily up to a maximum dose of 150 mg once daily, and dosage adjustment is based on platelet response after 2 weeks.
    c. Initial dose is 50 mg once daily up to a maximum dose of 100 mg once daily, and dosage adjustment is based on platelet response after 12 weeks.
    d. Initial dose is 25 mg once daily up to a maximum dose of 150 mg once, and dosage adjustment is based on platelet response after 4 weeks.

 Aplastic Anemia Quiz Answers

  1. Answer: a. Predictors of nonresponse to immunosuppression include older age, low absolute reticulocyte count (<20 K/mL), low lymphocyte count (<1 K/mL), and disease severity.
    2. Answer: d. HSCT is indicated if patients are fit and have a suitably matched donor: either a sibling (>40–50 years) or unrelated donor. Patients lacking a fully matched donor should be considered for a second course of immunosuppressive therapy. Any supportive care is essential at all stages of disease. Best supportive care continues through initial therapies, whether with HSCT or immunosuppressive therapy. Because response to ATG is delayed until approximately 3 months, best supportive care is vital to ensure optimal outcomes.
    3. Answer: d. No standard treatment is recommended for patients with refractory aplastic anemia or relapsed disease who are ineligible for HSCT and who do not respond to initial immunosuppressive therapies other than supportive care measures.
    4. Answer: b. In patients with refractory aplastic anemia who are treated with eltrombopag, the starting dose is 50 mg/ day with doses increased in 25-mg increments in nonresponders every 2 weeks if the platelet count has not increased by 20 K/mL up to a maximum dose of 150 mg/day.


The patient described in the vignette was treated with a repeat induction regimen of hATG, CsA, and prednisone during hospitalization. Follow-up clinic visits during the next 2 months revealed persistent pancytopenia resulting in the need for platelet and blood transfusions. Of note, her absolute neutrophil count was at the highest since relapse in July 2013 (1.32 K/mL in January 2014 versus 0.6 K/mL in July 2013), which may represent the onset of response. Though aplastic anemia was a devastating diagnosis in the past, most patients can be treated effectively and expect long-term overall survival. The preferred therapy is immunosuppression with hATG/ CsA in patients who are not candidates for a matched sibling donor HSCT. A MUD HSCT may be the preferred salvage therapy in younger patients with refractory aplastic anemia. A second course of immunosuppression should be offered if a MUD is unavailable. Mismatched unrelated, haploidentical, or umbilical cord HSCT are possible options but higher risks of GVHD, graft rejection, and infection should be considered. Other nonHSCT therapies, such as eltrombopag, androgens, or alternative immunosuppressants, may be appropriate options in patients who remain unresponsive or experience relapsed disease.


1. Marsh JC, Ball SE, Darbyshire P, et al. Guidelines for the diagnosis and management of aplastic anemia. Br J Haematol. 2009;147:43-70.

2. Scheinberg P, Nunez O, Weinstein B, et al. Hose versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365:430-438.

3. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012;120:1185-1196.

4. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509-2519.

5. Marsh JC, Kulasekararaj AG. Management of the refractory aplastic anemia patient: what are the options? Blood. 2013;122:3561-3567.

6. Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012:292-300.

7. Di Bona E, Rodeghiero F, Brunno B, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anemia patients unresponsive to a first course of intensive immmuosuppresive therapy. Br J Haematol. 1999;107:330-334.

8. Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti- thymocyte globulin and ciclosporin for patients with relapsed or refractory sever aplastic anemia. Br J Haematol. 2006;133:622-627.

9. Scheinberg P, Nunez O, Weinstein B, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naïve, relapsed, and refractory severe acquired aplatic anemia. Blood. 2012;119:345-354.

10. Tichelli A, Passweg J, Nissen c, et al. Repeated treatment with horse antilymphocyte globulin for severe aplastic anemia. Br J Haematol. 1998;100:393-400.

11. Scheinberg P, Townsley D, Dumitriu B, et al. Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia. Am J Hematol. 2014. Epub ahead of print.

12. Gupta V, Gordon-Smith EC, Cook G, et al. A third course of anti-thymocyte globulin in aplastic anemia is only beneficial in previous responders. Br J Haematol. 2005;129:110-117.

13. Scheinberg P, Wu CO, Nunez O, et al. Treatment of severe aplastic anemia with a combination of horse anti-thymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica. 2009;94:348-354.

14. Scheinberg P, Numez O, Wu C, Young NS. Treatment of severe aplastic anemia with combined immunosuppression: anti- thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol. 2006;133:606-611.

15. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in acquired severe aplastic anemia following high-dose cyclophosphamide. Blood. 1996;87:491-494.

16. Brodsky RA, Chen AR, Dorr D, et al. High-dose cyclophosphamide for severe aplastic anemia: long-term follow- up. Blood. 2010;115:2136-2141.

17. Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anemia: a randomized trial. Lancet. 2000;356:1554-1559.

18. Risitano AM, Selleri C, Serio B, et al. Alemtuzumab is safe and effective as immunosuppressive treatment for aplastic anemia and single-lineage marrow failure: a pilot study and a survey from the EBMT WPSAA. Br J Haematol. 2010;148:791-796.

19. Kim H, Min YJ, Baek JH, et al. A pilot dose-escalating study of alemtuzumab plus cyclosporine for patients with bone marrow failure syndrome. Leuk Res. 2009;33:222-231.

20. Saracoo P, Quarello P, Iori AP, et al. Cyclosporin A response and dependence in children with acquired aplastic anemia: a multicenter retrospective study with long-term observation follow-up. Br J Haematol. 2008;140:197-205.

21. Scheinberg P, Nunez O, Scheinberg P, Weinstein B, Wu CO, Young NS. Cyclosporine taper does not prevent relapse in severe aplastic anemia [abstract]. Blood. 2011;118:2406.

22. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-19.

23. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-19.

24. Isik A, Eliacik E, Haznedaroglu IC, et al. The impact of eltrombopag administration on the clinical course of severe refractory fate acquired aplastic anemia. Turk J Haematol. 2013;30:328-330.

25. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores tri-lineage hematopoiesis in refractory severe aplastic anemia which can be sustained on discontinuation of drug. Blood. 2013 [Epub ahead of print].

26. Bacigalupo A, Chaple M, Hows J, et al. Treatment of aplastic anemia (AA) with antilymphocyte globulin (ALG) and methylprednisolone (MPred) with and without androgens: a randomized trial from the EBMT SAA working party. Br J Haematol. 1993;83:145-151.

27. Chuhjo T, Yamazaki H, Omine M, Nakao S. Danazol therapy for aplastic anemia refractory to immunosuppression therapy. Am J Hematol. 2008;83:387-389.

28. Shao Y, X Li, Shi J, et al. Cyclosporin combined with levamisole for refractory or relapsed severe aplastic anemia. Br J Haematol. 2013;162:552-555.

29. Li X, Shao Y, Ge M, et al. A promising immunosuppressive strategy of cyclosporine alternately combined with levamisole is highly effective for moderate aplastic anemia. Ann Hematol. 2013;92:1239-1247.