Sections

Treatment

Approach Considerations

Therapy for aplastic anemia may consist of supportive care only, immunosuppressive therapy, or hematopoietic cell transplantation (HCT). Severe and very severe aplastic anemia (SAA and VSAA, respectively; see Workup/Staging) have a mortality rate of greater than 70% with supportive care alone^[72]and are therefore a hematologic emergency. Treatment should be instituted promptly for SAA or VSAA, and clinicians must stress the need for patient compliance with therapy.

Inpatient care for patients with aplastic anemia may be needed during periods of infection and for specific therapies, such as antithymocyte globulin (ATG) or HCT. In addition, iron chelation may be required in chronically transfused patients who develop elevated serum ferritin levels above 1000 µg/L.^[5] Phlebotomy can be done to decrease the iron overload post transplantation in aplastic anemia patients.^[5]

The British Committee for Standards in Haematology recommends treating infection or uncontrolled bleeding before administering immunosuppressive therapy, including in patients scheduled for HCT.^[5]In the presence of severe infection, however, it may be necessary to proceed directly to HCT to provide the patient with the best chance for early neutrophil recovery.^[5]

Both the British Committee for Standards in Haematology and the Pediatric Haemato-Oncology Italian Association recommend HCT from a matched sibling donor for severe aplastic anemia. If a matched donor is not available, options include immunosuppressive therapy or unrelated donor HCT.^{[6, 7]}

Approximately one third of patients with aplastic anemia do not respond to immunosuppression. The thrombopoietin receptor agonist eltrombopag is approved for use in patients with severe aplastic anemia who fail to respond adequately to immunosuppressive therapy. Independent of response or degree of response, risks include relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or leukemia.^{[18, 56, 57, 58, 59]}

Pregnant women with aplastic anemia have a 33% risk of relapse.^[5]Provide supportive care in these patients, maintain the platelet count above 20 × 10⁹/L, if possible, and consider administering cyclosporine.^[5]

Note that monotherapy with hematopoietic growth factors (eg, recombinant human erythropoietin [rHuEPO], granulocyte colony-stimulating factor [G-CSF]) is not recommended for newly diagnosed patients.^[5]

Frequent outpatient follow-up for patients with aplastic anemia is needed to monitor blood counts and any adverse effects of various drugs. Transfusions of packed red blood cells (RBCs) and platelets are administered on an outpatient basis.

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 hematologist and/or an HCT physician.

Blood Transfusion

Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted. The British Committee for Standards in Haematology recommends prophylactic transfusions in patients whose platelet counts fall below 10 × 10⁹/L (or < 20 × 10⁹/L if bleeding or febrile).^[5]However, it is important that transfusions be guided by the patient’s clinical status and not by numbers alone. Avoiding transfusions from family members is important because of possible sensitization against non-HLA (human leukocyte antigen) tissue antigens of potential donors.

For patients in whom hematopoietic cell transplantation (HCT) may be attempted, transfusions should be used judiciously because minimally transfused subjects have achieved superior therapeutic outcomes.

If using blood-bank support, attempt to minimize the risk of cytomegalovirus (CMV) infection. The blood products should, if possible, undergo leukocyte reduction to prevent alloimmunization and CMV transmission and should be irradiated to prevent transfusion-associated graft versus host disease (GVHD) in HCT candidates.

The British Committee for Standards in Haematology also recommends irradiated blood products for all patients receiving antithymocyte globulin (ATG) therapy. In patients with life-threatening neutropenic sepsis, the committee suggests consideration of irradiated granulocyte transfusions.^[5]

Development of a transfusion plan in consultation with a physician who is experienced in the management of aplastic anemia is essential.

Treatment of Infections

Infections are a major cause of mortality in patients with aplastic anemia.^{[73, 74]}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. Patients should maintain hygiene to reduce infection risk.

The British Committee for Standards in Haematology recommends prophylactic antibiotic and antifungal agents for patients whose neutrophil counts are below 0.2 ×10⁹/L.^[5]Patients on immunosuppressive therapy should receive prophylactic antiviral therapy.^[5]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; also consider early introduction of antifungal agents for individuals with persistent fever.

However, the strategy of empiric antibiotic use has also resulted in the development of resistant organisms and thus is not favored by some clinicians.^[75]

Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections, although the benefit of this therapy should be weighed against its cost and efficacy.^{[10, 76, 77, 78]}Discontinue cytokine support after 1 week if the neutrophil count does not rise.^[5]

Hematopoietic Cell Transplantation

Central venous catheter placement is required prior to hematopoietic cell transplantation (HCT). Note that the following recommendations do not apply to patients with Fanconi anemia and other types of inherited marrow failure;^[5]these patients require special consideration.

HCT using an HLA-matched sibling donor

Human leukocyte antigen (HLA)-matched sibling-donor HCT is the treatment of choice for a young patient with severe or very severe aplastic anemia (SAA or VSAA, respectively), being generally accepted for patients younger than 50 years.^[5]Persons undergoing this procedure do not require irradiation-based conditioning regimens.^[5]

A study of 692 German patients with SAA who received transplants from HLA-matched siblings found that in patients younger than 20 years, rates of chronic graft versus host disease (GVHD) and overall mortality were higher after transplantation of peripheral blood progenitor cell (PBPC) grafts than after bone marrow transplants.^[79]A multinational study of patients with SAA who received HCT from an HLA-matched sibling donor concluded that although bone marrow should definitely be the preferred graft source for these patients, PBPCs may be an acceptable alternative in countries with limited resources where patients present later in their disease course and risks of graft failure and infective complications are high.^[80]

Although evidence suggests that stem cells from bone marrow afford better outcomes compared with PBPCs, an additional consideration is the perspective of the donor, who must be informed of the difference between the methods of harvesting. Bone marrow harvesting is usually performed with the donor under general anesthesia, while with PBPC harvesting the donor is awake and connected via large-bore intravenous catheters to an apheresis machine, which separates out the stem cells (for descriptions of the two methods, see Bone Marrow Donor Procedure).

Along with the risks associated with anesthesia, bone marrow donors typically experience moderate pain for several days following the procedure. PBPC donors usually experience bone pain, which may be severe, from the filgrastim-induced bone marrow stimulation used to mobilize stem cells in advance of the procedure.

One of the major problems of HCT in aplastic anemia is the high rate of rejection (10%; range, 5-50%). The rejection rate correlates positively with the number of transfusions the patient received and the duration of his or her disease prior to transplantation.

Past attempts to reduce rejection rates included use of a higher stem cell dose, as well as the addition of total body irradiation to cyclophosphamide conditioning. Although that was associated with a reduced incidence of graft rejection, the benefit was negated by high transplant-related mortality (TRM) due to an increase in GVHD.

Currently, antithymocyte globulin (ATG) with cyclophosphamide is a commonly used conditioning regimen for transplantations in aplastic anemia. The addition of ATG to cyclophosphamide for conditioning has resulted in infrequent graft rejections, as well as improved overall survival.^{[20, 76, 77, 81]}

Fludarabine- and cyclophosphamide-based reduced-intensity conditioning (RIC) regimens with or without ATG reduced rejection and improved outcome in Indian patients undergoing allogeneic HCT for SAA.^[82]When compared with 26 patients previously transplanted using cyclophosphamide/antilymphocyte globulin, RIC regimens led to faster neutrophil engraftment (12 vs 16 days, respectively), with significantly lower rejection rates (2.9% vs 30.7%, respectively), and superior event-free (82.8% vs 38.4%, respectively) and overall (82.8% vs 46.1%, respectively) survival rates.^[82]

Standard conditioning regimens use a cyclophosphamide dose of 200 mg/kg, which is known to be associated with significant organ toxicity. In a multicenter phase I-II study of adult patients with SAA receiving bone marrow grafts from unrelated donors, Anderlini et al found that a regimen of cyclophosphamide in doses of 50 or 100 mg/kg, combined with total body irradiation 2 Gy, fludarabine, and ATG, provided effective conditioning and few early deaths.^[83]

The occurrence of GVHD as a complication of HCT 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 cyclosporine along with methotrexate is the standard GVHD approach for matched siblings.^[81]However, very few comparative data exist, and no data have reported an alternative approach to be superior to this regimen.

Although horse ATG is better than rabbit ATG as an immunosuppressive therapy, a multinational study of ATG used as part of the conditioning regimen, which included 546 HLA-matched sibling HCT transplants for severe aplastic anemia, found that 3-year overall survival rates were not significantly different with rabbit versus horse ATG. However, the day-100 incidences of both acute and chronic GVHD were higher with horse than with rabbit ATG (acute GHVD, 17% versus 6%, respectively, P < 0.001; chronic GVHD, 20% versus 9%, P < 0.001). The authors concluded that these results support the use of rabbit ATG for bone marrow conditioning.^[84]

Early referral to a transplantation center at diagnosis is recommended for all young patients, even if they lack a suitable related donor, because transplant planning needs to be done even if patients are receiving immunosuppressive therapy, given the significant failure rate of that approach.^[21]

Fertility

Patients receiving high-dose cyclophosphamide conditioning in allogeneic HCT from an HLA-identical sibling donor for aplastic anemia have relatively well-preserved fertility.^[5]Provide these patients with appropriate contraceptive advice to prevent unintended pregnancies.

Longer-term data are limited for patients with fludarabine-based regimens. Therefore, discussions related to potential fertility preservation, including cryopreservation of sperm and oocytes/embryos, is recommended.^[5]Cyclosporine is safe for use in pregnancy.

HCT using an unrelated donor

Unrelated-donor HCT is currently justified only if the donor is a full match and only if immunosuppressive therapy fails (failure of ≥1 course of immunosuppressive therapy) or treatment as part of a clinical trial fails.^[5]

High-resolution allelic matching, however, has improved outcomes in unrelated-donor HCT, especially in younger patients. 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.^[85]

GVHD

In the first cohorts transplanted, HCT using an unrelated donor was associated with very high mortality due to high rates of graft failure, infection, and GVHD. This poor outcome resulted primarily from the use of less stringent HLA matching in addition to the fact that these first patients had long-term disease, a history of infection, iron overload, transfusion resistance, and other related factors. However, more recent reports suggest a better outcome after unrelated transplants, an improvement that is due mainly to high-resolution HLA testing, optimization of the conditioning regimen, better supportive care, and better management of GVHD.

A 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.^[86]

Due to the rates of GVHD in unrelated donor transplantation, this procedure is not preferred over immunosuppressive therapy.^[52]

In unrelated donor HCT, partial T-cell depletion may decrease the risk of severe GVHD while still maintaining sufficient donor T lymphocytes to ensure engraftment.^[52]

Graft failure

In a study that evaluated data for unrelated matched HCT versus mismatched transplants, the probability of graft failure at 100 days after using a 1-antigen mismatched, related donor was 21%, whereas 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.^[21]

Conditioning regimens

In a multinational study that included 287 patients with severe aplastic anemia who received ATG as part of their conditioning regimen for unrelated-donor HCT, rabbit ATG resulted in a lower incidence of acute (but not chronic) GVHD and better survival (3-year overall survival, 83% for rabbit ATG versus 75% for horse ATG; P=0.02). The authors concluded that these data support the use of rabbit ATG in this setting.^[84]Typical regimens in this study population were horse ATG, cyclophosphamide, and low-dose total-body irradiation (TBI); and rabbit ATG, cyclophosphamide, fludarabine, and TBI.

It should be noted, however, that early results from a cyclophosphamide de-escalation study in a fludarabine-based conditioning regimen for unrelated donor HCT demonstrated life-threatening adverse events (excessive organ toxicity) at predefined cyclophosphamide dose levels.^[87]The investigators reported an association between such toxicity and cyclophosphamide 150 mg/kg plus TBI at 2 Gy, fludarabine at 120 mg/m², and ATG.^[87]

Conditioning regimens without TBI have also been studied. These include fludarabine, ATG, and cyclophosphamide^[53]and fludarabine, low-dose cyclophosphamide, and alemtuzumab.^[88]Hamad and colleagues reported on HCT using a conditioning regimen with intermediate-dose alemtuzumab (50 to 60 mg) and high-dose cyclophosphamide or fludarabine in 41 adult patients with aplastic anemia, and reported excellent survival with a favorable impact on GVHD and long-term health outcomes, but frequent viral complications. At 3 years, survival was 96% in patients younger than 40 years of age and 67% in those 40 years and older.^[89]

Although the optimal regimen for unrelated-donor HCT remains unclear, the British Committee for Standards in Haematology indicates that a non–irradiation-based fludarabine regimen appears to be favored for younger patients.^[5]

According to a study by Samarasinghe et al, a conditioning regimen with fludarabine, cyclophosphamide, and alemtuzumab with matched unrelated-donor (MUD) HCT appears to be very well-suited in children with severe aplastic anemia and has excellent outcomes.^[90]The investigators suggested that MUD HCT may be a reasonable alternative when immunosuppressive therapy fails.^[90]In a study of fludarabine, low-dose cyclophosphamide, and alemtuzumab as a conditioning regimen for HCT (21 transplants from unrelated donors, with 3 of those from HLA 9/10 mismatch donors and 6 from matched sibling donors), Sheth et al reported similar outcomes in patients aged 50 years or older and those younger than 50 years.^[88]

Haploidentical HCT

Nonmyeloablative peripheral blood stem cell transplantation from HLA-haploidentical family donors has been proposed as rescue therapy in patients with refractory SAA or VSAA.^[91]A systematic review and meta-analysis concluded that haploidentical HCT is a promising approach in idiopathic aplastic anemia, with high engraftment rates and reduced complication rates. In 15 studies that included 577 patients, successful engraftment occurred in 97.3% of patients (95% confidence interval [CI], 95.9-98.7). Grades II-IV acute and chronic GVHD were reported in 26.6% and 25.0% of patients, respectively. The pooled incidence of transplant-related mortality was 6.7% per year (95% CI, 4.0-9.4%).^[92]

Rates of successful engraftment were higher with reduced-intensity conditioning compared with nonmyeloablative conditioning (97.7% vs 91.7%, P = 0.03) and rates of acute GVHD were lower (29.5% vs 18.7%, P = 0.008). No differences in the incidence rates of chronic GVHD or mortality were found. Posttransplantation regimens containing cyclophosphamide were associated with reduced rates of acute GVHD, cytomegalovirus (CMV) viremia, and CMV disease in initially viremic patients, compared with methotrexate-containing regimens and other regimens. The authors of this study recommend prospective trials to identify the preferred conditioning regimen, GVHD prophylaxis, and graft source for haploidentical HCT for aplastic anemia.^[92]

Umbilical Cord Blood Transplantation

Early studies of unrelated umbilical cord blood transplantation (UCBT) reported high graft failure rates. However, subsequent studies of UCBT using conditioning regimens that included low-dose total-body irradiation (TBI) yielded improvements in engraftment and overall survival.^[93]

A nationwide prospective phase II study from France concluded that UCBT is a valuable option for young adults with refractory severe aplastic anemia (SAA) and no available matched unrelated donors. The conditioning regimen comprised fludarabine, cyclophosphamide, antithymocyte globulin (ATG), and 2-Gy TBI. Engraftment occurred in 23 of the 26 patients in the study, and all 23 were alive at 1 year, for an overall survival rate of 88.5%. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively.^[94]

Du et al reported successful use of an immunoablative conditioning regimen for UCBT that does not include TBI and does not include ATG, as previous studies have found reduced engraftment and survival rates with conditioning regimens containing ATG. In their 15 patients, the first 10 received fludarabine and cyclophosphamide, to which busulfan was added in the subsequent 5 patients. Sustained engraftment was observed in 13 patients and after median follow-up of 33.8 months, 12 patients remained alive.^[93]

Immunosuppressive Therapy

Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine is used as first-line therapy^[95]for patients with severe or very severe aplastic anemia (SAA or VSAA, respectively) who are older than 50 years (35-50 years in presence of comorbidities) and as second-line therapy in younger patients with SAA or VSAA if a human leukocyte antigen (HLA)–matched sibling donor is not available. Immunosuppressive therapy is also recommended in patients with nonsevere aplastic anemia who are transfusion dependent.^[5]Immunosuppressive therapy is associated with an overall response rate of 60-80% and a 5-year survival rate of 75% in most reports, but event-free survival rates are in the range of 35-50%.

Up to 50% of patients with aplastic anemia demonstrate small paroxysmal nocturnal hemoglobinuria (PNH) clones in the absence of evidence of hemolysis.^[5]Some, but not all, studies have found evidence that the presence of a PNH clone predicts a better response to immunosuppressive therapy. Patients with a significant PNH clone who are receiving immunosuppressive therapy, especially ATG, should be actively monitored for signs of hemolysis. In patients with a history of PNH-associated thrombosis, use of ATG is not recommended.

Adding granulocyte colony-stimulating factor (G-CSF) to ATG and cyclosporine does not provide a survival advantage, but the lack of a neutrophil response by day 30 in patients receiving G-CSF has been associated with significantly lower rate of response to immunosuppressive therapy, and this early identification of probable nonresponders may stimulate an urgent transplant approach.^[96]A study from the European Group of Blood and Marrow Transplantation found that adding G-CSF to ATG plus cyclosporine had no meaningful long-term effect. On median follow-up of 11.7 years, there was no significant difference in overall survival, event-free survival, or incidence of clonal disorders.^[97]

Central venous catheter placement may be required before the administration of immunosuppressive therapy, and patients with these catheters should be treated as inpatients. Patients may require blood product support during ATG therapy, as well as close monitoring for allergic or anaphylactic signs and symptoms and for prophylaxis and treatment of fevers.^[5]

ATG sources

ATG can be derived from horses or rabbits. Scheinberg et al reported a large difference in the rate of hematologic response at 6 months in favor of horse ATG (68%), as compared with rabbit ATG (37%), in 120 patients with aplastic anemia.^[98]Overall survival at 3 years also differed, with a survival rate of 96% in the horse-ATG group, compared with 76% in the rabbit-ATG group when data were censored at the time of stem-cell transplantation, and 94% versus 70% in the respective groups when stem-cell–transplantation events were not censored.^[98]

A meta-analysis by Hayakawa et al of 13 studies comparing horse ATG with rabbit ATG for immunosuppressive therapy in severe aplastic anemia concluded that horse ATG results in a higher response rate (P=0.015); further, a sensitivity analysis showed higher early mortality with rabbit ATG.^[99]Hence, these authors consider horse ATG the preferred choice in this setting.

However, other retrospective studies have failed to show significant differences between horse ATG and rabbit ATG.^[96]In a study of 955 patients with aplastic anemia who received rabbit ATG and cyclosporine as first line treatment (492 patients treated from 2001 to 2008 and 463 treated from 2009 to 2012, responses rose from 37% at 90 days to 52% at 180 days and 65% at 365 days. Mortality within 90 days was 5.7% in the 2001-2008 arm and 2.4% in the 2009-2012 arm. Response rates at 6 months were highest in patients treated within 30 days after diagnosis, and in patients younger than 21 years.^[100]

Cyclosporine

In a study of immunosuppressive therapy with cyclosporine alone, response rates were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate aplastic anemia.^[101]The only predictor of response to cyclosporine was an absolute neutrophil count (ANC) of less than 200/mm³. A prospective study from India concluded that for resource-poor patients, cyclosporine monotherapy, in a dosage of 5 mg/kg/day, is a relatively safe treatment option for aplastic anemia.^[102]

Response and complications

The treatment 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 may continue to improve slowly thereafter. Late responses may also occur. About 50% of patients respond by 3 months after ATG administration, and about 75% respond by 6 months. Full hematologic recovery is rare, but most patients improve to a functional hematologic recovery and become transfusion independent.

Failure to respond, relapse, and clonal evolution are major complications of immunosuppressive therapy for aplastic anemia.^[96]If the patient has not responded to a first course of ATG, then a second course may be given, using either the same preparation or another one. Approximately 30-60% of patients may respond to a second course of ATG (60% responses in relapsed and 35% in refractory patients).^{[103, 104, 105, 106, 107, 108, 109]}

To reduce the risk of relapse, continue cyclosporine for a minimum of 12 months after achieving maximal hematologic response, with a very slow tapering by 25 mg every 3 months thereafter.^[5]Approximately one third of patients have a relapse, most often at the time of cyclosporine taper. About one third of responders are cyclosporine dependent. Of patients without a response or who relapse, 40-50% respond to a second course of immunosuppressive therapy.

The risk of some form of clonal disease other than paroxysmal nocturnal hemoglobinuria (PNH) is 15-30% and may be due to the inability of these therapies to completely correct bone marrow function, a missed diagnosis of myelodysplastic syndrome (MDS), or the fact that the stem cells under proliferative stress may be more prone than other cells to mutation. MDS that evolves from aplastic anemia treated with immunosuppressive therapy responds similarly to hematopoietic stem cell transplantation as does de novo MDS,^[110]so patients who have received immunosuppressive therapy for severe aplastic anemia should have regular assessment of marrow cells, possibly at yearly intervals.^[96]

High-dose cyclophosphamide

At present, the use of high-dose cyclophosphamide should be limited to clinical trials.^[96]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. A prospective, randomized study comparing high-dose cyclophosphamide plus cyclosporine with ATG plus cyclosporine in 31 patients with previously untreated severe aplastic anemia was terminated early because of very high mortality and fungal infections in the cyclophosphamide arm.^[111]

A long-term follow-up study of high-dose cyclophosphamide treatment showed better results in treatment-naive patients than in those with refractory disease. At 10 years, in 44 treatment-naive SAA patients and 23 patients with refractory SAA, overall actuarial survival was 88% versus 62%, the response rate was 71% versus 48%, and the actuarial event-free survival was 58% versus 27%, respectively.

Thrombopoietin Receptor Agonist Therapy

Eltrobombopag (Promacta) is an oral thrombopoietin receptor agonist that was approved in 2014 for patients with severe aplastic anemia that failed to respond adequately to at least one prior immunosuppressive therapy (IST) regimen. Eltrombopag probably acts in aplastic anemia by stimulating the small number of residual stem cells in these patients' bone marrow. Approval of eltrombopag for this indication was supported by a phase II study in which 41% of patients experienced a hematologic response in at least one lineage (ie, platelets, red blood cells, neutrophils) after 12 weeks of treatment.^{[112, 113]} In the extension phase of the study, three patients achieved a multi-lineage response. Four of those patients subsequently tapered off treatment and maintained the response (median followup 8.1 months, range 7.2-10.6 months).^{[112, 113]}

Eltrombopag has also shown benefit as first-line therapy. Townsley et al combined standard IST with eltrombopag in previously untreated patients with severe aplastic anemia, using three different regimens. The best response was noted in patients receiving eltrombopag from day 1 to 6 months, along with horse ATG on days 1 to 4 and daily cyclosporine from day 1 to 6 months. In this cohort, at 6 months, complete responses were seen in 58% of patients and hematologic responses in 94%. This compared with 10% and 66% rates, respectively, observed in a historical cohort treated with IST alone. In addition, the improved blood counts were accompanied by increased marrow cellularity and hematopoietic progenitor numbers. No additional increase in risk of clonal evolution (15%) was noted with the addition of eltrombopag to ATG and cyclosporine.^[114]

Geng et al reported on upfront use of eltrombopag in two pediatric patients with non-severe aplastic anemia. Both patients achieved hematologic response with eltrombopag monotherapy.^[115]

In 2018, the FDA expanded approval for eltrombopag to include use as first-line therapy, in combination with standard IST, for adult and pediatric patients 2 years and older with severe aplastic anemia.^[116]

Romiplostim

Romiplostim is a peptibody (Fc antibody fusion protein) with thrombopoietin receptor (also known as c-MPL) agonist activity that stimulates endogenous thrombopoietin production, promoting the proliferation and differentiation of megakaryocytes in the bone marrow. As an alternative to eltrombopag in frontline treatment for severe aplastic anemia, romiplostim is still under evaluation in ongoing trials (NCT03957694). In an open-label randomized phase 2 trial in refractory aplastic anemia patients previously treated with IST, romiplostim at dose of 10 mcg/kg/week showed responses in around 70% patients at 9 weeks^[117]. Present studies are focusing on effectiveness of high-dose romiplostim (20 mcg/kg/week) in eltrombopag-refractory aplastic anemia.^[118]

Diet and Activity

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 by bacteria, fungus, or molds. Furthermore, a salt-limited diet is recommended during therapy with steroids or cyclosporine.

The patient should avoid any activity that increases the risk of trauma during periods of thrombocytopenia. Menstruating women are also advised to be on hormonal treatment to avoid menstrual cycles that are likely to be heavy due to thrombocytopenia.

Inform patients of the increased risk of community-acquired infections during periods of neutropenia and lymphopenia. Patients should maintain hygiene to reduce the risks of infection.

Medication

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Oral leukoplakia in dyskeratosis congenita.
Aplastic anemia. Low-power view of hematoxylin-eosin–stained bone marrow showing hypocellularity, with increased adipose tissue and decreased hematopoietic cells in the marrow space.